U.S. patent application number 15/917013 was filed with the patent office on 2019-02-14 for methods of treating crohn's disease and ulcerative colitis.
The applicant listed for this patent is AbbVie Inc.. Invention is credited to Jose Jeffrey V. ENEJOSA, Steven JUNGERWIRTH, Ben KLUNDER, Ana Paula Machado de LACERDA, Mohamed-Eslam F. MOHAMED, Ahmed A. OTHMAN, Aileen L. PANGAN, Anne M. ROBINSON, Roopal B. THAKKAR.
Application Number | 20190046527 15/917013 |
Document ID | / |
Family ID | 61750557 |
Filed Date | 2019-02-14 |
![](/patent/app/20190046527/US20190046527A1-20190214-C00001.png)
![](/patent/app/20190046527/US20190046527A1-20190214-C00002.png)
![](/patent/app/20190046527/US20190046527A1-20190214-C00003.png)
![](/patent/app/20190046527/US20190046527A1-20190214-C00004.png)
![](/patent/app/20190046527/US20190046527A1-20190214-C00005.png)
![](/patent/app/20190046527/US20190046527A1-20190214-C00006.png)
![](/patent/app/20190046527/US20190046527A1-20190214-C00007.png)
![](/patent/app/20190046527/US20190046527A1-20190214-C00008.png)
![](/patent/app/20190046527/US20190046527A1-20190214-C00009.png)
![](/patent/app/20190046527/US20190046527A1-20190214-C00010.png)
![](/patent/app/20190046527/US20190046527A1-20190214-C00011.png)
View All Diagrams
United States Patent
Application |
20190046527 |
Kind Code |
A1 |
THAKKAR; Roopal B. ; et
al. |
February 14, 2019 |
METHODS OF TREATING CROHN'S DISEASE AND ULCERATIVE COLITIS
Abstract
The present disclosure is directed to methods for treating
Crohn's disease, and in particular, to methods for inducing
clinical remission and/or endoscopic improvement of Crohn's
disease, using a JAK1 inhibitor. In certain embodiments, the
patient is administered an induction dose of the JAK1 inhibitor to
induce clinical remission and/or endoscopic improvement of the
Crohn's disease, followed by administration of at least one
maintenance dose of the JAK1 inhibitor thereafter. In other
embodiments, the present disclosure is directed to methods for
treating ulcerative colitis using a JAK1 inhibitor.
Inventors: |
THAKKAR; Roopal B.; (Lake
Forest, IL) ; JUNGERWIRTH; Steven; (Glencoe, IL)
; Machado de LACERDA; Ana Paula; (Evanston, IL) ;
ROBINSON; Anne M.; (Highland, IN) ; ENEJOSA; Jose
Jeffrey V.; (Evanston, IL) ; PANGAN; Aileen L.;
(LaGrange, IL) ; MOHAMED; Mohamed-Eslam F.;
(Gurnee, IL) ; OTHMAN; Ahmed A.; (Waukegan,
IL) ; KLUNDER; Ben; (Ludwigshafen, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc. |
North Chicago |
IL |
US |
|
|
Family ID: |
61750557 |
Appl. No.: |
15/917013 |
Filed: |
March 9, 2018 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
62469337 |
Mar 9, 2017 |
|
|
|
62470565 |
Mar 13, 2017 |
|
|
|
62483289 |
Apr 7, 2017 |
|
|
|
62593629 |
Dec 1, 2017 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 1/00 20180101; A61K
31/495 20130101; A61K 31/4985 20130101; A61K 9/48 20130101; A61K
9/0053 20130101 |
International
Class: |
A61K 31/4985 20060101
A61K031/4985; A61P 1/00 20060101 A61P001/00; A61K 9/48 20060101
A61K009/48; A61K 9/00 20060101 A61K009/00 |
Claims
1-103. (canceled)
104. A method of achieving clinical remission of moderately to
severely active Crohn's disease in an adult patient, the method
comprising: (i) orally administering to the patient once a day for
at least 12 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 45 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent; and
then (ii) orally administering to the patient once a day for at
least 36 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 15 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
whereby the patient achieves clinical remission, and wherein
clinical remission is an average daily liquid/very soft stool
frequency of .ltoreq.2.8 and not greater than baseline, and an
average daily abdominal pain of .ltoreq.1.0 and not greater than
baseline.
105. A method of achieving clinical remission of moderately to
severely active Crohn's disease in an adult patient, the method
comprising orally administering to the patient once a day for at
least 12 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 45 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
whereby the patient achieves clinical remission, and wherein
clinical remission is an average daily liquid/very soft stool
frequency of .ltoreq.2.8 and not greater than baseline, and an
average daily abdominal pain of .ltoreq.1.0 and not greater than
baseline.
106. The method of claim 105, further comprising maintaining
clinical remission of moderately to severely active Crohn's disease
in the adult patient, the method comprising orally administering to
the patient once a day for at least 36 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 15 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent,
wherein the patient maintains clinical remission for the at least
36 weeks.
107. The method of claim 105, further comprising maintaining
clinical remission of moderately to severely active Crohn's disease
in the adult patient, the method comprising orally administering to
the patient once a day for at least 36 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 30 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent,
wherein the patient maintains clinical remission for the at least
36 weeks.
108. A method of achieving clinical remission of moderately to
severely active ulcerative colitis in an adult patient, the method
comprising: (i) orally administering to the patient once a day for
at least 8 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 45 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent; and
then (ii) orally administering to the patient once a day for at
least 44 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 15 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
whereby the patient achieves clinical remission, and wherein
clinical remission is a stool frequency subscore of .ltoreq.1, a
rectal bleeding subscore of 0, and an endoscopic subscore of
.ltoreq.1.
109. A method of achieving clinical remission of moderately to
severely active ulcerative colitis in an adult patient, the method
comprising orally administering to the patient once a day for at
least 8 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 45 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
whereby the patient achieves clinical remission, and wherein
clinical remission is a stool frequency subscore of .ltoreq.1, a
rectal bleeding subscore of 0, and an endoscopic subscore of
.ltoreq.1.
110. The method of claim 109, further comprising maintaining
clinical remission of moderately to severely active ulcerative
colitis in the adult patient, the method comprising orally
administering to the patient once a day for at least 44 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 15 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent,
wherein the patient maintains clinical remission for the at least
44 weeks.
111. The method of claim 109, further comprising maintaining
clinical remission of moderately to severely active ulcerative
colitis in the adult patient, the method comprising orally
administering to the patient once a day for at least 44 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 30 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent,
wherein the patient maintains clinical remission for the at least
44 weeks.
112. A method of achieving clinical response of moderately to
severely active Crohn's disease in an adult patient, the method
comprising: (i) orally administering to the patient once a day for
at least 12 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 45 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent; and
then (ii) orally administering to the patient once a day for at
least 36 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 15 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
whereby the patient achieves clinical response, and wherein
clinical response is (i) an average daily liquid/very soft stool
frequency score of .gtoreq.30% decrease from baseline and an
average daily abdominal pain score reduction of not greater than
baseline, or (ii) an average daily abdominal pain score .gtoreq.30%
decrease from baseline and an average daily liquid/very soft stool
frequency score of not greater than baseline.
113. The method of claim 112, whereby the patient achieves an
enhanced clinical response, and wherein an enhanced clinical
response is a .gtoreq.60% decrease in an average daily liquid/very
soft stool frequency and/or .gtoreq.35% decrease in the average
daily abdominal pain score, and wherein both the average daily
liquid/very soft stool frequency and the average daily abdominal
pain score are not greater than baseline.
114. A method of achieving clinical response of moderately to
severely active Crohn's disease in an adult patient, the method
comprising orally administering to the patient once a day for at
least 12 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 45 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
whereby the patient achieves clinical response, and wherein
clinical response is (i) an average daily liquid/very soft stool
frequency score of .gtoreq.30% decrease from baseline and an
average daily abdominal pain score reduction of not greater than
baseline, or (ii) an average daily abdominal pain score .gtoreq.30%
decrease from baseline and an average daily liquid/very soft stool
frequency score of not greater than baseline.
115. The method of claim 114, further comprising maintaining
clinical response of moderately to severely active Crohn's disease
in the adult patient, the method comprising orally administering to
the patient once a day for at least 36 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 15 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent,
wherein the patient maintains clinical response for the at least 36
weeks.
116. The method of claim 114, further comprising maintaining
clinical response of moderately to severely active Crohn's disease
in the adult patient, the method comprising orally administering to
the patient once a day for at least 36 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 30 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent,
wherein the patient maintains clinical response for the at least 36
weeks.
117. A method of achieving clinical response of moderately to
severely active ulcerative colitis in an adult patient, the method
comprising: (i) orally administering to the patient once a day for
at least 8 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 45 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent; and
then (ii) orally administering to the patient once a day for at
least 44 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 15 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
whereby the patient achieves clinical response, and wherein
clinical response is a decrease from baseline in the Adapted Mayo
score of .gtoreq.2 points and .gtoreq.30% decrease from baseline
accompanied by (i) a decrease in rectal bleeding subscore of
.gtoreq.1 or (ii) an absolute rectal bleeding subscore of
.ltoreq.1.
118. A method of achieving clinical response of moderately to
severely active ulcerative colitis in an adult patient, the method
comprising orally administering to the patient once a day for at
least 8 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 45 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
whereby the patient achieves clinical response, and wherein
clinical response is a decrease from baseline in the Adapted Mayo
score of .gtoreq.2 points and .gtoreq.30% decrease from baseline
accompanied by (i) a decrease in rectal bleeding subscore of
.gtoreq.1 or (ii) an absolute rectal bleeding subscore of
.ltoreq.1.
119. The method of claim 118, further comprising maintaining
clinical response of moderately to severely active ulcerative
colitis in the adult patient, the method comprising orally
administering to the patient once a day for at least 44 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 15 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent,
wherein the patient maintains clinical response for the at least 44
weeks.
120. The method of claim 118, further comprising maintaining
clinical response of moderately to severely active ulcerative
colitis in the adult patient, the method comprising orally
administering to the patient once a day for at least 44 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 30 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent,
wherein the patient maintains clinical response for the at least 44
weeks.
121. A method of achieving endoscopic remission of moderately to
severely active Crohn's disease in an adult patient, the method
comprising: (i) orally administering to the patient once a day for
at least 12 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 45 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent; and
then (ii) orally administering to the patient once a day for at
least 36 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 15 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
whereby the patient achieves endoscopic remission, and wherein
endoscopic remission is a Simplified Endoscopic Score for Crohn's
disease (SES-CD) score of .ltoreq.4 and at least a two point
reduction in the SES-CD score versus baseline, and no subscore
>1 in any variable used to calculate the SES-CD score selected
from the group consisting of size of ulcers, ulcerated surface,
affected surface, and presence of narrowing.
122. A method of achieving endoscopic remission of moderately to
severely active Crohn's disease in an adult patient, the method
comprising orally administering to the patient once a day for at
least 12 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 45 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
whereby the patient achieves endoscopic remission, and wherein
endoscopic remission is a Simplified Endoscopic Score for Crohn's
disease (SES-CD) score of .ltoreq.4 and at least a two point
reduction in the SES-CD score versus baseline, and no subscore
>1 in any variable used to calculate the SES-CD score selected
from the group consisting of size of ulcers, ulcerated surface,
affected surface, and presence of narrowing.
123. The method of claim 122, further comprising maintaining
endoscopic remission of moderately to severely active Crohn's
disease in the adult patient, the method comprising orally
administering to the patient once a day for at least 36 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 15 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent,
wherein the patient maintains endoscopic remission for the at least
36 weeks.
124. The method of claim 122, further comprising maintaining
endoscopic remission of moderately to severely active Crohn's
disease in the adult patient, the method comprising orally
administering to the patient once a day for at least 36 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 30 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent,
wherein the patient maintains endoscopic remission for the at least
36 weeks.
125. A method of achieving endoscopic remission of moderately to
severely active ulcerative colitis in an adult patient, the method
comprising: (i) orally administering to the patient once a day for
at least 8 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 45 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent; and
then (ii) orally administering to the patient once a day for at
least 44 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 15 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
whereby the patient achieves endoscopic remission, and wherein
endoscopic remission is an endoscopic subscore of 0.
126. A method of achieving endoscopic remission of moderately to
severely active ulcerative colitis in an adult patient, the method
comprising orally administering to the patient once a day for at
least 8 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 45 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
whereby the patient achieves endoscopic remission, and wherein
endoscopic remission is an endoscopic subscore of 0.
127. The method of claim 126, further comprising maintaining
endoscopic remission of moderately to severely active ulcerative
colitis in the adult patient, the method comprising orally
administering to the patient once a day for at least 44 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 15 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent,
wherein the patient maintains endoscopic remission for the at least
44 weeks.
128. The method of claim 126, further comprising maintaining
endoscopic remission of moderately to severely active ulcerative
colitis in the adult patient, the method comprising orally
administering to the patient once a day for at least 44 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 30 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent,
wherein the patient maintains endoscopic remission for the at least
44 weeks.
129. A method of achieving endoscopic response of moderately to
severely active Crohn's disease in an adult patient, the method
comprising: (i) orally administering to the patient once a day for
at least 12 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 45 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent; and
then (ii) orally administering to the patient once a day for at
least 36 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 15 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
whereby the patient achieves endoscopic response, and wherein
endoscopic response is (i) a decrease of >50% in the Simplified
Endoscopic Score for Crohn's disease (SES-CD) score from baseline,
or (ii) for subjects with an SES-CD score of 4 at baseline, at
least a 2 point reduction.
130. A method of achieving endoscopic response of moderately to
severely active Crohn's disease in an adult patient, the method
comprising orally administering to the patient once a day for at
least 12 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 45 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
whereby the patient achieves endoscopic response, and wherein
endoscopic response is (i) a decrease of >50% in the Simplified
Endoscopic Score for Crohn's disease (SES-CD) score from baseline,
or (ii) for subjects with an SES-CD score of 4 at baseline, at
least a 2 point reduction.
131. The method of claim 130, further comprising maintaining
endoscopic response of moderately to severely active Crohn's
disease in the adult patient, the method comprising orally
administering to the patient once a day for at least 36 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 15 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent,
wherein the patient maintains endoscopic response for the at least
36 weeks.
132. The method of claim 130, further comprising maintaining
endoscopic response of moderately to severely active Crohn's
disease in the adult patient, the method comprising orally
administering to the patient once a day for at least 36 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 30 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent,
wherein the patient maintains endoscopic response for the at least
36 weeks.
133. A method of achieving endoscopic improvement of moderately to
severely active ulcerative colitis in an adult patient, the method
comprising: (i) orally administering to the patient once a day for
at least 8 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 45 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent; and
then (ii) orally administering to the patient once a day for at
least 44 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 15 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
whereby the patient achieves endoscopic improvement, and wherein
endoscopic improvement is an endoscopic subscore of .ltoreq.1.
134. A method of achieving endoscopic improvement of moderately to
severely active ulcerative colitis in an adult patient, the method
comprising orally administering to the patient once a day for at
least 8 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(-
2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a
pharmaceutically acceptable salt thereof, in an amount sufficient
to deliver 45 mg of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
whereby the patient achieves endoscopic improvement, and wherein
endoscopic improvement is an endoscopic subscore of .ltoreq.1.
135. The method of claim 134, further comprising maintaining
endoscopic improvement of moderately to severely active ulcerative
colitis in the adult patient, the method comprising orally
administering to the patient once a day for at least 44 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 15 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent,
wherein the patient maintains endoscopic improvement for the at
least 44 weeks.
136. The method of claim 134, further comprising maintaining
endoscopic improvement of moderately to severely active ulcerative
colitis in the adult patient, the method comprising orally
administering to the patient once a day for at least 44 weeks
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically
acceptable salt thereof, in an amount sufficient to deliver 30 mg
of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent,
wherein the patient maintains endoscopic improvement for the at
least 44 weeks.
137. The method of claim 104, comprising administering
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide as Freebase Hydrate Form
C.
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 62/469,337, filed Mar. 9, 2017, U.S. Provisional
Application No. 62/470,565, filed Mar. 13, 2017, U.S. Provisional
Application 62/483,289, filed Apr. 7, 2017 and U.S. Provisional
Application No. 62/593,629, filed Dec. 1, 2017, each of which is
incorporated by reference in its entirety.
FIELD OF THE DISCLOSURE
[0002] The present disclosure is directed to methods for treating
inflammatory bowel diseases, such as Crohn's disease and ulcerative
colitis, and in particular, to methods for inducing clinical
remission and endoscopic improvement of Crohn's disease or a
clinical remission and endoscopic improvement of ulcerative
colitis, using a JAK1 inhibitor. In certain embodiments, the
patient is administered an induction dose of the JAK1 inhibitor to
induce clinical remission and/or endoscopic improvement of the
Crohn's disease or a clinical remission of ulcerative colitis,
followed by administration of at least one maintenance dose of the
JAK inhibitor thereafter.
BACKGROUND OF THE DISCLOSURE
[0003] Inflammatory bowel disease (IBD) involves chronic
inflammation of a patient's digestive tract. IBD includes both
Crohn's disease and ulcerative colitis. The exact cause of IBD is
not known. The IBD can be idiopathic IBD.
[0004] Crohn's Disease (CD) encompasses a spectrum of clinical and
pathological processes manifested by focal asymmetric, transmural,
and occasionally granulomatous inflammation that can affect any
segment of the gastrointestinal tract (Lichtenstein G R, Hanauer S
B, Sandborn W J; Practice Parameters Committee of American College
of Gastroenterology. Management of Crohn's disease in adults, Am J
Gastroenterol. 2009; 104(2):465-83). The disease can affect persons
of any age, and its onset is most common in the second and third
decades. Females are affected slightly more than males, and the
risk for disease is higher in some ethnic groups (Loftus E V Jr.,
"Clinical epidemiology of inflammatory bowel disease: incidence,
prevalence, and environmental influences," Gastroenterology. 2004;
126(6):1504-17; Probert C S, Jayanthi V, Rampton D S, et al.,
"Epidemiology of inflammatory bowel disease in different ethnic and
religious groups: limitations and aetiological clues," Int. J
Colorectal Dis., 1996; 11(1):25-28). In North America, the
incidence of CD is estimated to be 3.1 to 14.6 cases per 100,000
persons. Prevalence rates range from 26 to 99 cases per 100,000
persons. In Europe, CD has an incidence of 0.7 to 9.8 cases per
100,000 persons and a prevalence of 8.3 to 214 cases per 100,000
persons (Loftus E V Jr. Clinical epidemiology of inflammatory bowel
disease: incidence, prevalence, and environmental influences.
Gastroenterology. 2004; 126(6):1504-17).
[0005] CD has been characterized by significant morbidity including
abdominal pain, diarrhea, weight loss/malnutrition, fatigue and a
progressive nature that leads to complications such as fistulas,
strictures and abscesses. In a population based study from
southeastern Norway, a substantial number of patients demonstrated
a structuring or penetrating phenotype at 10 years after diagnosis
(Solberg I C, Vatn M H, Hoie O, et al; IBSEN Study Group. Clinical
course in Crohn's disease: results of a Norwegian population-based
ten-year follow-up study. Clin Gastroenterol Heptaol. 2007;
5(12):1430-8). Moreover, approximately 80% of patients diagnosed
with CD will require at least 1 surgery related to the disease at
some point in time (Munkholm P, Langholz E, Davidsen M, et al.
Intestinal cancer risk and mortality in patients with Crohn's
disease. Gastroenterology. 1993:105(6):1716-23).
[0006] Ulcerative colitis (UC) is one of the two primary forms of
idiopathic inflammatory bowel disease (IBD). It is postulated that
UC is caused by unregulated and exaggerated local immune response
to environmental triggers in genetically susceptible individuals
(Hanauer S B. Update on the etiology, pathogenesis and diagnosis of
ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2004;
1(1):26-31). UC is a chronic, relapsing inflammatory disease of the
large intestine characterized by inflammation and ulceration of
mainly the mucosal and occasionally submucosal intestinal layers.
The highest annual incidence of UC was 24.3 per 100,000
person-years in Europe, 6.3 per 100,000 person-years in Asia and
the Middle East, and 19.2 per 100,000 person-years in North
America, with a prevalence of 505 cases per 100,000 persons in
Europe and 249 cases per 100,000 persons in North America.
(Molodecky N A, Soon I S, Rabi D M, et al. Increasing incidence and
prevalence of the inflammatory bowel diseases with time, based on
systematic review. Gastroenterology. 2012:142(1):46-54). There is
increasing incidence and prevalence of the inflammatory bowel
diseases with time, based on systematic review. (Gastroenterology.
2012; 142(1):46-54.e42; quiz e30.) The burden of UC on the
healthcare system is profound, accounting for nearly 500,000
physician visits and more than 46,000 hospitalizations per year in
the United States (US) alone. (Sandler R S, Everhart J E, Donowitz
M, et al., Gastroenterology, 2002; 122(5):1500-11).
[0007] The hallmark clinical symptoms of UC include bloody diarrhea
associated with rectal urgency and tenesmus. The clinical course is
marked by exacerbation and remission. The diagnosis of UC is
suspected on clinical grounds and supported by diagnostic testing,
and elimination of infectious causes. (Dignass A, Eliakim R, Magro
F, et al. Second European evidence-based consensus on the diagnosis
and management of ulcerative colitis part 1: definitions and
diagnosis. J Crohn's Colitis. 2012; 6(10):965-90)
[0008] The most severe intestinal manifestations of UC are toxic
megacolon and perforation. Extraintestinal complications include
arthritis (peripheral or axial involvement), dermatological
conditions (erythema nodosum, aphthous stomatitis, and pyoderma
gangrenosum), inflammation of the eye (uveitis), and liver
dysfunction (primary sclerosing cholangitis). Patients with UC are
at an increased risk for colon cancer, and the risk increases with
the duration of disease as well as extent of colon affected by the
disease. (Rutter M, Saunders B, Wilkinson K, et al. Severity of
inflammation is a risk factor for colorectal neoplasia in
ulcerative colitis. (Gastroenterology, 2004; 126(2):451-9).
[0009] The aim of medical treatment in UC is to control
inflammation and reduce symptoms. Available pharmaceutical
therapies are limited, do not always completely abate the
inflammatory process, and may have significant adverse effects.
Therapies for mild to moderate active UC include 5-aminosalicylic
acid derivatives and immunosuppressants.
[0010] Corticosteroids are used in patients with more severe UC
symptoms but are not useful for longer term therapy. (Truelove S C,
Witts L J, Cortisone and corticotrophin in ulcerative colitis. Br
Med J. 1959; 1(5119):387-94). The frequency and severity of
corticosteroid toxicities are significant, including infections,
emotional and psychiatric disturbances, skin injury, and metabolic
bone disease. Corticosteroids are not effective for the maintenance
of remission and the UC practice guidelines from the American
College of Gastroenterology recommend against chronic steroid
treatment. (Kornbluth A, Sachar D B; Practice Parameters Committee
of the American College of Gastroenterology. Ulcerative colitis
practice guidelines in adults: American College of
Gastroenterology, Practice Parameters Committee. Am J Gatroenterol.
2010; 105(3):501-23; quiz 524). Patients with moderate to severe
symptoms may derive some benefits from immunosuppressant agents
(azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate
[MTX]); however, the use of these agents is limited as induction
treatment due to a slow onset of action (3 to 6 months) and as
maintenance therapy due to adverse events (AEs), including bone
marrow suppression, infections, hepatotoxicity, pancreatitis, and
malignancies. (Kornbluth A, Sachar D B; Practice Parameters
Committee of the American College of Gastroenterology. Ulcerative
colitis practice guidelines in adults: American College of
Gastroenterology, Practice Parameters Committee. Am J
Gastroenterol., 2010; 105(3):501-23; quiz 524; Beaugerie L, Brousse
N, Bouvier A M, et al. Lymphoproliferative disorders in patients
receiving thiopurines for inflammatory bowel disease: a prospective
observational cohort study. Lancet. 2009; 374(9701):1617-25).
Despite these therapies, approximately 15% of ulcerative colitis
patients experience a severe clinical course, and 30% of these
patients require removal of the colon/rectum, to eliminate the
source of the inflammatory process, although accompanied by
significant morbidity (Aratari A, Papi C, Clemente V, et al.
Colectomy rate in acute severe ulcerative colitis in the infliximab
era. Dig Liver Dis. 2008; 40(10):821-6; Turner D, Walsh C M,
Steinhart A H, et al. Response to corticosteroids in severe
ulcerative colitis: a systematic review of the literature and a
meta-regression. Clin Gatroenterol Hepatol. 2007; 5(1):103-10).
[0011] Biological agents targeting specific immunological pathways
have been evaluated for their therapeutic effect in treating
patients with UC. Anti-tumor necrosis factor (TNF) agents were the
first biologics to be used for IBD. Infliximab, adalimumab, and
golimumab are successfully being used for the treatment of UC.
Recently, vedolizumab, an anti-adhesion therapy, has been approved
for the treatment of UC by the US Food and Drug Administration
(FDA) and the European Medicines Agency (EMA), and clinical
development is ongoing in Japan.
[0012] Anti-TNF therapies are an effective treatment for patients
who are steroid refractory or steroid dependent, who had inadequate
response to a thiopurine, or who are intolerant to these
medications. Potential risks with anti-TNF therapies include
infusion or injection site reactions, serious infections, lymphoma,
heart failure, lupus-like syndromes, and demyelinating conditions
(Sandborn W J. State-of-the-art: immunosuppression and biologic
therapy. Dig Dis. 2010; 28(3):536-42). Despite the beneficial
results achieved with the available biologic agents, only 17% to
45% of patients who receive them are able to achieve clinical
remission. (Rutgeerts P, Sandborn W, Feagan B, et al., Infliximab
for induction and maintenance therapy for ulcerative colitis. N
Engl J Med. 2005, 353(23):2462-76; Sandborn W J, van Assche G,
Reinisch W, et al. Adalimumab induces and maintains clinical
remission in patients with moderate-to-severe ulcerative colitis.
Gastroenterology, 2012, 142(2):257-65; Feagan B, Greenberg G, Wild
G. et al., Treatment of ulcerative colitis with a humanized
antibody to the alpha4beta7 integrin, N. Engl. J. Med. 2005,
352(24):2499-507; Sandborn W, Feagan B, Marano C, et al.
Subcutaneous golimumab induces clinical response and remission in
patients with moderate-to-severe ulcerative colitis.
Gastroenterology, 2014, 146(1):85-95; quiz e14-5). Thus, there
remains a clear medical need for additional therapeutic options in
UC for patients with inadequate response to or intolerance to
conventional therapies and biologic therapies
[0013] Given that no known medical or surgical cure currently
exists for CD, the therapeutic strategy is to reduce symptoms,
improve quality of life, reduce endoscopic evidence of
inflammation, and minimize short- and long term toxicity and
complications (Lichtenstein G R, Hanauer S B, Sandborn W J;
Practice Parameters Committee of American College of
Gastroenterology, Management of Crohn's disease in adults. Am J
Gastroenterol., 2009, 104(2):465-83). Currently, patients with
moderate to severe disease are usually treated with conventional
pharmacologic interventions, which include corticosteroids and
immunosuppressant agents such as azathioprine, 6-mercaptopurine, or
methotrexate (MTX) (Lichtenstein G R, Hanauer S B, Sandborn W J,
Practice Parameters Committee of American College of
Gastroenterology, Management of Crohn's disease in adults, Am J
Gastroenterol, 2009, 104(2):465-83; Dignass A, Van Assche G,
Lindsay J O, et al., European Crohn's and Colitis Oganisation
(ECCO), The second European evidence-based Consensus on the
diagnosis and management of Crohn's disease: current management, J
Crohn's Colitis, 2010, 4(1):28-62, Erratum in: J Crohn's Colitis,
2010, 4(3):353).
[0014] The potential risks from long term use of corticosteroids
are well-known. Adverse events (AEs) associated with short-term use
of corticosteroids include acne, moon face, edema, skin striae,
glucose intolerance, and sleep/mood disturbances, while potential
AEs observed with longer term use (usually 12 weeks or longer but
sometimes shorter durations) include posterior subcapsular
cataracts, osteoporosis, osteonecrosis of the femoral head,
myopathy, and susceptibility to infection (Irving P M, Gearry R B,
Sparrow M P, et al., Review article: appropriate use of
corticosteroids in Crohn's disease, Aliment Pharmacol Ther., 2007,
26(3):313-29; Rutgeerts P J, Review article: the limitations of
corticosteroid therapy in Crohn's disease, Aliment Pharmacol Ther.,
2001, 15(10):1515-25). The safety risks for azathioprine and
6-mercaptopurine include pancreatitis, bone marrow depression,
infectious complications, and malignant neoplasms (Sandborn, W J,
State-of-the-art: immunosuppression and biologic therapy, Dig Dis.,
2010, 28(3):536-42). MTX may be associated with nausea, bone marrow
depression and liver and pulmonary toxicity (Siegel, et al., Review
article: Practical Management of Inflammatory Bowel Disease
Patients Taking Immunosuppressants. Aliment Pharmacol Ther., 2005,
22:1-16). Patients who do not respond to conventional therapies are
treated with anti-TNF-.alpha. therapies (i.e., biologics)
(Lichtenstein G R, Hanauer S B, Sandborn W J, Practice Parameters
Committee of American College of Gastroenterology, Management of
Crohn's disease in adults, Am J Gastroenterol., 2009,
104(2):465-83; Dignass A, Van Assche G, Lindsay J O, et al.,
European Crohn's and Colitis Oganisation (ECCO). The second
European evidence-based Consensus on the diagnosis and management
of Crohn's disease: current management, J Crohn's Colitis, 2010,
4(1):28-62, Erratum in: J. Crohn's Colitis, 2010, 4(3):353).
Potential risks with biologics include infusion or injection site
reactions, serious infections, lymphoma and other malignancies,
heart failure, cytopenias, lupus-like syndromes, and demyelinating
conditions (Sandborn W J, State-of-the-art: immunosuppression and
biologic therapy, Dig. Dis., 2010, 28(3):536-42).
[0015] Despite the beneficial results achieved with the available
anti-TNF-.alpha. agents, approximately 40% of patients who receive
them for the first time do not have a clinically meaningful
response (primary nonresponders) (Targan S R, Hanauer S B, van
Deventer S J, et al., A short-term study of chimeric monoclonal
antibody cA2 to tumor necrosis factor alpha for Crohn's disease, N.
Engl. J. Med., 1997, 337(15):1029-35; Hanauer S B, Feagan B G,
Lichtenstein G R, et al., ACCENT I Study Group. Maintenance
infliximab for Crohn's disease: the ACCENT I randomized trial.
Lancet, 2002, 359(9317):1541-9; Hanauer S B, Sandborn W J,
Rutgeerts P, et al., Human anti-tumor necrosis factor monoclonal
antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial,
Gastroenterology, 2007, 132(1):52-65; Colombel J F, Sandborn W J,
Rutgeerts P, et al., Adalimumab for maintenance of clinical
response and remission in patients with Crohn's disease: the CHARM
trial, Gastroenterology, 2007, 132(1):52-65; Sandborn W J, Feagan B
G, Stoinov S, et al., PRECISE I Study Investigators, Certolizumab
pegol for the treatment of Crohn's disease, N. Engl. J. Med., 2007,
357(3):228-38). Among patients who initially respond and continue
to receive maintenance treatment for longer durations,
approximately 38% become nonresponders after 6 months (Schribeinger
S, Khaliq-Kareemi M, Lawrance I C, et al; PRECISE 2 Study
Investigators, Maintenance therapy with certolizumab pegol for
Crohn's disease, N. Engl. J. Med., 2007, 357(3):239-50, Erratum in:
N. Engl. J. Med., 2007, 357(13):1357) and approximately 50% become
nonresponders at 1 year lose response (secondary nonresponders)
(Hanauer S B, Feagan B G, Lichtenstein G R, et al., ACCENT I Study
Group, Maintenance infliximab for Crohn's disease: the ACCENT I
randomized trial, Lancet, 2002, 359(9317):1541-9; Colombel J F,
Sandborn W J, Rutgeerts P, et al., Adalimumab for maintenance of
clinical response and remission in patients with Crohn's disease:
the CHARM trial, Gastroenterology, 2007, 132(1):52-65). Patients
who initially respond to a first anti-TNF agent but then lose
response tend to have lower response and remission rates to the
second anti-TNF agent (Colombel J F, Sandborn W J, Rutgeerts P, et
al., Adalimumab for maintenance of clinical response and remission
in patients with Crohn's disease: the CHARM trial,
Gastroenterology, 2007, 132(1):52-65; Sandborn. et al.,
"Natalizumab induction and maintenance therapy for Crohn's
disease," N. Engl. J. Med., 2005, 353(18):1912-25).
[0016] New classes of biologics has been studied in patients with
prior anti-TNF use. Natalizumab, a humanized monoclonal antibody to
.alpha.4.beta.1 and .alpha.4.beta.7 integrins, showed promise for
patients with prior exposure to anti-TNF-.alpha. therapy; more than
half of the patients had a response to the induction regimen
(Sandborn, et al., "Natalizumab induction and maintenance therapy
for Crohn's disease," N. Engl. J. Med., 2005, 353(18):1912-25).
However, natalizumab's use after approval in 2008 has been severely
limited due to the serious risk for progressive multifocal
leukoencephalopathy (PML) attributed to activation of the latent JC
virus (Van Assche G. Van Ranst M, Sciot R, et al., "Progressive
multifocal leukoencephalopathy after natalizumab therapy for
Crohn's disease," N. Engl. J. Med., 2005, 353(4):362-8).
Vedolizumab is specific to the .alpha.4.beta.7 integrin, which does
not affect lymphocyte trafficking to the brain. Therefore, it is
presumed to not have the PML risk associated with natalizumab.
However, it does not fulfill many of the unmet needs of patients
who have failed treatment with anti-TNFs, such as the improvement
of extra-intestinal manifestations (Rubin, et al., Inflammatory
Bowel Diseases, 2016, 22 Suppl. 1:S42-S43). In the induction study
with vedolizumab, the primary endpoint of clinical remission in
patients who had previously failed treatment with an anti TNF was
not statistically significant nor was it clinically meaningful
since there was only a 3% difference from placebo (Sands, et al.,
"Effects of Vedolizumab Induction Therapy for Patients With Crohn's
Disease in Whom Tumor Necrosis Factor Antagonist Treatment Failed,"
Gastroenterology, 2014, 147:618-627). Ustekinumab, a human
monoclonal antibody that selectively targets IL-12 and IL-23, has
efficacy in both patients who have responded to and patients who
have not responded to prior anti-TNF.alpha. therapy. The efficacy
of ustekinumab, however, is broadly similar to that of anti-TNF
agents, and therefore subject to similar drawbacks (Ther. Adv.
Gastroenterology, 2016. Vol. 9(1). pp. 26-36). Clearly, the need
for additional therapeutic options in CD for patients who fail or
are intolerant to conventional therapies, and anti-TNF-.alpha.
agents or other biologic therapies remains.
SUMMARY OF THE DISCLOSURE
[0017] The present disclosure addresses the above needs and
provides methods for treating Crohn's disease and ulcerative
colitis. In some aspects, the present disclosure provides methods
for treating Crohn's disease in patients that have moderately to
severely active Crohn's disease. In some aspects, the present
disclosure provides methods for treating ulcerative colitis in
patients that have moderately to severely active ulcerative
colitis. The patient may have had an inadequate response to or
experienced intolerance to conventional treatment, such as
aminosalicylates, corticosteroids or immunosuppressants, or to a
previous treatment with an anti-TNF therapy or another biologic
agent. In one embodiment, the patient is an adult with moderately
to severely active Crohn's disease and has had an inadequate
response to, or were intolerant to, corticosteroid,
immunomodulator, or biologic therapy.
[0018] In one embodiment, the present disclosure is directed to a
method of inducing clinical remission of Crohn's disease in a
patient, said method comprising: a) administering to the patient at
least one induction dose of
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-
-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib), or
a pharmaceutically acceptable salt or solid state form thereof,
wherein said induction dose comprises 30 to 45 mg of upadacitinib,
or a pharmaceutically acceptable salt or solid state form thereof.
In one embodiment, the method further comprises maintaining the
clinical remission of Crohn's disease, wherein the method further
comprises b) administering a first maintenance dose of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof to the patient after the last induction dose is
administered; and c) administering at least one additional
maintenance dose once daily thereafter.
[0019] In another embodiment, the present disclosure is directed to
a method of inducing endoscopic improvement of Crohn's disease in a
patient, said method comprising: a) administering to the patient at
least one induction dose of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof, wherein said induction
dose comprises 30 to 45 mg of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, the
method further comprises maintaining the endoscopic improvement of
Crohn's disease, wherein the method further comprises b)
administering a first maintenance dose of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof to the
patient after the last induction dose is administered; and c)
administering at least one additional maintenance dose once daily
thereafter.
[0020] In another embodiment, the present disclosure is directed to
a method of inducing clinical remission of Crohn's disease in a
patient, said method comprising: a) administering to the patient at
least one induction dose of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof, wherein said induction
dose comprises 45 mg of upadacitinib, or a pharmaceutically
acceptable or solid state form salt thereof. In one embodiment, the
method further comprises maintaining the clinical remission of
Crohn's disease, wherein the method further comprises b)
administering a first maintenance dose of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof to the
patient after the last induction dose is administered; and c)
administering at least one additional maintenance dose once daily
thereafter.
[0021] In another embodiment, the present disclosure is directed to
a method of inducing endoscopic remission of Crohn's disease in a
patient, said method comprising: a) administering to the patient at
least one induction dose of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof, wherein said induction
dose comprises 45 mg of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, the
method further comprises maintaining the endoscopic remission of
Crohn's disease, wherein the method further comprises b)
administering a first maintenance dose of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof to the
patient after the last induction dose is administered; and c)
administering at least one additional maintenance dose once daily
thereafter.
[0022] In one embodiment, the induction dose comprises 45 mg of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof.
[0023] In one embodiment, the patient had an inadequate response to
or experienced intolerance to a previous treatment with a
corticosteroid, an immunosuppressant, or a biologic agent. In one
embodiment, the patient had an inadequate response to or
experienced intolerance to a previous treatment with an anti-TNF
agent. In one embodiment, the patient had moderately to severely
active Crohn's disease prior to administration of the induction
dose.
[0024] In one embodiment, the induction dose is administered orally
to the patient. In one embodiment, the induction dose is
administered once daily to the patient.
[0025] In one embodiment, clinical remission is achieved within 16
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, clinical remission is achieved within 12 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof.
[0026] In one embodiment, endoscopic improvement is achieved within
16 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, endoscopic improvement is achieved within 12 weeks
of initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof.
[0027] In one embodiment, clinical remission is achieved within 16
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, clinical remission is achieved within 12 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof.
[0028] In one embodiment, endoscopic remission is achieved within
16 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, endoscopic remission is achieved within 12 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof.
[0029] In one embodiment, after administration of at least one
induction dose, the patient's Simplified Endoscopic Score for
Crohn's Disease (SES-CD) is greater than a 50% decrease or
endoscopic remission versus the patient's baseline SES-CD. In one
embodiment, after administration of at least one induction dose,
the patient's Simplified Endoscopic Score for Crohn's Disease
(SES-CD) is at least a 2 point reduction versus the patient's
baseline SES-CD. In one embodiment, after administration of at
least one induction dose, the patient achieves an endoscopic
remission. In one embodiment, after administration of at least one
induction dose, the patient achieves a clinical response. In one
embodiment, the patient achieves a clinical response as early as
two weeks from the first induction dose. In one embodiment, after
administration of at least one induction dose, the patient achieves
a CDAI score of less than 150.
[0030] In one embodiment, the first maintenance dose comprises 15
mg of upadacitinib, or a pharmaceutically acceptable salt or solid
state form thereof. In one embodiment, the first maintenance dose
comprises 30 mg of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof.
[0031] In one embodiment, the at least one additional maintenance
dose comprises 15 mg of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, the
at least one additional maintenance dose comprises 30 mg of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof.
[0032] In one embodiment, the first maintenance dose and said at
least one additional maintenance dose are administered orally. In
one embodiment, the first maintenance dose and said at least one
additional maintenance dose are administered once daily.
[0033] In one embodiment, the patient maintains clinical remission.
In one embodiment, the patient maintains endoscopic improvement. In
one embodiment, the patient maintains endoscopic remission.
[0034] In one embodiment, the patient maintains a Simplified
Endoscopic Score for Crohn's Disease (SES-CD) that is greater than
a 50% decrease or endoscopic remission versus the patient's
baseline SES-CD. In one embodiment, the said patient maintains a
Simplified Endoscopic Score for Crohn's Disease (SES-CD) that is at
least a 2 point reduction versus the patient's baseline SES-CD. In
one embodiment, the patient maintains an endoscopic remission. In
one embodiment, the patient maintains a CDAI score of less than
150. In one embodiment, the patient maintains a clinical
response.
[0035] In one embodiment, the patient achieves a CDAI score of less
than 150 before administration of the first maintenance dose. In
one embodiment, the patient achieves a clinical response before
administration of the first maintenance dose.
[0036] In one embodiment, the induction dose comprises 45 mg of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, administered orally once daily, the first maintenance
dose comprises 30 mg of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof, administered orally
once daily, and the at least one additional maintenance dose
comprises 30 mg of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, administered orally once
daily.
[0037] In one embodiment, the induction dose comprises 45 mg of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, administered orally once daily, the first maintenance
dose comprises 15 mg of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof, administered orally
once daily, and the at least one additional maintenance dose
comprises 15 mg of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, administered orally once
daily.
[0038] In one embodiment, the induction dose is in a once-daily,
modified release formulation. In one embodiment, the first
maintenance dose and the at least one additional maintenance dose
are each in a once-daily, modified release formulation.
[0039] In one embodiment, the present disclosure is directed to a
method for treating Crohn's disease comprising administering to a
patient 15 mg to 45 mg of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, the
method comprising administering 15 mg of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, the method comprising administering 30 mg of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, the method comprising
administering 45 mg of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment,
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof is administered orally to the patient. In one
embodiment, upadacitinib, or a pharmaceutically acceptable salt or
solid state form thereof is administered once daily to the
patient.
[0040] In one embodiment, the present disclosure is directed to a
method for treating Crohn's disease comprising: a) administering to
a patient at least one induction dose of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof,
wherein said induction dose comprises 45 mg of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, the method further comprises b) administering a
first maintenance dose of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof to the patient after
the last induction dose is administered; and c) administering at
least one additional maintenance dose to the patient once daily
thereafter.
[0041] In one such embodiment, the first maintenance dose comprises
15 mg of upadacitinib, or a pharmaceutically acceptable salt or
solid state form thereof. In one embodiment, the first maintenance
dose comprises 30 mg of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, the
first maintenance dose is administered orally.
[0042] In one embodiment, the at least one additional maintenance
dose comprises 15 mg of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment the
at least one additional maintenance dose comprises 30 mg of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, the at least one additional
maintenance dose is administered orally.
[0043] In one embodiment, the patient maintains a CDAI score of
less than 150.
[0044] In one embodiment, the patient had an inadequate response to
or experienced intolerance to a previous treatment with a
corticosteroid, an immunosuppressant, or a biologic agent. In one
embodiment, the patient had an inadequate response to or
experienced intolerance to a previous treatment with an anti-TNF
agent.
[0045] In one embodiment, the patient achieves a clinical remission
after administration of at least one induction dose. In one
embodiment, the patient achieves an endoscopic improvement after
administration of at least one induction dose. In one embodiment,
the patient achieves an endoscopic remission after administration
of at least one induction dose. In one embodiment, the patient
achieves a clinical response after administration of at least one
induction dose.
[0046] In one embodiment, the induction dose comprises 45 mg of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, administered orally once daily, said first
maintenance dose comprises 30 mg of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof,
administered orally once daily, and said at least one additional
maintenance dose comprises 30 mg of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof,
administered orally once daily.
[0047] In one embodiment, the induction dose comprises 45 mg of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, administered orally once daily, said first
maintenance dose comprises 15 mg of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof,
administered orally once daily, and said at least one additional
maintenance dose comprises 15 mg of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof,
administered orally once daily.
[0048] In one embodiment, the induction dose is in a once-daily,
modified release formulation. In one embodiment, the first
maintenance dose and the at least one additional maintenance dose
are each in a once-daily, modified release formulation. In one
embodiment, the patient had moderately to severely active Crohn's
disease prior to administration of the induction dose.
[0049] In one embodiment, the present disclosure is directed to a
method of inducing remission in a patient having moderately to
severely active Crohn's disease, the method comprising
administering 45 mg of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof, to the patient. In one
such embodiment, the patient had an inadequate response to or was
intolerant to aminosalicylates, corticosteroids,
immunosuppressants, biologic agents, anti-TNF agents, or
combinations thereof.
[0050] In one embodiment, the present disclosure is directed to a
method of inducing clinical remission in a patient having
moderately to severely active Crohn's disease the method comprising
administering 45 mg of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof, to the patient. In one
such embodiment, the patient had an inadequate response to or was
intolerant to aminosalicylates, corticosteroids,
immunosuppressants, biologic agents, anti-TNF agents, or
combinations thereof.
[0051] In one embodiment, the present disclosure is directed to a
method of inducing endoscopic improvement in a patient having
moderately to severely active Crohn's disease the method comprising
administering 45 mg of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof to the patient. In one
such embodiment, the patient had an inadequate response to or was
intolerant to aminosalicylates, corticosteroids,
immunosuppressants, biologic agents, anti-TNF agents, or
combinations thereof.
[0052] In one embodiment, the present disclosure is directed to a
method of treating a refractory patient having moderately to
severely active Crohn's disease the method comprising administering
45 mg of upadacitinib, or a pharmaceutically acceptable salt or
solid state form thereof, to the patient. In one such embodiment,
clinical remission is induced within 16 weeks of administering the
initial dose of upadacitinib or a pharmaceutically acceptable salt
or solid state form thereof. In one such embodiment, endoscopic
improvement is induced within 12 weeks or within 16 weeks of
administering the initial dose of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof.
[0053] In one embodiment, the induction dose comprises 45 mg of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof. In another embodiment, the first maintenance dose
and/or the at least one additional maintenance doses comprise 15 mg
to 30 mg of upadacitinib, or a pharmaceutically acceptable salt or
solid state form thereof.
[0054] In one embodiment, the present disclosure is directed to a
method of inducing a clinical response in a patient with moderately
to severely active ulcerative colitis, said method comprising: a)
administering to the patient at least one induction dose of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, wherein said induction dose comprises 45 mg of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof. In one such embodiment, the clinical response is a
clinical response is wherein the patient has a decrease from a
baseline Adapted Mayo score greater than or equal to 2 points and
greater than or equal to 30% accompanied by a decrease in rectal
bleeding subscore of greater than or equal to 1 or an absolute
rectal bleeding subscore of 0 or 1. In another such embodiment, the
clinical response is a clinical response is wherein the patient has
a decrease from a baseline Full Mayo score greater than or equal to
3 points and greater than or equal to 30% accompanied by a decrease
in rectal bleeding subscore from baseline of greater than or equal
to 1 or an absolute rectal bleeding subscore of 0 or 1.
[0055] In yet another embodiment, the method further comprising
maintaining the clinical response, said method further comprising:
b) administering a first maintenance dose of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof to the
patient after the last induction dose is administered; and c)
administering at least one additional maintenance dose once daily
thereafter.
[0056] In another embodiment, the induction dose comprises 45 mg of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof. In another embodiment, the first maintenance dose
and/or the at least one additional maintenance dose comprises 15 mg
to 30 mg of upadacitinib, or a pharmaceutically acceptable salt or
solid state form thereof.
[0057] In one embodiment, the method of the present disclosure is a
method of inducing clinical remission of Crohn's disease in a
patient, the method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 4 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; and b) wherein said
patient achieves clinical remission within 12 weeks of
administration of the first induction dose.
[0058] In one embodiment, clinical remission of Crohn's disease is
induced within 4 weeks of the first induction dose of upadacitinib,
or a pharmaceutically acceptable salt thereof.
[0059] In one embodiment, the method is a method of inducing
clinical response of Crohn's disease in a patient, said method
comprising: a) administering to the patient an induction dose of
upadacitinib, or a pharmaceutically acceptable salt thereof,
wherein said induction dose is administered orally once a day for
at least 2 weeks and comprises 45 mg of upadacitinib or a 45 mg
free base equivalent amount of a pharmaceutically acceptable salt
thereof; and b) wherein said patient achieves clinical
response.
[0060] In one embodiment, the clinical response of Crohn's disease
is induced within 4 weeks of the first induction dose of
upadacitinib, or a pharmaceutically acceptable salt thereof. In one
embodiment, the clinical response of Crohn's disease is induced
within 12 weeks of the first induction dose of upadacitinib, or a
pharmaceutically acceptable salt thereof.
[0061] In one embodiment, the method is a method of inducing
endoscopic remission of Crohn's disease in a patient, said method
comprising: a) administering to the patient an induction dose of
upadacitinib, or a pharmaceutically acceptable salt thereof,
wherein said induction dose is administered orally once a day for
at least 12 weeks and comprises 45 mg of upadacitinib, or a 45 mg
free base equivalent amount of a pharmaceutically acceptable salt
thereof; and b) wherein said patient achieves endoscopic remission
within 12 weeks of administration of the first induction dose.
[0062] In one embodiment, the endoscopic remission of Crohn's
disease is induced within 4 weeks of the first induction dose of
upadacitinib, or a pharmaceutically acceptable salt thereof.
[0063] In one embodiment, the endoscopic remission of Crohn's
disease is induced within 12 weeks of the first induction dose of
upadacitinib, or a pharmaceutically acceptable salt thereof.
[0064] In one embodiment, the method is a method of inducing
endoscopic response of Crohn's disease in a patient, said method
comprising: a) administering to the patient an induction dose of
upadacitinib, or a pharmaceutically acceptable salt thereof,
wherein said induction dose is administered orally once a day for
at least 12 weeks and comprises 45 mg of upadacitinib, or a 45 mg
free base equivalent amount of a pharmaceutically acceptable salt
thereof; and b) wherein said patient achieves endoscopic response
within 12 weeks of administration of the first induction dose.
[0065] In one embodiment, the endoscopic response of Crohn's
disease is induced within 12 weeks of the first induction dose of
upadacitinib, or a pharmaceutically acceptable salt thereof.
[0066] In one embodiment, the method is a method of inducing
corticosteroid-free remission of Crohn's disease in a patient, said
method comprising: a) administering to the patient an induction
dose of upadacitinib, or a pharmaceutically acceptable salt
thereof, wherein said induction dose is administered orally once a
day for at least 12 weeks and comprises 45 mg of upadacitinib, or a
45 mg free base equivalent amount of a pharmaceutically acceptable
salt thereof; and b) wherein said patient achieves steroid-free
remission within 4 weeks of administration of the first induction
dose.
[0067] In one embodiment, the patient is an adult with moderately
to severely active Crohn's disease.
[0068] In one embodiment, the patient experiences a CDAI reduction
of greater than 150 within 12 weeks of administration of the first
induction dose.
[0069] In one embodiment, the patient had an inadequate response to
or experienced intolerance to a previous treatment with a
corticosteroid, an immunosuppressant, or a biologic agent.
[0070] In one embodiment, the patient had an inadequate response to
or experienced intolerance to a previous treatment with an anti-TNF
agent.
[0071] In one embodiment, the patient had an inadequate response to
or experienced intolerance to an infliximab, adalimumab or
certolizumab pegol.
[0072] In one embodiment, the patient has had a diagnosis of
Crohn's disease for more than ten years and has had an inadequate
response to or experienced intolerance to one or more previous
treatments. In one embodiment, the previous treatments are selected
from the group consisting of corticosteroids, immunosuppressants,
antibiotics and biologic therapies.
[0073] In one embodiment, the method comprises a method of inducing
and maintaining clinical remission of Crohn's disease in a patient,
said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 4 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; b) wherein said patient
achieves clinical remission within 12 weeks of administration of
the first induction dose; c) administering to the patient a first
maintenance dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said first maintenance dose is administered
orally once a day and comprises 30 mg of upadacitinib, or a 30 mg
free base equivalent amount of a pharmaceutically acceptable salt
thereof after the last induction dose is administered; d)
administering at least one additional maintenance dose to the
patient of upadacitinib, or a pharmaceutically acceptable salt
thereof; and e) wherein said patient maintains clinical remission
for 52 weeks after administration of the first induction dose.
[0074] In one embodiment, the method comprises a method of inducing
and maintaining clinical response of Crohn's disease in a patient,
said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 2 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; and b) wherein said
patient achieves clinical response within 2 weeks of administration
of the first induction dose; c) administering to the patient a
first maintenance dose of upadacitinib, or a pharmaceutically
acceptable salt thereof, wherein said first maintenance dose is
administered orally once a day and comprises 30 mg of upadacitinib,
or a 30 mg free base equivalent amount of a pharmaceutically
acceptable salt thereof after the last induction dose is
administered; d) administering at least one additional maintenance
dose to the patient of upadacitinib, or a pharmaceutically
acceptable salt thereof, and e) wherein said patient maintains
clinical response for 52 weeks after administration of the first
induction dose.
[0075] In one embodiment, the clinical response of Crohn's disease
is induced within 4 weeks of the first induction dose of
upadacitinib, or a pharmaceutically acceptable salt thereof.
[0076] In one embodiment, the clinical response of Crohn's disease
is induced within 12 weeks of the first induction dose of
upadacitinib, or a pharmaceutically acceptable salt thereof.
[0077] In one embodiment, the method comprises a method of inducing
and maintaining endoscopic remission of Crohn's disease in a
patient, said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 4 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; and b) wherein said
patient achieves endoscopic remission within 12 weeks of
administration of the first induction dose; c) administering to the
patient a first maintenance dose of upadacitinib, or a
pharmaceutically acceptable salt thereof, wherein said first
maintenance dose is administered orally once a day and comprises 30
mg of upadacitinib, or a 30 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof after the last induction
dose is administered; d) administering at least one additional
maintenance dose to the patient of upadacitinib, or a
pharmaceutically acceptable salt thereof; and e) wherein said
patient maintains endoscopic remission for 52 weeks after
administration of the first induction dose.
[0078] In one embodiment, the endoscopic remission of Crohn's
disease is induced within 12 weeks of the first induction dose of
upadacitinib, or a pharmaceutically acceptable salt thereof.
[0079] In one embodiment, the method is a method of inducing and
maintaining endoscopic response of Crohn's disease in a patient,
said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 4 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; and b) wherein said
patient achieves endoscopic response within 4 weeks of
administration of the first induction dose; c) administering to the
patient a first maintenance dose of upadacitinib, or a
pharmaceutically acceptable salt thereof, wherein said first
maintenance dose is administered orally once a day and comprises 30
mg of upadacitinib, or a 30 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof after the last induction
dose is administered; d) administering at least one additional
maintenance dose to the patient of upadacitinib, or a
pharmaceutically acceptable salt thereof; and e) wherein said
patient maintains endoscopic response for 52 weeks after
administration of the first induction dose.
[0080] In one embodiment, the endoscopic response of Crohn's
disease is induced within 12 weeks of the first induction dose of
upadacitinib, or a pharmaceutically acceptable salt thereof.
[0081] In one embodiment, the method is a method of inducing and
maintaining corticosteroid-free remission of Crohn's disease in a
patient, said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 12 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; b) wherein said patient
achieves steroid-free remission within 4 weeks of administration of
the first induction dose; c) administering to the patient a first
maintenance dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said first maintenance dose is administered
orally once a day and comprises 30 mg of upadacitinib, or a 30 mg
free base equivalent amount of a pharmaceutically acceptable salt
thereof after the last induction dose is administered and; d)
administering at least one additional maintenance dose to the
patient of upadacitinib, or a pharmaceutically acceptable salt
thereof; and e) wherein said patient maintains corticosteroid-free
remission for 52 weeks after administration of the first induction
dose.
[0082] In one embodiment, the patient is an adult with moderately
to severely active Crohn's disease.
[0083] In one embodiment, the patient experiences improvement in
stool frequency one week after the first induction dose. In one
embodiment the patient experiences improvement in abdominal pain at
8 weeks after the first induction dose.
[0084] In one embodiment, the patient experiences a CDAI reduction
of greater than 150 within 12 weeks of administration of the first
induction dose.
[0085] In one embodiment, the patient had an inadequate response to
or experienced intolerance to a previous treatment with a
corticosteroid, an immunosuppressant, or a biologic agent.
[0086] In one embodiment, the patient had an inadequate response to
or experienced intolerance to a previous treatment with an anti-TNF
agent.
[0087] In one embodiment, the anti-TNF agent is infliximab,
adalimumab or certolizumab pegol.
[0088] In one embodiment, the patient has had a diagnosis of
Crohn's disease for more than ten years and has had an inadequate
response to or experienced intolerance to a previous treatment.
[0089] In one embodiment, the previous treatments are selected from
corticosteroids, immunosuppressants, antibiotics and biologic
therapies.
[0090] In one embodiment, the method is a method of inducing and
maintaining clinical remission of Crohn's disease in a patient,
said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 4 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; b) wherein said patient
achieves clinical remission within 4 weeks of administration of the
first induction dose; c) administering to the patient a first
maintenance dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said first maintenance dose is administered
orally once a day and comprises 15 mg of upadacitinib, or a 15 mg
free base equivalent amount of a pharmaceutically acceptable salt
thereof after the last induction dose is administered; d)
administering at least one additional maintenance dose to the
patient of upadacitinib, or a pharmaceutically acceptable salt
thereof; and e) wherein said patient maintains clinical remission
for 52 weeks after administration of the first induction dose.
[0091] In one embodiment, the method is a method of inducing and
maintaining clinical response of Crohn's disease in a patient, said
method comprising: a) administering to the patient an induction
dose of upadacitinib, or a pharmaceutically acceptable salt
thereof, wherein said induction dose is administered orally once a
day for at least 2 weeks and comprises 45 mg of upadacitinib, or a
45 mg free base equivalent amount of a pharmaceutically acceptable
salt thereof; and b) wherein said patient achieves clinical
response within 2 weeks of administration of the first induction
dose; c) administering to the patient a first maintenance dose of
upadacitinib, or a pharmaceutically acceptable salt thereof,
wherein said maintenance dose is administered orally once a day and
comprises 15 mg of upadacitinib, or a 15 mg free base equivalent
amount of a pharmaceutically acceptable salt thereof after the last
induction dose is administered; d) administering at least one
additional maintenance dose to the patient of upadacitinib, or a
pharmaceutically acceptable salt thereof, and e) wherein said
patient maintains clinical response for 52 weeks after
administration of the first induction dose.
[0092] In one embodiment, the clinical response of Crohn's disease
is induced within 4 weeks of the first induction dose of
upadacitinib, or a pharmaceutically acceptable salt thereof.
[0093] In one embodiment, the clinical response of Crohn's disease
is induced within 12 weeks of the first induction dose of
upadacitinib, or a pharmaceutically acceptable salt thereof.
[0094] In one embodiment, the method is a method of inducing and
maintaining endoscopic remission of Crohn's disease in a patient,
said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 4 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; and b) wherein said
patient achieves endoscopic remission within 4 weeks of
administration of the first induction dose; c) administering to the
patient a first maintenance dose of upadacitinib, or a
pharmaceutically acceptable salt thereof, wherein said first
maintenance dose is administered orally once a day and comprises 15
mg of upadacitinib, or a 15 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof after the last induction
dose is administered; d) administering at least one additional
maintenance dose to the patient of upadacitinib, or a
pharmaceutically acceptable salt thereof; and e) wherein said
patient maintains endoscopic remission for 52 weeks after
administration of the first induction dose.
[0095] In one embodiment, the method is a method of inducing and
maintaining endoscopic remission of Crohn's disease in a patient,
said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 12 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; and b) wherein said
patient achieves endoscopic remission within 4 weeks of
administration of the first induction dose; c) administering to the
patient a first maintenance dose of upadacitinib, or a
pharmaceutically acceptable salt thereof, wherein said first
maintenance dose is administered orally once a day and comprises 15
mg of upadacitinib, or a 15 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof after the last induction
dose is administered; d) administering at least one additional
maintenance dose to the patient of upadacitinib, or a
pharmaceutically acceptable salt thereof; and e) wherein said
patient maintains endoscopic remission for 52 weeks after
administration of the first induction dose.
[0096] In one embodiment, the endoscopic remission of Crohn's
disease is induced within 12 weeks of the first induction dose of
upadacitinib, or a pharmaceutically acceptable salt thereof.
[0097] In one embodiment, the method is a method of inducing and
maintaining endoscopic response of Crohn's disease in a patient,
said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 4 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; and b) wherein said
patient achieves endoscopic response within 4 weeks of
administration of the first induction dose; c) administering to the
patient a first maintenance dose of upadacitinib, or a
pharmaceutically acceptable salt thereof, wherein said maintenance
dose is administered orally once a day and comprises 15 mg of
upadacitinib, or a 15 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof after the last induction
dose is administered; d) administering at least one additional
maintenance dose to the patient of upadacitinib, or a
pharmaceutically acceptable salt thereof; and e) wherein said
patient maintains endoscopic response for 52 weeks after
administration of the first induction dose.
[0098] In one embodiment, the endoscopic response of Crohn's
disease is induced within 12 weeks of the first induction dose of
upadacitinib, or a pharmaceutically acceptable salt thereof.
[0099] In one embodiment, the method is a method of inducing and
maintaining corticosteroid-free remission of Crohn's disease in a
patient, said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 12 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; b) wherein said patient
achieves steroid-free remission within 12 weeks of administration
of the first induction dose; c) administering to the patient a
first maintenance dose of upadacitinib, or a pharmaceutically
acceptable salt thereof, wherein said first maintenance dose is
administered orally once a day and comprises 15 mg of upadacitinib,
or a 15 mg free base equivalent amount of a pharmaceutically
acceptable salt thereof after the last induction dose is
administered and; d) administering at least one additional
maintenance dose to the patient of upadacitinib, or a
pharmaceutically acceptable salt thereof; and e) wherein said
patient maintains corticosteroid-free remission for 52 weeks after
administration of the first induction dose.
[0100] In one embodiment, the patient is an adult with moderately
to severely active Crohn's disease.
[0101] In one embodiment, the patient experiences a CDAI reduction
of >150 within 12 weeks of administration of the first induction
dose.
[0102] In one embodiment, the patient had an inadequate response to
or experienced intolerance to a previous treatment with a
corticosteroid, an immunosuppressant, or a biologic agent.
[0103] In one embodiment, the patient had an inadequate response to
or experienced intolerance to a previous treatment with an anti-TNF
agent.
[0104] In one embodiment, the patient had an inadequate response to
or experienced intolerance to a previous treatment anti-TNF agent
is infliximab, adalimumab or certolizumab pegol.
[0105] In one embodiment, the patient has had a diagnosis of
Crohn's disease for more than ten years and has had an inadequate
response to or experienced intolerance to one or more previous
treatment.
[0106] In one embodiment, the method comprises a method wherein the
previous treatments are selected from corticosteroids,
immunodulators, antibiotics and biologic therapies.
[0107] In one embodiment, the method comprises inducing clinical
remission of ulcerative colitis in a patient, said method
comprising: a) administering to the patient an induction dose of
upadacitinib, or a pharmaceutically acceptable salt thereof,
wherein said induction dose is administered orally once a day for
at least 4 weeks and comprises 45 mg of upadacitinib, or a 45 mg
free base equivalent amount of a pharmaceutically acceptable salt
thereof; and b) wherein said patient achieves clinical remission
within 4 weeks of administration of the first induction dose.
[0108] In one embodiment, the method comprises inducing clinical
remission of ulcerative colitis in a patient, said method
comprising: a) administering to the patient an induction dose of
upadacitinib, or a pharmaceutically acceptable salt thereof,
wherein said induction dose is administered orally once a day for
at least 6 weeks and comprises 45 mg of upadacitinib, or a 45 mg
free base equivalent amount of a pharmaceutically acceptable salt
thereof; and b) wherein said patient achieves clinical remission
within 6 weeks of administration of the first 45 mg induction
dose.
[0109] In one embodiment, the method comprises inducing clinical
remission of ulcerative colitis in a patient, said method
comprising: a) administering to the patient an induction dose of
upadacitinib, or a pharmaceutically acceptable salt thereof,
wherein said induction dose is administered orally once a day for
at least 8 weeks and comprises 45 mg of upadacitinib, or a 45 mg
free base equivalent amount of a pharmaceutically acceptable salt
thereof; and b) wherein said patient achieves clinical remission
within 8 weeks of administration of the first 45 mg induction
dose.
[0110] In one embodiment, the method comprises a method of inducing
endoscopic improvement of ulcerative colitis in a patient, said
method comprising: a) administering to the patient an induction
dose of upadacitinib, or a pharmaceutically acceptable salt
thereof, wherein said induction dose is administered orally once a
day for at least 8 weeks and comprises 45 mg of upadacitinib, or a
45 mg free base equivalent amount of a pharmaceutically acceptable
salt thereof, and b) wherein said patient achieves endoscopic
improvement within 8 weeks of administration of the first induction
dose.
[0111] In one embodiment, the method comprises a method of inducing
endoscopic remission of ulcerative colitis in a patient, said
method comprising: a) administering to the patient an induction
dose of upadacitinib, or a pharmaceutically acceptable salt
thereof, wherein said induction dose is administered orally once a
day for at least 8 weeks and comprises 45 mg of upadacitinib, or a
45 mg free base equivalent amount of a pharmaceutically acceptable
salt thereof; and b) wherein said patient achieves endoscopic
remission within 8 weeks of administration of the first 45 mg
induction dose.
[0112] In one embodiment, the patient has moderately to severely
active ulcerative colitis.
[0113] In one embodiment, the patient is taking corticosteroids at
the time of the first induction dose.
[0114] In one embodiment, the clinical remission, endoscopic
improvement or endoscopic remission is corticosteroid free.
[0115] In one embodiment, the patient demonstrated an inadequate
response to, loss of response to or intolerance to one or more
corticosteroids, immunosuppressants or biologic therapies.
[0116] In one embodiment, the immunosuppressants are selected form
oral azathioprine, 6-mercaptopurine, injectable methotrexate and
tacrolimus.
[0117] In one embodiment, the biologic therapy is selected from
infliximab, adalimumab, golimumab and vedolizumab.
[0118] In one embodiment, the inadequate response in said patient
taking corticosteroids is defined as said patient experiencing
signs and symptoms of persistently active disease despite a history
of at least one induction regimen that included a dose equivalent
to prednisone .gtoreq.40 mg/day orally for 3 to 4 weeks or
intravenously for one week.
[0119] In one embodiment, the patient is unable to taper
corticosteroid below a dose equivalent to prednisone 10 mg daily
orally without recurrent active disease.
[0120] In one embodiment, the intolerance of said patient to
corticosteroids leads to Cushing's syndrome, osteopenia,
osteoporosis, hyperglycemia, insominia or infection.
[0121] In one embodiment, the patient experiencing the inadequate
response to immunosuppressants experienced signs and symptoms of
persistently active disease despite a history of at least one
90-day regimen of oral azathioprine, 6-mercaptopurine, injectable
methotrexate or tacrolimus.
[0122] In one embodiment, the patient experiencing the inadequate
response to immunosuppressants experienced nausea, vomiting,
abdominal pain, pancreatitis, liver enzyme abnormalities,
lymphopenia or infection.
[0123] In one embodiment, the patient experiencing the inadequate
response to biologic therapies experienced signs and symptoms of
persistently active disease despite a history of a) at least one
6-week induction regimen of infliximab comprising a .gtoreq.5 mg/kg
intravenous dose at 0, 2 and 6 weeks; b) at least one 4-week
induction regimen of adalimumab comprising one 160 mg subcutaneous
dose followed by one 80 mg subcutaneous dose or one 80 mg
subcutaneous dose, followed by one 40 mg subcutaneous dose at least
two weeks apart; c) at least one 2-week induction regimen of
golimumab comprising one 200 mg subcutaneous dose followed by one
100 mg subcutaneous dose at least 2 weeks apart); d) at least one
6-week induction regimen of vedolizumab comprising a 300 mg
intravenous dose at 0, 2 and 6 weeks.
[0124] In one embodiment, the patient experiencing inadequate
response to biologic therapies experienced recurrence of symptoms
during scheduled maintenance dosing following prior clinical
benefit.
[0125] In one embodiment, the patient experiencing intolerance to
biologic therapies experienced infusion-related reaction,
demyelination, congestive heart failure or infection.
[0126] In one embodiment, the method is a method of inducing and
maintaining clinical remission of ulcerative colitis in a patient,
said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 4 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; b) wherein said patient
achieves clinical remission within 4 weeks of administration of the
first induction dose) administering to the patient a first
maintenance dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said first maintenance dose is administered
orally once a day and comprises 30 mg of upadacitinib, or a 30 mg
free base equivalent amount of a pharmaceutically acceptable salt
thereof after the last induction dose is administered; d)
administering at least one additional maintenance dose to the
patient of upadacitinib, or a pharmaceutically acceptable salt
thereof; and e) wherein said patient maintains clinical remission
for 52 weeks after administration of the first induction dose.
[0127] In one embodiment, the method is a method of inducing and
maintaining clinical remission of ulcerative colitis in a patient,
said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 6 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; b) wherein said patient
achieves clinical remission within 6 weeks of administration of the
first 45 mg induction dose; and c) administering to the patient a
first maintenance dose of upadacitinib, or a pharmaceutically
acceptable salt thereof, wherein said first maintenance dose is
administered orally once a day and comprises 30 mg of upadacitinib,
or a 30 mg free base equivalent amount of a pharmaceutically
acceptable salt thereof after the last induction dose is
administered; d) administering at least one additional maintenance
dose to the patient of upadacitinib, or a pharmaceutically
acceptable salt thereof; and e) wherein said patient maintains
clinical remission for 52 weeks after administration of the first
induction dose.
[0128] In one embodiment, the method is a method of inducing and
maintaining clinical remission of ulcerative colitis in a patient,
said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 8 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; and b) wherein said
patient achieves clinical remission within 8 weeks of
administration of the first 45 mg induction dose; c) administering
to the patient a first maintenance dose of upadacitinib, or a
pharmaceutically acceptable salt thereof, wherein said first
maintenance dose is administered orally once a day and comprises 30
mg of upadacitinib, or a 30 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof after the last induction
dose is administered; d) administering at least one additional
maintenance dose to the patient of upadacitinib, or a
pharmaceutically acceptable salt thereof; and e) wherein said
patient maintains clinical remission for 52 weeks after
administration of the first induction dose.
[0129] In one embodiment, the method is inducing and maintaining
endoscopic improvement of ulcerative colitis in a patient, said
method comprising: a) administering to the patient an induction
dose of upadacitinib, or a pharmaceutically acceptable salt
thereof, wherein said induction dose is administered orally once a
day for at least 8 weeks and comprises 45 mg of upadacitinib, or a
45 mg free base equivalent amount of a pharmaceutically acceptable
salt thereof; and b) wherein said patient achieves endoscopic
improvement within 8 weeks of administration of the first induction
dose; c) administering to the patient a first maintenance dose of
upadacitinib, or a pharmaceutically acceptable salt thereof,
wherein said first maintenance dose is administered orally once a
day and comprises 30 mg of upadacitinib, or a 30 mg free base
equivalent amount of a pharmaceutically acceptable salt thereof
after the last induction dose is administered; d) administering at
least one additional maintenance dose to the patient of
upadacitinib, or a pharmaceutically acceptable salt thereof; and e)
wherein said patient maintains clinical remission for 52 weeks
after administration of the first induction dose.
[0130] In one embodiment, the method comprises inducing and
maintaining endoscopic remission of ulcerative colitis in a
patient, said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 8 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; and b) wherein said
patient achieves endoscopic remission within 8 weeks of
administration of the first 45 mg induction dose; c) administering
to the patient a first maintenance dose of upadacitinib, or a
pharmaceutically acceptable salt thereof, wherein said first
maintenance dose is administered orally once a day and comprises 30
mg of upadacitinib, or a 30 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof after the last induction
dose is administered; d) administering at least one additional
maintenance dose to the patient of upadacitinib, or a
pharmaceutically acceptable salt thereof; and e) wherein said
patient maintains clinical remission for 52 weeks after
administration of the first induction dose.
[0131] In one embodiment, the method comprises inducing and
maintaining endoscopic remission of ulcerative colitis in a
patient, said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 8 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; and b) wherein said
patient achieves endoscopic remission within 8 weeks of
administration of the first 45 mg induction dose; c) administering
to the patient a first maintenance dose of upadacitinib, or a
pharmaceutically acceptable salt thereof, wherein said first
maintenance dose is administered orally once a day and comprises 15
mg of upadacitinib, or a 15 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof after the last induction
dose is administered; d) administering at least one additional
maintenance dose to the patient of upadacitinib, or a
pharmaceutically acceptable salt thereof; and e) wherein said
patient maintains clinical remission for 52 weeks after
administration of the first induction dose.
[0132] In one embodiment, the patient has moderately to severely
active ulcerative colitis. In one embodiment the patient is an
adult. In one embodiment, the patient has had an inadequate
response corticosteroid, immunomodulatory or biologic therapy. In
one embodiment, the patient has had loss of response to
aminosalicylate, corticosteroid, immunomodulatory or biologic
therapy. In one embodiment, the patient was intolerant to
corticosteroid, immunomodulatory or biologic therapy. In one
embodiment, the patient is an adult and has moderately to severely
active ulcerative colitis and has had an inadequate response to,
loss of response to, or was intolerant to aminosalicylate,
corticosteroid, immunomodulatory (IMM), or biologic therapy.
[0133] In one embodiment, the patient is taking corticosteroids at
the time of the first induction dose.
[0134] In one embodiment, the clinical remission, endoscopic
improvement or endoscopic remission is corticosteroid free.
[0135] In one embodiment, the patient demonstrated an inadequate
response to, loss of response to or intolerance to one or more
corticosteroids, immunosuppressants or biologic therapies.
[0136] In one embodiment, the immunosuppressants are selected form
oral azathioprine, 6-mercaptopurine, injectable methotrexate and
tacrolimus.
[0137] In one embodiment, the biologic therapy is selected from
infliximab, adalimumab, golimumab and vedolizumab.
[0138] In one embodiment, the inadequate response in said patient
taking corticosteroids is defined as said patient experiencing
signs and symptoms of persistently active disease despite a history
of at least one induction regimen that included a dose equivalent
to prednisone 240 mg/day orally for 3 to 4 weeks or intravenously
for one week.
[0139] In one embodiment, the patient is unable to taper
corticosteroid below a dose equivalent to prednisone 10 mg daily
orally without recurrent active disease.
[0140] In one embodiment, the intolerance of said patient to
corticosteroids leads to Cushing's syndrome, osteopenia,
osteoporosis, hyperglycemia, insomnia or infection.
[0141] In one embodiment, the patient experiencing the inadequate
response to immunosuppressants experienced signs and symptoms of
persistently active disease despite a history of at least one
90-day regimen of oral azathioprine, 6-mercaptopurine, injectable
methotrexate or tacrolimus.
[0142] In one embodiment, the patient experiencing the inadequate
response to immunosuppressants experienced nausea, vomiting,
abdominal pain, pancreatitis, liver enzyme abnormalities,
lymphopenia or infection.
[0143] In one embodiment, the ulcerative colitis or Crohn's disease
patient experiencing the inadequate response to biologic therapies
experienced signs and symptoms of persistently active disease
despite a history of a) at least one 6-week induction regimen of
infliximab comprising a .gtoreq.5 mg/kg intravenous dose at 0, 2
and 6 weeks; b) at least one 4-week induction regimen of adalimumab
comprising one 160 mg subcutaneous dose followed by one 80 mg
subcutaneous dose or one 80 mg subcutaneous dose, followed by one
40 mg subcutaneous dose at least two weeks apart; c) at least one
2-week induction regimen of golimumab comprising one 200 mg
subcutaneous dose followed by one 100 mg subcutaneous dose at least
2 weeks apart; d) at least one 6-week induction regimen of
vedolizumab comprising a 300 mg intravenous dose at 0, 2 and 6
weeks.
[0144] In one embodiment, the patient experiencing inadequate
response to biologic therapies experienced recurrence of symptoms
during scheduled maintenance dosing following prior clinical
benefit.
[0145] In one embodiment, the patient experiencing intolerance to
biologic therapies experienced infusion-related reaction,
demyelination, congestive heart failure or infection.
[0146] In one embodiment, the method is a method of inducing and
maintaining clinical remission of ulcerative colitis in a patient,
said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 4 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; b) wherein said patient
achieves clinical remission within 4 weeks of administration of the
first induction dose; c) administering to the patient a first
maintenance dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said first maintenance dose is administered
orally once a day and comprises 15 mg of upadacitinib, or a 15 mg
free base equivalent amount of a pharmaceutically acceptable salt
thereof after the last induction dose is administered; d)
administering at least one additional maintenance dose to the
patient of upadacitinib, or a pharmaceutically acceptable salt
thereof; and e) wherein said patient maintains clinical remission
for 52 weeks after administration of the first induction dose.
[0147] In one embodiment, the method is a method of inducing and
maintaining clinical remission of ulcerative colitis in a patient,
said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 6 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; b) wherein said patient
achieves clinical remission within 6 weeks of administration of the
first 45 mg induction dose; and c) administering to the patient a
first maintenance dose of upadacitinib, or a pharmaceutically
acceptable salt thereof, wherein said maintenance dose is
administered orally once a day and comprises 15 mg of upadacitinib,
or a 15 mg free base equivalent amount of a pharmaceutically
acceptable salt thereof after the last induction dose is
administered; d) administering at least one additional maintenance
dose to the patient of upadacitinib, or a pharmaceutically
acceptable salt thereof; and e) wherein said patient maintains
clinical remission for 52 weeks after administration of the first
induction dose.
[0148] In one embodiment, the method is a method of inducing and
maintaining clinical remission of ulcerative colitis in a patient,
said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 8 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; and b) wherein said
patient achieves clinical remission within 8 weeks of
administration of the first 45 mg induction dose; c) administering
to the patient a first maintenance dose of upadacitinib, or a
pharmaceutically acceptable salt thereof, wherein said first
maintenance dose is administered orally once a day and comprises 15
mg of upadacitinib, or a 15 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof after the last induction
dose is administered; d) administering at least one additional
maintenance dose to the patient of upadacitinib, or a
pharmaceutically acceptable salt thereof; and e) wherein said
patient maintains clinical remission for 52 weeks after
administration of the first induction dose.
[0149] In one embodiment, the method is a method of inducing and
maintaining endoscopic improvement of ulcerative colitis in a
patient, said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 8 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; and b) wherein said
patient achieves endoscopic improvement within 8 weeks of
administration of the first induction dose; c) administering to the
patient a first maintenance dose of upadacitinib, or a
pharmaceutically acceptable salt thereof, wherein said first
maintenance dose is administered orally once a day and comprises 15
mg of upadacitinib, or a 15 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof after the last induction
dose is administered; d) administering at least one additional
maintenance dose to the patient of upadacitinib, or a
pharmaceutically acceptable salt thereof; and e) wherein said
patient maintains clinical remission for 52 weeks after
administration of the first induction dose.
[0150] In one embodiment, the method is a method of inducing and
maintaining endoscopic remission of ulcerative colitis in a
patient, said method comprising: a) administering to the patient an
induction dose of upadacitinib, or a pharmaceutically acceptable
salt thereof, wherein said induction dose is administered orally
once a day for at least 8 weeks and comprises 45 mg of
upadacitinib, or a 45 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof; and b) wherein said
patient achieves endoscopic remission within 8 weeks of
administration of the first 45 mg induction dose; c) administering
to the patient a first maintenance dose of upadacitinib, or a
pharmaceutically acceptable salt thereof, wherein said first
maintenance dose is administered orally once a day and comprises 15
mg of upadacitinib, or a 15 mg free base equivalent amount of a
pharmaceutically acceptable salt thereof after the last induction
dose is administered; d) administering at least one additional
maintenance dose to the patient of upadacitinib, or a
pharmaceutically acceptable salt thereof; and e) wherein said
patient maintains clinical remission for 52 weeks after
administration of the first induction dose.
[0151] In one embodiment, the patient has moderately to severely
active ulcerative colitis.
[0152] In one embodiment, the patient is taking corticosteroids at
the time of the first induction dose.
[0153] In one embodiment, the clinical remission, endoscopic
improvement or endoscopic remission is corticosteroid free.
[0154] In one embodiment, the patient demonstrated an inadequate
response to, loss of response to or intolerance to one or more
corticosteroids, immunosuppressants or biologic therapies.
[0155] In one embodiment, the immunosuppressants are selected form
oral azathioprine, 6-mercaptopurine, injectable methotrexate and
tacrolimus.
[0156] In one embodiment, the biologic therapy is selected from
infliximab, adalimumab, golimumab and vedolizumab.
[0157] In one embodiment, the inadequate response in said patient
taking corticosteroids is defined as said patient experiencing
signs and symptoms of persistently active disease despite a history
of at least one induction regimen that included a dose equivalent
to prednisone .gtoreq.40 mg/day orally for 3 to 4 weeks or
intravenously for one week.
[0158] In one embodiment, the patient is unable to taper
corticosteroid below a dose equivalent to prednisone 10 mg daily
orally without recurrent active disease.
[0159] In one embodiment, the intolerance of said patient to
corticosteroids leads to Cushing's syndrome, osteopenia,
osteoporosis, hyperglycemia, insomnia or infection.
[0160] In one embodiment, the patient experiencing the inadequate
response to immunosuppressants experienced signs and symptoms of
persistently active disease despite a history of at least one
90-day regimen of oral azathioprine, 6-mercaptopurine, injectable
methotrexate or tacrolimus.
[0161] In one embodiment, the patient experiencing the intolerance
to immunosuppressants experienced nausea, vomiting, abdominal pain,
pancreatitis, liver enzyme abnormalities, lymphopenia or
infection.
[0162] In one embodiment, the patient experiencing the inadequate
response to biologic therapies experienced signs and symptoms of
persistently active disease despite a history of a) at least one
6-week induction regimen of infliximab comprising a .gtoreq.5 mg/kg
intravenous dose at 0, 2 and 6 weeks; b) at least one 4-week
induction regimen of adalimumab comprising one 160 mg subcutaneous
dose followed by one 80 mg subcutaneous dose or one 80 mg
subcutaneous dose, followed by one 40 mg subcutaneous dose at least
two weeks apart; c) at least one 2-week induction regimen of
golimumab comprising one 200 mg subcutaneous dose followed by one
100 mg subcutaneous dose at least 2 weeks apart; d) at least one
6-week induction regimen of vedolizumab comprising a 300 mg
intravenous dose at 0, 2 and 6 weeks.
[0163] In one embodiment, the patient experiencing inadequate
response to biologic therapies experienced recurrence of symptoms
during scheduled maintenance dosing following prior clinical
benefit.
[0164] In one embodiment, the patient experiencing intolerance to
biologic therapies experienced infusion-related reaction,
demyelination, congestive heart failure or infection.
BRIEF DESCRIPTION OF THE DRAWINGS
[0165] FIG. 1 is a schematic representation of the study design for
the clinical study described in Example 8.
[0166] FIG. 2 is a schematic representation of the 36 week
extension phase for the clinical study described in Example 8.
Patients who did not adequately respond during the double-blind
portion of the extension phase were eligible to receive open-label
therapy.
[0167] FIGS. 3A-3I are graphs depicting the relationship between
upadacitinib plasma concentration and clinical response (Week 16;
FIG. 3A), (NRI) clinical remission (Week 16; FIG. 3B), modified
clinical remission (Week 16; FIG. 3C); decrease in CDAI.gtoreq.70
(Week 16; FIG. 3D); decrease in CDAI.gtoreq.100 (Week 16; FIG. 3E);
CDAI<150 (Week 16; FIG. 3F); endoscopic response (Week 12 or
Week 16; FIG. 3G); endoscopic improvement (Week 16; FIG. 3H); and
endoscopic remission (Week 12 or Week 16; FIG. 3I) as determined in
the Example 8 clinical study. Arrows indicate the median exposure
(in mg) for each immediate release dose. The maximum and minimum
plasma concentrations for each exposure bin are indicated in
brackets.
[0168] FIGS. 4A-4F are graphs depicting the model-predicted
efficacy (NRI) for different upadacitinib doses for
immediate-release (IR) BID formulations or modified-release (MR) QD
formulations (simulating for 200 patients/arm) at Weeks 12 or 16.
The predicted results are based on the exposure-response
relationships as determined in the Example 8 study.
[0169] FIGS. 5A-5H are graphs depicting the relationship between
upadacitinib plasma concentration and the change from baseline for
select measured laboratory parameters at week 16 (LOCF) of the
Example 8 clinical study. The maximum and minimum plasma
concentrations for each data point are indicated in brackets.
[0170] FIGS. 6A and 6B are graphs depicting the percent of subjects
who achieved clinical response or clinical remission at week 12 of
the Example 8 study. FIG. 6A shows results for subjects who were
not on steroids at baseline, and FIG. 6B shows results for subjects
who were on steroids at baseline, and who underwent mandatory taper
of steroid dose, starting at week 2 of the Example 8 clinical
study.
[0171] FIG. 7 shows the upadacitinib mean plasma concentration
versus time following administration of 6 mg twice daily immediate
release capsules (Regimen K) or a 15 mg once-daily modified release
tablet (Regimen L) for seven days under fasting conditions.
[0172] FIG. 8 shows the upadacitinib mean plasma concentration
versus time following administration of 12 mg twice daily immediate
release capsules (Regimen M) or a 30 mg once-daily modified release
tablet (Regimen N) for seven days under fasting conditions.
[0173] FIG. 9 shows the clinical remission and endoscopic response
in a refractory patient population administered upadacitinib or
placebo in the Example 8 Crohn's disease clinical study.
[0174] FIGS. 10A-10E are graphs depicting the percentage of
subjects who achieved modified clinical remission at week 2 (FIG.
10A), week 4 (FIG. 10B), week 8 (FIG. 10C), week 12 (FIG. 10D) and
week 16 (FIG. 10E) of the Example 8 study.
[0175] FIGS. 11A-11E are graphs depicting the percentage of
subjects who achieved enhanced clinical response at week 2 (FIG.
11A), week 4 (FIG. 11B), week 8 (FIG. 11C), week 12 (FIG. 11D) and
week 16 (FIG. 11E) of the Example 8 study.
[0176] FIG. 12 shows the mean change in hs-CRP (percentage over
baseline) versus time (weeks) following administration of placebo
(PBO), upadacitinib at 3, 6, 12, 24 mg twice daily (BID) and 24 mg
once daily (QD) for 16 weeks. Modified clinical remission was
analyzed in patients with SF.gtoreq.4. AP.gtoreq.2.0 at
baseline.
[0177] FIG. 13 is a schematic representation of the study design
for the ulcerative colitis clinical study described in Example
12.
[0178] FIG. 14 schematically illustrates one method of preparing
the Amorphous Freebase.
[0179] FIG. 15 schematically illustrates one method of preparing
the Freebase Hydrate Form C.
[0180] FIG. 16 schematically illustrates one method of preparing
the Tartrate Hydrate.
[0181] FIGS. 17A and 17B are powder X-ray diffraction patterns
corresponding to the Amorphous Freebase (via precipitation) and the
Amorphous Freebase (via dehydration), respectively.
[0182] FIG. 18 is a powder X-ray diffraction pattern corresponding
to the Freebase Solvate Form A (Isopropyl Acetate/Water
Solvate).
[0183] FIG. 19 is a powder X-ray diffraction pattern corresponding
to the Freebase Hydrate Form B.
[0184] FIG. 20 is a powder X-ray diffraction pattern corresponding
to the Freebase Hydrate Form C.
[0185] FIG. 21 is a powder X-ray diffraction pattern corresponding
to the Tartrate Hydrate. The experimental PXRD pattern is shown at
the bottom of FIG. 21 and the calculated PXRD pattern is shown at
the top of FIG. 21.
[0186] FIG. 22 is a powder X-ray diffraction pattern corresponding
to the Freebase Anhydrate Form D.
[0187] FIGS. 23A-23F are graphs depicting the exposure-response
model-predicted efficacy for clinical and endoscopic endpoints for
extended-release formulation QD regimens. FIG. 23A is the
percentage of subjects predicted to achieve clinical response at
week 12; FIG. 23B is the percentage of subjects predicted to
achieve modified clinical remission at week 12; FIG. 23C is the
percentage of subjects expected to achieve CDAI remission at week
12; FIG. 23D is the percentage of subjects predicted to achieve
endoscopic response at week 12/16; FIG. 23E is the percentage of
patients predicted to achieve endoscopic improvement at week 12/16;
FIG. 23F is the percentage of patients predicted to achieve
endoscopic remission at week 12/16.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0188] This written description uses examples to disclose the
invention and also to enable any person skilled in the art to
practice the invention, including making and using any of the
disclosed compositions, and performing any of the disclosed methods
or processes. The patentable scope of the invention is defined by
the claims, and may include other examples that occur to those
skilled in the art. Such other examples are intended to be within
the scope of the claims if they have elements that do not differ
from the literal language of the claims, or if they include
equivalent elements.
I. Definitions
[0189] Section headings as used in this section and the entire
disclosure are not intended to be limiting.
[0190] Where a numeric range is recited, each intervening number
within the range is explicitly contemplated with the same degree of
precision. For example, for the range 6 to 9, the numbers 7 and 8
are contemplated in addition to 6 and 9, and for the range 6.0 to
7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9
and 7.0 are explicitly contemplated. In the same manner, all
recited ratios also include all sub-ratios falling within the
broader ratio.
[0191] The singular forms "a," "an" and "the" include plural
referents unless the context clearly dictates otherwise.
[0192] The term "about" generally refers to a range of numbers that
one of skill in the art would consider equivalent to the recited
value (i.e., having the same function or result). In many
instances, the term "about" may include numbers that are rounded to
the nearest significant figure.
[0193] The term "Adapted Mayo" or "Adapted Mayo score" when used in
connection with ulcerative colitis refers to the Mayo Scoring
System for Assessment of Ulcerative Colitis Activity, excluding the
Physician's Global Assessment subscore.
[0194] The term "adult" refers to a person 16 years of age or
older.
[0195] The abbreviation "AE" refers to adverse event.
[0196] The term "alkyl" refers to straight chained or branched
hydrocarbons which are completely saturated. For purposes of
exemplification, which should not be construed as limiting the
scope of this invention, examples of alkyls include methyl, ethyl,
propyl, isopropyl, butyl, pentyl, hexyl, and isomers thereof.
[0197] The term "alkenyl" refers to a hydrocarbon moiety containing
two to eight carbons, including straight chained or branched
hydrocarbons which contain one or more double bonds. Non-limiting
examples of alkenyls are ethenyl, propenyl, and butenyl.
[0198] The term "amorphous" as applied to a compound refers to a
state in which the material lacks long range order at the molecular
level and, depending upon temperature, may exhibit the physical
properties of a solid or a liquid. Typically such materials do not
give distinctive X-ray diffraction patterns and, while exhibiting
the properties of a solid, are more formally described as a liquid.
Upon heating, a change from solid to liquid properties occurs which
is characterized by a change of state, typically second order
("glass transition").
[0199] The term "anhydrate" as applied to a compound refers to a
solid state wherein the compound contains no structural water
within the crystal lattice.
[0200] The abbreviation "AP" refers to abdominal pain score. Unless
otherwise indicated, the AP measurement discussed herein is an
unweighted average of daily AP scores for seven days. The AP
measurements are calculated by averaging the daily AP score used in
calculating the CDAI (discussed below), without the weighting
factor applied.
[0201] The term "aryl" refers to a mono-, bi-, or tricyclic
aromatic hydrocarbon radical. Examples include phenyl, naphthyl,
biphenyl, and 1,2,3,4-tetrahydronaphthyl.
[0202] As used herein, the term "AUC.sub.24" refers to the area
under the plasma concentration time curve from time zero to
twenty-four hours after administration of the referent drug
following a single dose.
[0203] The term "baseline" refers to the day of first dosing with
the JAK1 inhibitor, and is also referred to herein as "Day 1" or
"Week 0".
[0204] The abbreviation "BID" means twice a day.
[0205] The abbreviation "BL" means baseline.
[0206] As used herein, the term "C.sub.12" is the plasma
concentration of the referent drug observed 12 hours after
administration of a single dose, or the indicated number of doses,
of the referent drug.
[0207] As used herein, the term "C.sub.24" is the plasma
concentration of the referent drug observed 24 hours after
administration of a single dose, or the indicated number of doses,
of the referent drug.
[0208] The term "C.sub.ave" refers to the average plasma
concentration of a drug during a dosage interval at steady-state
(multiple-dosing).
[0209] The abbreviation "Cbz" refers to carboxybenzyl.
[0210] The abbreviation "CDI" refers to carbonyldiimidazole.
[0211] The abbreviation "CI" means confidence interval.
[0212] The abbreviation "CDAI" means Crohn's Disease Activity
Index.
[0213] The term "clinical remission" when used in connection with
Crohn's disease means average daily liquid/very soft stool
frequency .ltoreq.2.8 and not greater than baseline and average
daily abdominal pain .ltoreq.1.0 and not greater than baseline. As
used in connection with clinical remission of Crohn's disease, the
phrase "not greater than baseline" means the average daily SF or
average daily AP score is not higher than the average daily SF
score or average daily AP score, respectively, at baseline (i.e.,
prior to treatment).
[0214] The term "clinical remission" when used in connection with
ulcerative colitis means a stool frequency (SF) subscore .ltoreq.1,
a rectal bleeding subscore (RBS) of 0, and an endoscopic subscore
of .ltoreq.0. The SF subscore, rectal bleeding subscore, and
endoscopic subscore refer to the subscores used in the Mayo Scoring
System for Assessment of Ulcerative Colitis Activity. This is also
referred to as "clinical remission per Adapted Mayo Score".
[0215] The term "clinical response" when used in connection with
Crohn's disease is defined as an average daily liquid/very soft SF
score reduction of at least 30% from BL (i.e., .gtoreq.30% decrease
from BL) and an average daily AP not greater than BL and/or
"clinical response" is defined as an average daily AP score
reduction of at least 30% from BL (i.e., .gtoreq.30% decrease from
BL), and an average daily liquid/very soft SF score not greater
than at BL (i.e., prior to treatment).
[0216] The term "clinical response" when used in connection with
ulcerative colitis is defined as a decrease from baseline in the
Adapted Mayo score .gtoreq.2 points and .gtoreq.30% from baseline
accompanied by a decrease in RBS.gtoreq.1 or an absolute
RBS.ltoreq.1.
[0217] The term "enhanced clinical response" when used in
connection with Crohn's disease is defined as .gtoreq.60% decrease
in average daily SF and/or .gtoreq.35% decrease in average daily AP
and both not greater than baseline, and/or clinical remission.
[0218] Unless the context requires otherwise, the terms "comprise,"
"comprises." and "comprising" are used on the basis and clear
understanding that they are to be interpreted inclusively, rather
than exclusively, and that Applicant intends each of those words to
be so interpreted in construing this patent, including the claims
below.
[0219] The term "C.sub.max" refers to the plasma concentration of
the referent drug at T.sub.max, expressed herein as ng/mL, produced
by the oral ingestion of a single dose, or indicated number of
doses, of the dosage form or pharmaceutical composition, such as
the dosage forms and compositions of the present disclosure. Unless
specifically indicated, C.sub.max refers to the overall maximum
observed concentration.
[0220] The term "C.sub.min" refers to the minimum concentration of
drug in blood plasma.
[0221] The term "corticosteroid-free" means a patient who was
taking corticosteroids at the time of the first induction dose of
upadacitinib and has completely discontinued use of
corticosteroids.
[0222] The term "C.sub.p" refers to plasma drug concentration at
any time t.
[0223] The term "crystalline" as applied to a compound refers to a
solid phase in which the material has a regular ordered internal
structure at the molecular level and gives a distinctive X-ray
diffraction pattern with defined peaks. Such materials when heated
sufficiently will also exhibit the properties of a liquid, but the
change from solid to liquid is characterized by a phase change,
typically first order ("melting point").
[0224] The term "crystallization" as used throughout this
application can refer to crystallization and/or recrystallization
depending upon the applicable circumstances relating to the
preparation of the compound.
[0225] The abbreviation "% CV" refers to the coefficient of
variation, expressed as a percent. % CV is calculated according to
the following equation: % CV=(SD/x)*100, wherein x is the mean
value and SD is the standard deviation.
[0226] A "disorder", as used herein, is any condition that would
benefit from treatment with a JAK1 inhibitor described herein. This
includes chronic and acute disorders or diseases including those
pathological conditions that predispose a mammal to the disorder in
questions.
[0227] The term "endoscopic healing" means an SES-CD ulcerated
surface subscore of 0 in subjects with SES-CD ulcerated surface
subscore .gtoreq.1 at baseline.
[0228] The term "endoscopic improvement" (also known as "endoscopic
response by 50%") when used in connection with Crohn's disease
means decrease in SES-CD>50% from baseline (or for subjects with
an SES-CD of 4 at baseline of the induction study, at least a 2
point reduction from baseline).
[0229] The term "endoscopic improvement" when used in connection
with ulcerative colitis means an endoscopic subscore .ltoreq.1 at
week 8 during the induction phase and an endoscopic subscore of 0
at week 8 during the maintenance phase. The endoscopic subscore
refers to the subscore used in the Mayo Scoring System for
Assessment of Ulcerative Colitis Activity.
[0230] The term "endoscopic remission", when used in connection
with Crohn's disease, unless otherwise indicated, means an SES-CD
of .ltoreq.4 (.ltoreq.2 for patients with isolated ileal CD) and at
least a two point reduction in SES-CD versus BL and no subscore
>1 in any individual variable used to calculate the SES-CD.
[0231] The term "endoscopic remission (by IOIBD (International
Organization for the Study of Inflammatory Bowel Diseases)
definition), when used in connection with Crohn's disease, means
SDS.ltoreq.2.
[0232] The term "endoscopic remission" when used in connection with
ulcerative colitis means an endoscopic subscore of 0. The
endoscopic subscore refer to the endoscopic subscore used in the
Mayo Scoring System for Assessment of Ulcerative Colitis
Activity.
[0233] The term "endoscopic response" when used in connection with
Crohn's disease means at least a 50% reduction in SES-CD score from
BL.
[0234] The abbreviation "EtOAc" refers to ethyl acetate.
[0235] The abbreviation "EtOH" refers to ethanol.
[0236] The term "Geboes score" means a histological score based on
measurement of fecal calprotein and high-sensitivity C-reactive
protein.
[0237] The term "histologic improvement" when used in connection
with ulcerative colitis means a decrease from baseline in Geboes
score.
[0238] The abbreviation "HDL" refers to high density
lipoprotein.
[0239] The abbreviation "Hgb" refers to hemoglobin.
[0240] The abbreviation "HOAc" refers to acetic acid.
[0241] The abbreviation "HPMC" refers to hydroxypropyl
methylcellulose.
[0242] As used herein, the term "inducing" or "induced", when used
in connection with a particular therapeutic effect, means the
therapeutic effect has been achieved. Typically, the therapeutic
effect is induced in a patient previously suffering from a disease
condition, such as in a patient having moderately to severely
active Crohn's disease or moderately to severely active ulcerative
colitis. For instance, in one embodiment, inducing a particular
therapeutic effect, when used in connection with Crohn's disease,
means the patient is brought from a state where the patient has 1)
an average daily liquid/very soft stool frequency score .gtoreq.2.5
or average daily abdominal pain score .gtoreq.2, 2) CDAI.gtoreq.220
and .ltoreq.450 or 3) Simplified Endoscopic Score for Crohn's
disease (SES-CD).gtoreq.6 (or .gtoreq.4 for subjects with disease
limited to the ileum) and bringing the patient to a state where the
patient achieve the parameters for the specified therapeutic effect
(e.g., endoscopic remission, clinical remission, endoscopic
response, clinical response).
[0243] The abbreviation "IPAc" refers to isopropyl acetate.
[0244] The abbreviation "IR" means immediate release, unless
otherwise indicated.
[0245] As used herein, the term "JAK1 inhibitor" or "upadacitinib"
refers to the compound
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide.
[0246] The abbreviation "LDL" refers to low density
lipoprotein.
[0247] The abbreviation "LOCF" means last observation carried
forward method.
[0248] The abbreviation "Mayo" means the Mayo Scoring System for
Assessment of Ulcerative Colitis Activity.
[0249] The term "moderately to severely active Crohn's disease",
unless otherwise indicated, is defined as average daily very soft
or liquid/soft stool frequency .gtoreq.4 and/or average daily
abdominal pain score .gtoreq.2.0 and evidence of mucosal
inflammation, defined as Simplified Endoscopic Score of or CD
(SES-CD).gtoreq.6 (.gtoreq.4 for subjects with isolated ileal
disease), excluding the presence of narrowing component.
[0250] The term "moderately to severely active ulcerative colitis",
unless otherwise indicated, is defined as having an Adapted Mayo
score of 5 to 9, with an endoscopy subscore of 2 or 3.
[0251] The term "modified clinical remission" when used in
connection with Crohn's disease is defined as an average daily
liquid/very soft SF score of .ltoreq.2.8 and not greater than BL
and an average daily AP score of .ltoreq.1.0 and not greater than
BL. As used in connection with clinical remission, the phrase "not
greater than baseline" means that average daily liquid/very soft SF
score or average daily AP score is not higher than the average
daily liquid/very soft SF score or average daily AP score,
respectively, at baseline (i.e., prior to treatment).
[0252] The abbreviation "MR" means modified release.
[0253] The abbreviation "MTX" refers to methotrexate.
[0254] The term "patient" or "subject", used interchangeably
herein, refers to a human patient or subject.
[0255] The term "NK cells" refers to natural killer cells.
[0256] The abbreviation "NRI" means non-responder imputation
method.
[0257] The abbreviation "PBO" means placebo.
[0258] The abbreviation "Pd/C" refers to palladium on carbon.
[0259] The abbreviation "Pd(OH.sub.2)/C" refers to palladium
hydroxide on carbon.
[0260] The term "pharmaceutically acceptable" (such as in the
recitation of a "pharmaceutically acceptable salt" or a
"pharmaceutically acceptable diluent") refers to a material that is
compatible with administration to a human subject, e.g., the
material does not cause an undesirable biological effect. Examples
of pharmaceutically acceptable salts are described in "Handbook of
Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and
Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Examples of
pharmaceutically acceptable excipients are described in the
"Handbook of Pharmaceutical Excipients," Rowe et al., Ed.
(Pharmaceutical Press, 7th Ed., 2012).
[0261] The abbreviation "pTsOH" refers to p-toluene sulfonic
acid.
[0262] The abbreviation "PVA" refers to polyvinyl acetate.
[0263] The abbreviation "PXRD" means powder X-ray diffraction.
[0264] The abbreviation "QD" means once daily.
[0265] The abbreviation "RBC" means red blood cells.
[0266] The abbreviation "RBS" means rectal bleeding subscore. The
rectal bleeding subscore refers to the subscore used in the Mayo
Scoring System for Assessment of Ulcerative Colitis Activity.
[0267] The term "refractory patient" means a patient with
moderately to severely active Crohn's disease, who has had Crohn's
disease for more than ten years and who has failed several
treatments, including biologic treatments.
[0268] The term "remission" when used in connection with Crohn's
disease is defined as both endoscopic remission and clinical
remission.
[0269] The term "response" when used in connection with Crohn's
disease is defined as both endoscopic response and clinical
response.
[0270] The abbreviation "SC" means subcutaneous.
[0271] The abbreviation "(S)-Segphos Ru(OAc).sub.2" refers to
diacetato[(S)-(-)5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole]rut-
henium(II).
[0272] The term "SES-CD" refers to the Simplified Endoscopic Score
for Crohn's disease, which is calculated using the parameters
listed in Table 2 below.
[0273] The abbreviation "SF" refers to stool frequency. Unless
otherwise indicated, the SF measurement discussed herein when used
in connection with Crohn's disease is an unweighted average of
daily liquid/very soft SF scores for seven days. The SF
measurements are calculated by averaging the daily liquid/very soft
SF scores used in calculating the CDAI (discussed below), without
the weighting factor applied. Unless otherwise indicated, the SF
measurement discussed herein when used in connection with
ulcerative colitis refers to the stool frequency subscore used in
the Mayo Scoring System for Assessment of Ulcerative Colitis
Activity.
[0274] The term "therapeutically effective amount" is used to refer
to an amount of an active agent that relieves or ameliorates one or
more of the symptoms of the disorder being treated. In another
aspect, the therapeutically effective amount refers to a target
serum concentration that has been shown to be effective in, for
example, slowing disease progression. Efficacy can be measured in
conventional ways, depending on the condition to be treated.
[0275] The abbreviation "6-TGN" refers to 6-tioguanine
(thioguanine) nucleotides.
[0276] The abbreviation "THF" refers to tetrahydrofuran.
[0277] As used herein, the term "T.sub.max" refers to the time to
peak plasma concentration of the referent drug after oral ingestion
of a single dose, or indicated number of doses, of the referent
drug.
[0278] The terms "treating", "treatment", and "therapy" and the
like, as used herein, are meant to include therapeutic as well as
prophylactic, or suppressive measures for a disease or disorder
leading to any clinical desirable or beneficial effect, including
but not limited to alleviation or relief of one or more symptoms,
regression, slowing or cessation of progression of the disease or
disorder. Thus, for example, the term treatment includes the
administration of an agent prior to or following the onset of a
symptom of a disease or disorder thereby preventing or removing one
or more signs of the disease or disorder. As another example, the
term includes the administration of an agent after clinical
manifestation of the disease to combat the symptoms of the disease.
Further, administration of an agent after onset and after clinical
symptoms have developed where administration affects clinical
parameters of the disease or disorder, such as the degree of tissue
injury or the amount or extent of metastasis, whether or not the
treatment leads to amelioration of the disease, comprises
"treatment" or "therapy" as used herein. Moreover, as long as the
compositions of the disclosure either alone or in combination with
another therapeutic agent alleviate or ameliorate at least one
symptom of a disorder being treated as compared to that symptom in
the absence of use of the JAK1 inhibitor composition, the result
should be considered an effective treatment of the underlying
disorder regardless of whether all the symptoms of the disorder are
alleviated or not.
[0279] The abbreviation "TNF" means tumor necrosis factor.
[0280] As used herein, the term "t.sub.1/2" refers to the terminal
half-life of the referent drug after oral ingestion of a single
dose, or indicated number of doses, of the referent drug.
[0281] The abbreviation "UC" refers to ulcerative colitis.
[0282] The abbreviation "w/w" refers to weight/weight.
II. JAK1-Associated Disorders and JAK1 Inhibitors
[0283] In one aspect, the present disclosure provides methods for
treating and/or inducing clinical remission, endoscopic
improvement, and/or endoscopic remission of Crohn's disease. In
another aspect, the present disclosure provides methods for
treating ulcerative colitis and/or for inducing a clinical
remission of ulcerative colitis. In one aspect, the methods
comprise administering a JAK1 inhibitor to the patient.
[0284] Targeting the JAK (Janus activated kinase) signaling pathway
for autoimmune diseases, such as rheumatoid arthritis (RA) and CD,
is well-supported by the involvement of various pro-inflammatory
cytokines that signal via JAK pathways in the pathogenesis of these
immune-related disorders. The activation of the JAK signaling
initiates expression of survival factors, cytokines, chemokines,
and other molecules that facilitate leukocyte cellular trafficking
and cell proliferation, which contribute to inflammatory and
autoimmune disorders.
[0285] Although the pathogenesis of CD is not completely
understood, the imbalance between anti-inflammatory and
pro-inflammatory cytokines in the mucosal immune system is thought
to play an important role in CD. Cells from the innate mucosal
immune system, i.e. TH1 or TH17, are over-activated and secrete
various pro-inflammatory cytokines such as interferon (INF)-g,
TNF.alpha., interleukin IL-6, IL1b, IL-12, IL23. These cytokines
signal via JAK pathways.
[0286] The JAK comprises four family members: JAK1, 2, 3, and
Tyrosine kinase 2 (Tyk2). These cytoplasmic tyrosine kinases
transduce cytokine-mediated signals, and are associated with
membrane cytokine receptors such as common gamma-chain (CGC)
receptors and the glycoprotein 130 (gp130) trans-membrane
proteins.
[0287] JAK3 and JAK1 are components of the CGC cytokine receptor
complexes and blockade of either inhibits signaling by the
inflammatory cytokines IL-2, -4, -7, -9, -15 and -21. Cytokines
such as IL-6 bind to gp130 and transduce its signal predominantly
via JAK1. Targeting the IL-6 receptor (IL-6R) is a promising
approach given the fact that expression of IL-6 and soluble IL-6
receptors is elevated in patients with active CD. Further, a proof
of concept study in patients with active CD with tocilizumab, a
humanized monoclonal antibody against IL-6R, showed an encouraging
clinical response. Thus, inhibition of JAK1 is expected to
attenuate the signaling of IL-6 and other pro-inflammatory
cytokines (i.e. IFN-g), that are involved in development of CD.
[0288] Thus, in one aspect, the present disclosure provides a
compound useful in the treatment of Crohn's Disease and ulcerative
colitis. In one aspect, the JAK1 inhibitor used in the methods of
the present disclosure is the compound
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide
(C.sub.17H.sub.19F.sub.3N.sub.6O), or a pharmaceutically acceptable
salt or solid state form thereof. The compound
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide is also referred to herein
as "upadacitinib", and has the structure shown below:
##STR00001##
[0289] "Pharmaceutically acceptable salts" refers to those salts
which retain the biological effectiveness and properties of the
free bases and which are obtained by reaction with inorganic acids,
for example, hydrochloric acid, hydrobromic acid, sulfuric acid,
nitric acid, and phosphoric acid or organic acids such as sulfonic
acid, carboxylic acid, organic phosphoric acid, methanesulfonic
acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid,
fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic
acid, lactic acid, mono-malic acid, mono oxalic acid, tartaric acid
such as mono tartaric acid (e.g., (+) or (-)-tartaric acid or
mixtures thereof), amino acids (e.g., (+) or (-)-amino acids or
mixtures thereof), and the like. These salts can be prepared by
methods known to those skilled in the art
III. Methods of Treatment of Crohn's Disease
[0290] In one aspect, the present disclosure is directed to methods
for the treatment of Crohn's disease. In one aspect the present
disclosure provides methods for treating Crohn's disease, in
particular methods comprising administering a JAK1 inhibitor to a
patient in certain amounts and/or at certain intervals. In one
aspect, the JAK1 inhibitor is upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof.
[0291] In one aspect, the present disclosure provides a JAK1
inhibitor for use in the treatment of Crohn's disease, by
administration in certain amounts and/or at certain intervals as
described herein. In one aspect, the JAK1 inhibitor is upadacitinib
or a pharmaceutically acceptable salt or solid state form
thereof.
[0292] In one aspect, the present disclosure provides for the use
of a JAK1 inhibitor for the preparation of a medicament for the
treatment of Crohn's disease, by administration in certain amounts
and/or at certain intervals as described herein. In one aspect, the
JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof.
[0293] In one aspect, the present disclosure is directed to methods
for inducing clinical remission and/or endoscopic remission of
Crohn's disease. In one aspect, the present disclosure provides
methods for inducing clinical remission and/or endoscopic remission
of Crohn's disease, in particular methods comprising administering
a JAK1 inhibitor to a patient in certain amounts and/or at certain
intervals. In one aspect, the JAK1 inhibitor is upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof.
[0294] In one aspect, the present disclosure provides a JAK1
inhibitor for use in inducing clinical remission and/or endoscopic
remission of Crohn's disease by administration in certain amounts
and/or at certain intervals as described herein. In one aspect, the
JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof.
[0295] In one aspect, the present disclosure provides for the use
of a JAK1 inhibitor for the preparation of a medicament for
inducing clinical remission and/or endoscopic remission of Crohn's
Disease by administration in certain amounts and/or at certain
intervals as described herein. In one aspect, the JAK1 inhibitor is
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof.
[0296] In one aspect, the present disclosure is directed to methods
for inducing clinical remission and/or endoscopic improvement of
Crohn's disease, in particular, methods comprising administering a
JAK1 inhibitor to a patient in certain amounts and/or at certain
intervals. In one aspect, the JAK1 inhibitor is upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof.
[0297] In one aspect, the present disclosure provides a JAK1
inhibitor for use in inducing clinical remission and/or endoscopic
improvement of Crohn's disease by administration in certain amounts
and/or at certain intervals as described herein. In one aspect, the
JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof.
[0298] In one aspect, the present disclosure provides for the use
of a JAK1 inhibitor for the preparation of a medicament for
inducing clinical remission and/or endoscopic improvement of
Crohn's disease, by administration in certain amounts and/or at
certain intervals as described herein. In one aspect, the JAK1
inhibitor is upadacitinib or a pharmaceutically acceptable salt or
solid state form thereof.
[0299] In one particular aspect, the disease is moderately to
severely active Crohn's disease. In one aspect, in the context of
the present disclosure, a patient is naive to, or was previously
treated with immunosuppressants (e.g., methotrexate),
aminosalicylates, corticosteroids, and/or a biologic agent (e.g.,
vedolizumab, ustekinumab, natalizumab, etc.). In one aspect, the
patient is naive to, or was previously treated with an anti-TNF
therapy (e.g., infliximab, adalimumab, certolizumab pegol,
golimumab, etc.). In one aspect, in the context of a method of the
present disclosure a patient was previously treated with one, two,
three or more TNF antagonist(s) (also referred to herein as
anti-TNF agents). In one embodiment, the patient is a patient who
had an inadequate response with, lost response, or was intolerant
to a TNF antagonist. In one aspect, in the context of a method of
the present disclosure a patient was previously treated with one,
two, three or more biologic(s). In one embodiment, the patient is a
patient who had an inadequate response with, lost response, or was
intolerant to a biologic agent. In one embodiment, the patient is a
patient who had an inadequate response with, lost response, or was
intolerant to a TNF antagonist, aminosalicylates, corticosteroids,
immunosuppressants, and/or a biologic agent. In one embodiment, the
patient is a refractory patient who has moderately to severely
active Crohn's disease. In one embodiment, the patient is either
naive to or has stopped using corticosteroids prior to treatment
with the JAK1 inhibitor.
Biologic Agents for Crohn's Disease:
[0300] 1) Demonstrated an inadequate response to, loss of response
to, recurrence of signs and symptoms or intolerance to any biologic
therapy as defined below: [0301] a. at least one 6-week induction
regimen of infliximab (.gtoreq.5 mg/kg intravenous [IV] at 0, 2 and
6 weeks), [0302] b. at least one 4-week induction regimen of
adalimumab (one 160 mg subcutaneous (SC) dose at Week 0, followed
by one 80 mg SC dose at Week 2 [or one 80 mg SC dose at Week 0,
followed by one 40 mg SC dose at at Week 2, in countries where this
dosing regimen is approved]), [0303] c. at least one 4-week
induction regimen of certolizumab pegol (400 mg SC at Weeks 0, 2
and 4), [0304] d. at least one 6-week induction regimen of
vedolizumab (300 mg IV at 0, 2 and 6 weeks), [0305] e. at least one
12-week induction regimen of natalizumab (300 mg IV every 4 weeks),
[0306] f. at least on 8-week induction regimen of ustekinumab [260
mg (<55 kg) or 390 mg (56-85 kg) or 520 mg (>86 kg), followed
by 90 mg SC at week 8] or [0307] 2) Recurrence of symptoms during
scheduled maintenance dosing following prior clinical benefit
(discontinuation despite clinical benefit does not qualify), or
[0308] 3) History of intolerance to at least one biologic agent
(including, but not limited to infusion-related reaction,
demyelination, congestive heart failure (CHF), infection).
[0309] Disease severity for Crohn's disease may be measured using a
variety of indexes, including the Crohn's Disease Activity Index
(CDAI), the Simplified Endoscopic Score for CD (SES-CD), average
daily liquid/very soft stool frequency (SF) (patient reported);
and/or average daily abdominal pain (AP) score (patient reported).
Unless otherwise indicated, the SF and AP scores discussed herein
refer to their respective unweighted average of the daily scores
that are used in calculation of the CDAI (discussed below).
Measures for assessing health-related quality of life include the
Inflammatory Bowel Disease Questionnaire (IBDQ). The IBDQ is a
well-known 32 item validated questionnaire that assesses a
patient's inflammatory bowel disease symptoms, general well-being,
and mood, and may be used as a tool to evaluate a patient's quality
of life (Guyatt, et al., Gastroenterology, 1989, 96:804-810). The
IBDQ questionnaire is described in further detail below.
[0310] CDAI is a composite score used to quantify symptoms of
patients with Crohn's disease. In one aspect, the index consists of
eight factors added together after adjusting for a predefined
weighting factor (see Table 1 below). CDAI scores range from 0 to
600. Index values of 150 and below are associated with quiescent
disease; values above 150 are associated with active disease, and
values above 450 are seen with extremely severe disease. In one
aspect, a patient to be treated by a method according to the
present disclosure has a CDAI score of 220 to 450 prior to
treatment, which may be indicative of moderately to severely active
CD.
TABLE-US-00001 TABLE 1 Format for Calculation of the CDAI Weighting
Clinical or laboratory variable factor Number of liquid or very
soft stools in the previous .times.2 7 days (sum of daily scores)
AP (graded from 0 (mild) to 3 (severe) on severity) .times.5 each
day for 7 days (sum of daily score) General wellbeing, subjectively
assessed .times.7 from 0 (generally well) to 4 (terrible) each day
for 7 days (sum of daily score) Number of complications patient now
has: (record 0 if none) .times.20 Arthritis/arthralgia
Iritis/uveitis Erythema nodosum/pyoderma gangrenosum/aphthous
stomatitis Fissure, abscess and/or anal fistula
(draining/non-draining) Other cutaneous fistula
(draining/non-draining) Fever over 100.degree. F. (37.8.degree. C.)
during past week Taking lomotil/imodium/loperamide or opiates
.times.30 for diarrhea (0 = no, 1 = yes) Presence of an abdominal
mass (0 as none, 2 .times.10 as questionable, 5 as defined)
Hematocrit (Male: 47-hematocrit; Female: 42-hematocrit; .times.6 if
hematocrit > normal, enter 0 Percentage under standard weight
.times.1
[0311] SES-CD is calculated using the following parameters listed
in Table 2:
TABLE-US-00002 TABLE 2 Parameters for Calculating SES-CD Sigmoid
Trans- and left verse Right Rectum colon Colon colon Ileum Total
Size of Ulcers Enter: 0 if none 1 if aphthous ulcer (O 0.01 to 0.5
cm) 2 if large ulcers (O 0.05 to 2 cm) 3 if very large ulcer (O
> 2 cm) Ulcerated Surface Enter: 0 if none 1 if <10% 2 if
10%-30% 3 if >30% Affected Surface Enter: 0 if unaffected
segments 1 if <50% 2 if 50%-75% 3 if >75% Presence of
Narrowing Enter: 0 if none 1 if single, can be passed 2 if
multiple, can be passed 3 if cannot be passed Total =
[0312] In one aspect, the patient to be treated has moderately to
severely active Crohn's disease. Moderately to severely active
Crohn's disease is characterized by a SES-CD of greater than or
equal to 6 (or a SES-CD of greater than or equal to 4 for patients
with disease limited to the ileum).
[0313] In one embodiment, the patient is a patient who had an
inadequate response with, lost response, or was intolerant to a
conventional therapy (e.g., aminosalicylates, corticosteroids,
immunosuppressants), or to a biologic agent. In one embodiment, the
patient is a patient who had an inadequate response with, lost
response, or was intolerant to a TNF antagonist. Examples of such
anti-TNF agents include infliximab, adalimumab, and certolizumab
pegol. Criteria for determining if a patient has had an inadequate
response to or experienced intolerance to previous treatment with
an anti-TNF agent is defined as: [0314] 1) Signs and symptoms of
persistently active disease despite a history of at least one
4-week induction regimen of one of the following agents: [0315]
Infliximab: 5 mg/kg IV, 2 doses at least 2 weeks apart, [0316]
Adalimumab: one 160 mg subcutaneous dose followed by one 80 mg
subcutaneous dose (or one 80 mg subcutaneous dose) followed by one
40 mg dose at least 2 weeks apart, [0317] Certolizumab pegol: 400
mg subcutaneous, two doses at least two doses apart; or 2)
Recurrence of symptoms during scheduled maintenance dosing
following prior clinical benefit (discontinuation despite clinical
benefit does not qualify); or [0318] 2) Recurrence of symptoms
during scheduled maintenance dosing following prior clinical
benefit (discontinuation despite clinical benefit does not
qualify); or [0319] 3) History of intolerance of at least one TNF
antagonist (including, but not limited to infusion related
reaction, demyelination, congestive heart failure and
infection).
[0320] In one aspect, the patient is one who has previously been
treated with, or is currently being treated with aminosalicylates,
immunosuppressants, corticosteroids, and/or a biologic agent.
[0321] In one aspect, CDAI or any of the evaluations described in
the Examples herein below is/are used to assess the efficacy of
upadacitinib in the treatment of Crohn's disease, for example
moderately to severely active Crohn's disease.
[0322] In one embodiment, in the context of the present disclosure,
the treatment of a patient or the induction of clinical remission
and/or endoscopic remission in a patient or the induction of
clinical remission and/or endoscopic improvement in a patient
comprises an induction phase and a maintenance phase. In the
induction phase, one or more doses of the JAK1 inhibitor, for
example referred to herein as induction doses, are administered to
the patient, for example, orally. In the maintenance phase, a first
dose of the JAK1 inhibitor, for example referred to herein as the
maintenance dose, is administered to the patient followed by at
least one additional dose of the JAK1 inhibitor, for example, also
referred to herein as a maintenance dose. The maintenance doses
are, for example, administered orally. The JAK1 inhibitor may be,
for example, upadacitinib, or a pharmaceutically acceptable salt or
solid state form thereof. Examples of induction phases and
maintenance phases are described herein.
[0323] In one aspect, a certain therapeutic result is achieved by
the patient during or at the end of the induction phase, for
example clinical remission, endoscopic remission, or both clinical
remission and endoscopic remission (referred to herein as
"remission"). In one aspect, the patient achieves clinical
remission during or by the end of the induction phase. In one
aspect, the patient achieves endoscopic remission during or by the
end of the induction phase.
[0324] In another aspect, a certain therapeutic result is achieved
by the patient during or at the end of the induction phase, for
example clinical remission, endoscopic improvement, or both
clinical remission and endoscopic improvement. In one aspect, the
patient achieves clinical remission during or by the end of the
induction phase. In one aspect, the patient achieves endoscopic
improvement during or by the end of the induction phase
[0325] In one embodiment, the induction phase lasts for up to 16
weeks (e.g., for up to 16 weeks following initiation of
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof). Thus, in one embodiment, the
induction phase is 16 weeks. In another embodiment, the induction
phase optionally lasts for less than 16 weeks, for instance, for 2
weeks, for 4 weeks, for 5 weeks, for 6 weeks, for 7 weeks, for 8
weeks, for 9 weeks, for 10 weeks, for 11 weeks, for 12 weeks, for
13 weeks, for 14 weeks, or for 15 weeks. In one aspect, the patient
achieves an endoscopic remission within 12 weeks, or within 16
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one aspect, the patient achieves a clinical remission within 16
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one aspect, the patient achieves an endoscopic improvement within
12 weeks, or within 16 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof. In one aspect, the patient achieves a clinical
remission within 12 weeks, or within 16 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof.
[0326] In one embodiment, the patient achieves clinical remission
within 2 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, the patient achieves clinical remission within 4
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof.
[0327] In one embodiment, the patient achieves both 1) average
daily liquid/very soft SF score of .ltoreq.1.5 and not worse than
BL, and 2) average daily AP score of .ltoreq.1.0 and not worse than
baseline within 2 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof. As used in connection with clinical remission, the
phrase "not worse than baseline" means that the average daily
liquid/very soft SF score or average daily AP score is not higher
than the average daily liquid/very soft SF score or average daily
AP score, respectively, at baseline (i.e., prior to treatment).
[0328] In one embodiment, the patient achieves both 1) average
daily liquid/very soft SF score of .ltoreq.1.5 and not worse than
BL, and 2) average daily AP score of .ltoreq.1.0 and not worse than
baseline within 4 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof. As used in connection with clinical remission, the
phrase "not worse than baseline" means that the average daily
liquid/very soft SF score or average daily AP score is not higher
than the average daily liquid/very soft SF score or average daily
AP score, respectively, at baseline (i.e., prior to treatment).
[0329] In one embodiment, the patient achieves endoscopic remission
and/or endoscopic improvement within 2 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, the patient
achieves endoscopic remission and/or endoscopic improvement within
12 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof.
[0330] In one embodiment, the patient achieves corticosteroid-free
remission within 12 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof.
[0331] In some embodiments, during or by the end of the induction
phase (e.g., lasting for up to 16 weeks, including for 2 weeks, 4
weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks or for 16 weeks), the
patient achieves at least one therapeutic result selected from the
group consisting of: [0332] 1) a CDAI of less than 150 within 16
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof,
[0333] 2) a CDAI of less than 150 within 12 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, [0334] 3) a CDAI of less than 150
within 4 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof,
[0335] 4) a decrease in CDAI of greater than or equal to 70 points
from baseline within 16 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, [0336] 5) a decrease in CDAI of greater than or equal
to 70 points from baseline within 12 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, [0337] 6) a decrease in CDAI of
greater than or equal to 70 points from baseline within 4 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof, [0338] 7) a clinical
remission within 12 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, [0339] 8) a clinical remission within 4 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. [0340] 9) remission
within 16 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof (i.e.,
both endoscopic remission within 12 weeks or within 16 weeks and
clinical remission within 16 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof), [0341] 10) remission within 12 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof (i.e., both endoscopic remission
within 12 weeks and clinical remission within 12 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof). [0342] 11) remission
within 4 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof (i.e.,
both endoscopic remission within 4 weeks and clinical remission
within 4 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof).
[0343] 12) response within 16 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof (i.e., both endoscopic response within 12 weeks or
within 16 weeks and clinical response within 16 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof), [0344] 13) response within 12
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof (i.e.,
both endoscopic response within 12 weeks and clinical response
within 12 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof),
[0345] 14) response within 4 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof (i.e., both endoscopic response within 4 weeks and
clinical response within 4 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof), [0346] 15) endoscopic response within 12 weeks or
within 16 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof,
[0347] 16) endoscopic response within 4 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, [0348] 17) clinical response
within 16 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof,
[0349] 18) clinical response within 12 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, [0350] 19) clinical response
within 4 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof.
[0351] 20) clinical response within 2 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof [0352] 21) a change from baseline
in fecal calprotectin level within 16 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, [0353] 22) a change from baseline
in fecal calprotectin level within 12 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, [0354] 23) a change from baseline
in fecal calprotectin level within 4 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, [0355] 24) a change from baseline
in hs-CRP (high sensitivity C-reactive protein) within 16 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof, [0356] 25) a change
from baseline in hs-CRP (high sensitivity C-reactive protein)
within 12 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof,
[0357] 26) a change from baseline in hs-CRP (high sensitivity
C-reactive protein) within 8 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, [0358] 27) a change from baseline in hs-CRP (high
sensitivity C-reactive protein) within 4 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, [0359] 28) a change from baseline
in hs-CRP (high sensitivity C-reactive protein) within 2 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof, [0360] 29) a change in
Inflammatory Bowel Disease Questionnaire (IBDQ) score from baseline
within 16 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof,
[0361] 30) a change in Inflammatory Bowel Disease Questionnaire
(IBDQ) score from baseline within 12 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, [0362] 31) a change in
Inflammatory Bowel Disease Questionnaire (IBDQ) score from baseline
within 8 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof,
[0363] 32) modified clinical remission within 4 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, [0364] 33) enhanced clinical
response within 8 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof and combinations thereof, [0365] 34) 4 steroid-free
endoscopic improvement within 4 weeks of administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, [0366] 35) steroid-free endoscopic improvement within
8 weeks of administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof, [0367] 36)
steroid-free endoscopic improvement within 16 weeks of
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, [0368] 37) steroid-free
endoscopic response within 4 weeks of administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, [0369] 38) steroid-free endoscopic response within 8
weeks of administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof, [0370] 39)
steroid-free endoscopic response within 16 weeks of administration
of upadacitinib, or a pharmaceutically acceptable salt or solid
state form thereof, [0371] 40) steroid-free endoscopic remission
within 4 weeks of administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof,
[0372] 41) steroid-free endoscopic remission within 8 weeks of
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, [0373] 42) steroid-free
endoscopic remission within 16 weeks of administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof.
[0374] In some embodiments, the patient achieves either a clinical
remission within 16 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, or an endoscopic remission within 12 weeks or within
16 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof, and
further achieves any combination of additional therapeutic results
selected from the group consisting of therapeutic results 1), 2),
3), 4), 5), 6), 7), 8), 9), 10), 11), 12), 13), 14), 15), 16), 17),
18), 19), 20), 21), 22), 23), 24), 25), 26), 27), 28), 29), and
combinations thereof. In one such embodiment, the induction phase
is 16 weeks.
[0375] In one embodiment, the induction phase is 12 weeks, and the
patient achieves either a clinical remission within 12 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof, or an endoscopic
remission within 12 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, and further achieves any combination of additional
therapeutic results selected from the group consisting of
therapeutic results 2), 3), 5), 6), 7), 8), 10), 11), 13), 14),
15), 16), 18), 19), 20), 22), 23), 25), 26), 28), 29), and
combinations thereof, wherein the therapeutic result is achieved
within 12 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof.
[0376] In one embodiment, the induction phase is 4 weeks, and the
patient achieves either a clinical remission within 4 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof, or an endoscopic
remission within 4 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, and further achieves any combination of additional
therapeutic results selected from the group consisting of
therapeutic results 3), 6), 8), 11), 14), 16), 19), 20), 23), 26),
29), and combinations thereof, wherein the therapeutic result is
achieved within 4 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof.
[0377] In one embodiment, the patient achieves a clinical remission
within 12 weeks, or within 16 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, and/or achieves an endoscopic improvement within 12
weeks or within 16 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, and further achieves any combination of additional
therapeutic results selected from the group consisting of
therapeutic results 1), 2), 3), 4), 5), 6), 7), 8), 9), 10), 11),
12), 13), 14), 15), 16), 17), 18), 19), 20), 21), 22), 23), 24),
25), 26), 27), 28), 29), and combinations thereof. In one such
embodiment, the induction phase is 16 weeks.
[0378] In one embodiment, the induction phase is 12 weeks, and the
patient achieves a clinical remission within 12 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, and/or achieves an endoscopic
improvement within 12 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, and further achieves any combination of additional
therapeutic results selected from the group consisting of
therapeutic results 2), 3), 5), 6), 7), 8), 10), 11), 13), 14),
15), 16), 18), 19), 20), 22), 23), 25), 26), 28), 29), and
combinations thereof, wherein the therapeutic result is achieved
within 12 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof.
[0379] In one embodiment, the induction phase is 16 weeks, and the
patient achieves a clinical remission within 16 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, and/or achieves an endoscopic
improvement within 16 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, and further achieves any combination of additional
therapeutic results selected from the group consisting of
therapeutic results 1), 2), 3), 4), 5), 6), 7), 8), 9), 10), 11),
12), 13), 14), 15), 16), 17), 18), 19), 20), 21), 22), 23), 24),
25), 26), 27), 28), 29), and combinations thereof, wherein the
therapeutic result is achieved within 16 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof.
[0380] In one embodiment, the induction phase is 4 weeks, and the
patient achieves a clinical remission within 4 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, and/or achieves an endoscopic
improvement within 4 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, and further achieves any combination of additional
therapeutic results selected from the group consisting of
therapeutic results 3), 6), 8), 11), 14), 16), 19), 20), 23), 26),
29), and combinations thereof, wherein the therapeutic result is
achieved within 4 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof.
[0381] In one embodiment, the patient achieves a clinical remission
within 4 weeks, 12 weeks, or within 16 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, and/or achieves an endoscopic
improvement within 4 weeks, 12 weeks or within 16 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof, and further achieves
an additional therapeutic result selected from the group consisting
of a CDAI of less than 150 within 16 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; a CDAI of less than 150 within 12
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; a
CDAI of less than 150 within 4 weeks of initiating administration
of upadacitinib, or a pharmaceutically acceptable salt or solid
state form thereof; an endoscopic remission within 16 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; an endoscopic
remission within 12 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; an endoscopic remission within 4 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; a clinical response within 16
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; a
clinical response within 12 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; a clinical response within 4 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; a clinical response within 2
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; and
combinations thereof. In one such embodiment, the induction phase
is 16 weeks, and the additional therapeutic result is selected from
the group consisting of a CDAI of less than 150 within 16 weeks, or
within 12 weeks, or within 4 weeks, or within 2 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, an endoscopic remission within 16
weeks or within 12 weeks or within 4 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; a clinical response within 16
weeks or within 12 weeks or within 4 weeks, or within 2 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; and combinations
thereof. In one such embodiment, the induction phase is 12 weeks,
and the additional therapeutic result is selected from the group
consisting of a CDAI of less than 150 within 12 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; an endoscopic remission within 12
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; a
clinical response within 12 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; and combinations thereof.
[0382] In one embodiment, the additional therapeutic result may
further be a clinical remission within 16 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, wherein the patient has an
average daily liquid/very soft SF score of greater than or equal to
2.5 and an average daily AP score of greater than or equal to 2.0
at baseline. In one embodiment, when the patient is one who was
taking corticosteroids at baseline but who discontinued
corticosteroid use during treatment with the JAK1 inhibitor, the
additional therapeutic result may be selected from the group
consisting of a CDAI score of less than 150 within 16 weeks of
initiating administration of upadacitinib. or a pharmaceutically
acceptable salt or solid state form thereof, an endoscopic
remission within 12 weeks or within 16 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof and a clinical remission within 16
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; a
clinical remission within 16 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; and an endoscopic remission within 12 weeks or within
16 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; and
combinations thereof. In one embodiment, when the patient has
isolated ileal Crohn's disease, the additional therapeutic result
may further be remission within 16 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof. In one aspect, a patient achieves
a CDAI score of less than 150 during or by the end of the induction
phase.
[0383] In one aspect, the patient may achieve an additional
therapeutic result selected from the group consisting of a clinical
remission (i.e., average daily SF score .ltoreq.2.8 and not greater
than baseline and average daily AP score .ltoreq.1.0 and not
greater than baseline) within 16 weeks of initiating administration
of upadacitinib, or a pharmaceutically acceptable salt or solid
state form thereof; an endoscopic improvement (i.e., SES-CD score
that is greater than a 50% decrease from baseline or at least a 2
point reduction in SES-CD score from baseline or endoscopic
remission) within 4 weeks, within 6 weeks, within 12 weeks, or
within 16 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; and
combinations thereof.
[0384] In one aspect, the patient may achieve an additional
therapeutic result selected from the group consisting of a decrease
in CDAI score from baseline of greater than or equal to 70, and a
decrease in CDAI score from baseline of greater than or equal to
100. In one embodiment, the induction phase is 16 weeks and the
decrease in CDAI occurs within 16 weeks or within 12 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, the
induction phase is 12 weeks and the decrease in CDAI occurs within
12 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof.
[0385] In one particular embodiment, the induction phase is 16
weeks, and the patient achieves a clinical remission within 16
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; an
endoscopic improvement (i.e., SES-CD score that is greater than a
50% decrease from baseline or at least a 2 point reduction in
SES-CD score from baseline, or endoscopic remission) within 4
weeks, within 6 weeks, within 12 weeks or within 16 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; and combinations
thereof. In another embodiment, the induction phase is 12 weeks,
and the patient achieves a clinical remission within 12 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; an endoscopic
improvement within 12 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; or combinations thereof.
[0386] In one embodiment, the patient is administered upadacitinib,
or a pharmaceutically acceptable salt or solid state form thereof,
for at least 52 weeks. The administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof, may
include an induction phase (e.g., an induction phase of up to 16
weeks), and additional weeks (e.g., 36 weeks or longer) of a
maintenance phase (discussed hereinafter). In other embodiments,
the administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof, may include a shorter
induction phase (e.g., up to 2 weeks, up to 4 weeks, 6 weeks, 8
weeks, 10 weeks, 12 weeks, etc.), and a longer maintenance phase
(e.g., a 12 week induction phase and a 40 week or longer
maintenance phase). In some such embodiments, the patient may
achieve at least one therapeutic result selected from the group
consisting of: remission within 52 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; endoscopic remission within 52
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof;
clinical remission within 52 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; endoscopic improvement within 52 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; response within 52 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; endoscopic response
within 52 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof pharm;
clinical response within 52 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; CDAI of less than 150 within 52 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; a decrease in CDAI of greater
than or equal to 70 points from baseline within 52 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; a change from baseline
in fecal calprotectin level within 52 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; a change from baseline in hs-CRP
within 52 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; a
change in IBDQ score from baseline within 52 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; a change in extra-intestinal
manifestations (EIMS) from baseline within 52 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; and combinations thereof.
[0387] In some embodiment when the patient is administered
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, for at least 52 weeks, when the patient is one who
was taking corticosteroids at baseline but who discontinued
corticosteroid use during treatment with the JAK1 inhibitor, the
additional therapeutic result may be selected from the group
consisting of a CDAI of less than 150 within 52 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; a remission within 52 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; a clinical remission
within 52 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof, and
an endoscopic remission within 52 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; and combinations thereof. In one
embodiment, when the patient has isolated ileal Crohn's disease,
the additional therapeutic result may further be remission within
52 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof.
[0388] In one embodiment, in a method of the present disclosure, a
patient is evaluated during or at the end of the induction phase
for a therapeutic result selected from the group consisting of
clinical remission, endoscopic improvement, endoscopic remission,
endoscopic response, clinical response, CDAI, average daily
liquid/very soft SF score, average daily AP score, fecal
calprotectin level, hs-CRP, IBDQ score, and combinations thereof.
In one embodiment, in a method of the present disclosure, a patient
is evaluated for clinical remission during or at the end of the
induction phase. In one embodiment, in a method of the present
disclosure, a patient is evaluated for endoscopic improvement
during or at the end of the induction phase. In one embodiment, in
a method of the present disclosure, a patient is evaluated for
endoscopic remission during or at the end of the induction
phase.
[0389] In one embodiment, the patient is administered at least 14
doses, at least 28 doses, at least 42 doses, at least 70 doses, or
at least 84 doses, or at least 112 doses, or at least 140 doses, or
at least 168 doses, or at least 224 doses, or 70 doses, or 84
doses, or 112 doses, or 140 doses, or 168 doses, or 224 doses of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, during the induction phase.
[0390] In one aspect, a certain therapeutic result is maintained by
the patient during the maintenance phase. The maintenance phase may
last for an indefinite period of time. In one embodiment, the
maintenance phase is at least 36 weeks, including at least 37
weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at
least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44
weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, or
at least 48 weeks. In one embodiment, the maintenance phase is at
least 40 additional weeks. In one embodiment, the therapeutic
result maintained by the patient during the maintenance phase is
selected from the group consisting of clinical remission,
endoscopic remission, and combinations thereof. In one embodiment,
the therapeutic result maintained by the patient during the
maintenance phase is selected from the group consisting of clinical
response, endoscopic improvement, and combinations thereof. In one
aspect, a patient maintains a CDAI score of less than 150 during
the maintenance phase. In one aspect, a patient maintains a SES-CD
that is greater than a 50% decrease versus the patient's baseline
SES-CD. In one embodiment, the patient maintains a SES-CD that is
at least a 2 point reduction versus the patient's baseline SES-CD.
In one embodiment, the therapeutic result maintained by the patient
during the maintenance phase is clinical response. In one
embodiment, the therapeutic result maintained by the patient during
the maintenance phase is endoscopic remission.
[0391] In one embodiment, in a method of the present disclosure, a
patient is evaluated for clinical remission during the maintenance
phase. In one embodiment, a patient is evaluated for endoscopic
improvement during the maintenance phase. In one embodiment, in a
method of the present disclosure, a patient is evaluated for
endoscopic remission during the maintenance phase.
[0392] In one embodiment, the present disclosure provides a method
for treating an inflammatory disease, in one aspect for treating
Crohn's Disease, comprising (a) administering to a patient a dose
of a JAK1 inhibitor (e.g., upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof) at week 0 and once
daily (QD) thereafter for 16 weeks, wherein the dose is 45 mg QD.
In one embodiment, the method further comprises (b) administering
to the patient additional doses once daily thereafter for at least
36 additional weeks, wherein the dose is 15 mg or 30 mg QD. In one
embodiment the dose is administered orally.
[0393] In one embodiment, at week 12 (i.e., 12 weeks after
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof), a patient is
evaluated for clinical remission (average daily liquid/very soft SF
score .ltoreq.2.8 and not worse than baseline and average daily AP
score .ltoreq.1.0 and not worse than baseline) and/or for
endoscopic remission (SES-CD.ltoreq.4 (or SES-CD.ltoreq.2 for
patients with isolated ileal CD) and at least a two point reduction
in SES-CD versus BL and no subscore >1 in any individual
variable used to calculate SES-CD). In one embodiment, at week 16
(i.e., 16 weeks after initiating administration of upadacitinib, or
a pharmaceutically acceptable salt or solid state form thereof), a
patient is evaluated for clinical remission and/or for endoscopic
remission.
[0394] In one embodiment, at week 4 (i.e., 4 weeks after initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof), a patient is evaluated for
clinical remission (average daily liquid/very soft SF score
.ltoreq.2.8 and not worse than baseline and average daily AP score
.ltoreq.1.0 and not worse than baseline) and/or for endoscopic
remission (SES-CD.ltoreq.4 (or SES-CD.ltoreq.2 for patients with
isolated ileal CD) and at least a two point reduction in SES-CD
versus BL and no subscore >1 in any individual variable used to
calculate SES-CD).
[0395] In one embodiment, at week 16 (i.e., 16 weeks after
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof), a patient is
evaluated for remission, for example defined as reaching clinical
remission (average daily liquid/very soft SF score .ltoreq.2.8 and
not worse than baseline and average daily AP score .ltoreq.1.0 and
not worse than baseline) and endoscopic remission (SES-CD.ltoreq.4
(or SES-CD.ltoreq.2 for patients with isolated ileal CD) and at
least a two point reduction in SES-CD versus BL and no subscore
>1 in any individual variable used to calculate SES-CD).
[0396] In one embodiment, at week 12 (i.e., 12 weeks after
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof), a patient is
evaluated for clinical remission and/or for endoscopic improvement.
In one embodiment, at week 16 (i.e., 16 weeks after initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof), a patient is evaluated for
clinical remission and/or for endoscopic improvement.
[0397] In one embodiment, at week 4 (i.e., 4 weeks after initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof), a patient is evaluated for
clinical remission and/or for endoscopic improvement. In one
embodiment, at week 2 (i.e., 2 weeks after initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof), a patient is evaluated for
clinical remission and/or for endoscopic improvement.
[0398] In one embodiment, the present disclosure provides a method
for treating Crohn's disease, comprising (a) administering to a
patient a dose of a JAK inhibitor (e.g., upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof) at
week 0 and once daily thereafter via an oral route, wherein the
doses of the JAK1 inhibitor comprise 15 mg, 30 mg, or 45 mg QD, or
any combination thereof.
[0399] In one embodiment, the present disclosure provides a method
for treating Crohn's disease, comprising administering to a patient
15 mg to 45 mg of a JAK1 inhibitor. In one embodiment, the present
disclosure provides a method for treating Crohn's disease,
comprising administering to a patient orally 15 mg of a JAK1
inhibitor QD. In one embodiment, the present disclosure provides a
method for treating Crohn's disease, comprising administering to a
patient orally 30 mg of a JAK1 inhibitor QD. In one embodiment, the
present disclosure provides a method for treating Crohn's disease,
comprising administering to a patient orally 45 mg of a JAK1
inhibitor QD. In any such embodiments, the JAK1 inhibitor may be
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof. In any such embodiment, the JAK1 inhibitor may be in
a once daily modified release formulation. In any such embodiment,
the patient may have moderately to severely active Crohn's disease
prior to treatment.
[0400] In one embodiment, the administration of a JAK1 inhibitor
according to the present disclosure is further described in the
Examples herein below or in FIG. 1.
[0401] In one embodiment, the present disclosure provides a method
for treating Crohn's disease, said method comprising a)
administering at least one induction dose of a JAK1 inhibitor
(e.g., upadacitinib or a pharmaceutically acceptable salt or solid
state form thereof) to a patient, wherein said induction dose
comprises 45 mg of the JAK 1 inhibitor. In one aspect, the
induction dose is administered orally. In one aspect, the induction
dose is administered QD. In one aspect, the induction dose is
administered for 12 weeks. In one aspect the induction dose is
administered for 16 weeks. In one embodiment, the induction dose is
administered for up to 16 weeks, including for 2 weeks, 3 weeks, 4
weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11
weeks, 12 weeks, 13 weeks, 14 weeks, or 15 weeks.
[0402] In one embodiment, the induction dose comprises 45 mg of the
JAK1 inhibitor administered QD.
[0403] In one embodiment, the JAK1 inhibitor is upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof.
[0404] In one embodiment, the induction dose is in a once daily
modified release formulation.
[0405] In one embodiment, the method further comprises b)
administering a first maintenance dose of a JAK1 inhibitor (e.g.,
upadacitinib, or pharmaceutically acceptable salt or solid state
form thereof), to the patient after the last induction dose is
administered; and c) administering at least one additional
maintenance dose to the patient once daily thereafter.
[0406] In one embodiment, the first maintenance dose comprises 15
mg to 30 mg of the JAK1 inhibitor. In one aspect, the first
maintenance dose comprises 15 mg or 30 mg of the JAK1 inhibitor. In
one aspect, the first maintenance dose is smaller than the
induction dose. In one aspect, the first maintenance dose is
administered QD. In one aspect the first maintenance dose is 15 mg.
In one aspect the first maintenance dose is 30 mg. In one aspect,
the first maintenance dose is administered orally. In one aspect,
the first maintenance dose is in a once daily modified release
formulation.
[0407] In one aspect, the at least one additional maintenance dose
comprises 15 mg to 30 mg of the JAK 1 inhibitor. In one aspect, the
at least one additional maintenance dose comprises 15 mg or 30 mg.
In one aspect, the at least one additional maintenance dose is
administered orally. In one aspect, the at least one additional
maintenance dose is administered QD. In one embodiment, the at
least one additional maintenance dose comprises 15 mg of the JAK1
inhibitor administered QD. In one embodiment, the at least one
additional maintenance dose comprises 30 mg of the JAK1 inhibitor
administered QD. In one aspect, the at least one additional
maintenance dose is in a once daily modified release
formulation.
[0408] In any of the foregoing embodiments, the JAK1 inhibitor may
be upadacitinib or a pharmaceutically acceptable salt or solid
state form thereof.
[0409] In one aspect, in any of the foregoing embodiments, the
patient maintains a CDAI score of less than 150.
[0410] In one aspect, in any of the foregoing embodiments, the
patient is one who had an inadequate response to or experienced
intolerance to conventional treatment (e.g., amninosalicylates,
corticosteroids, immunosuppressants) or to a previous treatment
with a biologic agent. In one aspect, in any of the foregoing
embodiments, the patient is one who had an inadequate response to
or experienced intolerance to a previous treatment with an anti-TNF
agent. In one aspect, in any of the foregoing embodiments, the
patient is a refractory patient.
[0411] In one aspect, in any of the foregoing embodiments, the
patient is one who is naive to previous treatment with
aminosalicylates, a corticosteroid an immunosuppressant, a biologic
agent or an anti-TNF agent.
[0412] In one aspect, in any of the foregoing embodiments, the
patient is one who had moderately to severely active Crohn's
disease prior to treatment or administration of the induction
dose.
[0413] In one embodiment, the present disclosure further provides a
method for inducing clinical remission of Crohn's Disease in a
patient, said method comprising a) administering to the patient at
least one induction dose of a JAK1 inhibitor as described above or
herein (e.g., upadacitinib or a pharmaceutically acceptable salt or
solid state form thereof). In one embodiment, the induction dose
comprises 45 mg of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, an induction
dose is administered at week 0 and once daily (QD) thereafter for
up to 16 weeks (e.g., for 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8
weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks,
15 weeks, or 16 weeks), wherein the dose is 45 mg QD. In one
embodiment, the method further comprises maintaining clinical
remission of Crohn's disease, said method further comprising b)
administering a first maintenance dose of said JAK1 inhibitor to
the patient after the last induction dose is administered and c)
administering at least one additional maintenance dose to the
patient as described above or herein. In one embodiment, the at
least one additional maintenance dose is administered once daily.
In one embodiment, the additional maintenance doses are
administered once daily for at least 36 additional weeks, including
for at least 37 weeks, at least 38 weeks, at least 39 weeks, at
least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43
weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at
least 47 weeks, or at least 48 weeks. In one embodiment, the
additional maintenance doses are administered once daily for at
least 40 additional weeks. In one embodiment, the maintenance dose
is 15 mg or 30 mg QD. In one embodiment the induction and
maintenance doses are administered orally. In one embodiment, the
patient has a CDAI score of 220 to 450 before administration of the
first induction dose. In one embodiment, the patient has moderately
to severely active Crohn's disease prior to administration of the
first induction dose. In one embodiment, the patient has had an
inadequate response to or experienced intolerance to conventional
treatment (e.g., aminosalicylates, corticosteroids,
immunosuppressants) or to a previous treatment with a biologic
agent and/or an anti-TNF agent. In one embodiment, the patient is
naive to previous treatment with a corticosteroid, an
immunosuppressant, a biologic agent, and/or an anti-TNF agent. In
one embodiment, the clinical remission is achieved within 16 weeks
of initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, the
clinical remission is achieved within 12 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, the clinical
remission is achieved within 4 weeks of initiating administration
of upadacitinib, or a pharmaceutically acceptable salt or solid
state form thereof. In one embodiment, the patient achieves a CDAI
score of less than 150 before administration of the first
maintenance dose. In one embodiment, the induction and maintenance
doses are in once-daily, modified release formulations.
[0414] In one embodiment, the present disclosure provides a method
for inducing endoscopic remission of Crohn's disease, the method
comprising (a) administering to a patient at least one induction
dose of a JAK1 inhibitor (e.g., upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof), wherein the induction
dose comprises 45 mg of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, an
induction dose is administered at week 0 and once daily (QD)
thereafter for up to 16 weeks (e.g., for 4 weeks, 5 weeks, 6 weeks,
7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks,
14 weeks, 15 weeks, or 16 weeks), wherein the dose is 45 mg QD. In
one embodiment, the method further comprises maintaining endoscopic
remission of Crohn's disease, said method further comprising (b)
administering to the patient a first maintenance dose of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, after the last induction dose is administered, and
(c) administering at least one additional maintenance dose once
daily thereafter. In one embodiment, the additional maintenance
doses are administered once daily for at least 36 additional weeks,
including for at least 37 weeks, at least 38 weeks, at least 39
weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at
least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46
weeks, at least 47 weeks, or at least 48 weeks. In one embodiment,
the additional maintenance doses are administered once daily for at
least 40 additional weeks. In one embodiment, the maintenance dose
is 15 mg or 30 mg QD. In one embodiment the induction and
maintenance doses are administered orally. In one embodiment, the
patient has a CDAI score of 220 to 450 before administration of the
first induction dose. In one embodiment, the patient has moderately
to severely active Crohn's disease prior to administration of the
first induction dose. In one embodiment, the patient has had an
inadequate response to or experienced intolerance to conventional
treatment (e.g., aminosalicylates, corticosteroids,
immunosuppressants) or to a previous treatment with a biologic
and/or an anti-TNF agent. In one embodiment, the patient is naive
to previous treatment with a corticosteroid, an immunosuppressant,
an anti-TNF agent and/or a biologic agent. In one embodiment, the
endoscopic remission is achieved within 12 weeks or within 16 weeks
of initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, the
endoscopic remission is achieved within 4 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, the patient
achieves a CDAI score of less than 150 before administration of the
first maintenance dose. In one embodiment, the induction and
maintenance doses are in once-daily, modified release
formulations.
[0415] In one embodiment, the present disclosure further provides a
method for inducing endoscopic improvement of Crohn's Disease in a
patient, said method comprising a) administering to the patient at
least one induction dose of a JAK1 inhibitor as described above or
herein (e.g., upadacitinib or a pharmaceutically acceptable salt or
solid state form thereof). In one embodiment, the induction dose
comprises 45 mg of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, an induction
dose is administered at week 0 and once daily (QD) thereafter for
up to 16 weeks (e.g., for 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8
weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks,
15 weeks, or 16 weeks), wherein the dose is 45 mg QD. In one
embodiment, the method further comprises maintaining endoscopic
improvement of Crohn's disease, said method further comprising b)
administering a first maintenance dose of said JAK1 inhibitor to
the patient after the last induction dose is administered and c)
administering at least one additional maintenance dose to the
patient as described above or herein. In one embodiment, the at
least one additional maintenance dose is administered once daily.
In one embodiment, the additional maintenance doses are
administered once daily for at least 36 additional weeks, including
for at least 37 weeks, at least 38 weeks, at least 39 weeks, at
least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43
weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at
least 47 weeks, or at least 48 weeks. In one embodiment, the
additional maintenance doses are administered once daily for at
least 40 additional weeks. In one embodiment, the maintenance dose
is 15 mg or 30 mg QD. In one embodiment the induction and
maintenance doses are administered orally. In one embodiment, the
patient has a CDAI score of 220 to 450 before administration of the
first induction dose. In one embodiment, the patient has moderately
to severely active Crohn's disease prior to administration of the
first induction dose. In one embodiment, the patient has had an
inadequate response to or experienced intolerance to a conventional
treatment (e.g., aminosalicylates, corticosteroids,
immunosuppressants) or to a previous treatment with a biologic
agent and/or an anti-TNF agent. In one embodiment, the patient is
naive to previous treatment with a corticosteroid, an
immunosuppressant, a biologic agent and/or an anti-TNF agent. In
one embodiment, the endoscopic improvement is achieved within 16
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, the endoscopic improvement is achieved within 12
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, the endoscopic improvement is achieved within 4
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, the patient achieves a CDAI score of less than 150
before administration of the first maintenance dose. In one
embodiment, the induction and maintenance doses are in once-daily,
modified release formulations.
[0416] In one embodiment, the present disclosure further provides a
method of maintaining clinical remission of Crohn's Disease in a
patient, said method comprising administering 15 mg or 30 mg of
upadacitinib or a pharmaceutically acceptable salt form thereof to
the patient. In one embodiment, the upadacitinib or a
pharmaceutically acceptable salt form thereof is administered once
daily for at least 36 weeks, including for at least 37 weeks, at
least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41
weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at
least 45 weeks, at least 46 weeks, at least 47 weeks, or at least
48 weeks. In one embodiment the upadacitinib or a pharmaceutically
acceptable salt form thereof is administered orally. In one
embodiment, the patient has had an inadequate response to or
experienced intolerance to a conventional treatment (e.g.,
aminosalicylates, corticosteroids, immunosuppressants) or to a
previous treatment with a biologic agent and/or an anti-TNF agent.
In one embodiment, the patient is naive to previous treatment with
a corticosteroid, an immunosuppressant, a biologic agent and/or an
anti-TNF agent. In one embodiment, the patient is a refractory
patient. In one embodiment, the upadacitinib or a pharmaceutically
acceptable salt form thereof is a once-daily, modified release
formulation.
[0417] In one embodiment, the present disclosure further provides a
method of maintaining endoscopic improvement of Crohn's Disease in
a patient, said method comprising administering 15 mg or 30 mg of
upadacitinib or a pharmaceutically acceptable salt form thereof to
the patient. In one embodiment, the upadacitinib or a
pharmaceutically acceptable salt form thereof is administered once
daily for at least 36 weeks, including for at least 37 weeks, at
least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41
weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at
least 45 weeks, at least 46 weeks, at least 47 weeks, or at least
48 weeks. In one embodiment the upadacitinib or a pharmaceutically
acceptable salt form thereof is administered orally. In one
embodiment, the patient has had an inadequate response to or
experienced intolerance to a conventional treatment (e.g.,
aminosalicylates, corticosteroids, immunosuppressants) or to a
previous treatment with a biologic agent and/or an anti-TNF agent.
In one embodiment, the patient is naive to previous treatment with
a corticosteroid, an immunosuppressant, a biologic agent and/or an
anti-TNF agent. In one embodiment, the patient is a refractory
patient. In one embodiment, the upadacitinib or a pharmaceutically
acceptable salt form thereof is a once-daily, modified release
formulation.
[0418] In one embodiment, the present disclosure further provides a
method of maintaining endoscopic remission of Crohn's Disease in a
patient, said method comprising administering 15 mg or 30 mg of
upadacitinib or a pharmaceutically acceptable salt form thereof to
the patient. In one embodiment, the upadacitinib or a
pharmaceutically acceptable salt form thereof is administered once
daily for at least 36 weeks, including for at least 37 weeks, at
least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41
weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at
least 45 weeks, at least 46 weeks, at least 47 weeks, or at least
48 weeks. In one embodiment the upadacitinib or a pharmaceutically
acceptable salt form thereof is administered orally. In one
embodiment, the patient has had an inadequate response to or
experienced intolerance to a conventional treatment (e.g.,
aminosalicylates, corticosteroids, immunosuppressants) or to a
previous treatment with a biologic agent and/or an anti-TNF agent.
In one embodiment, the patient is naive to previous treatment with
a corticosteroid, an immunosuppressant, a biologic agent and/or an
anti-TNF agent. In one embodiment, the patient is a refractory
patient. In one embodiment, the upadacitinib or a pharmaceutically
acceptable salt form thereof is a once-daily, modified release
formulation.
[0419] In one embodiment, the present disclosure further provides a
method of maintaining remission of Crohn's Disease in a patient,
said method comprising administering 15 mg or 30 mg of upadacitinib
or a pharmaceutically acceptable salt form thereof to the patient.
In one embodiment, the upadacitinib or a pharmaceutically
acceptable salt form thereof is administered once daily for at
least 36 weeks, including for at least 37 weeks, at least 38 weeks,
at least 39 weeks, at least 40 weeks, at least 41 weeks, at least
42 weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks,
at least 46 weeks, at least 47 weeks, or at least 48 weeks. In one
embodiment the upadacitinib or a pharmaceutically acceptable salt
form thereof is administered orally. In one embodiment, the patient
has had an inadequate response to or experienced intolerance to a
conventional treatment (e.g., aminosalicylates, corticosteroids,
immunosuppressants) or to a previous treatment with a biologic
agent and/or an anti-TNF agent. In one embodiment, the patient is
naive to previous treatment with a corticosteroid, an
immunosuppressant, a biologic agent and/or an anti-TNF agent. In
one embodiment, the patient is a refractory patient. In one
embodiment, the upadacitinib or a pharmaceutically acceptable salt
form thereof is in a once-daily, modified release formulation.
[0420] In one aspect, induction doses for the methods disclosed
herein are administered for 12 weeks in a dose regimen described in
Table 3. In one aspect, induction doses are administered for 16
weeks in a dose regimen described in Table 3. In one aspect,
maintenance doses are administered for 36 weeks or more in a dose
regimen described in Table 3. In one aspect, induction doses for
the methods disclosed herein are administered for 16 weeks and the
maintenance doses are administered for 36 weeks in a dosing regimen
as described in Table 3.
TABLE-US-00003 TABLE 3 Doses and Dosing Regimens (BID) Induction
Frequency of Maintenance Frequency of Dose (mg) induction doses
dose (mg) maintenance dose 3 BID 3 BID 6 BID 3 BID 6 BID 6 BID 12
BID 3 BID 12 BID 6 BID 12 BID 12 BID 24 BID 3 BID 24 BID 6 BID 24
BID 12 BID 24 QD.sup.1 3 BID 24 QD.sup.1 6 BID 24 QD.sup.1 12 BID
.sup.1The 24 mg QD dose is two 12 mg tablets administered
simultaneously.
[0421] In one aspect, the induction doses for the methods disclosed
herein are administered for 2 weeks in a dose regimen described in
Table 4. In one aspect, the induction doses for the methods
disclosed herein are administered for 4 weeks in a dose regimen
described in Table 4. In one aspect, induction doses for the
methods disclosed herein are administered for 12 weeks in a dose
regimen described in Table 4. In one aspect, induction doses are
administered for 16 weeks in a dose regimen described in Table 4.
In one aspect, maintenance doses are administered for 36 weeks or
more in a dose regimen described in Table 4. In one aspect,
induction doses for the methods disclosed herein are administered
for 2 weeks and the maintenance doses are administered for 36 or 40
weeks in a dosing regimen as described in Table 4. In one aspect,
induction doses for the methods disclosed herein are administered
for 4 weeks and the maintenance doses are administered for 36 or 40
weeks in a dosing regimen as described in Table 4. In one aspect,
induction doses for the methods disclosed herein are administered
for 12 weeks and the maintenance doses are administered for 36 or
40 weeks in a dosing regimen as described in Table 4. In one
aspect, induction doses for the methods disclosed herein are
administered for 16 weeks and the maintenance doses are
administered for 36 or 40 weeks in a dosing regimen as described in
Table 4.
TABLE-US-00004 TABLE 4 Doses and Dose Regimens (QD) Induction
Frequency of Maintenance Frequency of Dose (mg) induction doses
dose (mg) maintenance dose 45 QD 15 QD 45 QD 30 QD
[0422] In one particular embodiment, the induction dose is 45 mg of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof administered QD, and the maintenance dose, and any
additional maintenance dose administered thereafter, is 30 mg of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof administered QD. In another embodiment, the induction
dose is 45 mg of upadacitinib or a pharmaceutically acceptable salt
or solid state form thereof administered QD, and the maintenance
dose, and any additional maintenance dose administered thereafter,
is 15 mg of upadacitinib or a pharmaceutically acceptable salt or
solid state form thereof administered QD. In one embodiment, the
maintenance and induction doses are in once-daily, modified release
formulations.
IV. Methods of Treatment of Ulcerative Colitis
[0423] In one aspect, the present disclosure is directed to methods
for the treatment of ulcerative colitis. In one aspect, the present
disclosure provides methods for treating ulcerative colitis, in
particular methods comprising administering a JAK1 inhibitor to a
patient in certain amounts and/or at certain intervals. In one
aspect, the JAK1 inhibitor is upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof.
[0424] In one aspect, the present disclosure provides a JAK1
inhibitor for use in the treatment of ulcerative colitis, by
administration in certain amounts and/or at certain intervals as
described herein. In one aspect, the JAK1 inhibitor is upadacitinib
or a pharmaceutically acceptable salt or solid state form
thereof.
[0425] In one aspect, the present disclosure provides for the use
of a JAK1 inhibitor for the preparation of a medicament for the
treatment of ulcerative colitis, by administration in certain
amounts and/or at certain intervals as described herein. In one
aspect, the JAK1 inhibitor is upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof.
[0426] In one aspect, the present disclosure is directed to methods
for inducing clinical remission and/or endoscopic remission of
ulcerative colitis. In one aspect, the present disclosure provides
methods for inducing clinical remission and/or endoscopic remission
of ulcerative colitis, in particular methods comprising
administering a JAK1 inhibitor to a patient in certain amounts
and/or at certain intervals as described herein. In one aspect, the
present disclosure is further directed to methods for inducing
clinical remission wherein the patient has a SF score .ltoreq.1,
RBS of 0 and endoscopy score .ltoreq.1 at week 48 following
administration of the JAK1 inhibitor. In one aspect the patient
achieves clinical remission per Full Mayo score .ltoreq.2 with no
subscore >1) plus fecal calprotectin below 150 mg/kg at Week 8
following administration of the JAK1 inhibitor. In one aspect the
patient has an increase of IBDQ.gtoreq.16 from baseline at week 8
following administration of the JAK1 inhibitor. In one aspect, the
patient has a RBS.gtoreq.1 or an absolute RBS.ltoreq.1 at week 8
following administration of the JAK1 inhibitor. In one aspect, the
patient has a SF subscore .ltoreq.1 at week 8 following
administration of the JAK1 inhibitor. In one aspect, the patient
achieves a RBS of 0 at week 8. In one aspect the patient achieves a
fecal calprotectin below 150 mg/kg at week 8 following
administration of the JAK1 inhibitor. In one aspect the patient
achieves histologic improvement at week 8 following administration
of the JAK1 inhibitor. In one aspect, the JAK1 inhibitor is
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof.
[0427] In one aspect, the present disclosure provides a JAK1
inhibitor for use in inducing clinical remission of ulcerative
colitis by administration in certain amounts and/or at certain
intervals as described herein. In one aspect, the present
disclosure provides a JAK1 inhibitor for use in inducing clinical
remission and/or clinical response and/or endoscopic improvement
and/or endoscopic remission of ulcerative colitis by administration
in certain amounts and/or at certain intervals as described herein.
In one aspect, the JAK1 inhibitor is upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof.
[0428] In one aspect, the present disclosure provides for the use
of a JAK1 inhibitor for the preparation of a medicament for
inducing clinical remission of ulcerative colitis by administration
in certain amounts and/or at certain intervals as described herein.
In one aspect, the present disclosure provides for the use of a
JAK1 inhibitor for the preparation of a medicament for inducing
clinical remission and/or clinical response and/or endoscopic
improvement and/or endoscopic remission of ulcerative colitis by
administration in certain amounts and/or at certain intervals as
described herein. In one aspect, the JAK1 inhibitor is upadacitinib
or a pharmaceutically acceptable salt or solid state form
thereof.
[0429] In one particular aspect, the disease is moderately to
severely active ulcerative colitis. In one aspect, in the context
of the present disclosure, a patient is naive to, or was previously
treated with immunosuppressants (e.g., methotrexate),
aminosalicylate, corticosteroid, and/or a biologic agent (e.g.,
vedolizumab, ustekinumab, natalizumab, etc.). In one aspect, the
patient is naive to, or was previously treated with an anti-TNF
therapy (e.g., infliximab, adalimumab, certolizumab pegol,
golimumab, etc.). In one aspect, in the context of a method of the
present disclosure a patient was previously treated with one, two,
three or more TNF antagonist(s) (also referred to herein as
anti-TNF agents). In one embodiment, the patient is a patient who
had an inadequate response with, lost response, or was intolerant
to a TNF antagonist. In one aspect, in the context of a method of
the present disclosure a patient was previously treated with one,
two, three or more biologic agent(s). In one embodiment, the
patient is a patient who had an inadequate response with, lost
response, or was intolerant to a biologic agent. In one embodiment,
the patient is a patient who had an inadequate response with, lost
response, or was intolerant to a TNF antagonist, aminosalicylates,
corticosteroids, immunosuppressants, and/or a biologic agent. In
one embodiment, the patient is a refractory patient who has
moderately to severely active ulcerative colitis. In one
embodiment, the patient is either naive to or has stopped using
corticosteroids prior to treatment with the JAK1 inhibitor.
[0430] Disease severity for ulcerative colitis may be measured
using a variety of indexes, including the Mayo Scoring System for
Assessment of Ulcerative Colitis Activity ("Full Mayo"), the
Adapted Mayo Score (consisting of the stool frequency subscore,
rectal bleeding subscore and endoscopy subscore of the Full Mayo),
the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score
system, the Inflammatory Bowel Disease Questionnaire (IBDQ), the
Work Productivity and Activity Impairment Questionnaire for
Ulcerative Colitis (version 2.0) (WPAI:UC), the European Quality of
Life 5 Dimensions 5 Levels (EQ-5D-5L), the Short Form 36 Item
(SF-36) Health Survey (version 2), the Functional Assessment of
Chronic Illness Therapy-Fatigue (FACIT-F), Ulcerative Colitis
Symptoms Questionnaire (UC-SQ), and the Patient Global Impression
of Change (PGIC).
[0431] The Mayo Scoring System for Assessment of Ulcerative Colitis
Activity, shown below, is a composite of the following subscores:
Stool Frequency Subscore, Rectal Bleeding Subscore (RBS), Endoscopy
Subscore, and Physician's Global Assessment Subscore.
TABLE-US-00005 TABLE 5 Mayo Scoring System for Assessment of
Ulcerative Colitis Activity (Full Mayo) Stool frequency Subscore* 0
= Normal number of stools for this subject 1 = 1-2 stools more than
normal 2 = 3-4 stools more than normal 3 = 5 or more stools more
than normal Rectal bleeding Subscore** 0 = No blood seen 1 =
Streaks of blood with stool less than half the time 2 = Obvious
blood with stool most of the time 3 = Blood alone passed Endoscopy
Subscore: Findings of flexible sigmoidoscopy 0 = Normal or inactive
disease 1 = Mild disease (erythema, decreased vascular pattern,
mild friability) 2 = Moderate disease (marked erythema, absent
vascular pattern, friability, erosions) 3 = Severe disease
spontaneous bleeding, ulceration) Physician's Global Assessment
Subscore*** 0 = Normal (Subscores are 0) 1 = Mild disease
(Subscores are mostly 1's) 2 = Moderate disease (Subscores are 1 to
2) 3 = Severe disease (Subscores are 2 to 3) *Each patient serves
as his or her own control to establish normal stool frequency and
the degree of abnormal stool frequency. **The daily bleeding score
represents the most severe bleeding of the day. ***The physician's
global assessment acknowledges the three other subscores, the
subject's daily record of abdominal discomfort and functional
assessment, and other observations such as physical findings, and
the subject's performance status.
[0432] The IBDQ is a well-known 32 item validated questionnaire
that assesses a patient's inflammatory bowel disease symptoms,
general well-being, and mood, and may be used as a tool to evaluate
a patient's quality of life (Guyatt, et al., Gastroenterology,
1989, 96:804-810). The IBDQ questions and answer options are set
forth below in Table 6.
TABLE-US-00006 TABLE 6 IBDQ Question Answer Options 1. How frequent
have your 1 Bowel movements as or more bowel movements been during
frequent than they have ever the last two weeks? been 2 Extremely
Frequent 3 Very frequent 4 Moderate increase in frequency of bowel
movements 5 Some increase in frequency of bowel movements 6 Slight
increase in frequency of bowel movements 7 Normal, no increase in
frequency of bowel movements 2. How often has the feeling 1 All of
the time of fatigue or of being tired 2 Most of the time and worn
out been a problem 3 A good bit of the time for you during the last
2 weeks? 4 Some of the time 5 A little of the time 6 Hardly any of
the time 7 None of the time 3. How often during the last 2 1 All of
the time weeks have you felt frustrated, 2 Most of the time
impatient, or restless? 3 A good bit of the time 4 Some of the time
5 A little of the time 6 Hardly any of the time 7 None of the time
4. How often during the last 1 All of the time 2 weeks have you
been unable 2 Most of the time to attend school or do your 3 A good
bit of the time work because of your bowel 4 Some of the time
problem? 5 A little of the time 6 Hardly any of the time 7 None of
the time 5. How much of the time 1 All of the time during the last
2 weeks 2 Most of the time have your bowel movements 3 A good bit
of the time been loose? 4 Some of the time 5 A little of the time 6
Hardly any of the time 7 None of the time 6. How much energy 1 No
energy at all have you had during the 2 Very little energy last 2
weeks? 3 A little energy 4 Some energy 5 A moderate amount of
energy 6 A lot of energy 7 Full of energy 7. How often during the
last 1 All of the time 2 weeks did you feel worried 2 Most of the
time about the possibility of 3 A good bit of the time needing to
have surgery 4 Some of the time because of your bowel 5 A little of
the time problem? 6 Hardly any of the time 7 None of the time 8.
How often during the 1 All of the time last 2 weeks have you had 2
Most of the time to delay or cancel a social 3 A good bit of the
time engagement because 4 Some of the time of your bowel problem? 5
A little of the time 6 Hardly any of the time 7 None of the time 9.
How often during the 1 All of the time last 2 weeks have you been 2
Most of the time troubled by cramps in 3 A good bit of the time
your abdomen? 4 Some of the time 5 A little of the time 6 Hardly
any of the time 7 None of the time 10. How often during the last 1
All of the time 2 weeks have you felt 2 Most of the time generally
unwell? 3 A good bit of the time 4 Some of the time 5 A little of
the time 6 Hardly any of the time 7 None of the time 11. How often
during the 1 All of the time last 2 weeks have you been 2 Most of
the time troubled because of fear of 3 A good bit of the time not
finding a washroom? 4 Some of the time 5 A little of the time 6
Hardly any of the time 7 None of the time 12. How much difficulty 1
A great deal of difficulty; have you had, as a result activities
made impossible of your bowel problems, doing 2 A lot of difficulty
leisure or sports activities you 3 A fair bit of difficulty would
have liked to have done 4 Some difficulty during the last 2 weeks?
5 A little difficulty 6 Hardly any difficulty 7 No difficulty; the
bowel problems did not limit sports or leisure activities 13. How
often during the last 1 All of the time 2 weeks have you been
troubled 2 Most of the time by pain in the abdomen? 3 A good bit of
the time 4 Some of the time 5 A little of the time 6 Hardly any of
the time 7 None of the time 14. How often during the 1 All of the
time last 2 weeks have you had 2 Most of the time problems getting
a good 3 A good bit of the time night's sleep, or been 4 Some of
the time troubled by waking 5 A little of the time up during the
night? 6 Hardly any of the time 7 None of the time 15. How often
during the 1 All of the time last 2 weeks have you felt 2 Most of
the time depressed or discouraged? 3 A good bit of the time 4 Some
of the time 5 A little of the time 6 Hardly any of the time 7 None
of the time 16. How often during the 1 All of the time last 2 weeks
have you had 2 Most of the time to avoid attending events 3 A good
bit of the time where there was no 4 Some of the time washroom
close at hand? 5 A little of the time 6 Hardly any of the time 7
None of the time 17. Overall, in the last 2 1 A major problem
weeks, how much of a problem 2 A big problem have you had with
passing 3 A significant problem large amounts of gas? 4 Some
trouble 5 A little trouble 6 Hardly any trouble 7 No trouble 18.
Overall, in the last 2 weeks, 1 A major problem how much of a
problem have 2 A big problem you had maintaining or 3 A significant
problem getting to, the weight you 4 Some trouble would like to be
at? 5 A little trouble 6 Hardly any trouble 7 No trouble 19. Many
patients with 1 All of the time bowel problems often have 2 Most of
the time worries and anxieties related 3 A good bit of the time to
their illness. These include 4 Some of the time worries about
getting cancer, 5 A little of the time worries about never feeling
6 Hardly any of the time any better, and worries about 7 None of
the time having a relapse. In general, how often during the last 2
weeks have you felt worried or anxious? 20. How much of the time 1
All of the time during the last 2 weeks have 2 Most of the time you
been troubled by a 3 A good bit of the time feeling of abdominal 4
Some of the time bloating? 5 A little of the time 6 Hardly any of
the time 7 None of the time 21. How often during the 1 None of the
time last 2 weeks have you felt 2 A little of the time relaxed and
free of tension? 3 Some of the time 4 A good bit of the time 5 Most
of the time 6 Almost all of the time 7 All of the time 22. How much
of the time 1 All of the time dating the last 2 weeks have 2 Most
of the time you had a problem with 3 A good bit of the time rectal
bleeding with your 4 Some of the time bowel movements? 5 A little
of the time 6 Hardly any of the time 7 None of the time 23. How
much of the time 1 All of the time during the last 2 weeks have 2
Most of the time you felt embarrassed 3 A good bit of the time as a
result of your bowel 4 Some of the time problem? 5 A little of the
time 6 Hardly any of the time 7 None of the time 24. How much of
the time 1 All of the time during the last 2 weeks 2 Most of the
time have you been troubled by 3 A good bit of the time a feeling
of having to go 4 Some of the time to the bathroom even 5 A little
of the time though your bowels were 6 Hardly any of the time empty?
7 None of the time 25. How much of the time 1 All af the time
during the last 2 weeks have 2 Most of the time you felt tearful or
upset? 3 A good bit of the time 4 Some of the time 5 A little of
the time 6 Hardly any of the time 7 None of the time 26. How much
of the time 1 All of the time during the last 2 weeks 2 Most of the
time have you been troubled by 3 A good bit of the time accidental
soiling of your 4 Some of the time underpants? 5 A little of the
time 6 Hardly any of the time 7 None of the time 27. How much of
the time 1 All of the time during the last 2 weeks 2 Most of the
time have you felt angry as a 3 A good bit of the time result of
your bowel problem? 4 Some of the time 5 A little of the time 6
Hardly any of the time 7 None of the time 28. To what extent has
your 1 No sex as a result of bowel bowel problem limited sexual
disease activity during the last 2 weeks? 2 Major limitation as a
result of bowel disease 3 Moderate limitation as a result of bowel
disease 4 Some limitation as a result of bowel disease 5 A little
limitation as a result of bowel disease 6 Hardly any limitation as
a result of bowel disease 7 No limitation as a result of bowel
disease 29. How much of the time 1 All of the time during the last
2 weeks 2 Most of the time have you been troubled by 3 A good bit
of the time nausea or feeling sick to 4 Some of the time your
stomach? 5 A little of the time 6 Hardly any of the time 7 None of
the time 30. How much of the time 1 All of the time during the last
2 weeks 2 Most of the time have you felt irritable? 3 A good bit of
the time 4 Some of the time 5 A little of the time 6 Hardly any of
the time 7 None of the time 31. How often during the 1 All of the
time past 2 weeks have you 2 Most of the time felt a lack of
understanding 3 A good bit of the time from others? 4 Some of the
time 5 A little of the time 6 Hardly any of the time 7 None of the
time 32. How satisfied, happy, 1 Very dissatisfied, unhappy or
leased have you been most of the time with your personal life
during 2 Generally dissatisfied, unhappy the past 2 weeks? 3
Somewhat dissatisfied, unhappy 4 Generally satisfied, pleased 5
Satisfied most of the time, happy 6 Very satisfied most of the
time, happy
7 Extremely satisfied, could not have been more happy or
pleased
[0433] The Work Productivity and Activity Impairment Questionnaire
for Ulcerative Colitis (WPAI:UC) and Crohn's Disease (WPAI:CD)
assesses the impact of the condition on work productivity losses
and impairment in daily activity. WPAI:UC has six items covering
four domains: Absenteeism (work time missed), measured as the
number of hours missed from work in the past 7 days due to a
condition related problem. Scores are expressed as impairment
percentages, adjusting for hours actually worked according to the
WPAI:UC or WPAI:CD scoring algorithm; Presenteeism (impairment at
work/reduced on-the-job effectiveness), measured as the impact of
the condition on productivity while at work (i.e., reduced amount
or kind of work, or not as focused as usual). Responses are
recorded on a 0-10 Likert scale (where, 0=no effect of UC or CD on
work and 10=severe impact of UC or CD while at work); productivity
loss (overall work impairment), measured as the sum of hours missed
due to condition i.e., absenteeism and number of hours worked with
impairment i.e., product of number of hours worked and
presenteeism; and activity impairment (i.e., activities other than
paid work like work around house, cleaning, shopping, traveling,
studying), recorded and scored in the same way as presenteeism.
Higher numbers indicate greater impairment and less productivity.
The WPAI:UC/WPAI:CD questions and answer options are set forth in
Table 7.
TABLE-US-00007 TABLE 7 WPAI:UC* and WPAI:CD Questions Answer
Options 1. Are you currently employed (working for pay)? No or yes
If no, skip to question 6, 2. During the past seven days, how many
hours did you miss Number of hours from work because of problems
associated with your ulcerative colitis? Include hours you missed
on sick days, times you went in late, left early, etc,, because of
your ulcerative colitis. Do not include time you missed to
participate in this study. 3. During the past seven days, how many
hours did you miss Number of hours from work because of any other
reason, such as vacation, holidays, time off to participate in this
study? 4. During the past seven days, how many hours did you
actually Number of hours (if 0, skip to work? question 6) 5. During
the past seven days, how much did your ulcerative Select number on
a scale of 0 (UC colitis affect your productivity while you were
working? had no effect on work) to 10 (UC Think about days you were
limited in the amount or kind of completely prevented me from work
you could do, days you accomplished less than you would working),
representing how much like, or days you could not do your work as
carefully as usual. ulcerative colitis affected If ulcerative
colitis affected your work only a lttle, choose a low productivity
while at work number. Choose a high number if ulcerative colitis
affected your work a great deal. 6. During the past 7 days, how
much did your ulcerative colitis Select number on a scale of 0 (UC
affect your ability to do your regular daily activities, other than
had no effect on daily activities) to work at a job? 10 (UC
completely prevented me Regular activities means usual activities
such as work around from doing daily activities), the house,
shopping, childcare, exercising, studying, etc. representing how
much ulcerative Consider times you were limited in the amount or
kind of colitis affected ability to do activities you could do and
times you accomplished less than regular daily activities, other
than you would like. If ulcerative colitis affected your activities
only work at a job a little, choose a low number. Choose a high
number if ulcerative colitis affected your activities a great deal.
*Questions 2-7 are about the previous seven days, not including the
day the questionnaire is completed.
[0434] The European Quality of Life 5 Dimensions 5 Levels
(EQ-5D-5L) is a standardized non-disease specific instrument for
describing and valuing health-related quality of life. The EQ-5D-5L
consists of 5 dimensions: mobility, self-care, usual activity,
pain/discomfort, and anxiety/depression. Each dimension has 5
levels: no problem, slight problem, moderate problem, severe
problem or unable to do the activity. It also contains a Visual
Analogue Scale (VAS). Subjects are asked to indicate the level that
describes their current level of function or experience for each
dimension. As a measure of health status, it provides a descriptive
profile and can be used to generate a single index value for health
status, where full health is equal to 1 and death is equal to 0.
The VAS records the subject's assessment of his/her own health
along a vertical 20 cm line, which has health state scores between
0 and 100. The EQ-5D-5L questions and answer options are set forth
in Table 8.
TABLE-US-00008 TABLE 8 EQ-5D-5L Questionnaire Dimension Answer
Options Score Mobility I have no problems walking MB1 I have slight
problems walking MB2 I have moderate problems walking MB3 I have
severe problems walking MB4 I am unable to walk MB5 Self-Care I
have no problems washing or dressing SC1 myself I have slight
problems washing or dressing SC2 myself I have moderate problems
washing or SC3 dressing myself I have severe problems washing or
dressing SC4 myself I am unable to wash or dress myself SC5 Usual I
have no problems doing my usual activities UA1 Activities* I have
slight problems doing my usual UA2 activities I have moderate
problems doing my usual UA3 activities I have severe problems doing
my usual UA4 activities I am unable to do my usual activities UA5
Pain/ I have no pain or discomfort PD1 Discomfort I have slight
pain or discomfort PD2 I have moderate pain or discomfort PD3 I
have severe pain or discomfort PD4 I have extreme pain or
discomfort PD5 Anxiety/ I am not anxious or depressed AD1
Depression I am slightly anxious or depressed AD2 I am moderately
anxious or depressed AD3 I am severely anxious or depiessed AD4 I
am extremely anxious or depressed AD5 How good or We would like to
know how good or bad your bad is your health is TODAY. health
today? This scale is numbered from 0 to 100. 100 means the best
health you can imagine. 0 means the worst health you can imagine.
Mark an X on the scale to indicate how your health is TODAY. Now,
please write the number you marked on the scale in the box below.
*E.g., work, study, housework, family or leisure activities
[0435] The SF-36 questionnaire is a self-administered multi-domain
scale with 36 items. Eight subscales cover a range of functioning:
physical functioning (PF), role-physical (RP), bodily pain (BP),
general health (GH), vitality (VT), social functioning (SF),
role-emotional (RE), and mental health (MH). The scoring yields a
physical component score, a mental component summary score, and
subscale scores. Higher scores represent better outcomes. The
concepts measured by the SF-36 are not specific to any age,
disease, or treatment group, allowing comparison of relative burden
of different diseases and the benefit of different treatments. The
SF-36 questions and answer options are set forth below in Table
9.
TABLE-US-00009 TABLE 9 SF-36 Health Survey Function- Question
number Question Answer Options GH-1 In general, would you say your
health is: Excellent Very good Good Fair Poor Compared to one year
ago, how would you rate Much better now than one year ago your
health in general now? Somewhat better now than one year ago About
the same as one year ago Somewhat worse now than one year ago Much
worse now than one year ago PF-1.sup.1 Does your health now limit
you in vigorous Yes, limited a lot activities, such as running,
lifting heavy objects, Yes, limited a little participating in
strenuous sports? If so, how much? No, not limited at all
PT-2.sup.1 Does your health now limit you in moderate Yes, limited
a lot activities, such as moving a table, pushing a Yes, limited a
little vacuum cleaner, bowling, or playing golf? If so, No, not
limited at all how much? PF-3.sup.1 Does your health now limit you
in lifting or Yes, limited a lot canying groceries? If so, how
much? Yes, limited a little No, not limited at all PF-4.sup.1 Does
your health now limit you in climbing several Yes, limited a lot
flights of stairs? If so, how much? Yes, limited a little No, not
limited at all PF-5.sup.1 Does your health now limit you in
climbing one Yes, limited a lot flight of stairs? If so, how much?
Yes, limited a little No, not limited at all PF-6.sup.1 Does your
health now limit you in bending, Yes, limited a lot kneeling, or
stooping? If so, how much? Yes, limited a little No, not limited at
all PF-7.sup.1 Does your health now limit you in walking more Yes,
limited a lot than a mile? If so, how much? Yes, limited a little
No, not limited at all PF-8.sup.1 Does your health now limit you in
walking several Yes, limited a lot hundred yards? If so, how much?
Yes, limited a little No, not limited at all PF-9.sup.1 Does your
health now limit you in walking one Yes, limited a lot hundred
yards? If so, how much? Yes, limited a little No, not limited at
all PF-10.sup.1 Does your health now limit you in bathing or Yes,
limited a lot dressing yourself? If so, how much? Yes, limited a
little No, not limited at all RP-1.sup.2 Cut down on the amount of
time you spent on work All of the time or other activities as a
result of your physical health Most of the time Some of the time A
little of the time None of the time RP-2.sup.2 Accomplished less
than you would like as a result All of the time of your physical
health Most of the time Some of the time A little of the time None
of the time RP-3.sup.2 Were limited in the kind of work or other
activities All of the time as a result of your physical health Most
of the time Some of the time A little of the time None of the time
RP-4.sup.2 Had difficulty performing the work or other All of the
time activities as a result of your physical health (for Most of
the time example, it took extra effort) Some of the time A little
of the time None of the time RE-1.sup.2 Cut down on the amount of
time you spent on work All of the time or other activities as a
result of any emotional Most of the time problems (such as feeling
depressed or anxious) Some of the time A little of the time None of
the time RE-2.sup.2 Accomplished less than you would like as a
result All of the time of any emotional problems (such as feeling
Most of the time depressed or anxious) Some of the time A little of
the time None of the time RE-3.sup.2 Did work or other activities
less carefully than usual All of the time as a result of any
emotional problems (such as Most of the time feeling depressed or
anxious) Some of the time A little of the time None of the time
SF-1 During the past 4 weeks, to what extent has your Not at all
physical health or emotional problems interfered Slightly with your
normal social activities with amity, Moderately friends, neighbors,
or groups? Quite a bit Extremely BP-1 How much bodily pain have you
had during the past None 4 weeks? Very mild Mild Moderate Severe
Very severe BP-2 During the past 4 weeks, how much did pain Not at
all interfere with your normal work (including both A little bit
work outside the home and housework)? Moderately Quite a bit
Extremely VT-1.sup.3 How much of the time during the oast 4 weeks
did All of the time you feel full of life? Most of the time Some of
the time A little of the time None of the time MH-1.sup.3 How much
of the time during the past 4 weeks have All of the time you been
very nervous? Most of the time Some of the time A little of the
time None of the time MH-2.sup.3 How much of the time during the
past 4 weeks have All of the time you felt so down in the dumps
that nothing could Most of the time cheer you up? Some of the time
A little of the time None of the time MH-3.sup.3 How much of the
time during the past 4 weeks have All of the time you felt calm and
peaceful? Most of the time Some of the time A little of the time
None of the time VT-2.sup.3 How much of the time during the past 4
weeks did All of the time you have a lot of energy? Most of the
time Some of the time A little of the time None of the time
MH-4.sup.3 How much of the time during the past 4 weeks have All of
the time you felt downhearted and depressed? Most of the time Some
of the time A little of the time None of the time VT-3.sup.3 How
much of the time during the opast 4 weeks did All of the time you
feel worn out? Most of the time Some of the time A little of the
time None of the time MH-5.sup.3 How much of the time during the
past 4 weeks have All of the time you been happy? Most of the time
Some of the time A little of the time None of the time VT-4.sup.3
How much of the time during the past 4 weeks did All of the time
you feel tired? Most of the time Some of the time A little of the
time None of the time SF-2 During the past 4 weeks, how much of the
time has All of the time your physical health or emotional problems
Most of the time interfered with your social activities (like
visiting Some of the time with friends, relatives, etc.)? A little
of the time None of the time GH-2.sup.4 I seem to get sick a little
easier than other people. Definitely true Mostly true Don't know
Mostly false Definitely false GH-3.sup.4 I am as healthy as anybody
I know. Definitely true Mostly true Don't know Mostly false
Definitely false GH-4.sup.4 I expect my health to get worse.
Definitely true Mostly true Don't know Mostly false Definitely
false GH-5.sup.4 My health is excellent. Definitely true Mostly
true Don't know Mostly false Definitely false .sup.1Instructions:
The following question is about activities you might do during a
typical day .sup.2Instructions: During the past 4 weeks, how much
of the time have you had any of the following problems with your
work or other regular daily activities? .sup.3Instructions: This
question is about how you feel and how things have been with you
during the past 4 weeks. Please give the one answer that comes
closest to the way you have been feeling. .sup.4Instructions: How
TRUE or FALSE is the following statement for you?
[0436] The Functional Assessment of Chronic Illness Therapy (FACIT)
system is a collection of quality of life (QOL) questionnaires
targeted to the management of cancer and other chronic illnesses.
The FACIT fatigue (FACIT-F) questionnaire was developed to assess
fatigue associated with anemia. It consists of 13 fatigue-related
questions. The responses to the 13 items on the FACIT fatigue
questionnaire are each measured on a 4-point Likert scale. The
responses to the answers are the following: (i) not at all: 0
points; (ii) a little bit: 1 point; (iii) somewhat: 2 points; (iv)
quite a bit: 3 points; and (v) very much: 4 points. Thus, the total
score ranges from 0 to 52. High scores represent less fatigue. The
FACIT-F questions and answer options are set forth below in Table
10.
TABLE-US-00010 TABLE 10 FACIT-F Questionnaire Question Answer
Options I led fatigued . . . 0 Not at all I feel weak all over . .
. 1 A little bit I feel listless ("washed out") . . . 2 Somewhat I
feel tired . . . 3 Quite a bit I have trouble starting things
because I am tired., 4 Very much I have trouble finishing things
because I am tired . . . I have energy . . . I am able to do my
usual activities . . . I need to sleep during the day . . . I am
too tired to eat . . . I need help doing my usual activities . . .
I am frustrated by being too tired to do the things I want to do .
. . I have to limit my social activity because I am tired . . .
[0437] The Ulcerative Colitis Symptoms Questionnaire (UC-SQ) is a
UC-specific instrument composed of 17 Likert-type items. UC-SQ was
developed to assess UC related gastrointestinal and
non-gastrointestinal symptoms such as frequent bowel movements,
abdominal discomfort, nausea, loss of appetite, pain, and anemia
along with the impact on patients' sleep. Each question can be
answered using Likert-type options such as (i) Not at all: 0
points; (ii) A little bit: 1 point; (iii) Somewhat: 2 points; (iv)
Quite a bit: 3 points; and (v) Very much: 4 points based on how the
patient felt during the past week (i.e., 7 days). The total score
ranges can vary from 0 to 68 with lower scores indicating
improvement. The UC-SQ questions and answer options are set forth
below in Table 11.
TABLE-US-00011 TABLE 11 UC-SQ Questionnaire Question Answer Options
During the past week, were your bowel movements Not at all more
frequent than usual? A little bit During the past week, did you
pass gas more than Somewhat usual? Quite a bit During the past
week, did you have abdominal pain? Very much During the past week,
did you have rectal pain? During the past week, did you have
cramping? During the past week, have you felt tired or lacking
energy? During the past week, did you feel nauseated? During the
past week, did you experience loss of appetite? During the past
week, did you have joint pain? During the past week, did you have
difficulty sleeping? During the past week, did you experience
bloating? During the past week, did you have diarrhea? During the
past week, did you pass blood or have blood your stool? During the
past week, did you have mucus in your stool? During the past week,
were you constipated? During the past week, did you feel that you
needed to have a bowel movement--even when your bowels were empty?
During the past week, did you experience a sudden or intense need
to have a bowel movement?
[0438] The Patient Global Impression of Change (PGIC) is a
self-administered instrument that assesses change in the overall
symptoms due to Ulcerative Colitis. The PGIC is one item in which
subjects are asked to rate overall improvement since start of the
treatment. Patients are asked the question "Compared to before your
treatment began, how would you rate the change in your overall
symptoms due to your ulcerative colitis?", and rate their change as
"Very much improved." "Much improved," "Minimally improved", "No
change," "Minimally worse," "Much worse" and "Very much worse".
[0439] In one aspect, the patient to be treated has moderately to
severely active ulcerative colitis. Moderately to severely active
ulcerative colitis is characterized by an Adapted Mayo score of 5
to 9 points and an endoscopy subscore of 2 to 3.
[0440] In one embodiment, the patient is a patient who had an
inadequate response with, lost response, or was intolerant to a
conventional therapy (e.g., aminosalicylate, corticosteroids,
immunosuppressants), or to a biologic agent. In one embodiment, the
patient is a patient who had an inadequate response with, lost
response, or was intolerant to biologic therapies. Examples of such
biologic therapies include infliximab, adalimumab, vedolizumab,
golimumab, ustekinumab and certolizumab pegol. Criteria for
determining if a patient has had an inadequate response to, lost
response, or experienced intolerance to previous treatment with
corticosteroids, immunosuppressants, and/or a biologic therapy are
defined below:
Corticosteroids:
[0441] 1) Signs and symptoms of persistently active disease despite
a history of at least one induction regimen that included a dose
equivalent to prednisone .gtoreq.40 mg/day orally for 3 to 4 weeks
or intravenously for 1 week, or [0442] 2) Unable to taper
corticosteroid to below a dose equivalent to prednisone 10 mg daily
orally without recurrent active disease, or [0443] 3) History of
intolerance to corticosteroids (including, but no limited to
Cushing's syndrome, osteopenia/osteoporosis, hyperglycemia,
insomnia, infection).
Immunosuppressants:
[0443] [0444] 1) Signs and symptoms of persistently active disease
despite a history of at least one 90-day regimen of oral
azathioprine (.gtoreq.1.5 mg/kg/day; for subjects in Japan and
China only: .gtoreq.1.0 mg/kg/day), 6-mercaptopurine (.gtoreq.1
mg/kg/day [for subjects in Japan and China only: .gtoreq.0.6
mg/kg/day, rounded to the nearest available tablet of half tablet
formulation]; or a documented 6-TGN level of 230-450
pmol/8.times.10.sup.8 RBC or higher on the current dosing regimen),
injectable methotrexate (MTX.gtoreq.15 mg/week subcutaneous [SC] or
intramuscular), or tacrolimus (for subjects in Japan only:
documented trough level of 5-10 ng/mL), or [0445] 2) History of
intolerance to at least one immunosuppressant (including, but not
limited to nausea/vomiting, abdominal pain, pancreatitis, liver
enzyme abnormalities, lymphopenia, infection)
Biologic Agents for UC:
[0445] [0446] 1) Signs and symptoms of persistently active disease
despite a history of any of the following: [0447] a. at least one
6-week induction regimen of infliximab (.gtoreq.5 mg/kg intravenous
[IV] at 0, 2 and 6 weeks), [0448] b. at least one 4-week induction
regimen of adalimumab (one 160 mg SC dose followed by one 80 mg SC
dose [or one 80 mg SC dose, in countries where this dosing regimen
is allowed] followed by one 40 mg SC dose at least 2 weeks apart),
[0449] c. at least one 2-week induction regimen of golimumab (one
200 mg SC dose followed by one 100 mg SC dose at least 2 weeks
apart), [0450] d. at least one 6-week induction regimen of
vedolizumab (300 mg IV at 0, 2 and 6 weeks), or [0451] 2)
Recurrence of symptoms during scheduled maintenance dosing
following prior clinical benefit (discontinuation despite clinical
benefit does not qualify), or [0452] 3) History of intolerance to
at least one biologic agent (including, but not limited to
infusion-related reaction, demyelination, congestive heart failure
(CHF), infection)
[0453] In one aspect, the patient is one who has previously been
treated with, or is currently being treated with aminosalicylate,
immunosuppressants, corticosteroids, and/or a biologic agent.
[0454] In one aspect, the Mayo Scoring System for Assessment of
Ulcerative Colitis Activity or any of the evaluations described
hereinbefore or in the Examples herein below is/are used to assess
the efficacy of upadacitinib in the treatment of ulcerative
colitis, for example moderately to severely active ulcerative
colitis. In one embodiment, the evaluation used to assess the
efficacy of upadacitinib in the treatment of ulcerative colitis is
selected from the group consisting of the Full Mayo score, the
Partial Mayo score, the Adapted Mayo score, the IBDQ, the WPAI:UC,
the EQ-5D-5L, the SF-36, the FACIT-F, the UC-SQ, the PGIC, and
combinations thereof.
[0455] In one embodiment, in the context of the present disclosure,
the treatment of a patient having ulcerative colitis, and/or the
induction of clinical remission of ulcerative colitis and/or the
induction of clinical response and/or endoscopic improvement and/or
endoscopic remission in a patient comprises an induction phase and
a maintenance phase. In the induction phase, one or more doses of
the JAK1 inhibitor, for example referred to herein as induction
doses, are administered to the patient, for example, orally. In the
maintenance phase, a first dose of the JAK1 inhibitor, for example
referred to herein as the maintenance dose, is administered to the
patient followed by at least one additional dose of the JAK1
inhibitor, for example, also referred to herein as a maintenance
dose. The maintenance doses are, for example, administered orally.
The JAK1 inhibitor may be, for example, upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof.
Examples of induction phases and maintenance phases are described
herein.
[0456] In one aspect, a certain therapeutic result is achieved by
the patient during or at the end of the induction phase, for
example clinical remission. In other embodiments, the therapeutic
result achieved by the patient during or at the end of the
induction phase is selected from the group consisting of endoscopic
subscore of 0 or 1 at week 8, endoscopic subscore of 0 at week 8,
fecal calprotectin below 150 mg/kg at week 8. IBDQ response
(increase of IBDQ.gtoreq.16 from baseline) at week 8, RBS.gtoreq.1
or absolute RBS.ltoreq.1 at week 8, or RBS of 0 at week 8. In one
aspect, the patient achieves clinical remission during or by the
end of the induction phase. In one aspect, the patient achieves
endoscopic remission during or by the end of the induction
phase.
[0457] In one aspect, the patient achieves endoscopic improvement
of ulcerative colitis during or by the end of the induction phase.
In one aspect, the patient achieves clinical remission and
endoscopic improvement of ulcerative colitis during or at the end
of the induction phase.
[0458] In one embodiment, the induction phase lasts for up to 16
weeks (e.g., for up to 16 weeks following initiation of
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof). Thus, in one embodiment, the
induction phase is 16 weeks. In another embodiment, the induction
phase optionally lasts for less than 16 weeks, for instance, for 2
weeks, for 3 weeks, for 4 weeks, for 5 weeks, for 6 weeks, for 7
weeks, for 8 weeks, for 9 weeks, for 10 weeks, for 11 weeks, for 12
weeks, for 13 weeks, for 14 weeks, or for 15 weeks. In one aspect,
the patient achieves an endoscopic remission within 8 weeks, or
within 12 weeks, or within 16 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof. In one aspect, the patient achieves a clinical
remission within 8 weeks, or within 12 weeks, or within 16 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one aspect, the
patient achieves an endoscopic improvement within 8 weeks, or
within 12 weeks, or within 16 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof. In one aspect, the patient achieves a clinical
response within 8 weeks, or within 12 weeks, or within 16 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one aspect, the
patient achieves a clinical remission within 8 weeks, or within 12
weeks, or within 16 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof.
[0459] In one embodiment, the patient achieves clinical remission
within 2 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, the patient achieves clinical remission within 4
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof.
[0460] In one embodiment, the patient achieves clinical response
within 2 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, the patient achieves clinical response within 4
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof.
[0461] In one embodiment, the patient achieves endoscopic
improvement or endoscopic remission within 2 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, the patient
achieves endoscopic improvement or endoscopic remission within 4
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, the patient achieves endoscopic improvement or
endoscopic remission within 12 weeks of initiating administration
of upadacitinib, or a pharmaceutically acceptable salt or solid
state form thereof. In one embodiment, the patient achieves
endoscopic improvement or endoscopic remission within 16 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof.
[0462] In one embodiment, the patient achieves corticosteroid-free
remission within 12 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, the patient achieves
corticosteroid-free remission within 8 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, the
corticosteroid-free remission is a clinical remission. In one
embodiment, the corticosteroid-free remission is endoscopic
remission.
[0463] In some embodiments, during or by the end of the induction
phase (e.g., lasting for up to 16 weeks, including for 2 weeks, 4
weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks or for 16 weeks), the
patient achieves at least one therapeutic result selected from the
group consisting of: [0464] 1) endoscopic improvement (defined as
endoscopic subscore .ltoreq.1 within 8 weeks of initiating
administration of upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof, [0465] 2) a Full Mayo score
.ltoreq.2 with no subscore >1 within 8 weeks of initiating
administration of upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof, [0466] 3) clinical response
(defined as decrease from baseline in the Adapted Mayo score
.gtoreq.2 points and .gtoreq.30% from baseline, plus a decrease in
rectal bleeding subscore (RBS).gtoreq.1 or an absolute RBS of 0 or
1) within 8 weeks of initiating administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof,
[0467] 4) clinical response within 2 weeks of initiating
administration of upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof, [0468] 5) change in Full Mayo
score from Baseline to Week 8 after initiating administration of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof. [0469] 6) endoscopic remission (defined as endoscopic
subscore of 0) within 8 weeks of initiating administration of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof. [0470] 7) histologic improvement (defined as a
decrease from baseline in Geboes score) within 8 weeks of
initiating administration of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof, [0471] 8) decrease in
RBS.gtoreq.1 or an absolute RBS.ltoreq.1 within 8 weeks of
initiating administration of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof, [0472] 9) RBS of 0
within 8 weeks of initiating administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof.
[0473] 10) endoscopic improvement (endoscopic subscore of 0 or 1)
within 8 weeks of initiating administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof,
[0474] 11) stool frequency subscore .ltoreq.1 within 8 weeks of
initiating administration of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof, [0475] 12) maintenance
of clinical remission at Week 52 following initial administration
of upadacitinib or a pharmaceutically acceptable salt or solid
state form thereof in patients who achieved clinical remission
within 8 weeks of initiating administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof,
[0476] 13) endoscopic improvement within 52 weeks of initiating
administration of upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof, [0477] 14) a Full Mayo score
.ltoreq.2 with no subscore >1 within 52 weeks of initiating
administration of upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof, [0478] 15) clinical remission
within 52 weeks of initiating administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof in
patients who discontinued corticosteroid use prior to initiating
administration of upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof, [0479] 16) subjects who are
taking corticosteroids at Baseline and are steroid-free at within
52 weeks of initiating administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof,
[0480] 17) endoscopic improvement at Week 52 following initial
administration of upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof in patients who achieved clinical
remission within 8 weeks of initiating administration of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof. [0481] 18) clinical response within 44 weeks of
initiating administration of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof. [0482] 19) endoscopic
remission within 52 weeks of initiating administration of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof, [0483] 20) histologic improvement within 52 weeks of
initiating administration of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof, [0484] 21) clinical
remission per Adapted Mayo score (defined as SFS.ltoreq.1. RBS of
0, and endoscopy subscore .ltoreq.1), [0485] and combinations
thereof.
[0486] In some embodiments, the patient achieves a clinical
remission within 16 weeks or within 12 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, and further achieves any
combination of additional therapeutic results selected from the
group consisting of therapeutic results 1), 2), 3), 4), 5), 6), 7),
8), 9), 10), 11), 12), 13), 14), 15), 16), 17), 18), 19) 20), 21)
and combinations thereof. In one such embodiment, the induction
phase is 16 weeks. In one embodiment, the additional therapeutic
result is achieved within 8 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, and is selected from the group consisting of
therapeutic results 1), 2), 3), 4), 5), 6), 7), 8), 9), 10), 11)
and combinations thereof.
[0487] In one embodiment, the induction phase is 8 weeks, and the
patient achieves a clinical remission within 8 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, and further achieves any
combination of additional therapeutic results selected from the
group consisting of therapeutic results 1), 2), 3), 4), 5), 6), 7),
8), 9), 10), 11), 12), 13), 14), 15), 16), 17), 18), 19) 20), 21)
and combinations thereof. In one embodiment, the additional
therapeutic result is achieved within 8 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, the additional
therapeutic result is achieved within 8 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, and is selected from the group
consisting of therapeutic results 1), 2), 3), 4), 5), 6), 7), 8),
9), 10), 11) and combinations thereof.
[0488] In one embodiment, the induction phase is 4 weeks, and the
patient achieves a clinical remission within 4 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, and further achieves any
combination of additional therapeutic results selected from the
group consisting of therapeutic results 1), 2), 3), 4), 5), 6), 7),
8), 9), 10), 11), 12), 13), 14), 15), 16), 17), 18), 19) 20), 21)
and combinations thereof. In one embodiment, the additional
therapeutic result is achieved within 4 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, the additional
therapeutic result is achieved within 4 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, and is selected from the group
consisting of endoscopic improvement, clinical remission, clinical
response, endoscopic remission, histologic improvement, and
combinations thereof.
[0489] In one embodiment, the patient achieves a clinical remission
within 4 weeks, within 8 weeks, within 12 weeks, or within 16 weeks
of initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof, and/or achieves an
endoscopic improvement within 4 weeks, within 8 weeks, within 12
weeks or within 16 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, and further achieves an additional therapeutic result
selected from the group consisting of a decrease from baseline in
Partial Mayo score .gtoreq.2 points and .gtoreq.30% from baseline
plus a decrease in RBS.gtoreq.1 or an absolute RBS.ltoreq.1 over
time within 16 weeks of initiating administration of upadacitinib,
or a pharmaceutically acceptable salt or solid state form thereof;
clinical response per Partial Mayo score within 12 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; a decrease from
baseline in Partial Mayo score .gtoreq.2 points and .gtoreq.30%
from baseline plus a decrease in RBS.gtoreq.1 or an absolute
RBS.ltoreq.1 over time within 8 weeks of initiating administration
of upadacitinib, or a pharmaceutically acceptable salt or solid
state form thereof; a decrease from baseline in Partial Mayo score
.gtoreq.2 points and .gtoreq.30% from baseline plus a decrease in
RBS.gtoreq.1 or an absolute RBS.ltoreq.1 over time within 4 weeks
of initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; a decrease from
baseline in Partial Mayo score .gtoreq.2 points and .gtoreq.30%
from baseline plus a decrease in RBS.gtoreq.1 or an absolute
RBS.ltoreq.1 over time within 2 weeks of initiating administration
of upadacitinib, or a pharmaceutically acceptable salt or solid
state form thereof; an endoscopic remission within 16 weeks of
initiating administration of pharmaceutically upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; an
endoscopic remission within 12 weeks of initiating administration
of upadacitinib, or an acceptable salt or solid state form thereof;
an endoscopic remission within 8 weeks of initiating administration
of upadacitinib, or a pharmaceutically acceptable salt or solid
state form thereof; an endoscopic remission within 4 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; a clinical response
within 16 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; a
clinical response within 12 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; a clinical response within 8 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; a clinical response within 4
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; a
Full Mayo score .ltoreq.2 with no subscore >1 within 16 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; a Full Mayo score
.ltoreq.2 with no subscore >1 within 12 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; a Full Mayo score .ltoreq.2 with
no subscore >1 within 8 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; a Full Mayo score .ltoreq.2 with no subscore >1
within 4 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; an
endoscopic improvement within 16 weeks of initiating administration
of upadacitinib, or a pharmaceutically acceptable salt or solid
state form thereof; an endoscopic improvement within 12 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; an endoscopic
improvement within 8 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; an endoscopic improvement within 4 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; a decrease from
baseline in Full Mayo score .gtoreq.3 points and .gtoreq.30%
accompanied by a decrease in RBS of .gtoreq.1 or an absolute RBS of
0 or 1 within 16 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; a decrease from baseline in Full Mayo score .gtoreq.3
points and .gtoreq.30% accompanied by a decrease in RBS of
.gtoreq.1 or an absolute RBS of 0 or 1 within 12 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; a decrease from
baseline in Full Mayo score .gtoreq.3 points and .gtoreq.30%
accompanied by a decrease in RBS of .gtoreq.1 or an absolute RBS of
0 or 1 within 8 weeks of initiating administration of upadacitinib,
or a pharmaceutically acceptable salt or solid state form thereof;
a decrease from baseline in Full Mayo score .gtoreq.3 points and
.gtoreq.30% accompanied by a decrease in RBS of .gtoreq.1 or an
absolute RBS of 0 or 1 within 4 weeks of initiating administration
of upadacitinib, or a pharmaceutically acceptable salt or solid
state form thereof; and combinations thereof. In one embodiment,
the patient achieves a clinical remission within 12 weeks or within
16 weeks of initiating administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof,
and/or achieves a clinical remission per Adapted Mayo score
(defined as SFS.ltoreq.1, RBS or 0, and endoscopy subscore
.ltoreq.1) within 12 weeks of initiation administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, the patient achieves a clinical
response per Adapted Mayo score (defined as decrease from BL in the
Adapted Mayo score .gtoreq.2 points and .gtoreq.30% from BL, plus a
decrease in RBS.gtoreq.1 or an absolute RBS.ltoreq.1 at week 12 or
16. In one such embodiment, the induction phase is 16 weeks, and
the additional therapeutic result is selected from the group
consisting of a decrease from baseline in Partial Mayo score
.gtoreq.2 points and .gtoreq.30% from baseline plus a decrease in
RBS.gtoreq.1 or an absolute RBS.ltoreq.1 over time within 16 weeks,
within 12 weeks, within 8 weeks, within 4 weeks or within 2 weeks
of initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; an endoscopic
remission within 16 weeks, within 12 weeks, within 8 weeks, or
within 4 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; a
clinical response within 16, within 12 weeks, within 8 weeks, or
within 4 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; an
endoscopic improvement within 16 weeks, within 12 weeks, within 8
weeks, or within 4 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; a Full Mayo score .ltoreq.2 with no subscore >1
within 16 weeks, within 12 weeks, within 8 weeks, or within 4 weeks
of initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; a decrease from
baseline in Full Mayo score .gtoreq.3 points and .gtoreq.30%
accompanied by a decrease in RBS of .gtoreq.1 or an absolute RBS of
0 or 1 within 16 weeks, within 12 weeks, within 8 weeks, or within
4 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; and
combinations thereof. In one such embodiment, the induction phase
is 12 weeks, and the additional therapeutic result is selected from
the group consisting of a decrease from baseline in Partial Mayo
score .gtoreq.2 points and .gtoreq.30% from baseline plus a
decrease in RBS.gtoreq.1 or an absolute RBS.ltoreq.1 over time
within 12 weeks, within 8 weeks, within 4 weeks, or within 2 weeks
of initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; an endoscopic
remission within 12 weeks, within 8 weeks, or within 4 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; a clinical response
within 12 weeks, within 8 weeks, or within 4 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, an endoscopic improvement within
12 weeks, within 8 weeks, or within 4 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; a Full Mayo score .ltoreq.2 with
no subscore >1 within 12 weeks, within 8 weeks, or within 4
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; a
decrease from baseline in Full Mayo score .gtoreq.3 points and
.gtoreq.30% accompanied by a decrease in RBS of .gtoreq.1 or an
absolute RBS of 0 or 1 within 12 weeks, within 8 weeks, or within 4
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; and
combinations thereof. In one such embodiment, the induction phase
is 8 weeks, and the additional therapeutic result is selected from
the group consisting of a decrease from baseline in Partial Mayo
score .gtoreq.2 points and .gtoreq.30% from baseline plus a
decrease in RBS.gtoreq.1 or an absolute RBS.ltoreq.1 over time
within 48 weeks, 8 weeks, within 4 weeks, or within 2 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; an endoscopic
remission within 8 weeks or within 4 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; a clinical response within 8
weeks or within 4 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; an endoscopic improvement within 8 weeks or within 4
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; a
Full Mayo score .ltoreq.2 with no subscore >1 within 8 weeks or
within 4 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; a
decrease from baseline in Full Mayo score .gtoreq.3 points and
.gtoreq.30% accompanied by a decrease in RBS of .gtoreq.1 or an
absolute RBS of 0 or 1 within 8 weeks or within 4 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; and combinations
thereof.
[0490] In one embodiment, the patient achieves clinical remission
within 16 weeks, or within 12 weeks, or within 8 weeks, or within 4
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one such embodiment, the patient is one who was taking
corticosteroids at baseline but who discontinued corticosteroid use
during treatment with the JAK1 inhibitor.
[0491] In one embodiment, the additional therapeutic result may be
a Full Mayo score .ltoreq.2 with no subscore >1 within 16 weeks,
or within 12 weeks, or within 8 weeks, or within 4 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one such
embodiment, the patient is one who was taking corticosteroids at
baseline but who discontinued corticosteroid use during treatment
with the JAK1 inhibitor. In another embodiment, the additional
therapeutic result may be selected from the group consisting of an
endoscopic remission within 16 weeks, within 12 weeks, within 8
weeks, or within 4 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; a clinical response within 16 weeks, or 12 weeks, or
8 weeks, or 4 weeks of initiating administration of upadacitinib,
or a pharmaceutically acceptable salt or solid state form thereof;
a decrease from baseline in Partial Mayo score .gtoreq.2 points and
.gtoreq.30% from baseline, plus a decrease in RBS.gtoreq.1 or an
absolute RBS.ltoreq.1 over time within 16 weeks, or 12 weeks, or 8
weeks, or 4 weeks, or 2 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; a decrease from baseline in Full Mayo score .gtoreq.3
points and .gtoreq.30% accompanied by a decrease in RBS of
.gtoreq.1 or an absolute RBS of 0 or 1 within 16 weeks, or 12
weeks, or 8 weeks, or 4 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; and an endoscopic improvement within 16 weeks, or 12
weeks, or 8 weeks, or 4 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; and combinations thereof. In one such embodiment, the
patient is one who was taking corticosteroids at baseline but who
discontinued corticosteroid use during treatment with the JAK1
inhibitor.
[0492] In one embodiment, the additional therapeutic result may be
an Adapted Mayo score (defined as SFS.ltoreq.1, RBS of 0, and
endoscopy subscore .ltoreq.1) at 16 weeks, or within 12 weeks, or
within 8 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one such embodiment, the patient is one who was taking
corticosteroids at baseline but who discontinued corticosteroid use
during treatment with the JAK1 inhibitor. In another embodiment,
the additional therapeutic result may be selected from the group
consisting of an endoscopic remission within 16 weeks, within 12
weeks, or within 8 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; a clinical response within 16 weeks, or 12 weeks, or
8 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; a
decrease from baseline in Partial Mayo score .gtoreq.2 points and
.gtoreq.30% from baseline, plus a decrease in RBS.gtoreq.1 or an
absolute RBS.ltoreq.1 over time within 16 weeks, or 12 weeks, or 8
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; a
decrease from baseline in Full Mayo score .gtoreq.3 points and
.gtoreq.30% accompanied by a decrease in RBS of .gtoreq.1 or an
absolute RBS of 0 or 1 within 16 weeks, or 12 weeks, or 8 weeks, or
4 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; and
an endoscopic improvement within 16 weeks, or 12 weeks, or 8 weeks,
or 4 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; and
combinations thereof. In one such embodiment, the patient is one
who was taking corticosteroids at baseline but who discontinued
corticosteroid use during treatment with the JAK1 inhibitor.
[0493] In one particular embodiment, the induction phase is 8
weeks, and the patient achieves a clinical remission (SF subscore
.ltoreq.1, RBS of 0 and endoscopic subscore .ltoreq.1) within 8
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof and an
endoscopic improvement (i.e., an endoscopic subscore .ltoreq.1)
within 6 weeks or within 8 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof. In another embodiment, the induction phase is 4
weeks, and the patient achieves a clinical remission within 4 weeks
of initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof and an endoscopic
improvement within 4 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof.
[0494] In one particular embodiment, the induction phase is 8
weeks, and the patient achieves a clinical remission within 8 weeks
of initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof and further achieves a
full Mayo score .ltoreq.2, with no subscore >1 within 8 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; an endoscopic
improvement (i.e., an endoscopic subscore .ltoreq.1) within 6 weeks
or within 8 weeks of initiating administration of upadacitinib, or
a pharmaceutically acceptable salt or solid state form thereof; or
combinations thereof. In another embodiment, the induction phase is
4 weeks, and the patient achieves a clinical remission within 4
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof and
further achieves a full Mayo score .ltoreq.2, with no subscore
>1 within 4 weeks of initiating administration of upadacitinib,
or a pharmaceutically acceptable salt or solid state form thereof;
an endoscopic improvement within 4 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; or combinations thereof.
[0495] In one embodiment, the patient is administered upadacitinib,
or a pharmaceutically acceptable salt or solid state form thereof,
for at least 52 weeks. The administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof, may
include an induction phase (e.g., an induction phase of up to 16
weeks), and additional weeks (e.g., 36 weeks or longer) of a
maintenance phase (discussed hereinafter). In other embodiments,
the administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof, may include a shorter
induction phase (e.g., up to 4 weeks, 6 weeks, 8 weeks, 10 weeks,
12 weeks, etc.), and a longer maintenance phase (e.g., a 12 week
induction phase and a 40 week or longer maintenance phase).
[0496] In one embodiment, the induction phase is 8 weeks and the
maintenance phase is 44 weeks. In some such embodiments, the
patient may achieve at least one therapeutic result selected from
the group consisting of: clinical remission within 52 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; endoscopic remission
within 52 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; full
Mayo score .ltoreq.2, with no subscore >1 within 52 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; clinical response
within 52 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof;
endoscopic improvement within 52 weeks of initiating administration
of upadacitinib, or a pharmaceutically acceptable salt or solid
state form thereof; decrease from baseline in Partial Mayo score
.gtoreq.2 points and .gtoreq.30% from baseline, plus a decrease in
RBS.gtoreq.1 or an absolute RBS.ltoreq.1 over time within 52 weeks
of initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; a decrease from
baseline in Full Mayo score .gtoreq.3 points and .gtoreq.30%
accompanied by a decrease in RBS of .gtoreq.1 or an absolute RBS of
0 or 1 within 52 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; histologic improvement within 52 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; stool frequency subscore
.ltoreq.1 within 52 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, a RBS of 0 within 52 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; an endoscopic subscore .ltoreq.1
within 52 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof; a
change in IBDQ score from baseline within 52 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; and combinations thereof.
[0497] In some embodiment when the patient is administered
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, for at least 52 weeks, the patient is one who was
taking corticosteroids at baseline but who discontinued
corticosteroid use during treatment with the JAK1 inhibitor, and
the therapeutic result may be selected from the group consisting of
clinical remission within 52 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; a endoscopic remission within 52 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; a Full Mayo score .ltoreq.2 with
no subscore >1 within 52 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof; clinical response within 52 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof; decrease from baseline in Partial
Mayo score .gtoreq.2 points and .gtoreq.30% from baseline, plus a
decrease in RBS.gtoreq.1 or an absolute RBS.ltoreq.1 over time
within 52 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof;
decrease from baseline in Full Mayo score .gtoreq.3 points and
.gtoreq.30% accompanied by a decrease in RBS of .gtoreq.1 or an
absolute RBS of 0 or 1 within 52 weeks of initiating administration
of upadacitinib, or a pharmaceutically acceptable salt or solid
state form thereof; an endoscopic improvement within 52 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof; and combinations
thereof.
[0498] In one embodiment, in a method of the present disclosure, a
patient is evaluated during or at the end of the induction phase
for a therapeutic result selected from the group consisting of
clinical remission, a Full Mayo score .ltoreq.2 with no subscore
>1, endoscopic improvement, endoscopic remission, clinical
response, decrease from baseline in Full Mayo score .gtoreq.3
points and .gtoreq.30% accompanied by a decrease in RBS of
.gtoreq.1 or an absolute RBS of 0 or 1, a decrease from baseline in
Partial Mayo score .gtoreq.2 points and .gtoreq.30% from baseline,
plus a decrease in RBS.gtoreq.1 or an absolute RBS.ltoreq.1 over
time, SF sub score, rectal bleeding subscore, endoscopic subscore,
histologic improvement, fecal calprotectin level, hs-CRP, IBDQ
score, and combinations thereof. In one embodiment, in a method of
the present disclosure, a patient is evaluated for clinical
remission during or at the end of the induction phase. In one
embodiment, in a method of the present disclosure, a patient is
evaluated for endoscopic improvement during or at the end of the
induction phase. In one embodiment, in a method of the present
disclosure, a patient is evaluated for achievement of Full Mayo
score .ltoreq.2 with no subscore >1 during or at the end of the
induction phase. In one embodiment, in a method of the present
disclosure, a patient is evaluated for endoscopic remission during
or at the end of the induction phase. In one embodiment, in a
method of the present disclosure, a patient is evaluated for
clinical response during or at the end of the induction phase. In
one embodiment, in a method of the present disclosure, a patient is
evaluated for decrease from baseline in Partial Mayo score
.gtoreq.2 points and .gtoreq.30% from baseline, plus a decrease in
RBS.gtoreq.1 or an absolute RBS.ltoreq.1 over time during or at the
end of the induction phase. In one embodiment, in a method of the
present disclosure, a patient is evaluated for change in Full Mayo
score from baseline during or at the end of the induction phase. In
one embodiment, in a method of the present disclosure, a patient is
evaluated for histologic improvement during or at the end of the
induction phase. In one embodiment, the induction phase is 2 weeks.
In one embodiment, the induction phase is 8 weeks. In one
embodiment, the induction phase is 12 weeks.
[0499] In one embodiment, in a method of the present disclosure, a
patient is evaluated during or at the end of the maintenance phase
for a therapeutic result selected from the group consisting of
endoscopic improvement, achievement of Full Mayo score .ltoreq.2
with no subscore >1, discontinuation of corticosteroid use and
clinical remission per Adapted Mayo score, maintenance of clinical
remission among subjects who achieved clinical remission during the
induction phase, endoscopic improvement among subjects who achieved
clinical remission during the induction phase, clinical response,
endoscopic remission, histologic improvement, and combinations
thereof.
[0500] In one embodiment, in a method of the present disclosure, a
patient is evaluated for a therapeutic result by being
corticosteroid-free for 44 weeks after discontinuing
corticosteroids. In one embodiment, in a method of the present
disclosure, a patient is evaluated for a therapeutic result by
achieving clinical remission 4 weeks after initial administration
of upadacitinib or a pharmaceutically acceptable salt or solid
state form thereof. In one embodiment, in a method of the present
disclosure, a patient is evaluated for a therapeutic result by
achieving clinical remission 8 weeks after initial administration
of upadacitinib or a pharmaceutically acceptable salt or solid
state form thereof. In one embodiment, in a method of the present
disclosure, a patient is evaluated for a therapeutic result by
achieving clinical remission 12 weeks after initial administration
of upadacitinib or a pharmaceutically acceptable salt or solid
state form thereof. In one embodiment, in a method of the present
disclosure, a patient is evaluated for a therapeutic result by
achieving Full Mayo score .ltoreq.2 with no subscore >1 within
52 weeks after initial administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, in a method of the present disclosure, a patient is
evaluated for a therapeutic result by achieving clinical remission
defined as stool frequency subscore .ltoreq.1, rectal bleeding
subscore of 0, and endoscopic subscore .ltoreq.1 with absence of
friability within 52 weeks after initial administration of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, in a method of the present
disclosure, a patient is evaluated for a therapeutic result by
achieving a SF subscore of 0, a RBS of 0, and endoscopic subscore
of 0. In one embodiment, in a method of the present disclosure, a
patient is evaluated for a therapeutic result by achieving a
decrease from baseline in Partial Mayo score .gtoreq.2 points and
.gtoreq.30% from baseline, plus a decrease in RBS.gtoreq.1 or an
absolute RBS.ltoreq.1 over time within 2 weeks after initial
administration of upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, in a method of
the present disclosure, a patient is evaluated for a therapeutic
result by achieving a decrease from baseline in Partial Mayo score
.gtoreq.2 points and .gtoreq.30% from baseline, plus a decrease in
RBS.gtoreq.1 or an absolute RBS.ltoreq.1 over time within 4 weeks
after initial administration of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, in
a method of the present disclosure, a patient is evaluated for a
therapeutic result by achieving a decrease from baseline in Partial
Mayo score 12 points and .gtoreq.30% from baseline, plus a decrease
in RBS.gtoreq.1 or an absolute RBS.ltoreq.1 over time within 12
weeks after initial administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, in a method of the present disclosure, a patient is
evaluated for a therapeutic result by achieving clinical response
or a decrease from baseline in Full Mayo score .gtoreq.3 points and
.gtoreq.30% accompanied by a decrease in RBS of .gtoreq.1 or an
absolute RBS of 0 or 1. In one embodiment, in a method of the
present disclosure, a patient is evaluated for a therapeutic result
by achieving a decrease from baseline in Partial Mayo score
.gtoreq.2 points and .gtoreq.30% from baseline, plus a decrease in
RBS.gtoreq.1 or an absolute RBS.ltoreq.1 over time within 2 weeks
after initial administration of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, in
a method of the present disclosure, a patient is evaluated for a
therapeutic result by achieving clinical response or a decrease
from baseline in Full Mayo score .gtoreq.3 points and .gtoreq.30%
accompanied by a decrease in RBS of .gtoreq.1 or an absolute RBS of
0 or 1. In one embodiment, in a method of the present disclosure, a
patient is evaluated for a therapeutic result by achieving a
decrease from baseline in Partial Mayo score .gtoreq.2 points and
.gtoreq.30% from baseline, plus a decrease in RBS.gtoreq.1 or an
absolute RBS.ltoreq.1 over time within 4 weeks after initial
administration of upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, in a method of
the present disclosure, a patient is evaluated for a therapeutic
result by achieving clinical response or a decrease from baseline
in Full Mayo score .gtoreq.3 points and .gtoreq.30% accompanied by
a decrease in RBS of 1 or an absolute RBS of 0 or 1. In one
embodiment, in a method of the present disclosure, a patient is
evaluated for a therapeutic result by achieving a decrease from
baseline in Partial Mayo score .gtoreq.2 points and .gtoreq.30%
from baseline, plus a decrease in RBS.gtoreq.1 or an absolute
RBS.ltoreq.1 over time within 12 weeks after initial administration
of upadacitinib or a pharmaceutically acceptable salt or solid
state form thereof. In one embodiment, in a method of the present
disclosure, a patient is evaluated for a therapeutic result by
achieving stool frequency subscore .ltoreq.1 within 2 weeks after
initial administration of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, in
a method of the present disclosure, a patient is evaluated for a
therapeutic result by achieving stool frequency subscore .ltoreq.1
within 4 weeks after initial administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, in a method of the present disclosure, a patient is
evaluated for a therapeutic result by achieving stool frequency
subscore .ltoreq.1 within 12 weeks after initial administration of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, in a method of the present
disclosure, a patient is evaluated for a therapeutic result by
achieving rectal bleeding subscore of 0 over time. In one
embodiment, in a method of the present disclosure, a patient is
evaluated for a therapeutic result by achieving an endoscopic
subscore of .ltoreq.1 within 12 weeks after initial administration
of upadacitinib or a pharmaceutically acceptable salt or solid
state form thereof. In one embodiment, in a method of the present
disclosure, a patient is evaluated for a therapeutic result by
achieving an endoscopic improvement within 12 weeks after initial
administration of upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, in a method of
the present disclosure, a patient is evaluated for a therapeutic
result by achieving fecal calprotectin below 150 mg/kg within 4
weeks after initial administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, in a method of the present disclosure, a patient is
evaluated for a therapeutic result by achieving fecal calprotectin
below 150 mg/kg within 8 weeks after initial administration of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, in a method of the present
disclosure, a patient is evaluated for a therapeutic result by
achieving fecal calprotectin below 150 mg/kg within 12 weeks after
initial administration of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, in
a method of the present disclosure, a patient is evaluated for a
therapeutic result by achieving an IBDQ response (increase of
IBDQ.gtoreq.16 from Baseline) within 2 weeks after initial
administration of upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, in a method of
the present disclosure, a patient is evaluated for a therapeutic
result by achieving an IBDQ response (increase of IBDQ.gtoreq.16
from Baseline) within 8 weeks after initial administration of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, in a method of the present
disclosure, a patient is evaluated for a therapeutic result by
achieving an IBDQ response (increase of IBDQ.gtoreq.16 from
Baseline) within 12 weeks after initial administration of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, in a method of the present
disclosure, a patient is evaluated for a therapeutic result by
achieving a change from Baseline in hs-CRP within 2 weeks after
initial administration of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, in
a method of the present disclosure, a patient is evaluated for a
therapeutic result by achieving a change from Baseline in hs-CRP
within 8 weeks after initial administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, in a method of the present disclosure, a patient is
evaluated for a therapeutic result by achieving a change from
Baseline in hs-CRP within 12 weeks after initial administration of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, in a method of the present
disclosure, a patient is evaluated for a therapeutic result by
achieving a change in Baseline in fecal calprotectin within 8 weeks
after initial administration of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, in
a method of the present disclosure, a patient is evaluated for a
therapeutic result by achieving a change in Baseline in fecal
calprotectin within 12 weeks after initial administration of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, in a method of the present
disclosure, a patient is evaluated for a therapeutic result by
achieving a change in corticosteroid dose within 12 weeks after
initial administration of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, in
a method of the present disclosure, a patient is evaluated for a
therapeutic result by change from Baseline in Adapted Mayo score.
Full Mayo score, Partial Mayo score and/or Mayo subscores within 12
weeks after initial administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, in a method of the present disclosure, a patient is
evaluated for a therapeutic result by change form Baseline in UCEIS
scores within 12 weeks after initial administration of upadacitinib
or a pharmaceutically acceptable salt or solid state form thereof.
In one embodiment, in a method of the present disclosure, a patient
is evaluated for a therapeutic result by achieving histologic
remission (defined as Geboes score <2) within 8 weeks after
initial administration of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, in
a method of the present disclosure, a patient is evaluated for a
therapeutic result by achieving histologic remission (defined as
Geboes score <2) within 12 weeks after initial administration of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, in a method of the present
disclosure, a patient is evaluated for a therapeutic result by
change from Baseline in histologic score within 8 weeks after
initial administration of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, in
a method of the present disclosure, a patient is evaluated for a
therapeutic result by change from Baseline in histologic score
within 8 weeks after initial administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, in a method of the present disclosure, a patient is
evaluated for a therapeutic result by change from Baseline in
laboratory and nutritional parameters (e.g., hemoglobin,
hematocrit, albumin, total protein concentration, and weight)
within 8 weeks after initial administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, in a method of the present disclosure, a patient is
evaluated for a therapeutic result by change from Baseline in
laboratory and nutritional parameters (e.g., hemoglobin,
hematocrit, albumin, total protein concentration, and weight)
within 12 weeks after initial administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, in a method of the present disclosure, a patient is
evaluated for a therapeutic result by change in Baseline in
subject-reported stool frequency (absolute values) within 8 weeks
after initial administration of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, in
a method of the present disclosure, a patient is evaluated for a
therapeutic result by change in Baseline in subject-reported stool
frequency (absolute values) within 12 weeks after initial
administration of upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, in a method of
the present disclosure, a patient is evaluated for a therapeutic
result by change from Baseline in IBDQ score within 8 weeks after
initial administration of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, in
a method of the present disclosure, a patient is evaluated for a
therapeutic result by change from Baseline in IBDQ score within 12
weeks after initial administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, in a method of the present disclosure, a patient is
evaluated for a therapeutic result by change from Baseline in
EQ-5D-5L score within 8 weeks after initial administration of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, in a method of the present
disclosure, a patient is evaluated for a therapeutic result by
change from Baseline in EQ-5D-5L score within 12 weeks after
initial administration of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, in
a method of the present disclosure, a patient is evaluated for a
therapeutic result by change from Baseline in WPAI:UC scores within
8 weeks after initial administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, in a method of the present disclosure, a patient is
evaluated for a therapeutic result by change from Baseline in
WPAI:UC scores within 12 weeks after initial administration of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, in a method of the present
disclosure, a patient is evaluated for a therapeutic result by
change in SF-36, PCT, MCS components and domain scores within 8
weeks after initial administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, in a method of the present disclosure, a patient is
evaluated for a therapeutic result by change in SF-36, PCT, MCS
components and domain scores within 12 weeks after initial
administration of upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, in a method of
the present disclosure, a patient is evaluated for a therapeutic
result by change in PGIC score within 8 weeks after initial
administration of upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, in a method of
the present disclosure, a patient is evaluated for a therapeutic
result by change in PGIC score within 12 weeks after initial
administration of upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, in a method of
the present disclosure, a patient is evaluated for a therapeutic
result by change from Baseline in FACIT-F score within 8 weeks
after initial administration of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, in
a method of the present disclosure, a patient is evaluated for a
therapeutic result by change from Baseline in FACIT-F score within
12 weeks after initial administration of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, in a method of the present disclosure, a patient is
evaluated for a therapeutic result by change from Baseline in UC-SQ
score within 8 weeks after initial administration of upadacitinib
or a pharmaceutically acceptable salt or solid state form thereof.
In one embodiment, in a method of the present disclosure, a patient
is evaluated for a therapeutic result by change from Baseline in
UC-SQ score within 8 weeks after initial administration of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, the patient is administered at
least 14 doses, 28 doses, or at least 42 doses, or at least 56
doses of upadacitinib, or a pharmaceutically acceptable salt or
solid state form thereof, during the induction phase.
[0501] In one aspect, a certain therapeutic result is maintained by
the patient during the maintenance phase. The maintenance phase may
last for an indefinite period of time. In one embodiment, the
maintenance phase is at least 36 weeks, including at least 37
weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at
least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44
weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, or
at least 48 weeks after the patient achieves clinical remission or
clinical response after the patient achieves clinical remission or
clinical response. In one embodiment, the maintenance phase is at
least 40 additional weeks. In one embodiment, the maintenance phase
is at least 44 additional weeks after the patient achieves clinical
remission or clinical response. In one embodiment, the therapeutic
result maintained by the patient during the maintenance phase is
selected from the group consisting of clinical remission, a Full
Mayo score .ltoreq.2 with no subscore >1, endoscopic remission,
clinical response, a decrease from baseline in Partial Mayo score
.gtoreq.2 points and .gtoreq.30% from baseline plus a decrease in
RBS.gtoreq.1 or an absolute RBS.ltoreq.1, a decrease from baseline
in Full Mayo score .gtoreq.3 points and .gtoreq.30% accompanied by
a decrease in RBS of .gtoreq.1 or an absolute RBS of 0 or 1,
endoscopic improvement, and combinations thereof. In one
embodiment, the therapeutic result maintained by the patient during
the maintenance phase is endoscopic remission. In one embodiment,
the therapeutic result maintained by the patient during the
maintenance phase is endoscopic response. In one embodiment, the
therapeutic result maintained by the patient during the maintenance
phase is clinical remission. In one embodiment, the therapeutic
result maintained by the patient during the maintenance phase is
corticosteroid-free remission.
[0502] In one embodiment, in a method of the present disclosure, a
patient is evaluated for clinical remission during the maintenance
phase. In one embodiment, a patient is evaluated for endoscopic
improvement during the maintenance phase. In one embodiment, a
patient is evaluated for clinical remission a Full Mayo score
.ltoreq.2 with no subscore >1 during the maintenance phase. In
one embodiment, in a method of the present disclosure, a patient is
evaluated for endoscopic remission during the maintenance phase. In
one embodiment, in a method of the present disclosure, a patient is
evaluated for clinical response, or a decrease from baseline in
Partial Mayo score .gtoreq.2 points and .gtoreq.30% from baseline
plus a decrease in RBS.gtoreq.1 or an absolute RBS.ltoreq.1, or a
decrease from baseline in Full Mayo score .gtoreq.3 points and
.gtoreq.30% accompanied by a decrease in RBS of .gtoreq.1 or an
absolute RBS of 0 or 1 during the maintenance phase.
[0503] In one embodiment, the present disclosure provides a method
for treating an inflammatory disease, in one aspect for treating
ulcerative colitis, comprising (a) administering to a patient a
dose of a JAK1 inhibitor (e.g., upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof) at week 0 and once
daily (QD) thereafter for 8 weeks, wherein the dose is 45 mg QD. In
one embodiment, the method further comprises (b) administering to
the patient additional doses once daily thereafter for at least 44
additional weeks, wherein the dose is 15 mg or 30 mg QD. In one
embodiment the dose is administered orally.
[0504] In one embodiment, 8 weeks after initiating administration
of upadacitinib, or a pharmaceutically acceptable salt or solid
state form thereof, a patient is evaluated for clinical remission
and/or for a Full Mayo score .ltoreq.2 with no subscore >1. In
one embodiment, 8 weeks after initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, a patient is evaluated for clinical response and/or
for a decrease from baseline in Partial Mayo score .gtoreq.2 points
and .gtoreq.30% from baseline plus a decrease in RBS.gtoreq.1 or an
absolute RBS.ltoreq.1, and/or for a decrease from baseline in Full
Mayo score .gtoreq.3 points and .gtoreq.30% accompanied by a
decrease in RBS of .gtoreq.1 or an absolute RBS of 0 or 1 and/or
for endoscopic improvement and/or for endoscopic remission. In one
embodiment, 6 weeks after initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, a patient is evaluated for clinical remission and/or
a Full Mayo score .ltoreq.2 with no subscore .gtoreq.1 and/or for
endoscopic remission. In one embodiment, 6 weeks after initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, a patient is evaluated for a
decrease from baseline in Full Mayo score .gtoreq.3 points and
.gtoreq.30% accompanied by a decrease in RBS of .gtoreq.1 or an
absolute RBS of 0 or 1 and/or clinical response and/or a decrease
from baseline in Partial Mayo score .gtoreq.2 points and
.gtoreq.230% from baseline plus a decrease in RBS.gtoreq.1 or an
absolute RBS.ltoreq.1, and/or for endoscopic improvement. In one
embodiment, 4 weeks after initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, a patient is evaluated for clinical remission and/or
for a Full Mayo score .ltoreq.2 with no subscore >1 and/or for
endoscopic remission. In one embodiment, 4 weeks after initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, a patient is evaluated for a
decrease from baseline in Full Mayo score .gtoreq.3 points and
.gtoreq.30% accompanied by a decrease in RBS of .gtoreq.1 or an
absolute RBS of 0 or 1 and/or for clinical response and/or for a
decrease from baseline in Partial Mayo score .gtoreq.2 points and
.gtoreq.30% from baseline plus a decrease in RBS.gtoreq.1 or an
absolute RBS.ltoreq.1, and/or for endoscopic improvement. In one
embodiment, 2 weeks after initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, a patient is evaluated for clinical remission and/or
for a Full Mayo score .ltoreq.2 with no subscore >1 and/or for
endoscopic remission. In one embodiment, 2 weeks after initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof, a patient is evaluated for a
decrease from baseline in Full Mayo score .gtoreq.3 points and
.gtoreq.30% accompanied by a decrease in RBS of .gtoreq.1 or an
absolute RBS of 0 or 1 and/or for clinical response and/or for a
decrease from baseline in Partial Mayo score .gtoreq.2 points and
.gtoreq.30% from baseline plus a decrease in RBS.gtoreq.1 or an
absolute RBS.ltoreq.1, and/or for endoscopic improvement.
[0505] In one embodiment, 48 weeks after initiating administration
of upadacitinib, or a pharmaceutically acceptable salt or solid
state form thereof, a patient is evaluated for clinical remission
per Adapted Mayo score (defined sa SFS.ltoreq.1, RBS of 0, and
endoscopy subscore .ltoreq.1), clinical remission per Full Mayo
score (defined as a Full Mayo score .ltoreq.2 with no subscore
>1), clinical remission per Partial mayo score (defined as
Partial Mayo score .ltoreq.2 with no subscore >1) over time,
clinical remission defined as stool frequency subscore .ltoreq.1,
rRBS of 0 and endoscopic subscore .ltoreq.1 with absence of
friability and clinical response per Adapted mayo score (defined as
decrease from BL in the Adapted Mayo score .gtoreq.2 points and
.gtoreq.30% from BL, plus a decrease in RBS.gtoreq.1).
[0506] In one embodiment, the present disclosure provides a method
for treating ulcerative colitis, comprising (a) administering to a
patient a dose of a JAK1 inhibitor (e.g., upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof) at
week 0 and once daily thereafter via an oral route, wherein the
doses of the JAK1 inhibitor comprise 15 mg, 30 mg, or 45 mg QD, or
any combination thereof.
[0507] In one embodiment, the present disclosure provides a method
for treating ulcerative colitis, comprising administering to a
patient 15 mg to 45 mg of a JAK1 inhibitor. In one embodiment, the
present disclosure provides a method for treating ulcerative
colitis, comprising administering to a patient orally 15 mg of a
JAK1 inhibitor QD. In one embodiment, the present disclosure
provides a method for treating ulcerative colitis, comprising
administering to a patient orally 30 mg of a JAK1 inhibitor QD. In
one embodiment, the present disclosure provides a method for
treating ulcerative colitis, comprising administering to a patient
orally 45 mg of a JAK1 inhibitor QD. In any such embodiments, the
JAK1 inhibitor may be upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof. In any such embodiment, the JAK1
inhibitor may be in a once daily modified release formulation. In
any such embodiment, the patient may have moderately to severely
active ulcerative colitis prior to treatment.
[0508] In one embodiment, the administration of a JAK1 inhibitor
according to the present disclosure is further described in the
Examples herein below or in FIG. 13.
[0509] In one embodiment, the present disclosure provides a method
for treating ulcerative colitis, said method comprising a)
administering at least one induction dose of a JAK1 inhibitor
(e.g., upadacitinib or a pharmaceutically acceptable salt or solid
state form thereof) to a patient, wherein said induction dose
comprises 15 mg to 45 mg of the JAK 1 inhibitor. In one aspect, the
induction dose comprises 15 mg or 30 mg or 45 mg. In one aspect,
the induction dose comprises 45 mg. In one aspect, the induction
dose is administered orally. In one aspect, the induction dose is
administered QD. In one aspect, the induction dose is administered
for 8 weeks. In one aspect the induction dose is administered for 6
weeks. In one aspect the induction dose is administered for 4
weeks. In one embodiment, the induction dose is administered for up
to 12 weeks, including for 2 weeks, 4 weeks, 5 weeks, 6 weeks, 7
weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks.
[0510] In one embodiment, the induction dose comprises 45 mg of the
JAK inhibitor administered QD.
[0511] In one embodiment, the induction dose comprises 30 mg of the
JAK1 inhibitor administered QD.
[0512] In one embodiment, the induction dose comprises 15 mg of the
JAK1 inhibitor administered QD.
[0513] In one embodiment, the JAK1 inhibitor is upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof.
[0514] In one embodiment, the induction dose is in a once daily
modified release formulation.
[0515] In one embodiment, the method further comprises b)
administering a first maintenance dose of a JAK1 inhibitor (e.g.,
upadacitinib, or pharmaceutically acceptable salt or solid state
form thereof), to the patient after the last induction dose is
administered; and c) administering at least one additional
maintenance dose to the patient once daily thereafter.
[0516] In one embodiment, the first maintenance dose comprises 15
mg to 30 mg of the JAK1 inhibitor. In one aspect, the first
maintenance dose comprises 15 mg or 30 mg of the JAK1 inhibitor. In
one aspect, the first maintenance dose is smaller than the
induction dose. In one aspect, the first maintenance dose is
administered QD. In one aspect the first maintenance dose is 15 mg.
In one aspect the first maintenance dose is 30 mg. In one aspect,
the first maintenance dose is administered orally. In one aspect,
the first maintenance dose is in a once daily modified release
formulation.
[0517] In one aspect, the at least one additional maintenance dose
comprises 15 mg to 30 mg of the JAK 1 inhibitor. In one aspect, the
at least one additional maintenance dose comprises 15 mg or 30 mg.
In one aspect, the at least one additional maintenance dose is
administered orally. In one aspect, the at least one additional
maintenance dose is administered QD. In one embodiment, the at
least one additional maintenance dose comprises 15 mg of the JAK1
inhibitor administered QD. In one embodiment, the at least one
additional maintenance dose comprises 30 mg of the JAK1 inhibitor
administered QD. In one aspect, the at least one additional
maintenance dose is in a once daily modified release
formulation.
[0518] In any of the foregoing embodiments, the JAK1 inhibitor may
be upadacitinib or a pharmaceutically acceptable salt or solid
state form thereof.
[0519] In one aspect, in any of the foregoing embodiments, the
patient is one who had an inadequate response to or experienced a
loss of response to or intolerance to conventional treatment (e.g.,
aminosalicylate, corticosteroids, immunosuppressants) or to a
previous treatment with a biologic agent. In one aspect, in any of
the foregoing embodiments, the patient is one who had an inadequate
response to, a loss of response to, or experienced intolerance to a
previous treatment with an anti-TNF agent.
[0520] In one aspect, in any of the foregoing embodiments, the
patient is one who is naive to previous treatment with an
aminosalicylate, a corticosteroid, an immunosuppressant, a biologic
agent or an anti-TNF agent.
[0521] In one aspect, in any of the foregoing embodiments, the
patient is one who had moderately to severely active ulcerative
colitis prior to treatment or administration of the induction
dose.
[0522] In one embodiment, the present disclosure further provides a
method for inducing clinical remission of ulcerative colitis or a
Full Mayo score of .ltoreq.2 with no subscore >1 in a patient,
said method comprising a) administering to the patient at least one
induction dose of a JAK1 inhibitor as described above or herein
(e.g., upadacitinib or a pharmaceutically acceptable salt or solid
state form thereof). In one embodiment, the induction dose
comprises 30 mg to 45 mg of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, an
induction dose is administered at week 0 and once daily (QD)
thereafter for up to 12 weeks (e.g., for 4 weeks, 5 weeks, 6 weeks,
7 weeks, or 8 weeks, or 9 weeks, or 10 weeks, or 11 weeks, or 12
weeks), wherein the dose is 30 mg QD or 45 mg QD. In one
embodiment, the method further comprises maintaining clinical
remission of ulcerative colitis or a Full Mayo score of .ltoreq.2
with no subscore >1, said method further comprising b)
administering a first maintenance dose of said JAK1 inhibitor to
the patient after the last induction dose is administered and c)
administering at least one additional maintenance dose to the
patient thereafter as described above or herein. In one embodiment,
the at least one additional maintenance dose is administered once
daily. In one embodiment, the additional maintenance doses are
administered once daily for at least 36 additional weeks, including
for at least 36 weeks, at least 37 weeks, at least 38 weeks, at
least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42
weeks, at least 43 weeks, at least 44 weeks, at least 56 weeks, at
least 112 weeks, at least 308 weeks, or at least 420 weeks. In one
embodiment, the additional maintenance doses are administered once
daily for at least 44 additional weeks. In one embodiment, the
maintenance dose is 15 mg or 30 mg QD. In one embodiment the
induction and maintenance doses are administered orally. In one
embodiment, the patient has active ulcerative colitis with an
Adapted Mayo score of 5 to 9 points and endoscopy subscore of 2 or
3 before administration of the first induction dose. In one
embodiment, the patient has moderately to severely active
ulcerative colitis prior to administration of the first induction
dose. In one embodiment, the patient has had an inadequate response
to or experienced intolerance to conventional treatment (e.g.,
aminosalicylates, corticosteroids, immunosuppressants) or to a
previous treatment with a biologic agent and/or an anti-TNF agent.
In one embodiment, the patient is naive to previous treatment with
aminosalicylates, a corticosteroid, an immunosuppressant, a
biologic agent, and/or an anti-TNF agent. In one embodiment, the
clinical remission or Full Mayo score of .ltoreq.2 with no subscore
>1 is achieved within 4 weeks or within 8 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, the clinical
remission or a Full Mayo score of .ltoreq.2 with no subscore >1
is achieved within 12 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, the clinical remission or Full
Mayo score of .ltoreq.2 with no subscore >1 is achieved within
10 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, the clinical remission or Full Mayo score of
.ltoreq.2 with no subscore >1 is achieved within 8 weeks of
initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, the
patient achieves a stool frequency subscore .ltoreq.1, RBS of 0 and
endoscopic subscore .ltoreq.1 before administration of the first
maintenance dose. In one embodiment, the patient achieves a full
Mayo score of .ltoreq.2 with no subscore >1 before
administration of the first maintenance dose. In one embodiment,
the induction and maintenance doses are in once-daily, modified
release formulations.
[0523] In one embodiment, the present disclosure provides a method
for inducing endoscopic remission of ulcerative colitis, the method
comprising (a) administering to a patient at least one induction
dose of a JAK inhibitor (e.g., upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof), wherein the induction
dose comprises 30 to 45 mg of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, an
induction dose is administered at week 0 and once daily (QD)
thereafter for up to 12 weeks (e.g., for 4 weeks, 5 weeks, 6 weeks,
7 weeks, or 8 weeks, or 9 weeks, or 10 weeks, or 11 weeks, or 12
weeks), wherein the dose is 30 mg QD or 45 mg QD. In one
embodiment, the method further comprises maintaining endoscopic
remission of ulcerative colitis, said method further comprising (b)
administering to the patient a first maintenance dose of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, after the last induction dose is administered, and
(c) administering at least one additional maintenance dose once
daily thereafter as described above or herein. In one embodiment,
the at least one additional maintenance dose is administered once
daily. In one embodiment, the additional maintenance doses are
administered once daily for at least 36 additional weeks, including
for at least 36 weeks, at least 37 weeks, at least 38 weeks, at
least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42
weeks, at least 43 weeks, at least 44 weeks, at least 56 weeks, at
least 112 weeks, at least 308 weeks, or at least 420 weeks. In one
embodiment, the additional maintenance doses are administered once
daily for at least 44 additional weeks. In one embodiment, the
maintenance dose is 15 mg or 30 mg QD. In one embodiment the
induction and maintenance doses are administered orally. In one
embodiment, the patient has active ulcerative colitis with an
Adapted Mayo score of 5 to 9 points and an endoscopy subscore of 2
or 3 before administration of the first induction dose. In one
embodiment, the patient has moderately to severely active
ulcerative colitis prior to administration of the first induction
dose. In one embodiment, the patient has had an inadequate response
to or experienced intolerance to conventional treatment (e.g.,
aminosalicylates, corticosteroids, immunosuppressants) or to a
previous treatment with a biologic and/or an anti-TNF agent. In one
embodiment, the patient is naive to previous treatment with an
aminosalicylate, a corticosteroid, an immunosuppressant, an
anti-TNF agent and/or a biologic agent. In one embodiment, the
endoscopic remission is achieved within 4 weeks or within 8 weeks
of initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, the
endoscopic remission is achieved within 12 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, the endoscopic
remission is achieved within 10 weeks of initiating administration
of upadacitinib, or a pharmaceutically acceptable salt or solid
state form thereof. In one embodiment, the endoscopic remission is
achieved within 8 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, the patient achieves an endoscopic
subscore of 0 before administration of the first maintenance dose.
In one embodiment, the induction and maintenance doses are in
once-daily, modified release formulations.
[0524] In one embodiment, the present disclosure further provides a
method for inducing clinical response or inducing a decrease from
baseline in Full Mayo score .gtoreq.3 points and .gtoreq.30%
accompanied by a decrease in RBS of .gtoreq.1 or an absolute RBS or
0 or 1 or inducing a decrease from baseline in Partial Mayo score
.gtoreq.2 points and .gtoreq.30%, accompanied by a decrease in RBS
of .gtoreq.1 or an absolute rectal bleeding subscore of .ltoreq.1
in an ulcerative colitis in a patient, said method comprising a)
administering to the patient at least one induction dose of a JAK1
inhibitor as described above or herein (e.g., upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof). In
one embodiment, the induction dose comprises 30 mg to 45 mg of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, an induction dose is administered
at week 0 and once daily (QD) thereafter for up to 8 weeks (e.g.,
for 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks), wherein the
dose is 30 mg QD or 45 mg QD. In one embodiment, the method further
comprises maintaining clinical response of ulcerative colitis or
maintaining a decrease from baseline in Full Mayo score .gtoreq.3
points and .gtoreq.30%, accompanied by a decrease in RBS of
.gtoreq.1 or an absolute RBS or 0 or 1 or maintaining a decrease
from baseline in Partial Mayo score .gtoreq.2 points and
.gtoreq.30%, accompanied by a decrease in RBS of .gtoreq.1 or an
absolute rectal bleeding subscore of .ltoreq.1, said method further
comprising b) administering a first maintenance dose of said JAK1
inhibitor to the patient after the last induction dose is
administered and c) administering at least one additional
maintenance dose to the patient thereinafter as described above or
herein. In one embodiment, the at least one additional maintenance
dose is administered once daily. In one embodiment, the additional
maintenance doses are administered once daily for at least 36
additional weeks, including for at least 36 weeks, at least 37
weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at
least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44
weeks, at least 56 weeks, at least 112 weeks, at least 308 weeks,
or at least 420 weeks. In one embodiment, the additional
maintenance doses are administered once daily for at least 44
additional weeks. In one embodiment, the maintenance dose is 15 mg
or 30 mg QD. In one embodiment the induction and maintenance doses
are administered orally. In one embodiment, the patient has active
ulcerative colitis with an Adapted Mayo score of 5 to 9 points and
an endoscopy subscore of 2 or 3 before administration of the first
induction dose. In one embodiment, the patient has moderately to
severely active ulcerative colitis prior to administration of the
first induction dose. In one embodiment, the patient has had an
inadequate response to or experienced intolerance to a conventional
treatment (e.g., aminosalicylates, corticosteroids,
immunosuppressants) or to a previous treatment with a biologic
agent and/or an anti-TNF agent. In one embodiment, the patient is
naive to previous treatment with aminosalicylates, a
corticosteroid, an immunosuppressant, a biologic agent and/or an
anti-TNF agent. In one embodiment, the clinical response or the
decrease from baseline in Full Mayo score .gtoreq.3 points and
.gtoreq.30%, accompanied by a decrease in RBS of .gtoreq.1 or an
absolute RBS or 0 or 1 or the decrease from baseline in Partial
Mayo score .gtoreq.2 points and .gtoreq.30%, accompanied by a
decrease in RBS of .gtoreq.1 or an absolute rectal bleeding
subscore of .ltoreq.1 is achieved within 4 weeks or within 8 weeks
of initiating administration of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, the
clinical response or the decrease from baseline in Full Mayo score
.gtoreq.3 points and .gtoreq.30%, accompanied by a decrease in RBS
of .gtoreq.1 or an absolute RBS or 0 or 1 is achieved within 12
weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, the clinical response or the decrease from baseline
in Full Mayo score .gtoreq.3 points and .gtoreq.30%, accompanied by
a decrease in RBS of .gtoreq.1 or an absolute RBS or 0 or 1 or the
decrease from baseline in Partial Mayo score .gtoreq.2 points and
.gtoreq.30%, accompanied by a decrease in RBS of .gtoreq.1 or an
absolute rectal bleeding subscore of .ltoreq.1 is achieved within
10 weeks of initiating administration of upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof. In
one embodiment, the clinical response, or the decrease from
baseline in Full Mayo score .gtoreq.3 points and .gtoreq.30%,
accompanied by a decrease in RBS of .gtoreq.1 or an absolute RBS or
0 or 1 or the decrease from baseline in Partial Mayo score
.gtoreq.2 points and .gtoreq.30%, accompanied by a decrease in RBS
of .gtoreq.1 or an absolute rectal bleeding subscore of .ltoreq.1
is achieved within 8 weeks of initiating administration of
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof. In one embodiment, the patient achieves a decrease
from baseline in Adapted Mayo score .gtoreq.2 points and
.gtoreq.30%, accompanied by a decrease in RBS of .gtoreq.1 or an
absolute rectal bleeding subscore of 0 or 1 before administration
of the first maintenance dose. In one embodiment, the patient
achieves a decrease from baseline in Partial Mayo score .gtoreq.2
points and .gtoreq.30%, accompanied by a decrease in RBS of
.gtoreq.1 or an absolute rectal bleeding subscore of .ltoreq.1
before administration of the first maintenance dose. In one
embodiment, the patient achieves a decrease from baseline in Full
Mayo score .gtoreq.3 points and .gtoreq.30%, accompanied by a
decrease in RBS from baseline of .gtoreq.1 or an absolute rectal
bleeding subscore of 0 or 1 before administration of the first
maintenance dose. In one embodiment, the induction and maintenance
doses are in once-daily, modified release formulations.
[0525] In one embodiment, the present disclosure further provides a
method for inducing endoscopic improvement of ulcerative colitis in
a patient, said method comprising a) administering to the patient
at least one induction dose of a JAK1 inhibitor as described above
or herein (e.g., upadacitinib or a pharmaceutically acceptable salt
or solid state form thereof). In one embodiment, the induction dose
comprises 30 to 45 mg of upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, an
induction dose is administered at week 0 and once daily (QD)
thereafter for up to 12 weeks (e.g., for 4 weeks, 5 weeks, 6 weeks,
7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks or 12 weeks) wherein
the dose is 30 mg QD or 45 mg QD. In one embodiment, the method
further comprises maintaining endoscopic improvement of ulcerative
colitis, said method further comprising b) administering a first
maintenance dose of said JAK1 inhibitor to the patient after the
last induction dose is administered and c) administering at least
one additional maintenance dose to the patient thereinafter as
described above or herein. In one embodiment, the at least one
additional maintenance dose is administered once daily. In one
embodiment, the additional maintenance doses are administered once
daily for at least 36 additional weeks, including for at least 36
weeks, at least 37 weeks, at least 38 weeks, at least 39 weeks, at
least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43
weeks, at least 44 weeks, at least 56 weeks, at least 112 weeks, at
least 308 weeks, or at least 420 weeks. In one embodiment, the
additional maintenance doses are administered once daily for at
least 44 additional weeks. In one embodiment, the maintenance dose
is 15 mg or 30 mg QD. In one embodiment the induction and
maintenance doses are administered orally. In one embodiment, the
patient has active ulcerative colitis with an Adapted Mayo score of
5 to 9 points and an endoscopy subscore of 2 or 3 before
administration of the first induction dose. In one embodiment, the
patient has moderately to severely active ulcerative colitis prior
to administration of the first induction dose. In one embodiment,
the patient has had an inadequate response to or experienced
intolerance to a conventional treatment (e.g., aminosalicylate,
corticosteroids, and immunosuppressants) or to a previous treatment
with a biologic agent and/or an anti-TNF agent. In one embodiment,
the patient is naive to previous treatment with an aminosalicylate
a corticosteroid, an immunosuppressant, a biologic agent and/or an
anti-TNF agent. In one embodiment, the endoscopic improvement is
achieved within 8 weeks or within 16 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, the endoscopic
improvement is achieved within 12 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, the endoscopic
improvement is achieved within 10 weeks of initiating
administration of upadacitinib, or a pharmaceutically acceptable
salt or solid state form thereof. In one embodiment, the endoscopic
improvement is achieved within 8 weeks of initiating administration
of upadacitinib, or a pharmaceutically acceptable salt or solid
state form thereof. In one embodiment, the patient achieves an
endoscopic subscore .ltoreq.1 before administration of the first
maintenance dose. In one embodiment, the induction and maintenance
doses are in once-daily, modified release formulations.
[0526] In one embodiment, the present disclosure further provides a
method of maintaining clinical remission or a method of maintaining
a Full Mayo score .ltoreq.2 with no subscore >1 of ulcerative
colitis in a patient, said method comprising administering 15 mg or
30 mg of upadacitinib or a pharmaceutically acceptable salt or
solid state form thereof to the patient. In one embodiment, the
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof is administered once daily for at least 36 weeks,
including for at least 37 weeks, at least 38 weeks, at least 39
weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at
least 43 weeks, or at least 44 weeks. In one embodiment the
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof is administered orally. In one embodiment, the patient
has had an inadequate response to or experienced intolerance to a
conventional treatment (e.g., aminosalicylates, corticosteroids,
immunosuppressants) or to a previous treatment with a biologic
agent and/or an anti-TNF agent. In one embodiment, the patient is
naive to previous treatment with aminosalicylates, a
corticosteroid, an immunosuppressant, a biologic agent and/or an
anti-TNF agent. In one embodiment, the patient is a refractory
patient. In one embodiment, the upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof is a in once-daily,
modified release formulation.
[0527] In one embodiment, the present disclosure further provides a
method of maintaining clinical response or a method of maintaining
a decrease from baseline in Full Mayo score .gtoreq.3 points and
.gtoreq.30%, accompanied by a decrease in RBS of .gtoreq.1 or an
absolute RBS or 0 or 1 or a method of maintaining a decrease from
baseline in Partial Mayo score .gtoreq.2 points and .gtoreq.30%,
accompanied by a decrease in RBS of .gtoreq.1 or an absolute rectal
bleeding subscore of .ltoreq.1 in a patient, said method comprising
administering 15 mg or 30 mg of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof to the patient. In one
embodiment, the upadacitinib or a pharmaceutically acceptable salt
or solid state form thereof is administered once daily for at least
36 weeks, including for at least 37 weeks, at least 38 weeks, at
least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42
weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks, at
least 46 weeks, at least 47 weeks, or at least 48 weeks. In one
embodiment the upadacitinib or a pharmaceutically acceptable salt
or solid state form thereof is administered orally. In one
embodiment, the patient has had an inadequate response to or
experienced intolerance to a conventional treatment (e.g.,
aminosalicylates, corticosteroids, immunosuppressants) or to a
previous treatment with a biologic agent and/or an anti-TNF agent.
In one embodiment, the patient is naive to previous treatment with
aminosalicylates, a corticosteroid, an immunosuppressant, a
biologic agent and/or an anti-TNF agent. In one embodiment, the
patient is a refractory patient. In one embodiment, the
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof is a in once-daily, modified release formulation.
[0528] In one embodiment, the present disclosure further provides a
method of maintaining endoscopic improvement or endoscopic
remission of ulcerative colitis in a patient, said method
comprising administering 15 mg or 30 mg of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof to the
patient. In one embodiment, the upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof is administered once
daily for at least 36 weeks, including for at least 37 weeks, at
least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41
weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at
least 45 weeks, at least 46 weeks, at least 47 weeks, or at least
48 weeks. In one embodiment the upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof is administered orally.
In one embodiment, the patient has had an inadequate response to or
experienced intolerance to a conventional treatment (e.g.,
aminosalicylates, corticosteroids, immunosuppressants) or to a
previous treatment with a biologic agent and/or an anti-TNF agent.
In one embodiment, the patient is naive to previous treatment with
aminosalicylates, a corticosteroid, an immunosuppressant, a
biologic agent and/or an anti-TNF agent. In one embodiment, the
patient is a refractory patient. In one embodiment, the
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof is a in once-daily, modified release formulation.
[0529] In one aspect, induction doses for the methods disclosed
herein are administered for 8 weeks in a dose regimen described in
Table 12. In one aspect, induction doses are administered for 8
weeks in a dose regimen described in Table 12. In one aspect,
maintenance doses are administered for 44 weeks or more in a dose
regimen described in Table 12. In one aspect, induction doses for
the methods disclosed herein are administered for 8 weeks and the
maintenance doses are administered for 44 weeks in a dosing regimen
as described in Table 12.
TABLE-US-00012 TABLE 12 Doses and Dosing Regimens (QD) Induction
Frequency of Maintenance Frequency of Dose (mg) induction doses
dose (mg) maintenance dose 7.5 QD 7.5 QD 15 QD 15 QD 30 QD 15 QD 30
QD 30 QD 45 QD 15 QD 45 QD 30 QD
[0530] In one particular embodiment, the induction dose is 45 mg of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof administered QD, and the maintenance dose, and any
additional maintenance dose administered thereafter, is 30 mg of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof administered QD. In another embodiment, the induction
dose is 45 mg of upadacitinib or a pharmaceutically acceptable salt
or solid state form thereof administered QD, and the maintenance
dose, and any additional maintenance dose administered thereafter,
is 15 mg of upadacitinib or a pharmaceutically acceptable salt or
solid state form thereof administered QD. In one embodiment, the
induction dose is 30 mg of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof administered QD, and
the maintenance dose, and any additional maintenance dose
administered thereafter, is 30 mg of upadacitinib or a
pharmaceutically acceptable salt or solid state form thereof
administered QD. In one embodiment, the induction dose is 30 mg of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof administered QD, and the maintenance dose, and any
additional maintenance dose administered thereafter, is 15 mg of
upadacitinib or a pharmaceutically acceptable salt or solid state
form thereof administered QD. In one embodiment, the induction dose
is 30 mg or 45 mg of upadacitinib or a pharmaceutically acceptable
salt or solid state form thereof administered QD, and the
maintenance dose, and any additional maintenance dose administered
thereafter, is 15 mg of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof administered QD. In one
embodiment, the induction dose is 30 mg or 45 mg of upadacitinib or
a pharmaceutically acceptable salt or solid state form thereof
administered QD, and the maintenance dose, and any additional
maintenance dose administered thereafter, is 7.5 mg of upadacitinib
or a pharmaceutically acceptable salt or solid state form thereof
administered QD.
V. Preparation of Upadacitinib
[0531] The synthesis of the compounds of the disclosure, including
(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2--
trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib) and
pharmaceutically acceptable salts thereof is provided in U.S. Pat.
No. 8,426,411, the entire content of which is incorporated herein
by reference. In one embodiment, upadacitinib, and pharmaceutically
acceptable salts thereof, may be synthesized according to the
methods described in U.S. patent application Ser. No. 15/295,561,
which is herein incorporated by referenced. For example,
upadacitinib may be synthesized using synthetic transformations
such as those illustrated in Schemes I-IIIa. Starting materials are
commercially available, may be prepared by the procedures described
in U.S. patent application Ser. No. 15/295,561, by literature
procedures, or by procedures that would be well known to one
skilled in the an of organic chemistry (see, for example, Larock.
R. C. "Comprehensive Organic Transformations: A Guide to Functional
Group Preparations, 2.sup.nd edition", 1999, Wiley-VCH or Greene,
T. W. and Wuts, P. G. M. "Protective Groups in Organic Synthesis,
3.sup.rd Edition", 1999, Wiley-Interscience).
[0532] A process for preparing upadacitinib is illustrated in
Scheme I. Reaction of protected
(3R,4S)-4-ethylpyrrolidine-3-carboxylic acid (I) or a
pharmaceutically acceptable salt thereof with trimethylsulfoxonium
chloride gives sulfur ylide (II). Contacting sulfur ylide (II) with
LiX and a sulfonic acid yields the corresponding halomethyl ketone
(III). Reaction of (III) with (IV) in the presence of a base yields
(V). Cyclization of (V) in the presence of a perfluoro acid
anhydride and an organic base produces (VI). Removal of the
protecting group and contacting the deprotected compound with an
acid yields a pharmaceutically acceptable salt of (VII). Reacting
the pharmaceutically acceptable salt of (VII) with
2,2,2-trifluoroethylamine produces upadacitinib.
##STR00002## ##STR00003##
wherein: [0533] PG is a protecting group; [0534] X is Br or Cl;
[0535] R.sub.1 is selected from the group consisting of alkyl,
aryl, and --OR.sub.2; [0536] R.sub.2 is alkyl; and [0537] Ts is
tosyl.
[0538] The protecting group may be any suitable protecting group
known in the art. In some embodiments, the protecting group is
selected from the group consisting of carboxybenzyl,
p-methoxybenzyl carbonyl, benzyl, p-methoxybenzyl, and
3,4-dimethoxybenzyl. In another embodiment, the protecting group is
carboxybenzyl.
[0539] In another embodiment, R.sub.1 is --OR.sub.2, and R, is
methyl or ethyl. In such embodiments, the compound of formula (IV)
is a compound of formula (IVa):
##STR00004##
wherein R.sub.2 is methyl or ethyl.
[0540] In certain embodiments, a pharmaceutically acceptable salt
of a compound of the compound of formula (I) is used in the
reaction of step (a). In one embodiment, the pharmaceutically
acceptable salt of the compound of formula (I) is selected from the
group consisting of the naphthalenethane amine salt (Ia) and the
dicyclohexylamine salt (Ib)
##STR00005##
wherein Cbz is carboxybenzyl.
[0541] In one embodiment, the pharmaceutically acceptable salt of
compound (VII) is selected from the group consisting of (VIIa),
(VIIb), and (VIIc)
##STR00006##
[0542] Another process for preparing upadacitinib is illustrated in
Scheme Ia. Reaction of
(3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate
dicyclohexylamine salt (Ib) with trimethylsulfoxonium chloride in
the presence of carbonyldiimidazole and a strong base gives sulfur
ylide (IIa). Contacting sulfur ylide (IIa) with lithium bromide and
a sulfonic acid yields the corresponding bromomethyl ketone (IIIa).
Reaction of (IIIa) with alkyl
5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (IVa) in the
presence of lithium tert-butoxide yields (Va). Cyclization of (Va)
in the presence of a perfluoro acid anhydride and an organic base
produces (VIa). Removal of the carboxybenzyl protecting group and
contacting the deprotected compound with hydrochloric acid yields
the pharmaceutically acceptable salt (VIIa). Reacting the
pharmaceutically acceptable salt (VIIa) with
2,2,2-trifluoroethylamine produces upadacitinib.
##STR00007## ##STR00008##
wherein: [0543] Cbz is carboxybenzyl; [0544] Ts is tosyl; and
[0545] R.sub.2 is methyl or ethyl.
[0546] The reaction in step (a) of Schemes I and Ia is generally
accomplished in the presence of a coupling agent, such as
carbonyldiimidazole (CDI) and a strong base. The strong base may
be, for example, potassium tert-butoxide, sodium tert-butoxide, or
combinations thereof. The step (a) reaction may be conducted in any
suitable solvent including, but not limited to, tetrahydrofuran,
water, and methyl ten-butylether. In one embodiment, the reaction
is conducted in the presence of carbonyldiimidazole and potassium
tert-butoxide.
[0547] More particularly, in certain embodiments, a solution of a
compound of formula (I), (Ia), or (Ib) in solvent is slowly added
(e.g., over 30 minutes) to a slurry of CDI in solvent, and the
resulting mixture is stirred at room temperature for 30 minutes to
12 hours, and typically for about 1 hour. The resulting solution is
slowly added (e.g., over 15 minutes) to a suspension of the
trimethylsulfoxonium chloride, strong base, and solvent, while
maintaining the internal temperature below -1.degree. C. In another
embodiment, the reaction is quenched and the resulting compound of
formula (II) or (IIa) is isolated prior to step (b).
[0548] In some embodiments, the reaction of step (a) may further
involve contact of (Ia) or (Ib) with an acid prior to reaction with
the trimethylsulfoxonium chloride, in order to extract the amine to
obtain a compound of formula (I). Suitable acids include any
mineral acid or organic acid, such as phosphoric acid, hydrochloric
acid (HCl), acetic acid (HOAc), citric acid, and the like. The
compound of formula (I) may subsequently be taken up in a suitable
solvent, and reacted with trimethylsulfoxonium chloride, as
described herein. In one embodiment, a pharmaceutically acceptable
salt of a compound of formula (I) is used in step (a), wherein the
pharmaceutically acceptable salt is (Ia) or (Ib).
[0549] In step (b) of Schemes I and Ia, a compound of formula (II)
or (IIa) is contacted with LiX and a sulfonic acid to form a
compound of formula (III) or (IIIa), respectively. In one
embodiment, the sulfonic acid is selected from the group consisting
of methanesulfonic acid and p-toluenesulfonic acid. In one
embodiment, the sulfonic acid is p-toluenesulfonic acid. LiX may be
selected from lithium bromide and lithium chloride. In one
embodiment, LiX is lithium bromide. In one embodiment, the reaction
is conducted in lithium bromide and p-toluenesulfonic acid. The
reaction of step (b) may be conducted in any suitable solvent
including, but not limited to tetrahydrofuran, ethyl acetate,
heptanes, ethanol, water, and combinations thereof.
[0550] More particularly, in certain embodiments, the sulfonic acid
is added to a solution of the compound of formula (II) or (IIa) and
LiX in a solvent. The resulting mixture is warmed to about
35.degree. C. to about 65.degree. C. and stirred overnight. In one
embodiment, the mixture is warmed to about 40.degree. C. and
stirred overnight. The mixture is cooled to room temperature and
washed. The compound of formula (III) or (IIIa) may be isolated, or
optionally used in the next step without purification.
[0551] In step (c) of Schemes I and Ia a compound of formula (III)
or (IIIa) are reacted with a compound of formula (IV) or (IVa)
(prepared as described herein). The step (c) reaction is conducted
in the presence of a base, such as lithium tert-butoxide, sodium
tert-butoxide, or combinations thereof. In one embodiment, the base
is lithium tert-butoxide. The reaction of step (c) may be conducted
in any suitable solvent including, but not limited to
dimethylacetamide, tetrahydrofuran, dichloromethane, ethyl acetate,
heptanes, and combinations thereof.
[0552] More particularly, in certain embodiments, the base is added
to a cooled suspension of the compound of formula (III) or (IIIa)
in a solvent. The resulting solution is stirred for about 30
minutes to about 12 hours, or about 30 minutes, and cooled to about
-20.degree. C. to about 0.degree., or about -10.degree. C. In one
embodiment the solution is stirred for about 30 minutes and cooled
to about -20.degree. C. to about 0.degree.. A solution of a
compound of formula (IV) or (IVa) in a solvent is slowly added
(e.g., over 30 minutes), and the resulting mixture is stirred for
about 30 minutes to about 6 hours, or about 30 minutes, at a
temperature of about -20.degree. C. to about 0.degree. C., or about
-10.degree. C. In one embodiment, following addition of the
solution of the compound of formula (IV) or (IVa) in a solvent, the
resulting mixture is stirred for about 30 minutes at a temperature
of about -10.degree. C. In one embodiment, the reaction is
quenched, and, in some embodiments, the resulting product (V) or
(Va) is isolated prior to step (d).
[0553] In step (d) of Schemes I and Ia, a compound of formula (V)
or (Va) is contacted with a perfluoro acid anhydride and an organic
base to form a compound of formula (VI) or (VIa), respectively.
Non-limiting examples of suitable organic bases include pyridine,
triethylamine, and combinations thereof. Examples of suitable
perfluoro acid anhydrides include trifluoroacetic anhydride,
pentafluoropropionic anhydride, heptafluorobutyric anhydride, and
combinations thereof. In certain embodiments, the organic base is
pyridine and the perfluoro acid anhydride is trifluoroacetic
anhydride. In other embodiments, the organic base is triethylamine,
and the perfluoro acid anhydride is pentafluoropropionic anhydride.
Suitable solvents for use in step (d) include, but are not limited
to acetonitrile, toluene, and combinations thereof.
[0554] More particularly, in certain embodiments, the organic base
and the perfluoro acid anhydride are charged into a solution of a
compound of formula (V) or (Va) in solvent. The resulting mixture
is warmed to about 55.degree. C. to about 75.degree. C., or about
55.degree. C. and stirred for about 4 hours to about 18 hours, or
about 6 hours. In one embodiment, the mixture of perfluoro acid
anhydride and the compound of formula (V) or (Va) is warmed to
about 55.degree. C. and stirred for about 4 hours to about 18
hours. In one embodiment, the mixture is stirred for about 6 hours.
Upon completion of the reaction, in some embodiments, the reaction
mixture may be cooled, and concentrated prior to contacting with a
hydroxide solution to quench excess reagents, and remove the tosyl
protecting group. Suitable hydroxide solutions include a sodium
hydroxide (NaOH) solution, a potassium hydroxide (KOH) solution,
and the like. The resulting mixture may be stirred at room
temperature to about 85.degree. C., including at about 55.degree.
C., for about 30 minutes to about 8 hours. In one embodiment, the
mixture is stirred for about 1 hour. Upon completion, the solvent
may optionally be removed and switched to methanol, ethanol,
isopropanol, or other suitable solvents prior to step (e).
[0555] In step (e) of Schemes I and Ia, a compound of formula (VI)
or (VIa) is deprotected, and a pharmaceutically acceptable salt of
compound (VII), such as (VIIa), (VIIb), or (VIIc) is formed. The
protecting group on the compound of formula (VI) or (VIa) may be
removed using any suitable means known in the art. In one
embodiment, deprotection occurs by contacting the compound of
formula (VI) or (VIa) with palladium on carbon (e.g., Pd/C or
Pd(OH.sub.2)/C) under hydrogen pressure. In other embodiments,
deprotection occurs by contacting the compound of formula (VI) or
(VIa) with an acid. Non-limiting examples of suitable acids include
hydrochloric acid (HCl), hydrobromic acid (HBr), hydrobromic acid
in acetic acid (e.g., HBr/HOAc), and the like. In other
embodiments, deprotection occurs by subjecting the compound of
formula (VI) or (VIa) to heating, e.g., at a temperature of from
room temperature to about 85.degree. C., including about 50.degree.
C. Upon deprotection, the compound of formula (VII) is contacted
with the appropriate acid (e.g., hydrochloric acid or
p-toluenesulfonic acid) to form the pharmaceutically acceptable
salt.
[0556] Step (e) may occur in any suitable solvent including, but
not limited to ethanol, isopropyl acetate, ethyl acetate, and
combinations thereof.
[0557] More particularly, in some embodiments, palladium on carbon
and the compound of formula (VI) or (VIa) in solvent are mixed
under hydrogen pressure at about 1 psig to about 100 psig. In
another embodiment, the hydrogen pressure is about 20 psig. The
mixture is agitated for about 2 hours to about 24 hours, including
about 16 hours, at about 20.degree. C. to about 85.degree. C.,
including about 50.degree. C. In one embodiment, the mixture is
agitated for about 16 hours at about 20.degree. C. to about
80.degree. C. In one embodiment, the mixture is agitated for about
16 hours at about 50.degree. C. Upon completion of the reaction,
the reaction mixture is cooled and filtered, followed by addition
of the appropriate acid. The resulting salt is optionally isolated
prior to step (f).
[0558] In step (f), the salt produced in step (e) is reacted with
2,2,2-trifluoroethylamine to produce upadacitinib. The step (f)
reaction is conducted in the presence of a coupling agent, such as
carbonyldiimidazole (CDT), and optionally buffers, such as
dipotassium phosphate, potassium hydroxide, and combinations
thereof. In one embodiment, the step (f) reaction is conducted in
the presence of CDI, dipotassium phosphate, and potassium
hydroxide. The step (f) reaction may be conducted in any suitable
solvent including, but not limited to, tetrahydrofuran, ethyl
acetate, heptanes, ethanol, water, and combinations thereof.
[0559] More particularly, in certain embodiments,
2,2,2-trifluoroethyl amine is added slowly (e.g., over 20 minutes)
to a slurry of CDI in solvent, while maintaining an internal
temperature of less than 30.degree. C. The resulting solution is
stirred for about 10 minutes to about 12 hours, and in one
embodiment for about 1 hour, to form an imidazolide solution. The
pH of a biphasic mixture of the pharmaceutically acceptable salt
from step (e) in buffer and solvent is adjusted to about 7 to about
11, and in one embodiment to about 9, by addition of a base. The
imidazolide solution is added, and the resulting mixture is mixed
at about 25.degree. C. while maintaining a pH of about 9 by
portionwise addition of base for about 30 minutes to about 18
hours. In one embodiment, the mixture formed after addition of the
imidazolide solution is mixed at about 25.degree. C. while
maintaining a pH of about 9 by portionwise addition of base for
about 1 hour. In one embodiment, upon completion, the reaction is
quenched and the resulting product isolated.
[0560] An alternate process for preparing upadacitinib is
illustrated in Scheme II. Reaction of protected
(3R,4S)-4-ethylpyrrolidine-3-carboxylic acid (I) or a
pharmaceutically acceptable salt thereof with trimethylsulfoxonium
chloride gives sulfur ylide (II). Contacting sulfur ylide (II) with
LiX and a sulfonic acid yields the corresponding halomethyl ketone
(III). Reaction of (III) with (IV) in the presence of a base yields
(V). Cyclization of (V) in the presence of a perfluoro acid
anhydride and an organic base produces (VI). Removal of the
protecting group and contacting the deprotected compound (VII) (not
shown) with hydrochloric acid yields pharmaceutically acceptable
salt (VIIb). The pharmaceutically acceptable salt (VIIb) is
converted to the freebase (VII), which is reacted with
2,2,2-trifluoroethylamine to produce upadacitinib. Upadacitinib is
contacted with L-tartaric acid to form the corresponding tartrate
salt, followed by formation of the upadacitinib freebase.
##STR00009## ##STR00010##
wherein PG, Ts, X, and R1 are as defined above.
[0561] The protecting group may be any suitable protecting group
known in the art. In some embodiments, the protecting group is
selected from the group consisting of carboxybenzyl,
p-methoxybenzyl carbonyl, benzyl, p-methoxybenzyl, and
3,4-dimethoxybenzyl. In one embodiment, the protecting group is
carboxybenzyl.
[0562] In one embodiment, R.sub.1 is --OR.sub.2, and R.sub.2 is
ethyl or methyl.
[0563] In certain embodiments, a pharmaceutically acceptable salt
of the compound of formula (I) is used in the reaction of step (a).
In one embodiment, the pharmaceutically acceptable salt of the
compound of formula (I) is selected from the group consisting of
the naphthalenethane amine salt (Ia) and the dicyclohexylamine salt
(Ib).
[0564] Steps (a)-(e) of Scheme II are conducted as described above
for Scheme I, wherein following deprotection of the compound of
formula (VI), deprotected compound (VII) is contacted with
hydrochloric acid to form pharmaceutically acceptable salt
(VIIb).
[0565] In step (f) of Scheme II, salt (VIIb) is contacted with a
base to form the corresponding freebase (VII). Suitable bases
include, but are not limited to hydroxides, such as sodium
hydroxide, potassium hydroxide, and the like, and combinations
thereof. In one embodiment, the base is sodium hydroxide. The
reaction of step (f) may be conducted in any suitable
water-containing solvent including, but not limited to, water alone
or in combination with THF, 2-methyl tetrahydrofuran, ethanol,
methanol, and the like.
[0566] In step (g) compound (VII) is reacted with
2,2,2-trifluoroethylamine to produce upadacitinib. The step (g)
reaction is conducted in the presence of a coupling agent, such as
CDI. Step (g) in Scheme II is conducted using similar reagents and
under similar conditions as those set forth above for step (f) of
Scheme I.
[0567] In step (h) of Scheme II, upadacitinib is contacted with
L-tartaric acid to form the corresponding tartrate salt (step (h)).
Formation of the tartrate salt advantageously aids in removal of
impurities prior to isolation of the freebase. The tartrate salt is
subsequently converted back to the freebase form (step (i)) to
produce upadacitinib. In particular, in step (i) the tartrate salt
may be contacted with a base, such as an inorganic base, to produce
the corresponding freebase. Suitable bases include, but are not
limited to, sodium bicarbonate, sodium carbonate, sodium hydroxide,
potassium carbonate, potassium bicarbonate, potassium hydroxide,
and the like, or combinations thereof. In one embodiment, the
tartrate salt is contacted with sodium bicarbonate and sodium
carbonate to produce the corresponding freebase.
[0568] Suitable solvents for use in step (h) include, but are not
limited to, isopropyl acetate, methyl tert-butyl ether, water,
isopropyl alcohol, and combinations thereof. Suitable solvents for
use in step (i) include, but are not limited to, ethyl acetate,
ethanol, water, and combinations thereof.
[0569] In some embodiments, the products of steps (d), (e), (g),
and (h) of Scheme II are not isolated prior to the subsequent
step.
[0570] An alternate process for preparing upadacitinib is
illustrated in Scheme III. Compound (XIa) is hydrogenated to
produce (I). Reaction of protected
(3R,4S)-4-ethylpyrrolidine-3-carboxylic acid (I) with
trimethylsulfoxonium chloride gives sulfur yilde (II). Contacting
sulfur yilde (II) with an anhydrous source of HBr or HCl yields the
corresponding halomethyl ketone (III). Reaction of (III) with (IV)
in the presence of a base yields (V). Cyclization of (V) in the
presence of a perfluoro acid anhydride and an organic base produces
(VI). Removal of the protecting group and contacting the
deprotected compound with an acid yields a pharmaceutically
acceptable salt of (VII). Reacting the pharmaceutically acceptable
salt of (VII) with 2,2,2-trifluoroethylamine produces
upadacitinib.
##STR00011## ##STR00012##
wherein: [0571] PG is a protecting group; X is Br or Cl; [0572]
R.sub.1 is selected from the group consisting of alkyl, aryl, and
--OR.sub.2; [0573] R.sub.2 is alkyl; and Ts is tosyl.
[0574] The protecting group may be any suitable protecting group
known in the art. In some embodiments, the protecting group is
selected from the group consisting of carboxybenzyl,
p-methoxybenzyl carbonyl, benzyl, p-methoxybenzyl, and
3,4-dimethoxybenzyl. In another embodiment, the protecting group is
carboxybenzyl.
[0575] In another embodiment, R.sub.1 is --OR.sub.2, and R.sub.2 is
methyl or ethyl. In such embodiments, the compound of formula (IV)
is a compound of formula (IVa):
##STR00013##
wherein R.sub.2 is methyl or ethyl. It has surprisingly been
discovered that when R.sub.2 is ethyl or methyl, the compound of
formula (V) and subsequent downstream compounds can be isolated as
crystalline solids, which aids in purification of these
intermediates. In contrast, previously known processes, which use
compounds where R.sub.2 is t-butyl, result in formation of
compounds of formula (V) which are isolated as amorphous
solids.
[0576] Another process for preparing upadacitinib is illustrated in
Scheme IIIa.
1-((benzyloxy)carbonyl)-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic
acid (XI) is hydrogenated to produce (XII). Reaction of
(3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate
(XII) with trimethylsulfoxonium chloride gives sulfur yilde (IIa).
Contacting sulfur yilde (IIa) with an anhydrous source of HBr
yields the corresponding bromomethyl ketone (IIIa). Reaction of
(IIIa) with alkyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-ylcarbamate
(IVa) in the presence of lithium tert-butoxide yields (Va).
Cyclization of (Va) in the presence of a perfluoro acid anhydride
and an organic base produces (VIa). Removal of the carboxybenzyl
protecting group and contacting the deprotected compound with
hydrochloric acid yields the pharmaceutically acceptable salt
(VIIa). Reacting the pharmaceutically acceptable salt (VIIa) with
2,2,2-trifluoroethylamine produces upadacitinib.
##STR00014## ##STR00015##
wherein: [0577] Cbz is carboxybenzyl; Ts is tosyl; and R.sub.2 is
methyl or ethyl.
[0578] In step (a) of Schemes III and IIIa, (XIa) or (XI) (which
may be prepared as described in Scheme V) is converted to (I) or
(XII), respectively. In particular, in step (a), compound (XI) or
(XIa) may be contacted with a catalyst, such as a ruthenium
catalyst. Any catalyst comprising a chiral phosphine may be used.
One particular example of a suitable catalyst is
diacetato[(S)-(-)5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole]rut-
henium(II) (i.e., (S)-Segphos Ru(OAc).sub.2). Suitable solvents for
use in step (a) include, but are not limited to, methanol,
triethylamine, and combinations thereof.
[0579] In particular, in certain embodiments, a solution of (XI) or
(XIa) and the catalyst in solvent is hydrogenated at about
30.degree. C. to about 100.degree. C. for from about 1 hour to
about 18 hours. In one embodiment, the solution of (XI) or (XIa)
and the catalyst in solvent is hydrogenated at about 580 psi. In
one embodiment, the solution of (XI) or (XIa) and the catalyst in
solvent is hydrogenated at about 200 psi gauge (psig). In one
embodiment, the solution of (XI) or (XIa) and the catalyst in
solvent is hydrogenated at about 80.degree. C. for from about 1
hour to about 8 hours, or for about 2 hours, or for about 4 hours.
Upon completion, the reaction mixture is cooled to room
temperature, filtered, and concentrated.
[0580] The reaction in step (b) of Schemes III and IIIa, is
generally accomplished in the presence of a coupling agent, such as
carbonyldiimidazole (CDI), and a strong base. The strong base may
be, for example, potassium tert-butoxide, sodium tert-butoxide, or
combinations thereof. The step (b) reaction may be conducted in any
suitable solvent including, but not limited to, tetrahydrofuran,
water, and methyl tert-butyl ether. In one embodiment, the reaction
is conducted in the presence of carbonyldiimidazole and potassium
tert-butoxide.
[0581] More particularly, in certain embodiments, a suspension of
trimethylsulfoxonium chloride, strong base, and solvent is heated
(e.g., to about 35.degree. C. to about 65.degree. C., or to about
45.degree. C.) for about 30 minutes to about 8 hours, or for about
1 hour, followed by cooling. In one embodiment, the suspension is
cooled to a temperature of about -1.degree. C. or less, or to about
-5.degree. C. or less. In some embodiments, the concentrated
filtrate from step (a) is diluted with a suitable solvent (e.g.,
tetrahydrofuran), and to this solution is slowly added (e.g., over
30 minutes to 1 hour, or over 30 minutes) CDI. The resulting
mixture is stirred at room temperature for 30 minutes to 12 hours,
and typically for about 1 hour. The resulting solution is slowly
added (e.g., over 15 minutes to 1 hour, or over 1 hour) to the
suspension of the trimethylsulfoxonium chloride, strong base, and
solvent, while maintaining the internal temperature below
-1.degree. C. In embodiments, the reaction may be stirred for about
30 minutes to about 8 hours, or for about 1 hour at a temperature
of below about -1.degree. C., or at about -5.degree. C. In another
embodiment the reaction is quenched and the resulting compound of
formula (II) or (IIa) is isolated prior to step (c).
[0582] Steps (a) and (b) of Schemes III and IIIa advantageously
allow for preparation of a protected
(3R,4S)-4-ethylpyrrolidine-3-carboxylic acid without formation and
isolation of the naphthalenethane amine salt (Ia) or the
dicyclohexylamine salt (Ib), or isolation of (I) or (XI).
[0583] In step (c) of Schemes III and IIIa, a compound of formula
(II) or (IIa) is contacted with an anhydrous source of HBr or HCl
to form a compound of formula (III) or (IIIa), respectively. In
particular, the anhydrous source of HBr or HCl comprises no more
than 0.2% water (by volume), or no more than about 0.15% water (by
volume). The reaction of step (c) may be conducted in any suitable
solvent including, tetrahydrofuran.
[0584] More particularly, in certain embodiments, (II) or (IIa) is
combined with the HBr or HCl in a suitable solvent. In one
embodiment, the solvents are tetrahydrofuran and acetic acid. In
one embodiment, the solvent comprises no more than 0.2% water (by
volume). In one embodiment, (II) or (IIa) is combined with a
solvent (e.g., THF) and a solution of HBr in HOAc. The resulting
mixture is warmed to about 35.degree. C. to about 65.degree. C., or
about 40.degree. C. and agitated. In one embodiment, the mixture is
agitated for about 4 to about 12 hours, or for about 5 hours. In
one embodiment, the mixture is warmed to about 40.degree. C. and
agitated (e.g., stirred) for about 5 hours. In one embodiment, the
mixture is cooled to room temperature (e.g., around 20.degree. C.)
and distilled, followed by washing. In one particular embodiment,
the product (compound (III) or (IIIa)) is concentrated to dryness,
and resuspended in a solvent (e.g., N,N-dimethylacetamide) to form
a solution of (III) or (IIIa) for use in step (d).
[0585] Step (c) advantageously produces the halomethyl ketone (III)
or (IIIa) in higher purity than Scheme I or Ia.
[0586] In step (d) of Schemes III and IIIa, a compound of formula
(III) or (IIIa) is reacted with a compound of formula (IV) or (IVa)
(prepared as described herein). The step (d) reaction is conducted
in the presence of a base, such as lithium tert-butoxide, sodium
tert-butoxide, or combinations thereof. In one embodiment, the base
is lithium tert-butoxide. The reaction of step (d) may be conducted
in any suitable solvent including, but not limited to
dimethylacetamide, tetrahydrofuran, dichloromethane, ethyl acetate,
heptanes, and combinations thereof.
[0587] More particularly, in certain embodiments, the base is
slowly added (e.g., over about 30 minutes) to a cooled suspension
of the compound of formula (IV) or (IVa) in a solvent. In one
embodiment, the suspension of the compound of formula (IV) or (IVa)
is cooled to about 0.degree. C. The resulting solution is stirred
for about 30 minutes to about 12 hours, or about 30 minutes, and
cooled to about -20.degree. C. to about 0.degree. C., or about
-10.degree. C. In one embodiment, the solution is stirred for about
30 minutes and cooled to about -20.degree. C. to about 0.degree. C.
or about -10.degree. C. The halomethyl ketone solution prepared in
step (c) is then slowly added (e.g., over about 1 hour), and the
resulting mixture is agitated (e.g., stirred) for about 30 minutes
to about 6 hours, or about 30 minutes, at a temperature of about
-20.degree. C. to about 0.degree. C., or about -10.degree. C. In
one embodiment, following addition of the step (c) solution, the
resulting mixture is stirred for about 30 minutes at a temperature
of about -10.degree. C. In one embodiment, the reaction is
quenched, and, in some embodiments, the resulting product (V) or
(Va) is isolated prior to step (e).
[0588] Steps (e)-(g) of Schemes III and IIIa may be conducted as
described above for steps (d)-(f) of Scheme I, respectively.
VI. Solid State Forms
[0589] The present disclosure also relates to the use of solid
state forms of upadacitinib in the treatment of Crohn's disease and
ulcerative colitis. Solid state forms include the Amorphous
Freebase form of upadacitinib, Freebase Solvate Form A. Freebase
Hydrate Form B, Freebase Hydrate Form C, Tartrate Hydrate, and
Freebase Anhydrate Form D. These and other solid state forms of
upadacitinib are described in U.S. patent application Ser. No.
15/295,561, which is herein incorporated by reference. The sections
below also discuss solid state forms that have been identified and
selected properties of those solid state forms.
[0590] A. Amorphous Freebase
[0591] In one embodiment, the solid state form is amorphous
upadacitinib (the "Amorphous Freebase"). In one aspect, the
Amorphous Freebase comprises less than about 13% by weight water.
In another aspect, the Amorphous Freebase comprises less than about
12% by weight water. In another aspect, the Amorphous Freebase
comprises less than about 10% by weight water. In another aspect,
the Amorphous Freebase comprises less than about 9% by weight
water. In another aspect, the Amorphous Freebase comprises less
than about 8% by weight water. In another aspect, the Amorphous
Freebase comprises less than about 7% by weight water. In another
aspect, the Amorphous Freebase comprises less than about 6% by
weight water. In another aspect, the Amorphous Freebase comprises
less than about 5% by weight water. In another aspect, the
Amorphous Freebase comprises less than about 4% by weight water. In
another aspect, the Amorphous Freebase comprises less than about 3%
by weight water. In another aspect, the Amorphous Freebase
comprises less than about 2% by weight water. In another aspect,
the Amorphous Freebase comprises less than about 1% by weight
water. In another aspect, the Amorphous Freebase has a glass
transition temperature onset at about 119.degree. C. In another
aspect, the Amorphous Freebase has a glass transition temperature
midpoint at about 122.degree. C. In another aspect, the Amorphous
Freebase has a glass transition temperature onset at about
119.degree. C. and a glass transition temperature midpoint at about
122.degree. C.
[0592] The Amorphous Freebase generally has greater solubility, and
increased bioavailability, relative to the corresponding
crystalline forms of the compound. The Amorphous Freebase also has
acceptable chemical stability. In addition, the Amorphous Freebase
exhibits acceptable stability to light and peroxide. The Amorphous
Freebase, however, is hygroscopic and can comprise as much as 12%
by weight water at 25.degree. C./90% relative humidity.
Environmental controls potentially are required to ensure
appropriate control of potency and water content during storage,
dispensing, and handling of the Amorphous Freebase.
[0593] The Amorphous Freebase can be prepared, for example, using
anti-solvent crystallization to prepare the Freebase Solvate Form A
or Freebase Hydrate Form B (described below) followed by
dehydration or desolvation to yield the Amorphous Freebase. This
crystallization/dehydration/desolvation method allows for the
large-scale manufacture of the Amorphous Freebase without the need
for labor-intensive and expensive techniques such as spray-drying.
It also provides for appropriate control of the bulk properties of
the Amorphous Freebase (i.e., particle size, flow properties etc.).
When the Amorphous Freebase is prepared by desolvation of the
Freebase Solvate Form A or dehydration of the Freebase Hydrate Form
B, the Amorphous Freebase generally retains the morphology of the
Freebase Solvate Form A or Freebase Hydrate Form B (i.e., blades
with hexagonal crystal faces when prepared by dehydration of
Freebase Hydrate Form B, or irregular when desolvated from Freebase
Solvate Form A).
[0594] The process volumes required for crystallization during the
large-scale manufacture of the Freebase Solvate Form A or Freebase
Hydrate Form B generally are within conventional processing
volumes, but impurity rejection potentially may be lower than
desired. Drying and dehydration/desolvation of the Freebase Hydrate
Form B/Freebase Solvate Form A to the Amorphous Freebase generally
can be carried out with standard equipment under conventional
conditions and the isolated Amorphous Freebase typically can be
co-milled without adversely impacting the amorphous state.
[0595] B. Crystalline Freebase Solvates and Hydrates
[0596] In another embodiment, the solid state form is a crystalline
freebase of upadacitinib. In one aspect, the crystalline freebase
is a solvate. In another aspect, the crystalline freebase is an
isopropyl acetate/water solvate (the "Freebase Solvate Form A"). In
another aspect, the crystalline freebase is a hydrate (the
"Freebase Hydrate Form B"). The Freebase Solvate Form A and the
Freebase Hydrate Form B are further described in the Examples of
the application.
[0597] In one embodiment, the crystalline freebase solvate or
hydrate has an X-ray powder diffraction pattern characterized by
peaks at 3.1.+-.0.2, 9.3.+-.0.2, and 12.0.+-.0.2 degrees two theta
when measured at about 25.degree. C. with monochromatic K.alpha.1
radiation.
[0598] In one embodiment, the crystalline freebase solvate or
hydrate has an X-ray powder diffraction pattern characterized by
peaks at 3.1.+-.0.2, 9.3.+-.0.2, and 12.0.+-.0.2 degrees two theta,
and that is further characterized by a peak at one or more of
13.7.+-.0.2, 20.8.+-.0.2 and 25.0.+-.0.2 degrees two theta when
measured at about 25.degree. C. with monochromatic K.alpha.1
radiation.
[0599] In one embodiment, the crystalline freebase solvate or
hydrate has an X-ray powder diffraction pattern characterized by
peaks at 3.1.+-.0.2, 9.3.+-.0.2, 12.0.+-.0.2, and 20.8.+-.0.2
degrees two theta, when measured at about 25.degree. C. with
monochromatic K.alpha.1 radiation.
[0600] In one embodiment, the crystalline freebase solvate or
hydrate has an X-ray powder diffraction pattern characterized by
peaks at 3.1.+-.0.2, 9.3.+-.0.2, 12.0.+-.0.2, and 25.0.+-.0.2
degrees two theta, when measured at about 25.degree. C. with
monochromatic K.alpha.1 radiation.
[0601] In one embodiment, the crystalline freebase solvate or
hydrate has an X-ray powder diffraction pattern characterized by
peaks at 3.1.+-.0.2, 9.3.+-.0.2, 12.0.+-.0.2, 20.8.+-.0.2, and
25.0.+-.0.2 degrees two theta, when measured at about 25.degree. C.
with monochromatic K.alpha.1 radiation.
[0602] In one embodiment, the crystalline freebase solvate or
hydrate has an X-ray powder diffraction pattern characterized by
peaks at 3.1.+-.0.2, 9.3.+-.0.2, 12.0.+-.0.2, 13.7.+-.0.2,
20.8.+-.0.2, and 25.0.+-.0.2 degrees two theta when measured at
about 25.degree. C. with monochromatic K.alpha.1 radiation.
[0603] In one embodiment, the crystalline freebase solvate or
hydrate has an X-ray powder diffraction pattern without a
significant peak at one or more of 15.1.+-.0.2, and 21.7.+-.0.2
degrees two theta when measured at about 25.degree. C. with
monochromatic K.alpha.1 radiation.
[0604] In one embodiment, the crystalline freebase solvate or
hydrate has an X-ray powder diffraction pattern without a
significant peak at one or more of 3.9.+-.0.2, 6.8.+-.0.2, and
14.1.+-.0.2 degrees two theta when measured at about 25.degree. C.
with monochromatic K.alpha.1 radiation.
[0605] In one embodiment, the crystalline freebase solvate or
hydrate has an X-ray powder diffraction pattern without a
significant peak at one or more of 15.1-0.2, and 21.7.+-.0.2
degrees two theta, and without a significant peak at one or more of
3.9.+-.0.2, 6.8.+-.0.2, and 14.1.+-.0.2 degrees two theta, when
measured at about 25.degree. C. with monochromatic K.alpha.1
radiation.
[0606] In one embodiment, the crystalline freebase solvate or
hydrate has an X-ray powder diffraction pattern characterized by
peaks at 3.1.+-.0.2, 9.3.+-.0.2, and 12.0.+-.0.2 degrees two theta,
and without a significant peak at one or more of 15.1.+-.0.2, and
21.7.+-.0.2 degrees two theta, when measured at about 25.degree. C.
with monochromatic K.alpha.1 radiation.
[0607] In one embodiment, the crystalline freebase solvate or
hydrate has an X-ray powder diffraction pattern characterized by
peaks at 3.1.+-.0.2, 9.3.+-.0.2, and 12.0.+-.0.2 degrees two theta,
and without a significant peak at one or more of 3.9.+-.0.2,
6.8.+-.0.2, and 14.1.+-.0.2 degrees two theta, when measured at
about 25.degree. C. with monochromatic K.alpha.1 radiation.
[0608] In one embodiment, the crystalline freebase solvate or
hydrate has an X-ray powder diffraction pattern characterized by
peaks at 3.1.+-.0.2, 9.3.+-.0.2, and 12.0.+-.0.2 degrees two theta,
and without a significant peak at one or more of 15.1.+-.0.2, and
21.7.+-.0.2 degrees two theta, and without a significant peak at
one or more of 3.9.+-.0.2, 6.8.+-.0.2, and 14.1.+-.0.2 degrees two
theta, when measured at about 25.degree. C. with monochromatic
K.alpha.1 radiation.
[0609] In one embodiment, the crystalline freebase solvate or
hydrate has an X-ray powder diffraction pattern characterized by
peaks at 3.1.+-.0.2, 9.3.+-.0.2, and 12.0.+-.0.2, 13.7.+-.0.2,
20.8.+-.0.2, and 25.0.+-.0.2 degrees two theta, and without a
significant peak at one or more of 15.1.+-.0.2, and 21.7.+-.0.2
degrees two theta, when measured at about 25.degree. C. with
monochromatic K.alpha.1 radiation.
[0610] In one embodiment, the crystalline freebase solvate or
hydrate has an X-ray powder diffraction pattern characterized by
peaks at 3.1.+-.0.2, 9.3.+-.0.2, and 12.0.+-.0.2, 13.7.+-.0.2,
20.8.+-.0.2, and 25.0.+-.0.2 degrees two theta, and without a
significant peak at one or more of 3.9.+-.0.2, 6.8.+-.0.2, and
14.1.+-.0.2 degrees two theta, when measured at about 25.degree. C.
with monochromatic K.alpha.1 radiation.
[0611] In one embodiment, the crystalline freebase solvate or
hydrate has an X-ray powder diffraction pattern characterized by
peaks at 3.1.+-.0.2, 9.3.+-.0.2, and 12.0.+-.0.2, 13.7.+-.0.2,
20.8.+-.0.2, and 25.0.+-.0.2 degrees two theta, and without a
significant peak at one or more of 15.1.+-.0.2, and 21.7.+-.0.2
degrees two theta, and without a significant peak at one or more of
3.9.+-.0.2, 6.8.+-.0.2, and 14.1.+-.0.2 degrees two theta, when
measured at about 25.degree. C. with monochromatic K.alpha.1
radiation.
[0612] In one embodiment, the crystalline freebase solvate or
hydrate has an X-ray powder diffraction pattern characterized by
peaks substantially at the positions listed in Table 14-A.+-.0.2
degrees two theta, when measured at about 25.degree. C. with
monochromatic K.alpha.1 radiation.
[0613] In one embodiment, the crystalline freebase solvate or
hydrate has an X-ray powder diffraction pattern characterized by
peaks substantially at the positions listed in Table 14-B.+-.0.2
degrees two theta, when measured at about 25.degree. C. with
monochromatic K.alpha.1 radiation.
[0614] In one embodiment, the crystalline freebase solvate or
hydrate has an X-ray powder diffraction pattern characterized by
peaks substantially at the positions listed in Table 16-B.+-.0.2
degrees two theta that have a relative intensity of at least 10.0%,
when measured at about 25.degree. C. with monochromatic K.alpha.1
radiation.
[0615] In further aspects of each of the above embodiments, the
significant peak values have a variation of .+-.0.1 degrees two
theta rather than .+-.0.2 degrees two theta. In still further
aspects of each of the above embodiments, the significant peak
values have a variation of .+-.0.05 degrees two theta rather than
.+-.0.2 degrees two theta.
[0616] In one embodiment, the crystalline freebase has an X-ray
powder diffraction pattern substantially as shown in FIG. 19.
[0617] The Freebase Solvate Form A and Freebase Hydrate Form B are
not physically stable. As discussed above, they desolvate (or
dehydrate) and convert to the Amorphous Freebase upon drying.
Although the Freebase Solvate Form A and Freebase Hydrate Form B
generally do not exhibit pharmaceutically acceptable physical
stability for use as an active ingredient in a pharmaceutical
dosage form, they are useful intermediates in the preparation of
other solid state forms such as the Amorphous Freebase.
[0618] C. Crystalline Freebase Hydrate Form C (Hemihydrate)
[0619] In another embodiment, the solid state form is a crystalline
hydrate, wherein the crystalline hydrate is a hemihydrate. In
another embodiment, the solid state form is crystalline hemihydrate
of upadacitinib having a powder X-ray diffraction pattern
corresponding to Freebase Hydrate Form C. The Freebase Hydrate Form
C is further described in the Examples of the application.
[0620] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern characterized by peaks at 13.4.+-.0.2,
15.1.+-.0.2, and 21.7.+-.0.2 degrees two theta when measured at
about 25.degree. C. with monochromatic K.alpha.1 radiation.
[0621] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern characterized by peaks at 13.4.+-.0.2,
15.1.+-.0.2, and 21.7.+-.0.2 degrees two theta, and that is further
characterized by a peak at one or more of 7.7.+-.0.2, 7.9.+-.0.2,
9.6.+-.0.2, 10.3.+-.0.2, 13.9.+-.0.2, 15.5.+-.0.2, 15.9.+-.0.2,
17.0.+-.0.2, 17.2.+-.0.2, 17.8.+-.0.2, 18.1.+-.0.2, 18.3.+-.0.2,
19.3.+-.0.2, 19.7.+-.0.2, 20.5.+-.0.2, 20.9.+-.0.2, 21.9.+-.0.2,
22.2.+-.0.2, 23.5.+-.0.2, 24.4.+-.0.2, 24.9.+-.0.2, 28.2.+-.0.2,
and 29.5.+-.0.2 degrees two theta when measured at about 25.degree.
C. with monochromatic K.alpha.1 radiation.
[0622] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern that is characterized by peaks at
13.4.+-.0.2, 15.1.+-.0.2, 15.5.+-.0.2, and 21.7.+-.0.2 degrees two
theta when measured at about 25.degree. C. with monochromatic
K.alpha.1 radiation.
[0623] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern that is characterized by peaks at
13.4.+-.0.2, 15.1.+-.0.2, 17.0.+-.0.2, and 21.7.+-.0.2 degrees two
theta when measured at about 25.degree. C. with monochromatic
K.alpha.1 radiation.
[0624] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern that is characterized by peaks at
13.4.+-.0.2, 15.1.+-.0.2, 20.9.+-.0.2, and 21.7.+-.0.2 degrees two
theta when measured at about 25.degree. C. with monochromatic
K.alpha.1 radiation.
[0625] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern that is characterized by peaks at
13.4.+-.0.2, 15.1.+-.0.2, 15.5.+-.0.2, 17.0.+-.0.2, 20.9.+-.0.2,
and 21.7.+-.0.2 degrees two theta when measured at about 25.degree.
C. with monochromatic K.alpha.1 radiation.
[0626] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern characterized by peaks at 15.5.+-.0.2,
13.4.+-.0.2, 15.1.+-.0.2, 19.3.+-.0.2, 20.5.+-.0.2, and 21.7.+-.0.2
degrees two theta when measured at about 25.degree. C. with
monochromatic K.alpha.1 radiation.
[0627] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern without a significant peak at one or
more of 3.1.+-.0.2, 9.3.+-.0.2, and 12.0.+-.0.2 degrees two theta,
when measured at about 25.degree. C. with monochromatic K.alpha.1
radiation.
[0628] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern without a significant peak at one or
more of 3.9.+-.0.2, 6.8.+-.0.2, and 14.1.+-.0.2 degrees two theta,
when measured at about 25.degree. C. with monochromatic K.alpha.1
radiation.
[0629] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern without a significant peak at one or
more of 3.1.+-.0.2, 9.3.+-.0.2, and 12.0.+-.0.2 degrees two theta,
and without a significant peak at one or more of 3.9.+-.0.2,
6.8.+-.0.2, and 14.1.+-.0.2 degrees two theta, when measured at
about 25.degree. C. with monochromatic K.alpha.1 radiation.
[0630] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern characterized by peaks at 13.4.+-.0.2,
15.1.+-.0.2, and 21.7.+-.0.2 degrees two theta, and without a
significant peak at one or more of 3.1.+-.0.2, 9.3.+-.0.2, and
12.0.+-.0.2 degrees two theta, when measured at about 25.degree. C.
with monochromatic K.alpha.1 radiation.
[0631] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern characterized by peaks at 13.4.+-.0.2,
15.1.+-.0.2, and 21.7.+-.0.2 degrees two theta, and without a
significant peak at one or more of 3.9.+-.0.2, 6.8.+-.0.2, and
14.1.+-.0.2 degrees two theta, when measured at about 25.degree. C.
with monochromatic K.alpha.1 radiation.
[0632] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern characterized by peaks at 13.4.+-.0.2,
15.1.+-.0.2, and 21.7.+-.0.2 degrees two theta, and without a
significant peak at one or more of 3.1.+-.0.2, 9.3.+-.0.2, and
12.0.+-.0.2 degrees two theta, and without a significant peak at
one or more of 3.9.+-.0.2, 6.8.+-.0.2, and 14.1.+-.0.2 degrees two
theta, when measured at about 25.degree. C. with monochromatic
K.alpha.1 radiation.
[0633] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern characterized by peaks at 15.5.+-.0.2,
13.4.+-.0.2, 15.1.+-.0.2, 19.3.+-.0.2, 20.5.+-.0.2, and 21.7.+-.0.2
degrees two theta, and without a significant peak at one or more of
3.1.+-.0.2, 9.3.+-.0.2, and 12.0.+-.0.2 degrees two theta, when
measured at about 25.degree. C. with monochromatic K.alpha.1
radiation.
[0634] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern characterized by peaks at 15.5.+-.0.2,
13.4.+-.0.2, 15.1.+-.0.2, 19.3.+-.0.2, 20.5.+-.0.2, and 21.7.+-.0.2
degrees two theta, and without a significant peak at one or more of
3.9.+-.0.2, 6.8.+-.0.2, and 14.1.+-.0.2 degrees two theta, when
measured at about 25.degree. C. with monochromatic K.alpha.1
radiation.
[0635] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern characterized by peaks at 15.5.+-.0.2,
13.4.+-.0.2, 15.1.+-.0.2, 19.3.+-.0.2, 20.5.+-.0.2, and 21.7.+-.0.2
degrees two theta, and without a significant peak at one or more of
3.1.+-.0.2, 9.3.+-.0.2, and 12.0.+-.0.2 degrees two theta, and
without a significant peak at one or more of 3.9.+-.0.2,
6.8.+-.0.2, and 14.1.+-.0.2 degrees two theta, when measured at
about 25.degree. C. with monochromatic K.alpha.1 radiation.
[0636] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern characterized by peaks substantially at
the positions listed in Table 14-C.+-.0.2 degrees two theta, when
measured at about 25.degree. C. with monochromatic K.alpha.1
radiation.
[0637] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern characterized by peaks substantially at
the positions listed in Table 16-C.+-.0.2 degrees two theta that
have a relative intensity of at least 10.0%, when measured at about
25.degree. C. with monochromatic K.alpha.1 radiation.
[0638] In further aspects of each of the above embodiments, the
significant peak values have a variation of .+-.0.1 degrees two
theta rather than .+-.0.2 degrees two theta. In still further
aspects of each of the above embodiments, the significant peak
values have a variation of .+-.0.05 degrees two theta rather than
.+-.0.2 degrees two theta.
[0639] In one embodiment, the Freebase Hydrate Form C has an X-ray
powder diffraction pattern substantially as shown in FIG. 20 when
measured at about 25.degree. C. with monochromatic K.alpha.1
radiation.
[0640] The Freebase Hydrate Form C generally exhibits good chemical
stability, physical stability, and solid state properties
(including low hygroscopicity). Large-scale manufacture of the
Freebase Hydrate Form C is relatively straightforward with minimal
scaling, good yield, good impurity rejection, fast filtration,
conventional drying, and minimal milling issues (even after
subjecting the isolated material to high energy pinmilling). In
addition, different particle sizes can be achieved through
appropriate control of the crystallization process.
[0641] D. Crystalline Freebase Anhydrate Form D
[0642] In another embodiment, the solid state form is a crystalline
anhydrate freebase of upadacitinib having a powder X-ray
diffraction pattern corresponding to Freebase Anhydrate Form D. The
Freebase Anhydrate Form D is further described in the Examples of
the application.
[0643] In one embodiment the Freebase Anhydrate Form D has an X-ray
powder diffraction pattern characterized by peaks at 8.0.+-.0.2,
9.7.+-.0.2, 14.2.+-.0.2, 14.5.+-.0.2, and 20.3.+-.0.2 degrees two
theta when measured at about 25.degree. C. with monochromatic
K.alpha.1 radiation.
[0644] In one embodiment, the Freebase Anhydrate Form D has an
X-ray powder diffraction pattern characterized by peaks at
8.0.+-.0.2, 9.7.+-.0.2, 14.2.+-.0.2, 14.5.+-.0.2, and 20.3.+-.0.2
degrees two theta, and that is further characterized by a peak at
one or more of 4.0.+-.0.2, 18.4.+-.0.2, 19.0.+-.0.2, 23.0.+-.0.2,
and 24.7.+-.0.2 degrees two theta, when measured at about
25.degree. C. with monochromatic K.alpha.1 radiation.
[0645] In one embodiment, the Freebase Anhydrate Form D has an
X-ray powder diffraction pattern characterized by peaks at
4.0.+-.0.2, 8.0.+-.0.2, 9.7.+-.0.2, 14.2.+-.0.2, 14.5.+-.0.2, and
20.3.+-.0.2 degrees two theta, when measured at about 25.degree. C.
with monochromatic K.alpha.1 radiation.
[0646] In one embodiment, the Freebase Anhydrate Form D has an
X-ray powder diffraction pattern characterized by peaks at
8.0.+-.0.2, 9.7.+-.0.2, 14.2.+-.0.2, 14.5.+-.0.2, 18.4.+-.0.2 and
20.3.+-.0.2 degrees two theta, when measured at about 25.degree. C.
with monochromatic K.alpha.1 radiation.
[0647] In one embodiment, the Freebase Anhydrate Form D has an
X-ray powder diffraction pattern characterized by peaks at
8.0.+-.0.2, 9.7.+-.0.2, 14.2.+-.0.2, 14.5.+-.0.2, 19.0.+-.0.2 and
20.3.+-.0.2 degrees two theta, when measured at about 25.degree. C.
with monochromatic K.alpha.1 radiation.
[0648] In one embodiment, the Freebase Anhydrate Form D has an
X-ray powder diffraction pattern characterized by peaks at
4.0.+-.0.2, 8.0.+-.0.2, 9.7.+-.0.2, 14.2.+-.0.2, 14.5.+-.0.2,
19.0.+-.0.2 and 20.3.+-.0.2 degrees two theta, when measured at
about 25.degree. C. with monochromatic K.alpha.1 radiation.
[0649] In one embodiment, the Freebase Anhydrate Form D has an
X-ray powder diffraction pattern characterized by peaks at
8.0.+-.0.2, 9.7.+-.0.2, 14.2.+-.0.2, 14.5.+-.0.2, 20.3.+-.0.2, and
23.0.+-.0.2 degrees two theta, when measured at about 25.degree. C.
with monochromatic K.alpha.1 radiation.
[0650] In one embodiment, the Freebase Anhydrate Form D has an
X-ray powder diffraction pattern characterized by peaks at
8.0.+-.0.2, 9.7.+-.0.2, 14.2.+-.0.2, 14.5.+-.0.2, 20.3.+-.0.2, and
24.7.+-.0.2 degrees two theta, when measured at about 25.degree. C.
with monochromatic K.alpha.1 radiation.
[0651] In one embodiment, the Freebase Anhydrate Form D has an
X-ray powder diffraction pattern characterized by peaks at
4.0.+-.0.2, 14.5.+-.0.2, and 19.0.+-.0.2 degrees two theta, when
measured at about 25.degree. C. with monochromatic K.alpha.1
radiation.
[0652] In one embodiment, the Freebase Anhydrate Form D has an
X-ray powder diffraction pattern characterized by peaks at
4.0.+-.0.2, 14.5.+-.0.2, and 19.0.+-.0.2 degrees two theta, and
that is further characterized by a peak at one or more of
8.0.+-.0.2, 9.7.+-.0.2, 14.2.+-.0.2, 18.4.+-.0.2, 20.3.+-.0.2,
23.0.+-.0.2, and 24.7.+-.0.2 degrees two theta, when measured at
about 25.degree. C. with monochromatic K.alpha.1 radiation.
[0653] In one embodiment, the Freebase Anhydrate Form D has an
X-ray powder diffraction pattern without a significant peak at one
or more of 3.1.+-.0.2, 9.3.+-.0.2, and 20.8.+-.0.2 degrees two
theta, when measured at about 25.degree. C. with monochromatic
K.alpha.1 radiation.
[0654] In one embodiment, the Freebase Anhydrate Form D has an
X-ray powder diffraction pattern without a significant peak at one
or more of 6.8.+-.0.2, 15.7.+-.0.2, and 21.9.+-.0.2 degrees two
theta, when measured at about 25.degree. C. with monochromatic
K.alpha.1 radiation.
[0655] In one embodiment, the Freebase Anhydrate Form D has an
X-ray powder diffraction pattern without a significant peak at one
or more of 13.4.+-.0.2, 15.5.+-.0.2, and 21.7.+-.0.2 degrees two
theta, when measured at about 25.degree. C. with monochromatic
K.alpha.1 radiation.
[0656] In one embodiment, the Freebase Anhydrate Form D has an
X-ray powder diffraction pattern without a significant peak at one
or more of 13.4.+-.0.2, 15.5.+-.0.2, and 21.7.+-.0.2 degrees two
theta, and without a significant peak at one or more of 6.8.+-.0.2,
15.7.+-.0.2, and 21.9.+-.0.2 degrees two theta, and without a
significant peak at one or more of 3.1.+-.0.2, 9.3.+-.0.2, and
20.8.+-.0.2 degrees two theta, when measured at about 25.degree. C.
with monochromatic K.alpha.1 radiation.
[0657] In one embodiment the Freebase Anhydrate Form D has an X-ray
powder diffraction pattern characterized by peaks at 8.0.+-.0.2,
9.7.+-.0.2, 14.2.+-.0.2, 14.5.+-.0.2, and 20.3.+-.0.2 degrees two
theta, and without a significant peak at one or more of 3.1.+-.0.2,
9.3.+-.0.2, and 20.8.+-.0.2 degrees two theta, when measured at
about 25.degree. C. with monochromatic K.alpha.1 radiation.
[0658] In one embodiment the Freebase Anhydrate Form D has an X-ray
powder diffraction pattern characterized by peaks at 8.0.+-.0.2,
9.7.+-.0.2, 14.2.+-.0.2, 14.5.+-.0.2, and 20.3.+-.0.2 degrees two
theta, and without a significant peak at one or more of 6.8.+-.0.2,
15.7.+-.0.2, and 21.9.+-.0.2 degrees two theta, when measured at
about 25.degree. C. with monochromatic K.alpha.1 radiation.
[0659] In one embodiment the Freebase Anhydrate Form D has an X-ray
powder diffraction pattern characterized by peaks at 8.0.+-.0.2,
9.7.+-.0.2, 14.2.+-.0.2, 14.5.+-.0.2, and 20.3.+-.0.2 degrees two
theta, and without a significant peak at one or more of
13.4.+-.0.2, 15.5.+-.0.2, and 21.7.+-.0.2 degrees two theta, when
measured at about 25.degree. C. with monochromatic K.alpha.1
radiation.
[0660] In one embodiment the Freebase Anhydrate Form D has an X-ray
powder diffraction pattern characterized by peaks at 8.0.+-.0.2,
9.7.+-.0.2, 14.2.+-.0.2, 14.5.+-.0.2, and 20.3.+-.0.2 degrees two
theta, and without a significant peak at one or more of 3.1.+-.0.2,
9.3.+-.0.2, and 20.8.+-.0.2 degrees two theta, and without a
significant peak at one or more of 6.8.+-.0.2, 15.7.+-.0.2, and
21.9.+-.0.2 degrees two theta, and without a significant peak at
one or more of 13.4.+-.0.2, 15.5.+-.0.2, and 21.7.+-.0.2 degrees
two theta, when measured at about 25.degree. C. with monochromatic
K.alpha.1 radiation.
[0661] In one embodiment the Freebase Anhydrate Form D has an X-ray
powder diffraction pattern characterized by peaks at 4.0.+-.0.2,
8.0.+-.0.2, 9.7.+-.0.2, 14.2.+-.0.2, 14.5.+-.0.2, 19.0.+-.0.2, and
20.3.+-.0.2 degrees two theta, and without a significant peak at
one or more of 3.1.+-.0.2, 9.3.+-.0.2, and 20.8.+-.0.2 degrees two
theta, when measured at about 25.degree. C. with monochromatic
K.alpha.1 radiation.
[0662] In one embodiment the Freebase Anhydrate Form D has an X-ray
powder diffraction pattern characterized by peaks at 4.0.+-.0.2,
8.0.+-.0.2, 9.7.+-.0.2, 14.2.+-.0.2, 14.5.+-.0.2, 19.0.+-.0.2, and
20.3.+-.0.2 degrees two theta, and without a significant peak at
one or more of 6.8.+-.0.2, 15.7.+-.0.2, and 21.9.+-.0.2 degrees two
theta, when measured at about 25.degree. C. with monochromatic
K.alpha.1 radiation.
[0663] In one embodiment the Freebase Anhydrate Form D has an X-ray
powder diffraction pattern characterized by peaks at 4.0.+-.0.2,
8.0.+-.0.2, 9.7.+-.0.2, 14.2.+-.0.2, 14.5.+-.0.2, 19.0.+-.0.2, and
20.3.+-.0.2 degrees two theta, and without a significant peak at
one or more of 13.4.+-.0.2, 15.5.+-.0.2, and 21.7.+-.0.2 degrees
two theta, when measured at about 25.degree. C. with monochromatic
K.alpha.1 radiation.
[0664] In one embodiment the Freebase Anhydrate Form D has an X-ray
powder diffraction pattern characterized by peaks at 4.0.+-.0.2,
8.0.+-.0.2, 9.7.+-.0.2, 14.2.+-.0.2, 14.5.+-.0.2, 19.0.+-.0.2, and
20.3.+-.0.2 degrees two theta, and without a significant peak at
one or more of 3.1.+-.0.2, 9.3.+-.0.2, and 20.8.+-.0.2 degrees two
theta, and without a significant peak at one or more of 6.8.+-.0.2,
15.7.+-.0.2, and 21.9.+-.0.2 degrees two theta, and without a
significant peak at one or more of 13.4.+-.0.2, 15.5.+-.0.2, and
21.7.+-.0.2 degrees two theta, when measured at about 25.degree. C.
with monochromatic K.alpha.1 radiation.
[0665] In one embodiment, the Freebase Anhydrate Form D has an
X-ray powder diffraction pattern characterized by peaks
substantially at the positions listed in Table 14-E.+-.0.2 degrees
two theta, when measured at about 25.degree. C. with monochromatic
K.alpha.1 radiation.
[0666] In one embodiment, the Freebase Anhydrate Form D has an
X-ray powder diffraction pattern characterized by peaks
substantially at the positions listed in Table 14-E.+-.0.2 degrees
two theta that have a relative intensity of at least 10.0%, when
measured at about 25.degree. C. with monochromatic K.alpha.1
radiation.
[0667] In further aspects of each of the above embodiments, the
significant peak values have a variation of .+-.0.1 degrees two
theta rather than .+-.0.2 degrees two theta. In still further
aspects of each of the above embodiments, the significant peak
values have a variation of .+-.0.05 degrees two theta rather than
.+-.0.2 degrees two theta.
[0668] In one embodiment, the Freebase Anhydrate Form D has an
X-ray powder diffraction pattern substantially as shown in FIG. 22
when measured at about 25.degree. C. with monochromatic K.alpha.1
radiation.
[0669] Freebase Anhydrate Form D is reversibly hygroscopic (up to
1.8% water at 90% RH at 25.degree. C.), and is metastable relative
to Freebase Hydrate Form C at typical environmental conditions
(e.g., above 2.4% RH at 23.degree. C.) used during storage for
downstream processing. The manufacture of Freebase Anhydrate Form D
requires strict control of water, as the Freebase Anhydrate Form D
can be manufactured only when the water content of the
crystallization solvent is low (e.g., less than 0.15% at 23.degree.
C. corresponding to a water activity of 2.4%), and will convert to
Freebase Hydrate Form C in solutions at high water content.
Freebase Anhydrate Form D is slow to crystallize, and difficult to
manufacture in higher yield.
[0670] E. Crystalline Tartrate
[0671] In another embodiment, the solid state form is a tartrate of
upadacitinib. In one aspect, the tartrate is amorphous. In another
aspect, the tartrate is crystalline. In another aspect, the
crystalline tartrate is a solvate. In another aspect, the
crystalline tartrate is a hydrate. In another aspect, the tartrate
is a crystalline L-tartrate. In another aspect, the crystalline
L-tartrate is a hydrate. In another aspect, the crystalline
tartrate is a tetrahydrate (the "Tartrate Hydrate"). The Tartrate
Hydrate (a tetrahydrate) is further described in the Examples of
the application.
[0672] In one embodiment, the Tartrate Hydrate has an X-ray powder
diffraction pattern characterized by peaks at 3.9.+-.0.2,
6.8.+-.0.2, and 14.1.+-.0.2 degrees two theta when measured at
about 25.degree. C. with monochromatic K.alpha.1 radiation.
[0673] In one embodiment, the Tartrate Hydrate has an X-ray powder
diffraction pattern characterized by peaks at 3.9.+-.0.2,
6.8.+-.0.2, 14.1.+-.0.2, 15.7.+-.0.2, 21.9.+-.0.2, and 25.9.+-.0.2
degrees two theta when measured at about 25.degree. C. with
monochromatic K.alpha.1 radiation.
[0674] In one embodiment, the Tartrate Hydrate has an X-ray powder
diffraction pattern without a significant peak at one or more of
13.4.+-.0.2 and 15.1.+-.0.2 degrees two theta, when measured at
about 25.degree. C. with monochromatic K.alpha.1 radiation.
[0675] In one embodiment, the Tartrate Hydrate has an X-ray powder
diffraction pattern without a significant peak at one or more of
3.1.+-.0.2, 9.3.+-.0.2, and 12.0.+-.0.2 degrees two theta, when
measured at about 25.degree. C. with monochromatic K.alpha.1
radiation.
[0676] In one embodiment, the Tartrate Hydrate has an X-ray powder
diffraction pattern without a significant peak at one or more of
13.4.+-.0.2 and 15.1.+-.0.2 degrees two theta, and without a
significant peak at one or more of 3.1.+-.0.2 and 9.3.+-.0.2
degrees two theta, when measured at about 25.degree. C. with
monochromatic K.alpha.1 radiation.
[0677] In one embodiment, the Tartrate Hydrate has an X-ray powder
diffraction pattern characterized by peaks at 3.9.+-.0.2,
6.8.+-.0.2, and 14.1.+-.0.2 degrees two theta, and without a
significant peak at one or more of 13.4.+-.0.2 and 15.1.+-.0.2
degrees two theta, when measured at about 25.degree. C. with
monochromatic K.alpha.1 radiation.
[0678] In one embodiment, the Tartrate Hydrate has an X-ray powder
diffraction pattern characterized by peaks at 3.9.+-.0.2,
6.8.+-.0.2, and 14.1.+-.0.2 degrees two theta, and without a
significant peak at one or more of 3.1.+-.0.2, 9.3.+-.0.2, and
12.0.+-.0.2 degrees two theta, when measured at about 25.degree. C.
with monochromatic K.alpha.1 radiation.
[0679] In one embodiment, the Tartrate Hydrate has an X-ray powder
diffraction pattern characterized by peaks at 3.9.+-.0.2,
6.8.+-.0.2, and 14.1.+-.0.2 degrees two theta, and without a
significant peak at one or more of 13.4.+-.0.2 and 15.1.+-.0.2
degrees two theta, and without a significant peak at one or more of
3.1.+-.0.2, 9.3.+-.0.2, and 12.0.+-.0.2 degrees two theta, when
measured at about 25.degree. C. with monochromatic K.alpha.1
radiation.
[0680] In one embodiment, the Tartrate Hydrate has an X-ray powder
diffraction pattern characterized by peaks at 3.9.+-.0.2,
6.8.+-.0.2, 14.1.+-.0.2, 15.7.+-.0.2, 21.9.+-.0.2 degrees two
theta, and without a significant peak at one or more of 13.4.+-.0.2
and 15.1.+-.0.2 degrees two theta, when measured at about
25.degree. C. with monochromatic K.alpha.1 radiation.
[0681] In one embodiment, the Tartrate Hydrate has an X-ray powder
diffraction pattern characterized by peaks at 3.9.+-.0.2,
6.8.+-.0.2, 14.1.+-.0.2, 15.7.+-.0.2, 21.9.+-.0.2 degrees two
theta, and without a significant peak at one or more of 3.1.+-.0.2,
9.3.+-.0.2, and 12.0.+-.0.2 degrees two theta.
[0682] In one embodiment, the Tartrate Hydrate has an X-ray powder
diffraction pattern characterized by peaks at 3.9.+-.0.2,
6.8.+-.0.2, 14.1.+-.0.2, 15.7.+-.0.2, 21.9.+-.0.2 degrees two
theta, and without a significant peak at one or more of 13.4.+-.0.2
and 15.1.+-.0.2 degrees two theta, and without a significant peak
at one or more of 3.1.+-.0.2, 9.3.+-.0.2, and 12.0.+-.0.2 degrees
two theta.
[0683] In further aspects of each of the above embodiments, the
significant peak values have a variation of .+-.0.1 degrees two
theta rather than .+-.0.2 degrees two theta. In still further
aspects of each of the above embodiments, the significant peak
values have a variation of .+-.0.05 degrees two theta rather than
.+-.0.2 degrees two theta.
[0684] In one embodiment, the Tartrate Hydrate has an X-ray powder
diffraction pattern substantially as shown in FIG. 21, when
measured at about 25.degree. C. with monochromatic K.alpha.1
radiation.
[0685] The Tartrate Hydrate has acceptable chemical stability and
exhibits acceptable stability to light and peroxide. The Tartrate
Hydrate has good solubility (BCS Class I) and is not hygroscopic.
The Tartrate Hydrate, however, potentially will convert to an
amorphous tartrate below 10% relative humidity, when heated, or
when compressed or under shear.
[0686] The Tartrate Hydrate can be manufactured, for example, using
anti-solvent crystallization. Impurity rejection during the
large-scale manufacture of the Tartrate Hydrate generally is good,
but scaling may be greater than desired and specific anti-solvent
addition controls and process volume restrictions potentially may
be required. In addition, appropriate control of the filtration,
washing, and drying steps may be required to minimize consolidation
of the wet cake and formation of hard lumps in the isolated
material. For example, control of the relative humidity (e.g.,
greater than 10% and less than 100% relative humidity), temperature
(e.g., crystallization at about 10.degree. C. works well), and
mixing rate may be required during drying to minimize the formation
of hard lumps in the isolated material. Insufficient control of the
drying conditions potentially will produce a consolidated, harder
material that may be difficult to break up during subsequent
processing. As previously noted, shearing and compression
potentially will cause conversion to the amorphous tartrate. The
dried material typically is milled with mechanical impact mills
(e.g., Fitzmills and pin mills) because shear-based mills (e.g.,
comills) can lead to loss of crystallinity. In addition, loss of
crystallinity potentially can result from pressure or compression
forces during formulation (such as would be required for
tableting).
[0687] F. Crystalline Purity
[0688] In additional embodiments of the solid state forms discussed
above, the solid state form has a pharmaceutically acceptable
crystalline purity (or a pharmaceutically acceptable amorphous
purity in the case of the Amorphous Freebase). For example, in one
aspect, upadacitinib comprises at least about 75% by weight of the
desired solid state form. In another aspect, at least 80% by weight
is the desired solid state form. In another aspect, at least 85% by
weight is the desired solid state form. In another aspect, at least
90% by weight is the desired solid state form. In another aspect,
at least 95% by weight is the desired solid state form. In another
aspect, at least 96% by weight is the desired solid state form. In
another aspect, at least 97% by weight is the desired solid state
form. In another aspect, at least 98% by weight is the desired
solid state form. In another aspect, at least 99% by weight is the
desired solid state form. In another aspect, upadacitinib is
present as the substantially crystalline pure (or amorphous pure in
the case of the Amorphous Freebase) solid state form. In a
preferred aspect, the solid state form is the Amorphous Freebase.
In another aspect, the solid state form is Freebase Anhydrate Form
D. In a more preferred aspect, the solid state form is the Freebase
Hydrate Form B. In a particularly preferred aspect, the solid state
form is the Freebase Hydrate Form C. In a preferred aspect, the
solid state form is the Tartrate Hydrate.
VII. Solid State Preparation
[0689] The present disclosure also relates to methods for preparing
a solid state form of upadacitinib. In one aspect, the solid state
form prepared is the Amorphous Freebase. In another aspect, the
solid state form prepared is the Freebase Hydrate Form B. In
another aspect, the solid state form prepared is the Freebase
Hydrate Form C. In another aspect, the solid state form prepared is
the Tartrate Hydrate. In another aspect, the solid state form
prepared is the Freebase Anhydrate Form D.
[0690] A. Preparation of Amorphous Freebase
[0691] The present disclosure relates to methods for preparing the
Amorphous Freebase. In one embodiment, the method comprises
dehydrating the Freebase Hydrate Form B to provide the Amorphous
Freebase. In another embodiment, the method comprises desolvating
the Freebase Solvate Form A to provide the Amorphous Freebase. A
wide range of process conditions can be employed for the
dehydration/desolvation. The dehydration can be conducted, for
example, under ambient conditions or in a vacuum oven. FIG. 14
schematically illustrates one method of preparing the Amorphous
Freebase by dehydration of the Freebase Hydrate Form B.
[0692] In another embodiment, the method comprises dissolving
upadacitinib in a solvent or mixture of solvents; and adjusting the
pH of the solvent or mixture of solvents to a pH greater than about
8 to initiate precipitation of the Amorphous Freebase. In one
aspect, the solvent or mixture of solvents comprises water. In
another aspect the pH is adjusted to a pH greater than about 9. In
another aspect, the pH is adjusted to a pH greater than about 10.
In another aspect, the pH is adjusted to a pH greater than about
11. In another aspect, the pH is adjusted to a pH of at least about
9.
[0693] In still other embodiments, the method comprises preparing
the Amorphous Freebase using a method selected from the group
consisting of impinging jet, spray drying, and hot-melt
extrusion.
[0694] B. Preparation of Crystalline Freebase Solvate Form A and
Crystalline Freebase Hydrate Form B
[0695] The present disclosure additionally relates to methods for
preparing the Freebase Solvate Form A and Freebase Hydrate Form B.
In one embodiment, the method comprises dissolving upadacitinib in
a solvent or mixture of solvents comprising an anti-solvent; and
maintaining the solvent or mixture of solvents at a temperature
less than about 15.degree. C. for an amount of time sufficient to
initiate crystallization of the Freebase Solvate Form A or the
Freebase Hydrate Form B. The anti-solvent can comprise, for
example, water. The solvent or mixture of solvents can comprise a
polar solvent such as a solvent is selected from the group
consisting of methanol, ethanol, n-butylamine, acetone,
acetonitrile, ethyl formate, methyl acetate, ethyl acetate, methyl
ethyl ketone, methyl isobutyl ketone, methyl isobutyl ketone,
methyl tert-butyl ether, and isopropyl acetate. The Freebase
Solvate Form A and Freebase Hydrate Form B exhibit similar PXRD
patterns, and are therefore isostructural. The method generally is
conducted at sub-ambient temperatures, for example, less than about
10.degree. C. less than about 5.degree. C., or less than about
0.degree. C. In certain aspects, the process further comprises
seeding the solvent or mixture of solvents with crystals of the
Freebase Solvate Form A or the Freebase Hydrate Form B.
[0696] C. Preparation of Crystalline Freebase Hydrate Form C
[0697] The present disclosure additionally relates to methods for
preparing the Freebase Hydrate Form C. In one embodiment, the
method comprises dissolving upadacitinib in a solvent or mixture of
solvents, and initiating crystallization to provide the Freebase
Hydrate Form C. The solvent or mixture of solvents generally will
comprise an anti-solvent (such as water) which can be present in
the solvent or mixture of solvents before, or added to the solvent
or mixture of solvents after, the upadacitinib is dissolved in the
solvent or mixture of solvents. The solvent or mixture of solvents
can comprise, for example, one or more polar solvents (such as
polar solvent selected from the group consisting of ethanol and
ethyl acetate); one or more nonpolar solvents (such as a nonpolar
solvent is selected from the group consisting of hexane and
heptane); or at least one polar solvent and at least one nonpolar
solvent. In one aspect, the solvent or mixture of solvents is a
ternary solvent mixture comprising ethyl acetate, heptane, and
water. The method generally is conducted at temperatures less than
about 30.degree. C., less than about 20.degree. C. or less than
about 10.degree. C. In certain aspects, the initiating
crystallization step comprises mixing the solvent or mixture of
solvents to provide sufficient agitation to initiate
crystallization. In certain aspects, the initiating crystallization
step comprises seeding the solvent or mixture of solvents with
crystals of the Freebase Hydrate Form C. In certain aspects, the
initiating crystallization step comprises both mixing the solvent
or mixture of solvents and seeding the solvent or mixture of
solvents with crystals of the Freebase Hydrate Form C.
[0698] In one embodiment, upadacitinib is first prepared according
to any of the methods set forth herein, a reaction mixture
comprising upadacitinib is filtered, and the resulting solution is
suspended in a solvent or mixture of solvents. The solvent or
mixture of solvents can comprise, for example, one or more polar
solvents (such as polar solvent selected from the group consisting
of ethanol and ethyl acetate); one or more nonpolar solvents (such
as a nonpolar solvent is selected from the group consisting of
hexane and heptane); or at least one polar solvent and at least one
nonpolar solvent. In one particular embodiment, the solvent is
ethyl acetate, or a mixture of ethyl acetate and water. In certain
aspects, the initiating crystallization step comprises seeding the
solvent or mixture of solvents with crystals of the Freebase
Hydrate Form C. In one particular aspect, the crystallization
occurs in a wet mill.
[0699] FIG. 15 schematically illustrates one method of preparing
the Freebase Hydrate Form C.
[0700] D. Preparation of Crystalline Freebase Anhydrate Form D
[0701] The present disclosure additionally relates to methods for
preparing the Freebase Anhydrate Form D. In one embodiment, the
method comprises dissolving upadacitinib in a solvent or mixture of
solvents; and initiating crystallization to provide the Freebase
Anhydrate Form D. The solvent or mixture of solvents will be
water-free, or close to water-free. In embodiments, the solvent or
mixture of solvents will have a water content of less than about
0.15 wt %, or less than about 0.10 wt. %, or less than about 0.05
wt. %, or about 0 wt. % at 23.degree. C. In one embodiment, the
solvent or mixture of solvents will have a water activity of about
2.4% or less, or about 2.2% or less, or about 2.0% or less, or
about 1.5% or less. The solvent or mixture of solvents can
comprise, for example, ethyl acetate (EtOAc), heptane, and
combinations thereof. In one embodiment, the solvent system
comprises a mixture of heptane in ethyl acetate. In some
embodiments, the solvent system comprises about 10 wt. %, or about
20 wt. %, or about 30 wt. %, or about 40 wt. % heptane in ethyl
acetate. The method generally is conducted at temperatures of at
least about 7.degree. C. at least about 23.degree. C., at least
about 25.degree. C. or less, or at least about 30.degree. C. In one
embodiment, the method is conducted at about 23.degree. C. In
certain aspects, the initiating crystallization step comprises
mixing the solvent or mixture of solvents to provide sufficient
agitation to initiate crystallization. In certain aspects, the
initiating crystallization step comprises seeding the solvent or
mixture of solvents with crystals of the Freebase Anhydrate Form D.
In certain aspects, the initiating crystallization step comprises
both mixing the solvent or mixture of solvents and seeding the
solvent or mixture of solvents with crystals of the Freebase
Anhydrate Form D.
[0702] E. Preparation of Crystalline Tartrate Hydrate
[0703] The present disclosure additionally relates to methods for
preparing the Tartrate Hydrate. In one embodiment, the method
comprises dissolving upadacitinib and L-tartaric acid in a solvent
or mixture of solvents to form a crystallization solution; and
crystallizing the Tartrate Hydrate from the crystallization
solution. The solvent or mixture of solvents can comprise, for
example, water and/or, for example, one or more polar solvents
(such as isopropyl acetate). The solvent or mixture of solvents
also can comprise an anti-solvent (such as isopropyl acetate). In
certain aspects, the process further comprises seeding the solvent
or mixture of solvents with crystals of the Tartrate Hydrate.
[0704] The crystallization generally is conducted at a temperature
less than about 40.degree. C. When an anti-solvent is used, a
moderate rate of addition is employed for the anti-solvent as a
faster rate of addition typically results in the precipitation of
an amorphous tartrate and a slower rate of addition allows the
resulting slurry to thicken. Proper control of filtration, washing,
and drying may be needed to avoid potential issues associated with
consolidation of the filter cake, including solvent entrapment,
solid properties (e.g., hard, chunky solids) and handing, and
damage to equipment. Depending upon the properties of the dried
Tartrate Hydrate material, milling may require a mechanical
impact-type of mills rather than a shear-based mill (such as a
co-mill).
[0705] FIG. 16 schematically illustrates one method of preparing
the Tartrate Hydrate.
VIII. Pharmaceutical Compositions and Routes of Administration
[0706] One or more compounds of this disclosure can be administered
to a human patient by themselves or in pharmaceutical compositions
where they are mixed with biologically suitable carriers or
excipient(s) at doses to treat or ameliorate a disease or condition
as described herein. Mixtures of these compounds can also be
administered to the patient as a simple mixture or in suitable
formulated pharmaceutical compositions.
[0707] The pharmaceutical compositions of the present disclosure
may be manufactured in a manner that is itself known, e.g., by
means of conventional mixing, dissolving, granulating,
dragee-making, levigating, emulsifying, encapsulating, entrapping
or lyophilizing processes.
[0708] Pharmaceutical compositions for use in accordance with the
present disclosure thus may be formulated in a conventional manner
using one or more physiologically acceptable carriers comprising
excipients and auxiliaries which facilitate processing of the
active compounds into preparations which can be used
pharmaceutically. Proper formulation is dependent upon the route of
administration chosen.
[0709] In one embodiment, the active ingredient contained in the
dosage unit composition is upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof. In one embodiment, the
target or label amount of active ingredient (e.g., upadacitinib)
provided for inclusion in the compositions of the present
disclosure refers to the amount of upadacitinib freebase. For
instance, upadacitinib may be prepared in several solid state forms
including Amorphous Freebase, crystalline solvates and hydrates
(e.g., Freebase Solvate Form A, Freebase Hydrate Form B),
crystalline hemihydrates (e.g., Freebase Hydrate Form C),
crystalline anhydrate (e.g., Freebase Anhydrate Form D), and
crystalline tartrate (e.g., Tartrate Hydrate). Preparation of these
solid state forms is described herein and also in U.S. patent
application Ser. No. 15/295,561, which is herein incorporated by
reference. It should be understood that in embodiments, where the
dosage unit composition comprises, e.g., a solvate, hydrate,
hemihydrate, or tartrate of upadacitinib, the amount of solvate,
hydrate, hemihydrate, or tartrate of upadacitinib present in the
dosage unit composition may be slightly higher than the target
amount of upadacitinib (active ingredient), and preferably will be
present in the dosage unit composition in an amount sufficient to
deliver the target amount of upadacitinib freebase equivalent to a
patient. For example, if the target amount of upadacitinib (active
ingredient) in a dosage unit composition is 15 mg, a dosage unit
composition comprising, for example, a hydrate of upadacitinib, may
comprise the hydrate in an amount sufficient to deliver 15 mg of
the upadacitinib freebase equivalent.
[0710] In one embodiment, the pharmaceutical composition is a
tablet dosage form. In one aspect, the tablet is coated with a
pharmaceutically acceptable polymer. In one embodiment, the
pharmaceutical composition is a capsule dosage form.
[0711] In one embodiment, tablet is a controlled-release
formulation, such as an extended release tablet dosage form (also
referred to herein as a modified release or sustained release
formulation). Such formulations permit the sustained release of the
active ingredient over an extended period of time, as compared to
intermediate release solid dosage forms, which permit the release
of most or all of the active ingredient over a short period of time
(e.g., typically around 60 minutes or less). In one aspect, the
tablet comprises an active ingredient (e.g., upadacitinib) and at
least one additive selected from the group consisting of a release
control polymer, a filler, a glidant, a lubricant (e.g., for use in
compacting the granules), a pH modifier, a surfactant, and
combinations thereof. In one aspect, the tablet comprises an active
ingredient, a release control polymer, a filler, a glidant, and a
lubricant. In one aspect, the tablet comprises an active
ingredient, a release control polymer, a filler, a glidant, a
lubricant, and a pH modifier.
[0712] In certain embodiments, the release control polymer will be
a hydrophilic polymer. Examples of suitable release control
polymers include, but are not limited to a cellulose derivative
with a viscosity of between 1000 and 150.000 mPA-s,
hydroxypropylmethyl cellulose (e.g., Hypromellose 2208 or
controlled release grades of hydroxypropylmethyl cellulose,
including the E, F. and K series), copolymers of acrylic acid
crosslinked with a polyalkenyl polyether (e.g., Carbopol.RTM.
polymers), hydroxypropyl cellulose, hydroxyethyl cellulose,
non-ionic homopolymers of ethylene oxide (e.g., Polyox.TM.), water
soluble natural gums of polysaccharides (e.g., xanthan gum,
alginate, locust bean gum, etc.), crosslinked starch, polyvinyl
acetates, polyvinylpyrrolidone, mixtures of polyvinyl acetates and
polyvinyl pyrrolidone, and combinations thereof. In one embodiment,
the release control polymer is selected from the group consisting
of hydroxypropylmethyl cellulose, copolymers of acrylic acid
crosslinked with a polyalkenyl polyether (e.g., Carbopol.RTM.
polymers), and combinations thereof. Examples of suitable fillers
("bulking agents") include, but are not limited to,
microcrystalline cellulose (e.g., Avicel.RTM. PH 101; Avicel.RTM.
PH 102), mannitol (e.g., Pearlitol.RTM. 100 SD or Pearlitol.RTM.
200 SD), lactose, sucrose, sorbitol, and the like. In one
embodiment, the filler is selected from the group consisting of
microcrystalline cellulose, mannitol, and combinations thereof.
Examples of suitable glidants include, but are not limited to,
silicone dioxide (e.g., colloidal silicon dioxide), calcium
silicate, magnesium silicate, talc, and combinations thereof. In
one embodiment, the glidant is colloidal silicone dioxide. Examples
of suitable lubricants include, but are not limited to,
polyethylene glycol (e.g., having a molecular weight of from 1000
to 6000), magnesium stearate, calcium stearate, sodium stearyl
fumarate, talc, and the like. In one embodiment, the lubricant is
magnesium stearate. Examples of suitable pH modifiers include, but
are not limited to, organic acids, such as tartaric acid, citric
acid, succinic acid, fumaric acid; sodium citrate; magnesium or
calcium carbonate or bicarbonate; and combinations thereof. In one
embodiment, the pH modifier is tartaric acid. Examples of suitable
surfactants include sodium lauryl sulfate.
[0713] In one embodiment, the pharmaceutical composition comprises
from about 10 w/w % to about 35 w/w % of a pH modifier, and in
particular, tartaric acid, fumaric acid, citric acid, succinic
acid, malic acid, or combinations thereof. In other embodiments,
the formulation comprises from about 20 w/w % to about 35 w/w %, or
from about 20 w/w % to about 30 w/w %, or from about 20 w/w % to
about 25 w/w %, or about 10 w/w %, about 15 w/w %, about 20 w/w %,
about 25 w/w % or about 30 w/w % pH modifier. In one embodiment,
the pH modifier is tartaric acid. Sustained peak plasma
concentrations can theoretically be achieved by means of sustained
release matrix systems. However, when such systems are made of
hydrophilic polymers, such as HPMC, they seldom provide pH
independent drug release of pH-dependent soluble drugs, and they
are normally incapable of attaining zero-order release except for
practically insoluble drugs. Is has been discovered that when a pH
modifier, such as tartaric acid, fumaric acid, citric acid,
succinic acid, malic acid, or combinations thereof, is used in a
hydrophilic sustained release matrix system, it allows upadacitinib
or a pharmaceutically acceptable salt or solid state form thereof
to be released at a steady rate regardless of the pH of the
environment. It has been discovered that as a tablet containing the
hydrophilic polymer matrix system erodes, upadacitinib reacts with
the HPMC, creating a thicker gel layer which slows the release of
upadacitinib from the tablet. The resulting gel layer provides an
environment suitable for upadacitinib to dissolve.
[0714] Thus, in one embodiment, the pharmaceutical composition of
the present disclosure exhibits a pH-independent release of the
active ingredient (upadacitinib). Advantageously, it has been
discovered that including organic acids, such as a tartaric acid,
in the composition as a pH modifier improves the release profile,
and results in a pH independent release of the active ingredient.
Without wishing to be bound to any particular theory, it is
believed that the pH modifier and hydrophilic polymer create a
microenvironment in which the active ingredient dissolves, and then
is released. The release from the microenvironment occurs at
approximately the same rate, regardless of pH. This is particularly
advantageous, since the pH of the gastrointestinal tract may vary
significantly from the stomach (e.g., pH of about 1.5-3), to the
duodenum (e.g., pH of about 4-5), to the lower part of the small
intestines (e.g., pH of about 6.5-7.5).
[0715] Thus, in one embodiment, the pharmaceutical composition is a
modified release formulation comprising upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof, a
hydrophilic polymer, and a pH modifier, wherein the hydrophilic
polymer, in contact with water, forms a gel layer that provides an
environment suitable for upadacitinib, or a pharmaceutically
acceptable salt or solid state form thereof, to dissolve. In some
embodiments, the environment suitable for upadacitinib, or a
pharmaceutically acceptable salt or solid state form thereof, to
dissolve has a pH equal to or less than about 3.8 at 37.degree. C.
In some such embodiments, the environment has a pH of from about
1.5 to about 3.7, or from about 2.0 to about 3.7, or from about 2.5
to about 3.6, or from about 3.0 to about 3.6, or from about 3.0 to
about 3.5.
[0716] In one such embodiment, the environment suitable for
upadacitinib, or a pharmaceutically acceptable salt or solid state
form thereof, to dissolve is as set forth above, and the modified
release formulation comprises from about 10 w/w % to about 35 w/w %
of a pH modifier, and in particular, tartaric acid, fumaric acid,
citric acid, succinic acid, malic acid, or combinations thereof. In
other embodiments, the formulation comprises from about 20 w/w % to
about 35 w/w %, or from about 20 w/w % to about 30 w/w %, or from
about 20 w/w % to about 25 w/w %, or about 10 w/w %, about 15 w/w
%, about 20 w/w %, about 25 w/w % or about 30 w/w % pH modifier. In
any of these embodiments, the pH modifier may be selected from the
group consisting of tartaric acid, fumaric acid, citric acid,
succinic acid, malic acid, and combinations thereof. In one such
embodiment, the pH modifier is selected from the group consisting
of tartaric acid, fumaric acid, citric acid, succinic acid, and
combinations thereof. In one such embodiment, the pH modifier is
selected from the group consisting of tartaric acid and fumaric
acid. In one embodiment, the pH modifier is tartaric acid. In one
embodiment, the pH modifier is fumaric acid or citric acid. The
weight % tartaric acid set forth herein is by weight of the
uncoated composition (e.g., uncoated tablet). In any of the
foregoing embodiments, the hydrophilic polymer may be a cellulose
derivative with a viscosity of between 1000 and 150,000 mPA-s. In
one embodiment, the hydrophilic polymer is selected from the group
consisting of hydroxypropylmethyl cellulose, hydroxyethyl
cellulose, and mixtures or combinations thereof. In one embodiment,
the hydrophilic polymer is hydroxypropylmethyl cellulose. In one
embodiment, the hydrophilic polymer is hydroxypropylmethyl
cellulose Grade E, F, or K. In one embodiment, the hydrophilic
polymer is Hypromellose 2208.
[0717] In one embodiment, the tablet is a compressed and/or milled
tablet. For example, in some embodiments, the tablet is formed by
blending the composition components (e.g., including the active
ingredient and at least one pharmaceutically acceptable carrier).
The composition can then be either directly compressed, or one or
more of the composition components can be granulated prior to
compression. In one embodiment, milling is performed using a mill
fitted with any suitable size screen (e.g., a fitted with a screen
size of from about 600 to about 1400 .mu.m or about 610 .mu.m or
about 1397 .mu.m). Compression can be done in a tablet press, such
as in a steel die between two moving punches.
[0718] In other embodiments, the compressed and/or milled tablet is
formulated using a wet granulation process. Use of wet granulation
helps reduce and/or eliminate sticking that may occur when
compression without wet granulation (e.g., direct compression) is
used to formulate the tablets. In one embodiment, the wet
granulation process may include the following steps: (a) combining
the active ingredient (e.g., upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof or a solid state form
of upadacitinib) and at least a portion of one additional
composition component to form a dry granulation mixture; (b)
contacting the dry granulation mixture with a granulation fluid to
form a wet granulation mixture; (c) drying the wet granulation
mixture to form a granulated material; (d) milling the granulated
material to form a milled granulated material; (e) combining the
milled granulation material with the remaining composition
components; and (f) compressing the composition into the solid
dosage unit (e.g., a tablet).
[0719] In step (a) of this process, the active ingredient may be
combined with, for example, a portion of the release control
polymer (e.g., HPMC), a portion of the filler (e.g.,
microcrystalline cellulose, such as Avicel.RTM. PH101), or both a
portion of the release control polymer and a portion of the filler
to form the dry granulation mixture. Any suitable portion of the
release control polymer may be used in step (a). In one embodiment,
from about 5 to 10 wt. % or from about 6 to 8 wt. % of the total
amount of the release control polymer in the composition is used in
step (a).
[0720] In certain embodiments, the granulation fluid used in step
(b) may comprise water, a suitable solvent (e.g., ethanol,
isopropanol, etc.), or combinations thereof. In one embodiment, the
granulation fluid comprises water. In one embodiment, the active
ingredient may be combined with a portion of the filler, while a
portion of the release control polymer (e.g., HPMC) is dissolved in
a liquid, such as water, to form the granulation fluid. In one
embodiment, the granulation fluid is sprayed on the dry granulation
mixture.
[0721] The dried granulation material may be milled using, for
example, a comill fit with any suitable screen size. In one
embodiment, the screen size is from about 600 to about 900 microns,
or from about 610 to about 813 microns. In one embodiment, the
granulated material is milled using a comill fitted with a 610
.mu.m screen. In one embodiment, the granulated material is milled
using a comill fitted with a 813 .mu.m screen.
[0722] In step (e), the milled granulation material is combined
with any remaining composition components, such as any remaining
filler (e.g., microcrystalline cellulose, such as Avicel.RTM.
PH102), any remaining release control polymer, glidants,
lubricants, pH modifiers, surfactants, and the like. In one
embodiment, the filler and/or release control polymer included in
the granulated material may be the same or different than the
filler and/or release control polymer added in step (e). For
instance, in one embodiment, the filler included in the granulated
material (e.g., Avicel.RTM.PH101) may have a smaller particle size
distribution than the filler added in step (e) (e.g.,
Avicel.RTM.PH102).
[0723] In one embodiment, the composition may be sieved, and the
sieved composition blended, for example, after step (e), and prior
to compressing the composition (step (f)). In one embodiment, the
formulation is sieved prior to addition of any lubricant. In one
embodiment, the pH modifier (e.g., tartaric acid) is optionally
milled prior to combining with the granulated material.
[0724] In some embodiments, the tablet further comprises a film
coat. A film coat on the tablet further may contribute to the ease
with which it can be swallowed. A film coat can also improve taste
and provides an elegant appearance. In certain embodiments, the
film-coat includes a polymeric film-forming material such as
hydroxypropyl methylcellulose, hydroxypropylcellulose, and acrylate
or methacrylate copolymers. Besides a film-forming polymer, the
film-coat may further comprise a plasticizer, e.g. polyethylene
glycol, a surfactant, e.g. polysorbates, and optionally a pigment,
e.g. titanium dioxide or iron oxides. The film-coating may also
comprise talc as anti-adhesive. In one embodiment, the film coat
accounts for less than 5% by weight of a pharmaceutical composition
of the present disclosure.
[0725] In another embodiment, the pharmaceutical composition is a
capsule dosage form.
[0726] For the prevention or treatment of disease, the appropriate
dosage of JAK1 inhibitor will depend on a variety of factors such
as the type of disease to be treated, as defined above, the
severity and course of the disease, whether the JAK1 inhibitor is
administered for preventive or therapeutic purposes, previous
therapy, the patient's clinical history and response to the
antibody, and the discretion of the attending physician. The JAK1
inhibitor is suitably administered to the patient at one time or
over a series of treatments.
[0727] The JAK1 inhibitor is formulated, dosed, and administered in
a fashion consistent with good medical practice. Factors for
consideration in this context include the particular disorder
being, treated, the particular mammal being treated, the clinical
condition of the individual patient, the cause of the disorder, the
scheduling of administration, and other factors known to medical
practitioners. The "therapeutically effective amount" of the JAK1
inhibitor will be governed by such considerations.
[0728] Pharmaceutical compositions suitable for use in the present
disclosure include compositions wherein the active ingredients are
contained in an effective amount to achieve its intended purpose.
More specifically, a therapeutically effective amount means an
amount effective to prevent development of or to alleviate the
existing symptoms of the patient being treated. Determination of
the effective amounts is well within the capability of those
skilled in the art. In one particular embodiment, the composition
will be a once-daily modified release formulation comprising 7.5
mg, 15 mg, 30 mg, or 45 mg of upadacitinib or a pharmaceutically
acceptable salt or solid state form thereof.
IX. Examples
Example 1: Preparation of Amorphous Freebase
[0729] A. Method A: Precipitation from Water
[0730] Upadacitinib (approximately 300 g) was dissolved in water
(10 L) and 50% sodium hydroxide (160 g) was added drop-wise over a
two hour period to adjust the pH to greater than 12. Solids formed
immediately. The solids were filtered, washed with two 500 mL
aliquots of water, and then dried in a vacuum oven. The solids were
equilibrated for a short period of time at ambient temperature
prior to characterization. Conversion to Amorphous Freebase of
upadacitinib was confirmed by PXRD analysis.
[0731] B. Method B: Dehydration of Freebase Hydrate Form B
[0732] A sample of the Freebase Hydrate Form B form of upadacitinib
(crystallized from ethanol/water at sub-ambient temperatures as
described in Example 2, Method C below) was placed in a vacuum oven
at 40.degree. C. overnight. The solids removed from the vacuum oven
were equilibrated for a short time at 23.degree. C. prior to
characterization. Conversion to Amorphous Freebase of upadacitinib
was confirmed by PXRD analysis.
Example 2: Preparation of Freebase Solvate Form A and Freebase
Hydrate Form B
[0733] A. Method A: Freebase Solvate Form a (Isopropyl
Acetate/Water Solvate)
[0734] A sample of the Amorphous Freebase of upadacitinib (25 mg)
was added to a vial followed by isopropyl acetate (125 .mu.L) and
water (10 .mu.L). All solids dissolved at ambient temperature. The
solution was placed in a freezer at -16.degree. C. for 4 days. The
liquor was decanted and the crystallized solids were isolated. The
isolated crystals were analyzed by PXRD while still wet. Conversion
to Freebase Solvate Form A (isopropyl acetate/water solvate) of
upadacitinib was confirmed by PXRD analysis.
[0735] B. Method B: Freebase Hydrate Form B from Methanol/Water
[0736] A sample of the Amorphous Freebase of upadacitinib (164 mg)
and MeOH (621 mg) were added to a vial. The components were mixed
at ambient temperature until the solids dissolved. Water
(approximately 680 .mu.L) was added to the vial and the vial was
placed in an ice/sodium chloride bath at approximately -3.degree.
C. Crystal seeds comprising Freebase Hydrate Form B were added to
the vial and the vial was placed in a freezer at -16.degree. C. A
sample was pulled from the crystallized suspension and the solids
were immediately analyzed with PXRD and TGA-MS. Conversion to
Freebase Hydrate Form B of upadacitinib was confirmed by PXRD and
TGA-MS analysis.
[0737] C. Method C: Freebase Hydrate Form B from Ethanol/Water
[0738] A sample of the Amorphous Freebase of upadacitinib (4.2 g)
was dissolved in EtOH (15.3 g) in a jacketed reactor. Water (23.3
g) was slowly added to the reactor. The reactor solution was cooled
to approximately 2.degree. C. A small portion of a seed solution
comprising the Freebase Hydrate Form B was charged to the reactor.
The suspension was mixed at approximately 2.degree. C. for 3 hours
and water (36 g) in was charged to the reactor in small aliquots
over several hours while maintaining the suspension at a
temperature of approximately 2.degree. C. The crystallized
suspension was mixed at approximately 2.degree. C. and the solids
were isolated via filtration. Conversion to Freebase Hydrate Form B
of upadacitinib was confirmed by PXRD analysis.
[0739] The Freebase Solvate Form A and Freebase Hydrate Form B do
not readily crystallize from solution. In general, sub-ambient
temperatures and sufficient water activity are needed to
crystallize Freebase Solvate Form A and Freebase Hydrate Form B
from solution.
[0740] Crystalline freebase hydrates and solvates have been
isolated from several solvent systems either through primary
nucleation (without seeding) or through seeding. In addition to
crystallization from isopropyl acetate/water (as described in
Method A above), crystalline freebase hydrates or solvates also
have been isolated through primary nucleation (without seeding)
from, e.g., n-butylamine/water and ethanol/water solvent systems.
In addition to crystallization from methanol/water (as described in
Method B above) and ethanol/water (as described in Method C above),
crystalline freebase hydrates or solvates also have been isolated
through seeding from, e.g., acetone/water; acetonitrile/water,
ethyl formate/water; methyl acetate/water; ethyl acetate/water;
methyl ethyl ketone/water, methyl isobutyl ketone/water, methyl
isobutyl ketone/methyl tert-butyl ether/water; and isopropyl
acetate/methyl tert-butyl ether/water solvent systems. The Freebase
Solvate Form A (isopropyl acetate/water solvate) prepared in Method
A above, the Freebase Hydrate Form B prepared in Methods B and C
above, and these other crystalline freebase solvates or hydrates
that have been prepared are isostructural and exhibit similar PXRD
patterns. Notably, these crystalline freebase solvates and hydrates
are distinguishable from and exhibit a different PXRD pattern than
Freebase Hydrate Form C (a hemihydrate), which is described
below.
[0741] The Freebase Solvate Form A and Freebase Hydrate Form B that
were prepared were not stable after isolation at ambient conditions
and readily dehydrated to the Amorphous Freebase.
Example 3: Preparation of Freebase Hydrate Form C
[0742] A. Method A: Freebase Hydrate Form C from Ethanol/Water
[0743] A sample of the Amorphous Freebase of upadacitinib (2 g) was
transferred to a 500 mL beaker equipped with a stirring bar. EtOH
(50 g) was added to the beaker and stirred until all solids
dissolved. The solution was transferred to a 250 mL jacketed flask
equipped with a dispersing device. The solution was cooled to
6.degree. C. Water (150 g) was added to the solution and the
solution was subjected to high shear for two hours using the
dispersing device. After solid formation was observed, an
additional amount of water (50 g) was added to the resulting
suspension. The suspension was held overnight at ambient
temperature. Solids were isolated and examined on the following
day. Conversion to upadacitinib Freebase Hydrate Form C was
confirmed by PXRD analysis.
[0744] B. Method B: Freebase Hydrate Form C From Ethyl
Acetate/Heptane/Water
[0745] A crude reaction mixture assaying for 11.1 g of upadacitinib
was taken up in 2% water in EtOAc (70 g) and seeded with Freebase
Hydrate Form C (100 mg). The suspension was stirred overnight and
heptane (70 g) was added. The solids were collected by filtration,
washed with water saturated EtOAc/heptane (1/1, 100 mL), and dried
under vacuum at 50.degree. C. Conversion to upadacitinib Freebase
Hydrate Form C was confirmed by PXRD analysis.
[0746] As was observed with the Freebase Solvate Form A and the
Freebase Hydrate Form B, the Freebase Hydrate Form C also does not
readily crystallize from solution.
Example 4: Preparation of Tartrate Hydrate
[0747] Three methods for the preparation of upadacitinib tartrate
tetrahydrate (the "Tartrate Hydrate") are described below. Method A
describes an initial procedure that was used to prepare the
tartrate tetrahydrate. Method B describes a modified procedure used
to prepare the tartrate tetrahydrate at a larger scale. Method C
describes a further modified procedure used to prepare the tartrate
tetrahydrate. The modified procedure of Method C relative to the
procedure of Method B further reduces solidification of the filter
cake, a potential problem that potentially can impact
manufacturability and downstream processing.
[0748] A. Method A
[0749] A sample of the Amorphous Freebase of upadacitinib (28.2 mg)
was transferred to an amber vial. Water (200 .mu.L) and L-tartaric
acid (34.5 mg (approximately 3 equivalents)) were added to the
vial. The suspension was vortexed under ambient conditions until
all the solids dissolved. The solution in the vial was magnetically
stirred at 0.degree. C. The following day, the solids were isolated
from the solution and left at ambient temperature for a short
period of time prior to characterization. Conversion to the
upadacitinib Tartrate Hydrate (tetrahydrate) was confirmed by PXRD
analysis.
[0750] B. Method B
[0751] Upadacitinib (4.6 g) was added to a jacketed reactor
followed by the addition of isopropanol (6.5 mL) and IPAc (7.8 mL).
The slurry was mixed at ambient condition until the solids
dissolved. In a separate vial, L-tartaric acid (1.96 g) was
dissolved in deionized water (3.92 mL). The L-tartaric acid
solution was added to the reactor followed by the addition of
tartrate tetrahydrate seed crystals (28 mg). The suspension was
mixed for 30 minutes under ambient conditions. IPAc (71 mL) was
added in small aliquots over 2 hours. The crystallized suspension
was cooled to 5.degree. C. and equilibrated at 5.degree. C.
overnight. The suspension was discharged onto a filter and the
filter cake rinsed with 20 mL of water saturated IPAc. The filtered
solids were air-dried for two days. Conversion to the upadacitinib
Tartrate Hydrate (tetrahydrate) was confirmed by PXRD analysis.
[0752] C. Method C
[0753] Crystallization:
[0754] Upadacitinib (104 g) was added to a flask together with
isopropanol (222.7 g) and IPAc (375.8 g). The components were mixed
under ambient conditions until the solids dissolved. In a separate
flask, L-tartaric acid (61.6 g) was dissolved in water (98.3 g).
The contents of the two flasks were then added to a jacketed
reactor. Tartrate tetrahydrate seed crystals (1.55 g) were added to
the reactor solution. The resulting suspension was mixed overnight
under ambient conditions. IPAc (2542 g) was charged to the reactor
suspension over an 8 hour period.
[0755] Filtration, Washing and Drying:
[0756] Approximately half of the crystallized tartrate suspension
was charged to a jacketed agitated filter dryer. The suspension was
cooled inside the filter dryer to approximately 11.degree. C. The
suspension was filtered using positive pressure until a wet cake
was obtained. Water saturated IPAc (438 g) was charged to the
filter dryer and the suspension was mixed overnight at
approximately 11.degree. C. The suspension was filtered using
positive pressure until a wet cake was obtained. Water saturated
MTBE (110 g) was charged to the filter dryer. After 10 minutes, the
suspension was filtered with positive pressure until a wet cake was
obtained. Water saturated MTBE (261 g) was charged to the filter
dryer and the suspension was mixed at approximately 11.degree. C.
for 3.5 hours. The suspension was filtered with agitation using
positive pressure until a wet cake was obtained. The wet cake was
dried with constant agitation at a temperature of approximately
11.degree. C. under humidified nitrogen and positive pressure for
two days. Conversion to the upadacitinib Tartrate Hydrate
(tetrahydrate) was confirmed by PXRD analysis.
Example 5: Preparation of Freebase Anhydrate Form D
[0757] A sample of the Amorphous Freebase of upadacitinib was
dissolved in water-free EtOAc at a concentration of 19.6% (w/w). An
aliquot comprising approximately 1 mL was transferred to a 4 mL
vial equipped with a magnetic stirrer. The vial was sealed with
parafilm and mixed at 400 rpm on a magnetic stir plate at around
23.degree. C. for almost 8 weeks. The resulting slurry was filtered
and left at ambient conditions for a short period of time prior to
characterization. Conversion to Freebase Anhydrate Form D was
confirmed by PXRD analysis.
Example 6: Microscopy/Crystal Morphology
[0758] The solid state forms of upadacitinib were evaluated by
microscopy. Samples were examined by microscopic visual examination
using a polarizing microscope (model Eclipse E-600 POL, Nikon
Corp., Garden City, N.Y.). A color video camera was used to record
digital images (model DXC 390. Fryer Co., Inc., Huntley, Ill.).
Images were captured using MetaMorph Imaging System (version 4.6R8,
Universal Imaging Corporation, Downingtown, Pa.). Observations
regarding the crystal morphology of the samples are reported in
Table 13 below. Those of skill in the art will recognize that
variation in crystal shape and size may be observed depending upon
the specific crystallization conditions employed. The solvation
states and PXRD profiles reported in Table 13 correspond to the
information presented in the figures and subsequent examples of
this application.
TABLE-US-00013 TABLE 13 Solid Form Solvation/ Nomenclature Species
Hydration State Morphology Amorphous Freebase Anhydrous Blades
(when Freebase prepared via precipitation or dehydration of
Freebase Hydrate Form B) Freebase Solvate Freebase Isopropyl
Acetate/ Irregular Form A Water Solvate Freebase Hydrate Freebase
Labile Hydrate Blades Form B Freebase Hydrate Freebase Hemihydrate
Prisms Form C Tartrate Hydrate Tartrate Tetrahydrate Needles
Freebase Freebase Anhydrous Not Determined Anhydrate Form D
Example 7: PXRD Analysis
[0759] The solid state forms of upadacitinib listed in Table 13
were analyzed by X-ray powder diffraction ("PXRD"). The PXRD data
were collected with a G3000 diffractometer (Inel Corp., Artenay,
France) equipped with a curved position sensitive detector and
parallel beam optics. The diffractometer was operated with a copper
anode tube (1.5 kW fine focus) at 40 kV and 30 mA. An incident beam
germanium monochromator provided monochromatic K.alpha.1 radiation
.lamda.=1.540562 .ANG.). The diffractometer was calibrated using
the attenuated direct beam at one-degree intervals. Calibration was
checked using a silicon powder line position reference standard
(NIST 640c). Samples were prepared by spreading the sample powder
in a thin layer on an aluminum sample holder and gently leveling
with a glass microscope slide. The instrument was computer
controlled using the Symphonix software (Inel Corp., Artenay.
France) and the data was analyzed using the Jade software (version
6.5. Materials Data. Inc., Livermore, Calif.). The aluminum sample
holder was mounted on the rotating sample holder of the G3000
diffractometer and the diffraction data collected at ambient
conditions.
[0760] Tables 14-A through 14-E set out the significant parameters
of the main peaks in terms of 2.THETA. values and intensities for
the crystalline forms analyzed. It is known in the art that an
X-ray powder diffraction pattern may be obtained which has one or
more measurement errors depending on measurement conditions (such
as equipment, sample preparation or machine used). In particular,
it is generally known that intensities in an X-ray powder
diffraction pattern may fluctuate depending on measurement
conditions and sample preparation. For example, persons skilled in
the art of X-ray powder diffraction will realize that the relative
intensities of peaks may vary according to the orientation of the
sample under testing and on the type and setting of the instrument
used. The skilled person also will realize that the position of
reflections can be affected by the precise height at which the
sample sits in the diffractometer and the zero calibration of the
diffractometer. The surface planarity of the sample also may have
an effect on the results. A person skilled in the art will
appreciate that the diffraction pattern data presented below is not
to be construed as absolute and any crystalline form that provides
a power diffraction pattern substantially identical to those
disclosed below fall within the scope of the present disclosure
(for further information see Jenkins, R & Snyder, R. L.
`Introduction to X-Ray Powder Diffractometry`. John Wiley &
Sons, 1996).
[0761] The PXRD pattern corresponding to the Amorphous Freebase
(via precipitation) and the Amorphous Freebase (via dehydration)
are shown in FIGS. 17A and 17B, respectively.
[0762] The PXRD pattern corresponding to the Freebase Solvate Form
A is shown in FIG. 18. Peak listing of the experimental PXRD
pattern with relative intensities is given in Table 14-A below.
TABLE-US-00014 TABLE 14-A PXRD Peak Listing Freebase Solvate Form A
(Isopropyl Acetate/Water Solvate) PEAK POSITION (.degree. 2.THETA.)
RELATIVE INTENSITY 3.1 100.0 5.4 15.4 6.6 10.7 8.2 8.7 9.4 74.7
10.8 9.2 11.1 6.7 12.1 33.5 13.1 7.4 15.1 6.4 16.2 11.6 17.0 7.1
19.1 13.3 21.1 20.7 22.3 7.2 22.9 11.9 26.2 5.8 29.6 4.4
[0763] The PXRD pattern corresponding to the Freebase Hydrate Form
B is shown in FIG. 19. Peak listing of the experimental PXRD
pattern with relative intensities is given in Table 14-B below.
TABLE-US-00015 TABLE 14-B PXRD Peak Listing Freebase Hydrate Form B
PEAK POSITION (.degree. 2.THETA.) RELATIVE INTENSITY 3.1 100.0 6.1
3.4 7.9 4.6 9.3 54.8 10.7 3.1 12.0 27.1 12.4 6.3 13.0 3.3 13.7 4.3
14.9 7.5 15.6 4.2 16.0 3.5 17.1 3.7 18.8 7.0 20.8 13.4 22.9 6.6
23.3 4.5 24.0 6.6 24.6 4.2 25.0 12.4 26.0 4.7 26.9 5.1 28.1 3.3
28.9 2.5 29.8 4.1
[0764] The PXRD pattern corresponding to the Freebase Hydrate Form
C is shown in FIG. 20. Peak listing of the experimental PXRD
pattern with relative intensities is given in Table 14-C below.
TABLE-US-00016 TABLE 14-C PXRD Peak Listing Freebase Hydrate Form C
PEAK POSITION (.degree. 2.THETA.) RELATIVE INTENSITY 7.7 28.8 7.9
41.1 9.6 10.2 10.3 35.0 12.4 9.8 13.4 72.5 13.9 16.9 15.1 74.6 15.5
93.7 15.9 11.7 17.0 76.1 17.2 46.8 17.8 21.6 18.1 10.0 18.3 37.2
19.3 33.0 19.7 24.7 20.5 52.4 20.9 54.9 21.2 7.9 21.7 100.0 21.9
34.6 22.2 21.7 22.6 6.2 23.5 27.2 24.0 5.0 24.4 18 24.9 35.1 27.4
9.8 28.2 19.8 29.2 8.2 29.5 13.7 31.5 6.9
[0765] The PXRD pattern corresponding to the Tartrate Hydrate is
shown in FIG. 21. Peak listing of the experimental PXRD pattern
with relative intensities is given in Table 14-D below. The
experimental PXRD pattern is shown at the bottom of FIG. 21 and the
calculated PXRD pattern is shown at the top of FIG. 21.
TABLE-US-00017 TABLE 14-D PXRD Peak Listing Tartrate Hydrate PEAK
POSITION (.degree. 2.THETA.) RELATIVE INTENSITY 3.9 80.3 6.8 24.6
10.4 12.8 11.8 21.6 14.1 100.0 15.7 63.3 16.1 10.4 17.1 4.5 18.0
22.1 18.4 11.6 18.8 12.4 19.7 5.2 20.0 3.1 21.2 15.2 21.9 55.9 24.0
11.9 24.8 3.0 25.2 3.6 25.9 32.6 26.7 9.2 27.0 6.8 27.6 11.5 28.7
6.3 30.4 4.9 30.9 4.9 32.4 4.3 33.4 3.0
[0766] The PXRD pattern corresponding to the Freebase Anhydrate
Form D is shown in FIG. 22. Peak listing of the experimental PXRD
pattern with relative intensities is given in Table 14-E below.
TABLE-US-00018 TABLE 14-E PXRD Peak Listing Freebase Anhydrate Form
D PEAK POSITION (.degree. 2.THETA.) RELATIVE INTENSITY 4.0 20.6 8.0
29.3 9.7 52.1 11.2 7.5 12.0 9.8 13.0 1.4 14.2 100.0 14.5 65.7 16.1
3.1 17.2 7.5 18.4 24.3 19.0 23.5 20.3 43.1 21.4 18.5 23.0 35.7 23.8
18.3 24.7 35.8 25.6 6.0 26.1 14.5 27.4 11.7 28.2 9.3 28.7 5.2 30.3
6.6 31.1 1.3 31.9 3.8 32.7 1.0 33.3 5.1 34.8 0.7
Example 8: Clinical Study for Crohn's Disease
[0767] This trial was a multicenter, randomized, double-blind
placebo-controlled study of upadacitinib for the induction of
symptomatic and endoscopic remission in patient with moderately to
severely active Crohn's disease who have inadequately responded to
or are intolerant to immunosuppressants or anti-TNF therapy.
[0768] The trial consisted of a screening period of up to 30 days,
a 16 week double blind induction period, re-randomization at week
16, a 36 week double blind and open label phase and a 30 day follow
up period.
[0769] Approximately 220 patients with moderately to severely
active Crohn's disease--defined for purposes of this study as
having 1) Simplified Endoscopic Score for CD (SES-CD).gtoreq.6, (or
SES-CD.gtoreq.4 for patients with disease limited to the ileum), 2)
a CDAI.gtoreq.220 and .ltoreq.450, and 3) an average daily
liquid/soft stool frequency (SF).gtoreq.2.5 or an average daily
abdominal pain (AP) score .gtoreq.2.0)--were randomized in a
1:1:1:1:1:1 ratio to one of the schematics of the overall study
design shown in FIG. 1. [0770] 1. Group 1: upadacitinib 3 mg BID
capsules (IR) [0771] 2. Group 2: upadacitinib 6 mg BID capsules
(IR) [0772] 3. Group 3: upadacitinib 12 mg BID capsules (IR) [0773]
4. Group 4: upadacitinib 24 mg BID capsules (IR) [0774] 5. Group 5:
upadacitinib 24 mg QD dose (IR) (two 12 mg capsules administered
simultaneously) [0775] 6. Group 6: Placebo
[0776] The 16 week induction period began at the BL visit (week 0)
and ended at the week 16 visit. The randomization at BL was
stratified by endoscopic disease severity (SES-CD<15 and
.gtoreq.15). Safety and efficacy evaluations were performed through
the end of the study. The end of the study was defined as the date
the last patient completed the last follow up visit.
[0777] At week 16, patients who had completed the induction period
were re-randomized to one of four double-blinded doses of
upadacitinib: 3 mg BID, 6 mg BID, 12 mg BID, or 24 mg QD (patients
administered two 12 mg capsules simultaneously). The
re-randomization were stratified by dose received during the first
16 weeks and overall response (responder versus non-responder) at
week 16.
[0778] Each treatment group received the corresponding dose of
upadacitinib or placebo orally twice daily. Patients receiving the
24 mg QD dose were administered two 12 mg capsules simultaneously
orally once daily. At week 12 and week 16, patients were evaluated
for clinical remission (average daily SF.ltoreq.1.5 and not worse
than baseline and average daily AP.ltoreq.1.0 and not worse than
baseline). Patients were randomly assigned (1:1) to have an
endoscopy at either week 12 or at week 16, and were evaluated for
endoscopic remission (SES-CD.ltoreq.4 and at least a two point
reduction in SES-CD versus BL and no subscore >1 in any
individual variable used to calculate SES-CD) at week 12 or week
16.
[0779] The central reader endoscopic score was used for calculating
the endoscopic response for the evaluation of the efficacy
endpoints. However, for stratification at the time of
re-randomization, the endoscopic score at BL from central reader
and the endoscopic score at week 12 or week 16 from site local
reader were used in order to determine response status.
[0780] The co-primary endpoints for efficacy were: [0781]
endoscopic remission at week 12 or 16 [0782] clinical remission at
week 16
[0783] Secondary endpoints to measure efficacy included: [0784]
CDAI<150 at week 16 [0785] decrease in CDAI of .gtoreq.70 points
from BL at week 16 [0786] clinical remission at week 12 [0787]
remission at week 16 (endoscopic remission at week 12 or 16 and
clinical remission at week 16) [0788] response at week 16
(endoscopic response at week 12 or 16 and clinical response at week
16) [0789] endoscopic response at week 12 or 16 [0790] clinical
response at week 16 [0791] whether a subject with an average daily
SF.gtoreq.2.5 and an average daily AP score .gtoreq.2.0 at BL
achieves clinical remission at week 16 [0792] whether a subject
taking corticosteroids at BL who discontinues corticosteroid use
achieves CDAI<150 at week 16 [0793] whether a subject taking
corticosteroids at BL who discontinues corticosteroid use achieves
endoscopic remission at week 12 or week 16 and clinical remission
at week 16 [0794] whether a subject taking corticosteroids at BL
who discontinues corticosteroid use achieves clinical remission at
week 16 [0795] whether a subject taking corticosteroids at BL who
discontinues corticosteroid use achieves endoscopic remission at
week 12 or week 16 [0796] change from BL in fecal calprotectin
level at week 16 [0797] change from BL in hs-CRP (high sensitivity
C-reactive protein) at week 16 [0798] change in the Inflammatory
Bowel Disease Questionnaire (IBDQ) from BL at week 16 [0799]
whether a subject with isolated ileal Crohn's Disease achieves
remission at week 16 [0800] whether a subject achieves remission at
week 52 [0801] whether a subject achieves endoscopic remission at
week 52 [0802] whether a subject achieves clinical remission at
week 52 [0803] whether a subject achieves response at week 52
[0804] endoscopic response at week 52 [0805] clinical response at
week 52 [0806] whether a subject taking corticosteroids at BL who
discontinued corticosteroid use achieves CDAI<150 at week 52
[0807] whether a subject taking corticosteroids at BL who
discontinued corticosteroid use achieves remission at week 52
[0808] whether a subject taking corticosteroids at BL who
discontinued corticosteroid use achieves clinical remission at week
52 [0809] whether a subject taking corticosteroids at BL who
discontinued corticosteroid use achieves endoscopic remission at
week 52 [0810] CDAI<150 at week 52 [0811] decrease in
CDAI.gtoreq.70 points from BL at week 52 [0812] change from BL in
fecal calprotectin level at week 52 [0813] change from BL in hs-CRP
at week 52 [0814] change in IBDQ from BL at week 52 [0815] whether
subject with isolated ileal Crohn's Disease achieves remission at
week 52 [0816] change in extra-intestinal manifestations (EIMS)
from BL at week 52
Methods
[0817] The study comprised two treatment periods: a 16 week
double-blind induction period and a 36 week double-blind extension
phase. In the induction period, patients with a diagnosis of ileal,
colonic, or ileocolonic Crohn's disease for .gtoreq.3 months prior
to BL and confirmed by endoscopy during the screening period, a
CDAI.gtoreq.220 and .ltoreq.450, and who have inadequately
responded to or experienced intolerance to previous treatment with
an anti-TNF agent (e.g. infliximab, adalimumab or certolizumab
pegol), were assigned to receive one of the following doses of
upadacitinib 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID or 24 mg QD
or placebo. The co-primary endpoints were endoscopic remission at
week 12 or week 16 and clinical remission at week 16. Secondary
endpoints included CDAI<150 at week 16 and endoscopic response
at week 12 or 16.
[0818] Eligible patients were aged 18 to 75 years. They had a
diagnosis of CD for at least three months and at screening had
moderate-to-severe CD, defined as a 1) SES-CD.gtoreq.6 (or
.gtoreq.4 for patients with disease limited to the ileum), 2) a
CDAI of 220-450, and 3) an average daily liquid/soft SF score
.gtoreq.2.5 or an average daily AP score .gtoreq.2.0. Patients had
inadequately responded to or experienced intolerance to previous
treatment with an anti-TNF agent. Patients with a current diagnosis
of ulcerative colitis, collagenous colitis or indeterminate colitis
as well as patients with previous exposure to a JAK inhibitor were
excluded. See Table 15 below for key demographics and BL
characteristics.
TABLE-US-00019 TABLE 15 Key Demographics and Baseline
Characteristics PBO 3 mg BID 6 mg BID 12 mg BID 24 mg BID 24 mg QD*
N = 37 N = 39 N = 37 N = 36 N = 36 N = 35 Demographics and
Characteristics Female, n (%) 24 (64.9) 19 (48.7) 21 (56.8) 17
(47.2) 25 (69.4) 19 (54.3) Median Age, yrs 40.0 37.0 39.0 41.0 43.5
41.0 Disease duration, yrs 11.80 13.25 11.82 13.29 14.83 14.22
CDAI, mean 288.4 298.0 316.1 305.1 294.3 315.1 SF, mean 5.85 5.63
7.38 6.45 5.64 6.73 AP score, mean 1.67 1.87 1.80 1.82 1.63 1.89
SES-CD, mean 15.8 14.7 16.2 15.6 14.3 13.4 hsCRP, mean (mg/dL) 20.8
23.6 17.9 26.9 17.1 17.1 IBDQ, mean 118.0 115.2 113.7 115.2 113.8
120.7 Prior anti-TNFs, n (%) 0 2 (5.4) 2 (5.1) 1 (2.7) 2 (5.6) 0 2
(5.7) 1 15 (40.5) 18 (46.2) 12 (32.4) 6 (16.7) 10 (27.8) 10 (28.6)
2 15 (40.5) 15 (38.5) 20 (54.1) 24 (66.7) 15 (41.7) 16 (45.7) 3 5
(13.5) 4 (10.3) 4 (10.8) 4 (11.1) 9 (25.0) 7 (20.0) .gtoreq.4 0 0 0
0 2 (5.6) 0 Steroid use at BL, n (%) 15 (40.5) 20 (51.3) 18 (48.6)
18 (50.0) 15 (41.7) 10 (28.6) Prior non-anti-TNF 14 (38) 15 (39) 19
(51) 15 (42) 16 (44) 14 (40) biologics (%) vedolilzumab, n (%) 10
(27) 12 (31) 14 (38) 15 (42) 12 (33) 12 (34) *24 mg QD dose is two
12 mg doses given simultaneously
TABLE-US-00020 TABLE 16 Analysis of Primary Efficacy Endpoints PBO
3 mg BID 6 mg BID 12 mg BID 24 mg BID 24 mg QD* N = 37 N = 39 N =
37 N = 36 N = 36 N = 35 Endoscopic 0 (0.0%) 4 (10.3%) 3 (8.1%) 3
(8.3%) 8 (22.2%) 5 (14.3%) Remission.sup.1 (week 12 or16) Risk
Difference 10.3 8.1 8.3 22.2 14.3 P-value 0.056 0.108 0.099 0.004
0.025 94% CI -(0.3, 201.) (-1.6, 16.4) (-1.5, 6.8) (6.8, 35.2)
(1.8, 25.5) Clinical Remission.sup.2 4 (10.8%) 5 (12.8%) 10 (27.0%)
4 (11.1%) 8 (22.2%) 5 (14.3%) (week 16) Risk difference 2.0 0.3
11.4 3.5 P-value 0.740 0.082 0.952 0.205 0.607 95% CI (-12.3, 17.3)
(-2.0, 34.3) (-14.1, 15.0) (-6.1, 28.5) (-11.5, 19.6) Note:
Statistical significance was indicated by p value .ltoreq. 0.10
.sup.1Endoscopic remission: SES-CD .ltoreq. 4 and at least two
point reduction in SES-CD versus BL and no subscore > 1 in any
individual variable .sup.2clinical remission: average daily
liquid/very soft SF score .ltoreq. 1.5 and not worse than BL AND
average daily AP score .ltoreq. 1.0 and not worse than BL *24 mg QD
dose is two 12 mg doses given simultaneously
TABLE-US-00021 TABLE 17 Analysis of Secondary Efficacy Endpoints
(NRI) PBO 3 mg BID 6 mg BID 12 mg BID 24 mg BID 24 mg QD.sup.&
N = 37 N = 39 N = 37 N = 36 N = 36 N = 35 Week 16 Clinical
Response.sup.1 12 (32.4%) 17 (43.6%) 21 (56.8%)* 17 (47.2%) 22
(61.1%)* 17 (48.6%) Endoscopic Response 5 (13.5%) 9 (23.1%) 16
(43.2%)* 14 (38.9%)* 18 (50.0%)* 17 (48.6%)* (weeks 12/16).sup.2
Clinical Remission and 0 1 (2.6%) 2 (5.4%) 1 (2.8%) 3 (8.3%)* 2
(5.7%) Endoscopic Remission Clinical and 1 (2.7%) 6 (15.4%)* 12
(32.4%)* 10 (27.8%)* 14 (38.9%)* 12 (34.3%)* Endoscopic Response
CDAI < 150 6 (16.2%) 8 (20.5%) 11 (29.7%) 14 (38.9%)* 11 (30.6%)
7 (20.0%) CR100.sup.5 10 (27.0%) 13 (33.3%) 15 (40.5%) 16 (44.4%)
20 (55.6%)* 11 (31.4%) CR70.sup.6 13 (35.1%) 18 (46.2%) 20 (54.1%)
16 (44.4%) 23 (63.9%)* 17 (48.6%) Steroid-free 0/15 (0%) 0/20 (0)%)
1/18 (5.6%) 1/18 (5.6%) 2/15 (13.3%) 0/10 (0%) remisison.sup.3
Steroid-free and 0/15 (0%) 4/20 (20.0%) 4/18 (22.2%) 7/18 (38.9%)*
5/15 (33.3%)* 1/10 (10.0%) CDAI < 150.sup.3 Steroid-free and
0/15 (0%) 5/20 (25%) 9/18 (50%) 8/18 (44%) 10/15 (67%) 3/10 (30%)
clinical response.sup.3 Week 12 Clinical Remission.sup.4 4 (10.8%)
4 (10.3%) 11 (29.7%)* 5 (13.9%) 9 (25.0%) 3 (8.6%) Clinical
Response.sup.1 13 (35.1%) 21 (53.8%) 24 (64.9%)* 19 (52.8%) 20
(55.6%) 18 (51.4%) CDAI < 150 24.3% 18.4% 41.7% 47.2%* 38.9%
22.9% CR70.sup.6 35.1% 38.5% 59.5%* 47.2% 58.3%* 51.4% CR100.sup.5
29.7% 30.8% 51.4%* 41.7% 52.8%* 40.0% *Statistical significance was
indicated by p value .ltoreq. 0.10 .sup.&24 mg QD dose is two
12 mg doses given simultaneously .sup.1Clinical response: average
daily liquid/very soft SF score .gtoreq. 30% reduction from BL and
average daily AP not greater than BL and/or average daily AP score
.gtoreq. 30% reduction from BL and average daily liquid/very soft
SF score not greater than BL .sup.2Endoscopic response: >25%
decrease in SES-CD from BL, as scored by central reviewer
.sup.3Among subjects taking steroids at BL .sup.4Clinical
remission: average daily liquid/very soft stool frequency score
.ltoreq. 1.5 and not worse than BL AND average daily AP .ltoreq.
1.0 and not worse than BL .sup.5Decrease in CDAI score .gtoreq. 100
from baseline .sup.6Decrease in CDAI score .gtoreq. 70 from
baseline
TABLE-US-00022 TABLE 18 Analysis of Additional Efficacy Endpoints
PBO 3 mg BID 6 mg BID 12 mg BID 24 mg BID 24 mg QD**
Endpoints.sup.& N = 33 N = 38 N -33 N = 34 N -30 N = 32
Modified Clinical 4 (12.1%) 6 (15.8%) 10 (30.3%)* 9 (26.5%) 11
(36.7%)* 6 (18.8%) Remission.sup.1 (week 16) Endoscopic 1 (3.0%)
12.8% 18.9%* 27.8%* 36.1%* 25.7%* Improvement.sup.2 (Week 12 or 16)
.sup.&Includes subjects with baseline SF .gtoreq. 4.0 or AP
.gtoreq. 2.0. *Statistical significance was indicated by p value
.ltoreq. 0.10. **24 mg QD dose is two 12 mg doses given
simultaneously .sup.1Clinical remission: average daily SF .ltoreq.
2.8 and not greater than Baseline AND average daily AP .ltoreq. 1.0
and not greater than Baseline .sup.2Endoscopic improvement: SES-CD
> 50% reduction from BL or at least a 2 point reduction in
SES-CD from BL or endoscopic remission
Results
[0819] Baseline demographics and disease characteristics were
similar between study arms. In total there were 95 males and 125
females, with a mean age of 42.5 years and mean CDAI of 302.83;
96.0% percent of patients had previously been exposed to 21 TNF
antagonists. At week 12/16, endoscopic remission was achieved by
10.3%, 8.1%, 8.3%, 22.2% and 14.3% of patients treated with 3 mg
BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg QD, respectively, of
upadacitinib, compared with 0% of patients treated with placebo
(p=0.056, p=0.108, p=0.099, p=0.004, p=0.025, respectively, see
Table 16). At week 16, clinical remission was achieved by 12.8%,
27.0%, 11.1%, 22.2% and 14.3% of patients treated with 3 mg BID, 6
mg BID, 12 mg BID, 24 mg BID and 24 mg QD, respectively, of
upadacitinib, compared 10.8% of patients treated with placebo
(p=0.740, p=0.082, p=0.952, p=0.205, p=0.607, respectively, see
Table 16). Clinical remission was observed in some patients as
early as week 12. The percentage of patients achieving clinical
remission at week 12 is shown in FIG. 6A (patients not on baseline
steroids) and FIG. 6B (patients who were on steroids at baseline,
and underwent mandatory taper of steroid dose starting at week 2).
The steroid taper consisted of a weekly decrease by 5 mg/day of
prednisone (or equivalent) for doses >10/mg/day of prednisone
(or equivalent) until a 10 mg/day (or equivalent) dose was reached,
then a weekly decrease by 2.5 mg/day (or equivalent) until
discontinuation. Upadacitinib was shown to induce clinical
remission as early as week 12.
[0820] Clinical response was achieved at week 16 by 43.6%, 56.8%,
47.2%, 61.1% and 48.6% of patients treated with 3 mg BID, 6 mg BID,
12 mg BID, 24 mg BID and 24 mg QD, respectively, of upadacitinib,
compared with 32.4% of patients treated with placebo. Endoscopic
response was achieved at week 12 or week 16 by 23.1%, 43.2%, 38.9%,
50.0% and 48.6% of patients treated with 3 mg BID, 6 mg BID, 12 mg
BID, 24 mg BID and 24 mg QD, respectively, of upadacitinib,
compared with 13.5% of patients treated with placebo.
[0821] Clinical remission and endoscopic remission was achieved at
week 16 by 2.6%, 5.4%, 2.8%, 8.3% and 5.7% of patients treated with
3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg QD,
respectively, of upadacitinib, compared with 0% of patients treated
with placebo. Clinical and endoscopic response was achieved at week
16 by 15.4%, 32.4%, 27.8%, 38.9% and 34.3% of patients treated with
3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg QD,
respectively, of upadacitinib, compared with 2.70/o of patients
treated with placebo. Results are shown in Table 17.
[0822] Clinical remission was achieved at week 12 by 10.3%, 29.7%,
13.9%, 25.0%/0 and 8.6% of patients treated with 3 mg BID, 6 mg
BID, 12 mg BID, 24 mg BID and 24 mg QD, respectively, of
upadacitinib, compared with 10.8% of patients treated with placebo.
Clinical response was achieved at week 12 by 53.8%, 64.9%, 52.8%,
55.6% and 51.4% of patients treated with 3 mg BID, 6 mg BID, 12 mg
BID, 24 mg BID and 24 mg QD, respectively, of upadacitinib,
compared with 35.1% of patients treated with placebo. Results are
shown in Table 17. The percentage of patients achieving clinical
response at week 12 is shown in FIG. 6A (patients not on baseline
steroids) and FIG. 6B (patients who were on steroids at baseline,
and underwent mandatory taper of steroid dose starting at week
2).
[0823] Modified clinical remission was achieved at week 16 by
15.8%, 30.3%, 26.5%, 36.7%, and 18.8% of patients treated with 3 mg
BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg QD, respectively, of
upadacitinib, compared with 12.1% of patients treated with placebo.
Results are shown in Table 18.
[0824] Endoscopic improvement was achieved at week 12 or week 16 by
12.8%, 18.9%, 27.8%, 36.1%, and 25.7% of patients treated with 3 mg
BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg QD, respectively, of
upadacitinib, compared with 3.0% of patients treated with placebo.
Results are shown in Table 18. Of the patients who were evaluated
for endoscopic improvement at week 12, 10.5%, 13.3%, 25%, 33.3%,
and 12.5% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID,
24 mg BID and 24 mg QD, respectively, of upadacitinib, achieved
endoscopic improvement by week 12, compared with 0% of patients
treated with placebo. Of the patients who were evaluated for
endoscopic improvement at week 16, 15.8%, 27.8%, 27.3%, 25%, and
31.3% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID, 24 mg
BID and 24 mg QD, respectively, of upadacitinib, achieved
endoscopic improvement by week 16, compared with 6.7% of patients
treated with placebo. These results are shown in Table 19. These
results show that endoscopic improvement was observed as early as
week 12.
[0825] By week 4 of the induction period, among Crohn's patients
tapering corticosteroids, 13.3%, 9.5%, 11.1%, 11.8%, 6.7% and 10%
respectively were able to discontinue steroids with placebo, 3 mg
BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg BID, respectively. By
week 8 of the induction period, among Crohn's patients tapering
corticosteroids, 26.7%, 23.8%, 44.4%, 64.7%, 53.3% and 40%
respectively were able to discontinue steroids 3 mg BID, 6 mg BID,
12 mg BID, 24 mg BID and 24 mg BID, respectively. By week 12 of the
induction period, among Crohn's patients were able to discontinue
steroids, 33.3%, 28.6%, 55.6%, 76.5%, 60% and 40% respectively were
able to reduce their steroid dose by .gtoreq.50% with placebo, 3 mg
BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg BID, respectively. By
week 16 of the induction period, among Crohn's patients tapering
corticosteroids, 20%, 38.1%, 55.6%, 64.7%, 74.3% and 40%
respectively were able to reduce their steroid dose by .gtoreq.50%
with placebo, 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg
BID, respectively.
[0826] By week 4 of the induction period, among Crohn's patients
tapering corticosteroids, 20%, 42.9%, 50%, 82.4%, 46.7% and 40%
respectively were able to reduce their steroid dose by .gtoreq.50%
with placebo, 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg
BID, respectively. By week 8 of the induction period, among Crohn's
patients tapering corticosteroids, 55.3%, 42.9%, 66.7%, 88.2%,
66.7% and 60/o respectively were able to reduce their steroid dose
by 50/o with placebo, 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and
24 mg BID, respectively. By week 12 of the induction period, among
Crohn's patients tapering corticosteroids, 46.7%, 38.1%, 61.1%,
88.2%, 60% and 40% respectively were able to reduce their steroid
dose by .gtoreq.50% with placebo, 3 mg BID, 6 mg BID, 12 mg BID, 24
mg BID and 24 mg BID, respectively. By week 16 of the induction
period, among Crohn's patients tapering corticosteroids, 33.3%,
38.1%, 66.7%, 88.4%, 77.3% and 40% respectively were able to reduce
their steroid dose by .gtoreq.50% with placebo, 3 mg BID, 6 mg BID,
12 mg BID, 24 mg BID and 24 mg BID, respectively.
[0827] At the end of the 16 week induction period, among Crohn's
patients who discontinued corticosteroids, 11.1%, 5.9%, 20% and 10%
achieved endoscopic remission with, 6 mg BID, 12 mg BID, 24 mg BID
and 24 mg BID, respectively. At the end of the 16 week induction
period, among patients who discontinued corticosteroids, 6.7%,
4.8%, 16.7%, 17.6%, 20% and 20% achieved endoscopic response with
placebo, 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 MG BID,
respectively. At the end of the 16 week induction period, among
patients who discontinued corticosteroids, 14.3%, 22.2%, 11.8%,
33.3% and 10% achieved clinical remission with 3 mg BID, 6 mg BID,
12 mg BID, 24 mg BID and 24 MG BID, respectively. At the end of the
16 week induction period, among patients who discontinued
corticosteroids 14.3%, 26.7%, 25.0%, 36.4% and 10% achieved
modified clinical remission with 3 mg BID, 6 mg BID, 12 mg BID, 24
mg BID and 24 MG BID, respectively. At the end of the 16 week
induction period, among patients who discontinued corticosteroids
19.0%, 22.2%, 41.2%, 33.3% and 10% achieved CDAI<150 with 3 mg
BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 MG BID, respectively.
The taper consisted of a weekly decrease by 5 mg/day of prednisone
(or equivalent) for doses >10/mg/day of prednisone (or
equivalent) until a 10 mg/day (or equivalent) dose was reached,
then a weekly decrease by 2.5 mg/day (or equivalent) until
discontinuation.
TABLE-US-00023 TABLE 19 Analysis of Endoscopic Improvement by Week
Evaluated PBO 3 mg BID 6 mg BID 12 mg BID 24 mg BID 24 mg QD Week
12 N = 18 N = 19 N = 15 N = 12 N = 18 N = 16 Endoscopic 0% 10.5%*
13.3% 25%* 33.3%* 12.5% Improvement PBO 3 mg BID 6 mg BID 12 mg BID
24 mg BID 24 mg QD Week 16 N = 15 N = 19 N = 18 N = 22 N = 12 N =
16 Endoscopic 6.7% 15.8% 27.8% 27.3% 25% 31.3%* Improvement
*Statistical significance was indicated by p value
.ltoreq.0.10.
[0828] This study included refractory patients with moderately to
severely active Crohn's disease, who have had Crohn's disease for
more than ten years and who have failed several treatments,
including biologic treatments. Table 15 above shows the number of
patients in the study that received prior anti-TNF treatment,
treatment with prior non-anti-TNF biologics, treatment with
vedolilzumab, and who were being treated with steroids at baseline,
as well as the average duration of Crohn's disease at baseline.
Typically, because refractory patients are treated with different
therapeutics, the efficacy of each treatment progressively
decreases. Surprisingly, however, the current study demonstrated
that when treated with upadacitinib, the refractory patients showed
unprecedented efficacy. The results for refractory patients in the
study are shown in FIG. 9.
[0829] As shown by FIG. 9, refractory patients treated with
upadacitinib achieved clinical remission and endoscopic response at
unprecedented rates. At week 16, 15.8% of refractory patients
treated with 3 mg BID of upadacitinib achieved clinical remission.
At week 16, 30.3% of refractory patients treated with 6 mg BID of
upadacitinib achieved clinical remission. At week 16, 26.5% of
refractory patients treated with 12 mg BID of upadacitinib achieved
clinical remission. At week 16, 36.7% of refractory patients
treated with 24 mg QD (two 12 mg BID doses given simultaneously)
achieved clinical remission.
[0830] In addition, as also shown in FIG. 9, a surprising
proportion of refractory patients treated with upadacitinib
achieved endoscopic remission at 12 or 16 weeks. 13.2% of
refractory patients treated with 3 mg BID of upadacitinib achieved
endoscopic remission at 12 or 16 weeks. 21.2% of refractory
patients treated with 6 mg BID of upadacitinib achieved endoscopic
remission at 12 or 16 weeks. 29.4% of refractory patients treated
with 2 mg BID of upadacitinib achieved endoscopic remission at 12
or 16 weeks. 33.3% of refractory patients treated with 24 mg QD
(two 12 mg doses given simultaneously) of upadacitinib achieved
endoscopic remission at 12 or 16 weeks.
[0831] The relationship between upadacitinib plasma concentrations
and the primary endpoints and certain secondary and additional
endpoints is set forth in FIGS. 3A-3I. Exposure-response
relationships were observed for clinical response, clinical
remission, CDAI remission (CDAI<150), endoscopic response,
endoscopic improvement, and endoscopic remission.
Safety
[0832] The incident of adverse events was numerically higher
(.about.3-13%) in upadacitinib dose groups, compared to placebo,
with no clear dose-relationship. Severe adverse events and
treatment discontinuations due to adverse events were
lower/comparable across all upadacitinib dose groups compared to
placebo except in the 12 mg BID dose group. There were no treatment
emergent deaths in the study. Overall, the incidence of adverse
events of special interest were low (except for infections) and
similar across all treatment groups. Infections were increased in
all upadacitinib BID dose groups compared to placebo. Two
adjudicated major adverse cardiac events (MACE) were observed in
the 12 mg BID dose group (two had an acute myocardial
infarction).
[0833] The relationship between upadacitinib plasma concentration
and the change from baseline in hemoglobin levels, anemia. LDL and
HDL cholesterol, neutropenia, lymphopenia, and natural killer (NK)
cell levels was determined, and the results shown in FIGS. 5A-5H.
Exposure-response relationships for effects of upadacitinib on NK
cells, neutrophils, LDL and HDL cholesterol in Crohn's patients
were generally consistent with those previously observed in RA
patients. Compared to RA patients (data not shown), subjects with
Crohn's had lower decreases in hemoglobin (FIG. 5A).
Example 9: Model Predicted Efficacy for Once-Daily Doses
[0834] Based on the data obtained in Example 8 for administration
of an immediate release (IR) formulation of upadacitinib BID, the
exposure-response relationships (simulating for 200 patients/arm)
for 15 mg, 30 mg, and 45 mg modified-release QD doses of
upadacitinib, for placebo, for 6 mg, 12 mg, 18 mg, and 24 mg IR BID
doses of upadacitinib, and for 24 mg IR QD doses of upadacitinib
was predicted. The full time-course for the different clinical
endpoints was analyzed using Markov analyses. The Marko models
allowed transition between response, no response, and dropouts. The
models evaluated C.sub.p, C.sub.ave, C.sub.min, and C.sub.max as
predictors for drug efficacy. The different endoscopic endpoints at
Week 12/16 were analyzed using logistic regression analyses. Then,
the models were used to simulate clinical response, clinical
remission, CDAI<150, endoscopic response, endoscopic improvement
and endoscopic remission at Weeks 12 and 16 (when applicable) for
different dose regimens for both the immediate and modified release
formulation by back transforming exposures to doses. The results
are set forth in FIGS. 4A-4F.
[0835] This modelling suggests 1-3% improvements in clinical
parameters between doses with the MR formulation.
Example 10: Clinical Study for Crohn's Disease: Long-Term Efficacy
and Safety of Upadacitinib in Moderate to Severe Crohn's
Disease
[0836] In Example 10, the extension phase of the Example 8 clinical
study was studied and discussed. The trial was a multicenter,
randomized, double-blind placebo-controlled study of upadacitinib
for the induction of symptomatic and endoscopic remission in
patient with moderately to severely active Crohn's disease who have
inadequately responded to or are intolerant to immunosuppressants
or anti-TNF therapy.
[0837] The trial consisted of a screening period of up to 30 days,
a 16 week double blind induction period, re-randomization at week
16, a 36 week double blind and open label phase and a 30 day follow
up period.
[0838] Approximately 220 patients with moderately to severely
active Crohn's disease--defined for purposes of this study as
having 1) Simplified Endoscopic Score for CD (SES-CD).gtoreq.6, (or
SES-CD.gtoreq.4 for patients with disease limited to the ileum), 2)
a CDAI.gtoreq.220 and .ltoreq.450, and 3) an average daily
liquid/soft stool frequency (SF).gtoreq.2.5 or an average daily
abdominal pain (AP) score .gtoreq.2.0)--were randomized in a
1:1:1:1:1:1 ratio to one of the schematics of the overall study
design shown in FIG. 1. [0839] 1. Group 1: upadacitinib 3 mg BID
capsules (IR) [0840] 2. Group 2: upadacitinib 6 mg BID capsules
(IR) [0841] 3. Group 3: upadacitinib 12 mg BID capsules (IR) [0842]
4. Group 4: upadacitinib 24 mg BID capsules (IR) [0843] 5. Group 5:
upadacitinib 24 mg QD dose (IR) (two 12 mg capsules administered
simultaneously) [0844] 6. Group 6: Placebo
[0845] The 16 week induction period began at the BL visit (week 0)
and ended at the week 16 visit. The randomization at BL was
stratified by endoscopic disease severity (SES-CD<15 and
.gtoreq.15). Safety and efficacy evaluations were performed through
the end of the study. The end of the study was defined as the date
the last patient completed the last follow up visit.
[0846] At week 16, patients who completed the 16-week induction
phases were re-randomised 1:1:1 to double-blind upadacitinib at 3
mg twice daily (BID), 12 mg BID or 24 mg daily (QD) for 36 weeks. A
protocol amendment stopped enrolment in the 24 mg QD arm and
initiated a 6 mg BID arm. A total of 180 patients were
re-randomised to one of four double-blinded doses of upadacitinib:
[0847] 1. Group 1: upadacitinib 3 mg BID capsules (IR) [0848] 2.
Group 2: upadacitinib 6 mg BID capsules (IR) [0849] 3. Group 3:
upadacitinib 12 mg BID capsules (IR) [0850] 4. Group 4:
upadacitinib 24 mg QD dose (IR) (two 12 mg capsules administered
simultaneously)
[0851] The re-randomization was stratified by dose received during
the first 16 weeks and overall response (responder versus
non-responder) at week 16.
[0852] Each treatment group received the corresponding dose of
upadacitinib orally once or twice daily. Patients receiving the 24
mg QD dose were administered two 12 mg capsules simultaneously
orally once daily. At week 52, patients were evaluated for clinical
remission (average daily SF.ltoreq.1.5 and not worse than baseline
and average daily AP.ltoreq.1.0 and not worse than baseline),
CDAI<150, modified clinical remission (SF.ltoreq.2.8 and
AP.ltoreq.1.0, both not worse than BL in patients with SF.gtoreq.4.
AP.gtoreq.2.0 at BL), clinical response (.gtoreq.30% decrease in SF
or AP, both not worse than BL), endoscopic remission
(SES-CD.ltoreq.4 and .gtoreq.2-point reduction from BL and no
subscore >1), endoscopic response (SES-CD reduction >50% from
BL or endoscopic remission) and change from BL in C-reactive
protein (CRP) and faecal calprotectin (FC).
[0853] The co-primary endpoints for efficacy were the same as the
endpoints in Example 8 study.
Methods
[0854] The study comprised two treatment periods: a 16 week
double-blind induction period and a 36 week double-blind extension
phase. In the induction period, patients with a diagnosis of ileal,
colonic, or ileocolonic Crohn's disease for .gtoreq.3 months prior
to BL and confirmed by endoscopy during the screening period, a
CDAI.gtoreq.220 and .ltoreq.450, and who have inadequately
responded to or experienced intolerance to previous treatment with
an anti-TNF agent (e.g. infliximab, adalimumab or certolizumab
pegol), were assigned to receive one of the following doses of
upadacitinib 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID or 24 mg QD
or placebo. The co-primary endpoints were endoscopic remission at
week 12 or week 16 and clinical remission at week 16. Secondary
endpoints included CDAI<150 at week 16 and endoscopic response
at week 12 or 16. In the extension phase, patients who completed
the 16-week induction phases were re-randomised 1:1:1 to
double-blind upadacitinib at 3 mg twice daily (BID), 12 mg BID or
24 mg daily (QD) for 36 weeks. A protocol amendment stopped
enrolment in the 24 mg QD arm and initiated a 6 mg BID arm.
Clinical remission (average daily stool frequency [SF].ltoreq.1.5
and abdominal pain score [AP].ltoreq.1.0, both not worse than
Baseline [BL]), CDAI<150, modified clinical remission
(SF.ltoreq.2.8 and AP.ltoreq.1.0, both not worse than BL in
patients with SF.gtoreq.4. AP.gtoreq.2.0 at BL), clinical response
(.gtoreq.30% decrease in SF or AP, both not worse than BL),
endoscopic remission (SES-CD.ltoreq.4 and .gtoreq.2-point reduction
from BL and no subscore >1), endoscopic response (SES-CD
reduction >50% from BL or endoscopic remission) and change from
BL in C-reactive protein (CRP) and faecal calprotectin (FC) were
analysed at week 52 in patients with either both clinical and
endoscopic response or clinical response at week 16. Endoscopies
were evaluated at BL, 12/16 and 52 weeks by a central reader.
Patients who received open label upadacitinib (escape) or
prematurely discontinued prior to week 52 were considered
non-responders (non-responder imputation). Adverse events were
collected throughout the study up to 30 days after the last
upadacitinib dose.
[0855] Eligibility, key demographics and BL characteristics of the
patients were essentially the the same as those in Example 8
study.
TABLE-US-00024 TABLE 20 Analysis of Primary and Secondary Efficacy
Endpoints (Clinical and endoscopic endpoints at Week 52 in the
CELEST study) 3 mg BID 6 mg BID 12 mg BID 24 mg QD.sup.&
Endpoint at Week 52 N = 32 N = 14 N = 29 N = 19 Among subjects who
achieved clinical response and endoscopic response at Week 16
Modified clinical remission.sup.a, n(%) 7 (41.2).sup.b 5
(62.5).sup.b 11 (73.3).sup.b 4 (40.0).sup.b Endoscopic
response.sup.c, % 10 (50.0).sup.d 4 (50.0).sup.d 11 (68.8).sup.d 3
(30.0).sup.d Among subjects who achieved clinical response at Week
16 Modified clinical remission, n (%) 8 (28.6).sup.e 6 (42.9).sup.e
14 (51.9).sup.e 7 (38.9).sup.e Endoscopic response.sup.c, % 11
(34.4).sup.f 5 (35.7).sup.f 13 (44.8).sup.f 7 (36.8).sup.f Clinical
remission.sup.g, n (X) 8 (25) 4 (29) 12 (41) 6 (32) CDAI <150, %
(n) 14 (44) 7 (50) 16 (55) 7 (37) Enhanced clinical response.sup.h,
n (%) 15 (47) 10 (71) 18 (62) 8 (42) Clinical response.sup.i, n (%)
16 (50) 10 (71) 18 (62) 8 (42) Endoscopic remission.sup.j, n (%) 5
(16) 3 (21) 7 (24) 5 (26) Mean change from BL in hs-CRP .+-. SD
-2.8 .+-. 18.9 -2.1 .+-. 18.4 -13.9 .+-. 37.1 10.2 .+-. 55.7 Mean
change from BL in FC .+-. SD 1.0 .+-. 2457.2 -239.3 .+-. 1443.1
-2617.4 .+-. 3232.0 -1510.3 .+-. 2773.9 .sup.&24 mg QD dose is
two 12 mg doses given simultaneously .sup.aModified clinical
remission: SF .ltoreq. 2.8 and AP .ltoreq. 1.0, both not worse than
BL in patients with SF .gtoreq. 4 or AP .gtoreq. 2.0 at BL
.sup.bFor 3, 6, and 12 mg BID and 24 mg QD, n = 17, 8, 15, and 10
.sup.cEndoscopic response: SES-CD reduction > 50% from BL or
endoscopic remission, in responders and 28, 14, 27, and 18 in
clinical responders, respectively .sup.dFor 3, 6, and 12 mg BID and
24 mg QD, n = 20, 8, 16, and 10 .sup.eFor 3, 6, and 12 mg BID and
24 mg QD, n = 28, 14, 27, and 18 .sup.fFor 3, 6, and 12 mg BID and
24 mg QD, n = 32, 14, 29, and 19 .sup.gClinical remission: SF
.ltoreq. 1.5 and AP .ltoreq. 1.0 and both not worse than BL
.sup.hEnhanced clinical response: .gtoreq.60% reduction from
induction BL in SE or .gtoreq.35% reduction from induction BL in AP
and both not worse than BL or modified clinical remission
.sup.iClinical response: .gtoreq.30% reduction from BL in SE or
.gtoreq.30% reduction from BL in AP and both not worse than BL.
.sup.jEndoscopic remission: SES-CD .ltoreq. 4 and at least 2-point
reduction from BL and no subscore > 1 Results
[0856] Baseline demographics and disease characteristics were
similar between study arms. At week 52, endoscopic remission was
achieved by 16%, 21%, 24%, and 26% of patients treated with 3 mg
BID, 6 mg BID, 12 mg BID, and 24 mg QD, respectively, of
upadacitinib. At week 52, clinical remission was achieved by 25%,
29%, 41%, and 32% of patients treated with 3 mg BID, 6 mg BID, 12
mg BID, and 24 mg QD, respectively, of upadacitinib. Results are
shown in Table 20.
[0857] Clinical response was achieved at week 52 by 50%, 71%, 62%,
and 42% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID, and
24 mg QD, respectively, of upadacitinib. Enhanced clinical response
was achieved at week 52 by 47%, 71%, 62%, and 42% of patients
treated with 3 mg BID, 6 mg BID, 12 mg BID and 24 mg QD,
respectively, of upadacitinib. Results are shown in Table 20.
[0858] Among subjects who achieved clinical response and endoscopic
response at week 16, endoscopic response was achieved at week 52 by
50.0%, 50.0%, 68.8%, and 30.0% of patients treated with 3 mg BID, 6
mg BID, 12 mg BID, and 24 mg QD, respectively, of upadacitinib.
Among subjects who achieved clinical response at week 16,
endoscopic response was achieved at week 52 by 34.4%, 35.7%, 44.8%,
and 36.8% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID,
and 24 mg QD, respectively, of upadacitinib. Results are shown in
Table 20. Among subjects who achieved clinical response and
endoscopic response at week 16, endoscopic response was achieved at
week 52 by 34.4, 35.7, 44.8 and 36.8% of patients treated with 3 mg
BID, 6 mg BID, 12 mg BID and 24 mg QD, respectively.
[0859] Among subjects who achieved clinical response and endoscopic
response at week 16, modified clinical remission was achieved at
week 52 by 41.2%, 62.5%, 73.3%, and 40.0% of patients treated with
3 mg BID, 6 mg BID, 12 mg BID, and 24 mg QD, respectively, of
upadacitinib. Among subjects who achieved clinical response at week
16, modified clinical remission was achieved at week 52 by 28.6%,
42.9%, 51.9%, and 38.9% of patients treated with 3 mg BID, 6 mg
BID, 12 mg BID, and 24 mg QD, respectively, of upadacitinib.
Results are shown in Table 20.
Safety
[0860] The incident of adverse events (AEs) was numerically higher
with upadacitinib 3 and 12 mg BID (45 [75.0%] and 43 [72.9%]) than
that with 6 mg BID and 24 mg QD (14 [60.9%] and 23 [63.9%]),
respectively. Serious AEs were numerically higher with 3 mg BID and
infections with 3 and 12 mg BID than that in the other arms. Two
malignancies occurred with 12 mg BID.
Conclusion
[0861] Dose-dependent improvements in clinical and endoscopic
outcomes and markers of inflammation were observed with 36-week
upadacitinib treatment in patients who responded to a 16-week
induction regimen. The overall safety profile of upadacitinib is
consistent with other studies in rheumatoid arthritis.
Example 11: Clinical Study for Crohn's Disease: Rapidity of
Clinical and Laboratory Improvements Following Upadacitinib
Induction Treatment
[0862] This analysis evaluates the rapidity of clinical remission,
clinical response, and changes in markers of inflammation during
the induction phase of the clinical study discussed in Example
8.
Methods
[0863] Adult patients with Crohn's Disease Activity Index (CDAI)
220-450, average daily liquid/very soft stool frequency
(SF).gtoreq.2.5 or daily abdominal pain score (AP).gtoreq.2.0, and
Simplified Endoscopic Score for CD (SES-CD).gtoreq.6 [or .gtoreq.4
for those with isolated ileal disease), were randomized to
double-blind therapy with placebo (PBO) or immediate release
formulation of upadacitinib at 3, 6, 12, 24 mg twice daily (BID) or
24 mg once daily (QD) for 16 weeks. Patients were randomized at
baseline for follow-up ileocolonoscopy at either Week 12 or 16.
Proportion of patients with modified clinical remission and
enhanced clinical response, both defined in Figure, mean change
from baseline in C-reactive protein (CRP) and faecal calprotectin
(FC) were assessed over time in all patients unless otherwise
mentioned. Comparisons between each upadacitinib dose with PBO was
tested by Cochran-Mantel-Haenszel test stratified by SES-CD at BL.
Non-responder imputation was applied to patients who received
open-label upadacitinib or prematurely discontinued prior to Week
16 or initiated corticosteroids or had dose increase higher than
baseline.
Results
[0864] Baseline demographics and disease characteristics were
similar between study arms. A total of 220 patients were enrolled
(mean age 40.7.+-.12.9 years, CDAI 302.7.+-.63.4, disease duration
13.2.+-.10.0 years). Overall, patients receiving upadacitinib
achieved modified clinical remission as early as week 4 and
enhanced clinical response at week 8. Over time, there were
sustained clinical improvements in several upadacitinib dosage
groups for up to 16 weeks (FIGS. 10A-10E and FIGS. 11A-11E). Mean
C-reactive protein (CRP) levels significantly decreased in all
upadacitinib doses at week 4 and were sustained for up to 16 weeks
in the 12 and 24 mg BID and 24 mg QD arms (FIG. 12). Statistically
significant decrease in mean faecal calprotectin (FC) from baseline
was observed with upadacitinib at 12 and 24 mg BID at week 4 and 24
mg BID at week 16.
Conclusions
[0865] Early and significant effects of upadacitinib in clinical
parameters were demonstrated in a refractory patient population
with active Crohn's disease, concurrent with rapid and sustainable
decrease in the markers of inflammation hsCRP and faecal
calprotectin.
Example 12: Clinical Study for Ulcerative Colitis
[0866] This trial is a multicenter, randomized, double-blind
placebo-controlled study of upadacitinib for the induction and
maintenance of clinical remission (using the Mayo Scoring System
for Assessment of Ulcerative Colitis Activity, excluding
Physician's Global Assessment [i.e., Adapted Mayo score]) in
patients with moderately to severely active ulcerative colitis.
[0867] The trial consists of a screening period of up to 35 days,
an 8 week double blind induction period (Substudy 1), a second 8
week double blind and open label induction period (Substudy 2),
re-randomization at week 8, a 44 week double blind and open label
maintenance phase (Substudy 3), and a 30 day follow up period.
[0868] Approximately 250 patients with moderately to severely
active ulcerative colitis are randomized in a 1:1:1:1:1 ratio for
Substudy 1 to one of the treatment arms of the overall study design
shown in FIG. 13. [0869] 1. Group 1: upadacitinib 7.5 mg QD MR
capsules [0870] 2. Group 2: upadacitinib 15 mg QD MR capsules
[0871] 3. Group 3: upadacitinib 30 mg QD MR capsules [0872] 4.
Group 4: upadacitinib 45 mg QD MR capsules [0873] 5. Group 5:
Placebo QD dose
[0874] The first 8 week induction period begins at the BL visit
(week 0) and ends at the week 8 visit. Once the 250 randomized
patients have completed an 8 week induction, an analysis of
efficacy and safety of upadacitinib versus placebo will be
performed. Based on this analysis, one induction dose of
upadacitinib (Dose A) will be identified for further evaluation in
Substudy 2. During the analysis period, approximately 100
additional subjects will continue to be randomized into Groups 3
and 4 of Substudy 1 to receive either 30 mg QD or 45 mg QD
treatment (50 patients per dose group).
[0875] Substudy 2 consists of two parts. In Part 1, approximately
375 patients with moderately to severely active ulcerative colitis
are randomized in a 2:1 ratio to one of the double-blinded
induction treatment arms as shown in FIG. 13: upadacitinib Dose A
mg QD or placebo QD. Dose A is the dose determined in Substudy 1
for further evaluation. Part 2 of Substudy 2 is open label.
Approximately 330 subjects will be enrolled in Part 2 of Substudy 2
to receive open-label upadacitinib Dose A QD. This second 8 week
induction period begins at the BL visit (week 0) and ends at the
week 8 visit.
[0876] Approximately 450 patients who received the 15, 30 or 45 mg
QD of upadacitinib in Substudy 1 and those who received the
selected induction dose in Substudy 2 and who also achieved a
clinical response (i.e., a decrease from baseline in the Adapted
Mayo score .gtoreq.2 points and .gtoreq.30% from baseline
accompanied by a decrease in RBS.gtoreq.1 or an absolute
RBS.ltoreq.1) will be re-randomized in the maintenance portion of
the study (Substudy 3). This period will begin at the baseline
visit (Week 8 of Substudy 1 or Substudy 2) and will end at the Week
44 visit. The treatment assignment in Substudy 3 will depend on the
treatment received in Substudies 1 and 2, as follows:
[0877] Placebo: continue placebo
[0878] 7.5 mg QD upadacitinib: continue 7.5 mg QD upadacitinib
[0879] 15 mg QD upadacitinib: randomized 1:1 to receive either
upadacitinib 15 mg QD or matching placebo
[0880] 30 mg QD or 45 mg QD upadacitinib: randomized 1:1:1 to
receive either upadacitinib 15 mg QD, upadacitinib 30 mg QD, or
matching placebo.
[0881] During Substudy 3, subjects who meet the criteria for loss
of response after at least 4 weeks of follow up will have the
option receive open label upadacitinib. Loss of response is defined
as follows: a subject who presents with an stool frequency subscore
and RBS score at least 1 point greater than the end-of-induction
value (Week 8 of Substudy 1 or 2) on two consecutive visits at
least 14 days apart. The schematics of the overall study design are
shown in FIG. 13.
[0882] The primary endpoints for efficacy for Substudy 1 and
Substudy 2 are the proportion of patients who achieve clinical
remission per Adapted Mayo score (defined as stool frequency
subscore .ltoreq.1, rectal bleeding subscore of 0, and endoscopic
subscore .ltoreq.1) at week 8. The primary efficacy endpoint for
Substudy 3 is the proportion of patients who achieve clinical
remission per Adapted Mayo score at week 44. Secondary efficacy
endpoints for both Substudy 1 and Substudy 2 are: [0883] endoscopic
improvement (defined as endoscopic subscore .ltoreq.1) [0884]
achieving Full Mayo score .ltoreq.2 with no subscore >1) at week
8 [0885] Clinical response (i.e., decrease from baseline in the
Adapted Mayo score .gtoreq.2 points and .gtoreq.30% from baseline,
plus a decrease in rectal bleeding subscore (RBS)_1 or an absolute
RBS.ltoreq.1) at week 8 [0886] decrease from baseline in the
Partial Mayo score .gtoreq.2 points and .gtoreq.30% from baseline
plus a decrease in rectal bleeding subscore (RBS).gtoreq.1 or an
absolute RBS.ltoreq.1) at week 2 [0887] Change in Full Mayo score
from Baseline to Week 8 [0888] Endoscopic remission (defined as
endoscopic subscore of 0) at Week 8 [0889] Histologic improvement
(defined as decrease from baseline in Geboes score) at week 8
[0890] Secondary efficacy endpoints for Substudy 3 maintenance are:
[0891] Endoscopic improvement at week 44 [0892] Full Mayo score
.ltoreq.2 with no subscore >1) at week 44 [0893] Subjects who
discontinued corticosteroid use and achieved clinical remission per
Adapted Mayo score at week 44 [0894] Subjects who maintain clinical
remission at Week 44 among subjects who achieved clinical remission
per Adapted Mayo score in Substudy 1 or 2 [0895] Subjects who are
taking corticosteroids at baseline and are corticosteroid-free at
week 44 [0896] Subjects with endoscopic improvement at week 44
among subjects who achieved clinical remission in Substudy 1 or 2
[0897] Subjects achieving clinical response (i.e., decrease from
baseline in the Adapted Mayo score .gtoreq.2 points and .gtoreq.30%
from baseline accompanied by a decrease in RBS.gtoreq.1 or an
absolute RBS.ltoreq.1) at week 44 [0898] Subjects with endoscopic
remission at week 44 [0899] Subjects who achieved histologic
improvement at week 44
Methods
[0900] The study comprised three treatment periods: Substudy 1
comprising an 8 week double-blind induction period; Substudy 2
comprising two parts: Part 1 is an 8 week double-blind induction
period and Part 2 is an 8 week open-label option of the substudy;
Substudy 3 evaluates patients from Substudy 1 and Substudy 2 who
achieved clinical response.
[0901] Eligible patients are aged 18 to 75 years. They have a
diagnosis of ulcerative colitis for 90 days or greater prior to
baseline, confirmed by colonoscopy during the screening period,
with exclusion of current infection, colonic dysplasia and/or
malignancy. Patients have active ulcerative colitis with an Adapted
Mayo score of 5 to 9 points and an endoscopic subscore of 2 to 3 at
baseline. Eligible patients are those who have demonstrated an
inadequate response to or experienced intolerance to
corticosteroids, immunosuppressants and/or biologic therapies, as
defined below: [0902] Corticosteroids: [0903] Signs and symptoms of
persistently active disease despite a history of at least one
induction regimen that included a dose equivalent to prednisone
.gtoreq.40 mg/day orally for 3 to 4 weeks or intravenously for 1
week or [0904] Unable to taper corticosteroids to below a doses
equivalent to prednisone 10 mg daily orally without recurrent
active disease or [0905] History of intolerance to corticosteroids
(including, but not limited to Cushing's syndrome,
osteopenia/osteoporosis, hyperglycemia, insomnia, infection) [0906]
Immunosuppressants: [0907] Signs and symptoms of persistently
active disease despite a history of at least one 90-day regimen of
oral azathioprine (.gtoreq.1.5 mg/kg/day for subjects in Japan and
China only: .gtoreq.1.0 mg/kg/day), 6-mercaptopurine (.gtoreq.1
mg/kg/day; for subjects in Japan and China only: .gtoreq.0.6
mg/kg/day) or a documents 6-TGN level of 230-450
pmol/8.times.10.sup.8 RBC or higher on the current dosing regimen),
injectable methotrexate (MTX.gtoreq.15 mg/week subcutaneously or
intramuscular), or tacrolimus or [0908] History of intolerance to
at least one immunosuppressant (including, but not limited to
nausea/vomiting, abdominal pain, pancreatitis, liver enzyme
abnormalities, lymphopenia, infection) [0909] Biologic agents for
UC: [0910] Signs and symptoms of persistently active disease
despite a history of any of the following: [0911] At least one
6-week induction regimen of infliximab (.gtoreq.5 mg/kg intravenous
at 0, 2 and 6 weeks), [0912] At least one 4-week induction regimen
of adalimumab (one 160 mg subcutaneous dose followed by 80 mg
subcutaneous dose [or one 80 mg subcutaneous dose) followed by one
40 mg subcutaneous dose at least 2 weeks apart), [0913] At least
one 2-week induction regimen of golimumab (one 200 mg subcutaneous
dose followed by one 100 mg subcutaneous dose at least two weeks
apart), [0914] At least one 6-week induction regimen of vedolizumab
(300 mg intravenous at 0, 2 and 6 weeks), or [0915] Recurrence of
symptoms during scheduled maintenance dosing following prior
clinical benefit (discontinuation despite clinical benefit does not
qualify) or [0916] History of intolerance to at least one biologic
agent (including, but not limited to infusion-related reaction,
demyelination, congestive heart failure CHF), infection)
[0917] Oral MTX use is allowed during the study, however prior or
current use of oral MTX is not sufficient for inclusion into the
study unless these subjects were previously treated with
corticosteroids or immunosuppressants (azathioprine or 6-MP) and in
the judgment of the investigator have failed to respond to or could
not tolerate their treatment.
Examples 13-16: Modified Release Tablets
[0918] Modified release tablets containing either 7.5 mg (Example
13) 15 mg (Example 14), 30 mg (Example 15), or 45 mg (Example 16)
of upadacitinib were prepared using a wet granulation process.
[0919] Upadacitinib (hemi-hydrate), microcrystalline cellulose
(MCC), and hydroxypropyl methylcellulose (HPMC) were added to a
granulator and mixed. Water was sprayed to granulate. The
granulated material was then dried and milled using a comill fitted
with a 610 micron screen to form a granulate composition containing
25% drug load. The granulate composition is summarized in Table
21.
TABLE-US-00025 TABLE 21 Granulate Composition (25% Drug Load)
Amount in Granulation Component Function Composition (%)
Upadacitinib freebase Active 25.0% (hemi-hydrate).sup.1
Microcrystalline cellulose Filler 67.0% (Avicel .RTM. PH 101) HPMC
(Hypromellose Release control 8.0% 2208) polymer .sup.1Upadacitinib
used in Examples 13-16 was a hemi-hydrate (Freebase Hydrate Form C,
as described herein and in U.S. Patent Application No. 15/295,561).
As used herein, the amount of upadacitinib present in the Examples
13-16 formulations refers to the amount of upadacitinib freebase
equivalent provided by the hemi-hydrate.
[0920] The granulation composition was combined with the remaining
formulation components other than magnesium stearate, and sieved
using a comill fitted with a 1397 micron screen, followed by
blending. The magnesium stearate was then added to the bin and
blended. The lubricated granulation was compressed into tablets
using a rotary tablet press. The tablets were coated using a film
coater, which sprayed a solution containing the Opadry.RTM. II
Yellow film coat and purified water until the desired amount of
coating had been applied to the tablets.
[0921] The formulations of the tablets are set forth in Table
22.
TABLE-US-00026 TABLE 22 Modified Release Tablets Ex. 13 Ex. 14 Ex.
15 Ex. 16 Component Function (mg) (mg) (mg) (mg) Tablet Core
Granulation composition Active 30.7.sup.1 61.4.sup.2 122.8.sup.3
184.3.sup.4 (25% drug load) Microcrystalline cellulose Filler 149.5
121.3 64.8 8.3 (Avicel .RTM. PH 102) Mannitol (Pearlitol .RTM.
Filler 100.6 100.6 100.6 100.6 100SD) Tartaric acid (crystalline pH
96.0 96.0 96.0 96.0 or powder) modifier HPMC (Hypromellose Release
93.5 91.1 96.2 81.3 2208) control polymer Colloidal silicon dioxide
Glidant 2.4 2.4 2.4 2.4 Magnesium stearate Lubricant 7.2 7.2 7.2
7.2 Uncoated weight of tablet 479.9 480.0 480.0 480.1 Opadry .RTM.
II Yellow Film coat 14.4 14.4 14.4 14.4 Purified Water.sup.5
Processing n/a n/a n/a n/a aid Total weight of tablet 494.3 494.4
494.4 494.5 .sup.1Provides 7.5 mg of upadacitinib freebase
equivalent. .sup.2Provides 15 mg of upadacitinib freebase
equivalent. .sup.3Provides 30 mg of upadacitinib freebase
equivalent. .sup.4Provides 45 mg of upadacitinib freebase
equivalent. .sup.5Processing aid removed during coating.
Example 17: Observed Steady State Exposures for 15 mg Modified
Release Tablets and 6 mg Immediate Release Capsules Under Fasting
Conditions
[0922] The steady state pharmacokinetic profile of a 15 mg once
daily modified release (MR) tablet (comprising upadacitinib
hemi-hydrate) under fasting conditions was evaluated, and compared
to that of a 6 mg immediate release (IR) twice daily (BID) capsule
comprising upadacitinib (tartrate tetrahydrate) as the active. The
15 mg MR tablet had the following formulation set forth in Table
23.
TABLE-US-00027 TABLE 23 15 mg Modified Release Tablet Amount (mg)
Component Function (ER7) Upadacitinib (hemi-hydrate).sup.1 Active
15.4 Microcrystalline cellulose Filler 162.4 (Avicel .RTM. PH 102)
Mannitol (Pearlitol .RTM. 100 SD) Filler 52.6 Tartaric acid pH
modifier 144.0 HPMC (Hypromellose 2208) Release control polymer
96.0 Colloidal silicon dioxide Glidant 2.4 Magnesium stearate
Lubricant 7.2 impalpable powder Uncoated weight of tablet 480.0
Opadry .RTM. II Yellow Film coat 14.40 (PVA based) Total weight of
tablet 494.39 .sup.1Upadacitinib was a hemi-hydrate (Freebase
Hydrate Form C, as described herein and in U.S. Patent Application
No. 15/295,561). The hemi-hydrate provides about 15 mg of
upadacitinib freebase equivalent.
[0923] The tablet was prepared by first milling the tartaric acid
through a Fitz mill Model M5A, fitted with a 1512-0027 screen. The
upadacitinib hemi-hydrate, microcrystalline cellulose, mannitol
(when present), milled tartaric acid, release control polymer, and
colloidal silicone dioxide (when present) were combined and
blended. The blend was milled using a Mobil Mill fitted with a 610
or 1397 micron screen. The magnesium stearate was screened through
mesh #30 and was then added to the bin and blended. The lubricated
granulation was compressed into about 480 mg weight tablets using a
rotary tablet press. The tablet was coated using a film coater,
which sprayed a solution containing the Opadry.RTM. II Yellow film
coat and purified water until 14.40 mg of coating had been applied
to the tablets.
[0924] Healthy human subjects were assigned to one of two regimens
under fasting conditions in a randomized, two-period, cross-over
study design. Subjects in Regimen K (n=12 at onset; n=1 on Day 7)
were administered the 6 mg IR capsule twice daily for seven days
under fasting conditions. Subjects in Regimen L (n=12) were
administered the 15 mg MR tablet once daily for seven days under
fasting conditions. On days one and seven, serial blood samples
were collected from each subject prior to the daily dosing and up
to 24 hours after dosing. Blood samples were also collected at 48,
72, 96 and 120 hours after initial dosing. Upon collection, the
samples were promptly placed in an ice bath, and within 2 hours
after sample collection they were centrifuged at about 4.degree. C.
The resulting plasma samples were placed in clean
polypropylene-tubes and stored in a freezer until analysis. The
plasma samples were assayed for upadacitinib using appropriate
liquid chromatography mass spectrometry procedures. Pharmacokinetic
parameters were estimated using non-compartmental methods, and
summary statistics were computed for each parameter by regimen.
[0925] The results are summarized in Table 24. The mean plasma
concentration of upadacitinib at each time point measured for each
of the two regimens is set forth in FIG. 7.
TABLE-US-00028 TABLE 24 Mean (% CV).sup.e Pharmacokinetic
Parameters for Upadacitinib Following Administration of 6 mg BID
(IR) Capsules and 15 mg QD (MR) Tablets for Seven Days (Tasting
Conditions) Regimen K Regimen L (6 mg IR Capsules (BID)) (15 mg MR
Tablet (QD)) PK Parameter Units Day 1 Day 7 Day 1 Day 7 C.sub.max
ng/mL 36.5 (25) 33.9 (26) 31.7 (40) 31.9 (35) T.sub.max.sup.a hours
1.0 (1.0-13) 1.0 (0.5-14) 3.0 (1.5-6.0) 2.5 (1.5-4.0) AUC.sub.24 ng
h/mL 289 (21) 288 (22) 249 (29) 279 (26) C.sub.12 ng/mL 2.0 (30)
2.8 (24) -- -- C.sub.24 ng/mL 3.2 (36) 3.6 (23) 1.9 (42) 3.1 (37)
C.sub.min ng/mL -- 2.7 (26) -- 3.1 (37) Fluctuation % 303 (13) 259
(13) 299 (22) 246 (21) Index t.sub.1/2.sup.b hours -- 14.7 (77) --
10.3 (76) C.sub.max to C.sub.24 ratio.sup.a -- 12 (7.7-19) 8.8
(7.4-13) 22 (5.8-43) 12 (4.2-20) C.sub.max to C.sub.min ratio.sup.a
-- -- 13 (8.3-18) -- 12 (4.2-20) AUC.sub.24/Dose (ng h/mL)/mg 24.8
(23) 24.0 (22) 16.6 (29) 18.6 (26) R.sub.AUC.sup.c -- -- 1.02
(0.88-1.09) -- 1.11 (0.87-1.99) R.sub.Cmax.sup.d -- -- 0.97
(0.68-1.17) -- 1.01 (0.65-3.01) .sup.aMedian (minimum-maximum)
.sup.bHarmonic mean (pseudo-% CV) .sup.cR.sub.AUC =
AUC.sub.24Day7/AUC.sub.24Day 1; median (range) .sup.dR.sub.Cmax =
C.sub.maxDay 7/C.sub.maxDay 1; median (range) .sup.eData in
parentheses is the coefficient of variance of the PK parameter (%
CV), unless otherwise indicated
[0926] The relative bioavailability for the once-daily (MR) tablet
formulation (Regimen L) relative to the twice daily (IR) capsule
formulation (Regimen K) at steady state was also determined based
on analysis of the natural logarithms of C.sub.max, AUC.sub.24,
C.sub.min, and C.sub.24. The results are summarized in Table 25
below.
TABLE-US-00029 TABLE 25 Relative Bioavailability Estimates and 90%
Confidence Intervals for 15 mg QD Tablets Relative to 6 mg BID
Capsules at Steady State under Fasting Conditions Relative
Rioavailability 90% Confidence PK Parameter Point Estimate Interval
C.sub.max 0.909 0.736-1.122 AUC.sub.24 0.939 0.837-1.053 C.sub.min
1.090 0.852-1.395
[0927] The ratio of steady-state AUC for the 15 mg QD tablets
relative to the 6 mg BID capsules was approximately 1, with the 90%
confidence intervals within the equivalence boundaries. The ratio
of the steady-state C.sub.min was approximately 1 for the 15 mg QD
tablet relative to the 6 mg BID capsules.
[0928] As can be seen from this data, at steady state under fasting
conditions, the 15 mg QD tablets provided equivalent AUC.sub.24 and
comparable C.sub.max and C.sub.min relative to the 6 mg BID
capsules. The steady state C.sub.max was 10% lower for the 15 mg QD
tablet compared to the 6 mg BID capsule.
Example 18: Observed Steady State Exposures for 30 mg Modified
Release Tablets and 12 mg Immediate Release Capsules Under Fasting
Conditions
[0929] The steady state pharmacokinetic profile of a 30 mg once
daily modified release (MR) tablet (comprising upadacitinib
hemi-hydrate) under fasting conditions was evaluated, and compared
to that of a 12 mg immediate release (IR) twice daily (BID) capsule
comprising upadacitinib (tartrate tetrahydrate) as the active. The
30 mg MR tablet had the following formulation set forth in Table
26.
TABLE-US-00030 TABLE 26 30 mg Modified Release Tablet Amount (mg)
Component Function (ER8) Upadacitinib (hemi-hydrate).sup.1 Active
30.7 Microcrystalline cellulose Filler 147.1 (Avicel .RTM. PH 102)
Mannitol (Pearlitol .RTM. 100 SD) Filler 52.6 Tartaric acid pH
modifier 144.0 HPMC (Hypromellose 2208) Release control polymer
96.0 Colloidal silicon dioxide Glidant 2.4 Magnesium stearate
Lubricant 7.2 impalpable powder Uncoated weight of tablet 480.0
Opadry .RTM. II Yellow (PVA Film coat 14.40 based) Total weight or
tablet 494.43 .sup.1Upadacitinib was a hemi-hydrate (Freebase
Hydrate Form C, as described in U.S. Patent Application No.
15/295,561), The hemi-hydrate provides about 30 mg of upadacitinib
freebase equivalent.
[0930] The tablet was prepared by first milling the tartaric acid
through a Fitz mill Model M5A, fitted with a 1512-0027 screen. The
upadacitinib hemi-hydrate, microcrystalline cellulose, mannitol
(when present), milled tartaric acid, release control polymer, and
colloidal silicone dioxide (when present) were combined and
blended. The blend was milled using a Mobil Mill fitted with a 610
or 1397 micron screen. The magnesium stearate was screened through
mesh #30 and was then added to the bin and blended. The lubricated
granulation was compressed into about 480 mg weight tablets using a
rotary tablet press. The tablet was coated using a film coater,
which sprayed a solution containing the Opadry.RTM. II Yellow film
coat and purified water until 14.40 mg of coating had been applied
to the tablets.
[0931] Healthy human subjects were assigned to one of two regimens
under fasting conditions in a randomized, two-period, cross-over
study design. Subjects in Regimen M (n=11) were administered the 12
mg IR capsule twice daily for seven days under fasting conditions.
Subjects in Regimen N (n=12 at onset; n=11 at Day 7) were
administered the 30 mg MR tablet once daily for seven days under
fasting conditions. On days one and seven, serial blood samples
were collected from each subject prior to the daily dosing and up
to 24 hours after dosing. Blood samples were also collected at 48,
72, 96 and 120 hours after initial dosing. Upon collection, the
samples were promptly placed in an ice bath, and within 2 hours
after sample collection they were centrifuged at about 4.degree. C.
The resulting plasma samples were placed in clean
polypropylene-tubes and stored in a freezer until analysis. The
plasma samples were assayed for upadacitinib using appropriate
liquid chromatography mass spectrometry procedures. Pharmacokinetic
parameters were estimated using non-compartmental methods, and
summary statistics were computed for each parameter by regimen.
[0932] The results are summarized in Table 27. The mean plasma
concentration of upadacitinib at each time point measured for each
of the two regimens is set forth in FIG. 8.
TABLE-US-00031 TABLE 27 Mean (% CV).sup.e Pharmacokinetic
Parameters for Upadacitinib Following Administration of 12 mg BID
(IR) Capsules and 30 mg QD (MR) Tablets for Seven Days (Fasting
Conditions) Regimen 14 Regimen N (12 mg IR Capsules (BID)) (30 mg
MR Tablet (QD)) PK Parameter Units Day 1 Day 7 Day 1 Day 7 ng/mL
80.8 (23) 73.9 (19) 65.7 (22) 68.2 (30) T.sub.max.sup.a hours 1.0
(0.5-13) 1.0 (0.5-1.5) 2.5 (1.5-4.0) 3.0 (2.0-4.0) AUC.sub.24 ng
h/mL 497 (15) 534 (18) 454 (23) 525 (23) C.sub.12 ng/mL 3.0 (46)
4.1 (55) -- -- C.sub.24 ng/mL 6.5 (54) 6.9 (37) 2.8 (37) 4.4 (39)
C.sub.min ng/mL -- 3.8 (58) -- 3.8 (43) Fluctuation Index % 388
(15) 317 (14) 349 (12) 291 (17) t.sub.1/2.sup.b hours -- 7.3 (60)
-- 14.4 (64) C.sub.max to C.sub.24 ratio.sup.a -- 15 (5.4-20) 12
(5.9-16) 29 (13-38) 17 (4.1-33) C.sub.max to C.sub.min ratio.sup.a
-- -- 19 (8.4-31) -- 17 (11-37) AUC.sub.24/Dose (ng h/mL)/mg 21.1
(1.7) 22.3 (18) 15.1 (22) 17.5 (23) R.sub.AUC.sup.c -- -- 1.08
(0.97-1.18) -- 1.11 (0.79-1.67) R.sub.Cmax.sup.d -- -- 0.98
(0.65-1.18) -- 1.03 (0.40-1.82) .sup.aMedian (minimum-maximum)
.sup.bHarmonic mean (pseudo-% CV) .sup.cR.sub.AUC =
AUC.sub.24Day7/AUC.sub.24Day 1; median (range) .sup.dR.sub.Cmax =
C.sub.maxDay 7/C.sub.maxDay 1; median (range) .sup.eData in
parentheses is the coefficient of variance of the PK parameter (%
CV), unless otherwise indicated
[0933] The relative bioavailability for a single dose of the
once-daily (MR) tablet formulation (Regimen N) relative to the
twice daily (IR) capsule formulation (Regimen M) was also
determined based on analysis of the natural logarithms of
C.sub.max, AUC.sub.24, C.sub.min, and C.sub.24. The results are
summarized in Table 28 below.
TABLE-US-00032 TABLE 28 Relative Bioavailability Estimates and 90%
Confidence Intervals for 30 mg QD Tablets Relative to 12 mg BID
Capsules at Steady State under Fasting Conditions Relative
Bioavailability 90% Confidence PK Parameter Point Estimate interval
C.sub.max 0.900 0.732-1.107 AUC.sub.24 0.974 0.869-1.092 C.sub.min
0.874 0.747-1.022
[0934] The ratio of steady-state AUC for the 30 mg QD tablets
relative to the 12 mg BID capsules was approximately 1, with the
90% confidence intervals within the equivalence boundaries. The
steady-state C.sub.min, for the 30 mg QD tablet was approximately
13% lower than for the 12 mg BID capsules. Outliers with high
C.sub.min in the 12 mg BID dose may have contributed to this
difference.
[0935] As can be seen from this data, at steady state under fasting
conditions, the 30 mg QD tablets provided equivalent AUC.sub.24 and
comparable C.sub.max and C.sub.min relative to the 12 mg BID
capsules. The steady state C.sub.min was 10% lower for the 30 mg QD
tablet compared to the 12 mg BID capsules.
[0936] This written description uses examples to disclose the
invention, including the best mode, and also to enable any person
skilled in the art to practice the invention, including making and
using any devices or systems and performing any incorporated
methods. The patentable scope of the invention is defined by the
claims, and may include other examples that occur to those skilled
in the art. Such other examples are intended to be within the scope
of the claims if they have structural elements that do not differ
from the literal language of the claims, or if they include
equivalent structural elements with insubstantial differences from
the literal languages of the claims.
* * * * *