U.S. patent application number 17/174201 was filed with the patent office on 2021-06-10 for safe and effective method of treating ulcerative colitis with anti-il12/il23 antibody.
The applicant listed for this patent is Janssen Biotech, Inc.. Invention is credited to Omoniyi Adedokun, Jewel Johanns, Katherine Li, Colleen Marano, Christopher O'Brien, Kimberly Shields-Tuttle, Richard Strauss, Hongyan Zhang.
Application Number | 20210171622 17/174201 |
Document ID | / |
Family ID | 1000005407380 |
Filed Date | 2021-06-10 |
United States Patent
Application |
20210171622 |
Kind Code |
A1 |
Johanns; Jewel ; et
al. |
June 10, 2021 |
Safe and Effective Method of Treating Ulcerative Colitis with
Anti-IL12/IL23 Antibody
Abstract
Described are methods and compositions for clinical proven safe
and effective treatment of ulcerative colitis, particularly
moderately to severely active ulcerative colitis in patients who
have had an inadequate response to or are intolerant of a
conventional or existing therapy by intravenous and/or subcutaneous
administration of an anti-IL-12/IL-23p40 antibody.
Inventors: |
Johanns; Jewel; (Devon,
PA) ; Li; Katherine; (Wallingford, PA) ;
Marano; Colleen; (Malvern, PA) ; Strauss;
Richard; (Doylestown, PA) ; Zhang; Hongyan;
(Malvern, PA) ; O'Brien; Christopher; (Lafayette
Hill, PA) ; Adedokun; Omoniyi; (Phoenixville, PA)
; Shields-Tuttle; Kimberly; (West Chester, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Janssen Biotech, Inc. |
Horsham |
PA |
US |
|
|
Family ID: |
1000005407380 |
Appl. No.: |
17/174201 |
Filed: |
February 11, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16580509 |
Sep 24, 2019 |
10961307 |
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17174201 |
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62735501 |
Sep 24, 2018 |
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62769818 |
Nov 20, 2018 |
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62895774 |
Sep 4, 2019 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 2039/54 20130101;
A61K 47/26 20130101; C07K 16/244 20130101; A61K 9/08 20130101; A61K
39/00 20130101; A61K 2039/545 20130101; C07K 2317/565 20130101;
A61K 9/0019 20130101; A61K 47/22 20130101; C07K 2317/31 20130101;
A61K 47/183 20130101; A61P 1/04 20180101; A61K 2039/505
20130101 |
International
Class: |
C07K 16/24 20060101
C07K016/24; A61K 47/18 20170101 A61K047/18; A61K 47/22 20060101
A61K047/22; A61K 47/26 20060101 A61K047/26; A61K 39/00 20060101
A61K039/00; A61P 1/04 20060101 A61P001/04; A61K 9/08 20060101
A61K009/08; A61K 9/00 20060101 A61K009/00 |
Claims
1. A pharmaceutical composition of an anti-IL-12/IL-23p40 antibody
for use in treating a subject with moderately to severely active
ulcerative colitis (UC), comprising an antibody comprising a heavy
chain variable region and a light chain variable region, the heavy
chain variable region comprising a complementarity determining
region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO:1; a
CDRH2 amino acid sequence of SEQ ID NO:2; and a CDRH3 amino acid
sequence of SEQ ID NO:3; and the light chain variable region
comprising a complementarity determining region light chain 1
(CDRL1) amino acid sequence of SEQ ID NO:4; a CDRL2 amino acid
sequence of SEQ ID NO:5; and a CDRL3 amino acid sequence of SEQ ID
NO:6 and wherein the subject is a responder to treatment by at
least one measure of response to treatment selected from the group
consisting of: (i) having a clinical remission based on at least
one of the global definition of clinical remission with Mayo score
.ltoreq.2 points with no individual subscore >1 and the US
definition of clinical remission with absolute stool number
.ltoreq.3, rectal bleeding subscore of 0 and Mayo endoscopy
subscore of 0 or 1, (ii) having an endoscopic healing with a Mayo
endoscopy subscore of 0 or 1, (iii) achieving a clinical response
based on the Mayo endoscopy subscore, (iv) having improvements from
baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) score,
(v) having a mucosal healing, (vi) having a decrease from baseline
in Mayo score, and (vii) in clinical response as determined by a
decrease from baseline in the Mayo score by .gtoreq.30% and
.gtoreq.3 points and a decrease from baseline in the rectal
bleeding subscore .gtoreq.1 points or a rectal bleeding subscore of
0 or 1, and had previously failed or was intolerant of at least one
therapy selected from the group consisting of: an anti-TNF,
vedolizumab, corticosteroids, azathioprine (AZA), and 6
mercaptopurine (6 MP), or the subject had demonstrated
corticosteroid dependence.
2. The pharmaceutical composition of claim 1, wherein the antibody
comprises a heavy chain variable region of the amino acid sequence
of SEQ ID NO:7 and a light chain variable region of the amino acid
sequence of SEQ ID NO:8.
3. The pharmaceutical composition of claim 1, wherein the antibody
comprises a heavy chain of the amino acid sequence of SEQ ID NO:10
and a light chain of the amino acid sequence of SEQ ID NO:11.
4. The pharmaceutical composition of any one of claims 1-3, wherein
the pharmaceutical composition is for intravenous administration in
a solution comprising 10 mM L-histidine, 8.5% (w/v) sucrose, 0.04%
(w/v) polysorbate 80, 0.4 mg/mL L-methionine, and 20 .mu.g/mL EDTA
disodium salt, dehydrate, at pH 6.0.
5. The pharmaceutical composition of any one of claims 1-3, wherein
the pharmaceutical composition is for subcutaneous administration
in a solution comprising 6.7 mM L-histidine, 7.6% (w/v) sucrose,
0.004% (w/v) polysorbate 80, at pH 6.0.
6. A pharmaceutical composition of an anti-IL-12/IL-23p40 antibody,
comprising: a. an antibody comprising: (i) a heavy chain variable
region and a light chain variable region, the heavy chain variable
region comprising: a complementarity determining region heavy chain
1 (CDRH1) amino acid sequence of SEQ ID NO:1; a CDRH2 amino acid
sequence of SEQ ID NO:2; and a CDRH3 amino acid sequence of SEQ ID
NO:3; and the light chain variable region comprising: a
complementarity determining region light chain 1 (CDRL1) amino acid
sequence of SEQ ID NO:4; a CDRL2 amino acid sequence of SEQ ID
NO:5; and a CDRL3 amino acid sequence of SEQ ID NO:6; (ii) a heavy
chain variable region of the amino acid sequence of SEQ ID NO:7 and
a light chain variable region of the amino acid sequence of SEQ ID
NO:8; or (iii) a heavy chain of the amino acid sequence of SEQ ID
NO:10 and a light chain of the amino acid sequence of SEQ ID NO:11;
and b. packaging comprising one or more drug product label elements
disclosed in Annex I including data from a randomized,
double-blind, placebo-controlled, clinical study in adult men and
women with moderately to severely active ulcerative colitis (UC).
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S. patent
application Ser. No. 16/580,509, filed 24 Sep. 2019, currently
allowed, which claims the benefit of U.S. Provisional Application
Ser. No. 62/895,774, filed 4 Sep. 2019, U.S. Provisional
Application Ser. No. 62/769,818, filed 20 Nov. 2018 and U.S.
Provisional Application Ser. No. 62/735,501, filed 24 Sep. 2018,
the entire contents of which are incorporated herein by reference
in their entireties.
REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY
[0002] This application contains a sequence listing, which is
submitted electronically via EFS-Web as an ASCII formatted sequence
listing with a file name "JBI6010USDIV1Sequence Listing.txt"
creation date of 9 Feb. 2021, and having a size of 15 kilobytes.
The sequence listing submitted via EFS-Web is part of the
specification and is herein incorporated by reference in its
entirety.
FIELD OF THE INVENTION
[0003] The invention relates to methods of providing a clinically
proven safe and clinically proven effective treatment of ulcerative
colitis, particularly moderately to severely active ulcerative
colitis in patients who have had an inadequate response to or are
intolerant of a conventional or existing therapy by intravenous
and/or subcutaneous administration of an anti-IL-12/IL-23p40
antibody.
BACKGROUND OF THE INVENTION
[0004] Inflammatory bowel diseases (IBDs), including ulcerative
colitis (UC), are chronic relapsing disorders characterized by
destructive inflammation and epithelial injury in the
gastrointestinal (GI) tract (Baumgart and Sandborn, J Clin Invest.
98:1010-1020 (1996); Danese and Fiocchi, N Engl J Med.
365:1715-1725 (2011)). The incidence of UC in the United States is
estimated to be between 9 and 12 per 100,000 persons with a
prevalence of 205 to 240 per 100,000 persons (Tally et al., Am J
Gastroenterol. 106 Suppl 1:S2-S25 (2011)). The estimate of the
prevalence of UC in Europe is approximately 1 million people
(Loftus, Gastroenterology. 126(6):1504-1517 (2004); Loftus,
Gastoenterol Clin N Am. 31:1-20 (2002)). The etiology of UC is
unknown. However, abnormal immune responses to contents in the gut,
including intestinal microbes, are thought to drive disease in
genetically predisposed individuals (Geremia et al., Autoimmun Rev.
13:3-10 (2014)). Dysregulated innate and adaptive immune pathways
contribute to aberrant intestinal inflammation in IBD, and
cytokines, including interleukin (IL)-12, interferon-gamma
(IFN.gamma.), and IL-23 have been implicated in the pathogenesis of
UC (Geremia et al., Autoimmune Rev. 2014; 13:3-10; Neurath, Nat Rev
Immunol. 14(5):329-42 (2014)).
[0005] The involvement of the IL-12/23 pathway in the pathogenesis
of IBD is well established, and an important role for IL-12/IL-23
pathway in intestinal inflammation has been elucidated in colitis
(Ahern et al., Immunity. 33(2):279-288 (2010); Investigator's
Brochure: STELARA.RTM. (ustekinumab), edition 18. Janssen Research
& Development, LLC (2017); Uhlig et al., Immunity. 25:309 318
(2006); Yen et al., J Clin Invest. 116(5):1310-1316 (2006)). Early
studies showed that treatment with anti-IFN.gamma. (Berg et al., J
Clin Invest. 98:1010-1020 (1996); Davidson et al., J Immunol.
161:3143-3149 (1998)) or anti-IL-12p40 monoclonal antibodies (mAb)
prevented disease in experimental colitis models, suggesting an
important role for type 1 T helper (Th-1) cells in promoting
intestinal inflammation (Neurath et al., J Exp Med.
182(5):1281-1290 (1995)). Genome-wide association studies have
implicated several genetic loci in humans in the IL-12/23 pathway
that are associated with increased susceptibility to UC, including
IL-23R and IL-12B (Anderson et al., Nat Genet. 43(3):246-252
(2011); Brant et al., Clin Gastroenterol Hepatol. 11(1):22-26
(2013)). Subjects with active UC were shown to have significantly
more IL-23, IL-22, IL-22R1 and p-STAT3-positive cells than subjects
with inactive UC and normal controls (Yu et al., World J
Gastroenterol. 19(17):2638-2649 (2013)).
[0006] Biologic therapies currently approved for the treatment of
UC are either tumor necrosis factor (TNF) or integrin inhibitors
(Colombel et al., Gastroenterology. 132:52-65 (2007); Hanauer et
al., Lancet. 359:1541-1549 (2002); Sandborn et al., N Engl J Med.
369:711-721 (2013); Sandborn et al., Gastroenterology. 142:257-265
(2012)). However, only 1 therapy of all currently approved
treatments, vedolizumab, has demonstrated efficacy in subjects who
have had an inadequate response to (i.e., primary nonresponse or
secondary loss of response) or are intolerant of anti-TNFs (Feagan
et al., N Engl J Med. 369:699 710 (2013)). Anti-TNFs have safety
risks associated with immunosuppression and not all subjects
adequately respond to such therapy. Furthermore, as was observed
with the anti-TNFs, inadequate response, and intolerance has been
identified in subjects receiving vedolizumab for the treatment of
their UC. Therefore, there remains an unmet need for novel
therapies with alternative mechanisms of action.
[0007] When tested, biologic therapies that are currently approved
for the treatment of UC have also demonstrated efficacy in Crohn's
disease (Sandborn et al., Gastroenterology. 135(4):1130-1141
(2008)). Multiple lines of evidence suggest that inflammatory bowel
disease (UC and Crohn's disease) is mediated by Th1 or Th17 cells
with strong contribution from the proinflammatory cytokines, IL-12,
and IL-23. Ustekinumab (STELARA.RTM.) is a fully human
immunoglobulin G1 mAb to human IL-12/23p40 that prevents IL-12 and
IL-23 bioactivity by inhibiting their interaction with their cell
surface IL-12R.beta.1 receptor protein (Investigator's Brochure:
STELARA.RTM. (ustekinumab), edition 18. Janssen Research &
Development, LLC (2017)). Through this mechanism of action,
ustekinumab effectively neutralizes IL-12 (Th1)- and IL-23
(Th17)-mediated cellular responses. Ustekinumab has received
marketing approval globally, including countries in North America,
Europe, South America, and the Asia-Pacific region, for the
treatment of adult subjects with moderately to severely active
Crohn's disease (the first approval for Crohn's disease was
received on 11 Nov. 2016), moderate to severe plaque psoriasis, or
active psoriatic arthritis, as well as for pediatric subjects (12
to 17 years old) with moderate to severe plaque psoriasis.
[0008] The efficacy and safety of intravenous (IV) ustekinumab as
induction therapy in Crohn's disease have been evaluated in
clinical studies CRD3001 and CRD3002. In study CRD3001, subjects
with demonstrated prior failure or intolerance to one or more TNF
antagonists were evaluated, and in CRD3002 subjects with history of
inadequate response to or intolerance of corticosteroids or
immunomodulators, but without a history of an inadequate response
or intolerance to TNF antagonists were evaluated. In these studies,
two IV doses were evaluated: a 130 mg IV fixed dose (.about.2 mg/kg
on a mg/kg basis) was chosen for the low-dose group, while
body-weight range based doses approximating .about.6 mg/kg IV
(weight <55 kg: ustekinumab 260 mg; weight >55 and <85 kg:
ustekinumab 390 mg; weight >85 kg: ustekinumab: 520 mg) were
chosen as the high-dose group. In both studies, ustekinumab
demonstrated clinically significant efficacy compared with placebo
and was well-tolerated with a favorable safety profile.
[0009] Prior to the present invention, no studies had been
conducted with ustekinumab for UC. there is a need in the art for
improved methods of treating UC, particularly moderately to
severely active UC, in subjects who had previously failed or were
intolerant of a biologic therapy or other conventional therapy, or
subjects who had demonstrated corticosteroid dependence.
BRIEF SUMMARY OF THE INVENTION
[0010] The present application relates to clinically proven safe
and clinically proven effective methods and compositions for
treatment of moderately to severely active ulcerative colitis (UC),
particularly in subjects who have had an inadequate response to or
are intolerant of a conventional or existing therapy, by
administration of an anti-IL-12/IL-23p40 antibody to subjects,
thereby addressing a clear unmet medical need in this subject
population.
[0011] In one general aspect, the application relates to a
clinically proven safe and clinically proven effective method of
treating moderately to severely active ulcerative colitis (UC) in a
subject in need thereof, comprising administering to the subject a
pharmaceutical composition comprising a safe and effective amount
of an anti-IL-12/IL-23p40 antibody, wherein the antibody comprises
a heavy chain variable region and a light chain variable region,
the heavy chain variable region comprising: a complementarity
determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ
ID NO:1; a CDRH2 amino acid sequence of SEQ ID NO:2; and a CDRH3
amino acid sequence of SEQ ID NO:3; and the light chain variable
region comprising: a complementarity determining region light chain
1 (CDRL1) amino acid sequence of SEQ ID NO:4; a CDRL2 amino acid
sequence of SEQ ID NO:5; and a CDRL3 amino acid sequence of SEQ ID
NO:6.
[0012] In certain embodiments, the anti-IL-12 and/or anti-IL-23
antibody is administered intravenously to the subject, preferably
at week 0, at a dosage of about 6.0 mg/kg body weight of the
subject or 130 mg per administration.
[0013] In certain embodiments, the anti-IL-12 and/or anti-IL-23
antibody is administered intravenously or subcutaneously to the
subject, preferably at week 8, at a dosage of about 6.0 mg/kg body
weight of the subject or 90 mg per administration,
respectively.
[0014] Preferably, the subject treated by methods according to
embodiments of the application has had an inadequate response to or
are intolerant of a conventional or existing therapy. In some
embodiments, the subject had previously failed or were intolerant
of a biologic therapy, such as an anti-TNF and/or vedolizumab. In
some embodiments, the subject had previously failed or were
intolerant of a non-biologic therapy, such as a treatment with
corticosteroids, azathioprine (AZA), and/or 6 mercaptopurine (6
MP). In some embodiments, the subject had demonstrated
corticosteroid dependence.
[0015] In another general aspect, the application relates to a
clinically proven safe and clinically proven effective method of
treating moderately to severely active ulcerative colitis (UC) in a
subject in need thereof, comprising:
[0016] intravenously administering to the subject a pharmaceutical
composition comprising an anti-IL-12/IL-23p40 antibody at a dosage
of about 6.0 mg/kg body weight of the subject or 130 mg of the
antibody per administration at week 0 of the treatment, and
[0017] subcutaneously administering to the subject a pharmaceutical
composition comprising the anti-IL-12/IL-23p40 antibody at a dosage
of 90 mg of the antibody per administration at week 8 of the
treatment,
[0018] wherein the antibody comprises a heavy chain variable region
and a light chain variable region, the heavy chain variable region
comprising: a complementarity determining region heavy chain 1
(CDRH1) amino acid sequence of SEQ ID NO:1; a CDRH2 amino acid
sequence of SEQ ID NO:2; and a CDRH3 amino acid sequence of SEQ ID
NO:3; and the light chain variable region comprising: a
complementarity determining region light chain 1 (CDRL1) amino acid
sequence of SEQ ID NO:4; a CDRL2 amino acid sequence of SEQ ID
NO:5; and a CDRL3 amino acid sequence of SEQ ID NO:6; and
[0019] wherein the subject had previously failed or were intolerant
of at least one therapy selected from the group consisting of: an
anti-TNF, vedolizumab, corticosteroids, azathioprine (AZA), and 6
mercaptopurine (6 MP), or the subject had demonstrated
corticosteroid dependence
[0020] In certain embodiments, methods of the present application
comprise intravenously (IV) and/or subcutaneously (SC)
administering to the subject a pharmaceutical composition
comprising an anti-IL-12 and/or anti-IL-23 antibody or antigen
binding fragment comprising: (i) a heavy chain variable domain
amino acid sequence of SEQ ID NO:7; and (ii) a light chain variable
domain amino acid sequence of SEQ ID NO:8.
[0021] In certain embodiments, methods of the present application
comprise intravenously (IV) and/or subcutaneously (SC)
administering to the subject a pharmaceutical composition
comprising the anti-IL-12/23p40 antibody ustekinumab, which
comprises: (i) a heavy chain amino acid sequence of SEQ ID NO:10;
and (ii) a light chain amino acid sequence of SEQ ID NO:11.
[0022] In certain embodiments, the IV dose at week 0 is about 6.0
mg/kg. For example, the IV dose is 260 mg for subjects with body
weight >35 kg and <55 kg, 390 mg for subjects with body
weight >55 kg and <85 kg, and 520 mg for subjects with body
weight >85 kg.
[0023] In certain embodiments, the subject is a responder to a
treatment of a method according to an embodiment of the application
and is identified as having at least one of: (1) a clinical
remission based on at least one of the global submissions and the
US submissions; (2) an endoscopic healing; (3) a clinical response;
(4) a change from baseline in Inflammatory Bowel Disease
Questionnaire (IBDQ) score; (5) a mucosal healing; (6) a decrease
from baseline in Mayo score; and (7) a normalization of one or more
biomarkers selected from the group consisting of C-reactive
protein, fecal lactoferrin and fecal calprotectin. Preferably, at
least one of (1) to (7) above is identified from the subject by
week 16, more preferably by week 8 or week 4, and most preferably
by week 2 of the treatment.
[0024] In certain embodiments, the present invention provides a
clinically proven safe and clinically proven effective method of
treating moderately to severely active UC in a subject, wherein the
subject is a responder to the treatment with the antibody and is
identified as having a statistically significant improvement in
disease activity as determined by endoscopic healing with a Mayo
endoscopy subscore of 0 or 1 by week 8 of treatment with the
antibody.
[0025] In other embodiments, the present invention provides a
clinically proven safe and clinically proven effective method of
treating moderately to severely active UC in a subject, wherein the
subject is a responder to the treatment with the antibody and is
identified as having a statistically significant improvement in
disease activity as determined by an Ulcerative Colitis Endoscopic
Index of Severity (UCEIS) score of .ltoreq.4 by week 8 of treatment
with the antibody.
[0026] In certain embodiments, the subject is in clinical response
as determined by a decrease from baseline in the Mayo score by
.gtoreq.30% and .gtoreq.3 points and a decrease from baseline in
the rectal bleeding subscore .gtoreq.1 points or a rectal bleeding
subscore of 0 or 1 by week 8 of treatment with the antibody.
[0027] In other embodiments, a maintenance dose of the
anti-IL-12/IL-23p40 antibody is administered every 8 weeks after
the treatment at week 8 or every 12 weeks after the treatment at
week 8 and clinical response is maintained by the subject for at
least 44 weeks.
[0028] In certain embodiments, the present invention provides a
clinically proven safe and clinically proven effective method of
treating moderately to severely active UC in a subject, wherein a
subject identified as a non-responder to an initial treatment is
administered a second treatment, preferably with an administration
route different from the initial treatment. For example, a subject
identified as a non-responder to an initial treatment with an IV
administration of an antibody or antibody binding fragment can be
treated with a subsequent subcutaneous administration of the
antibody or antibody binding fragment according to embodiments of
the invention.
[0029] In certain embodiments, the present application provides for
a method of treating moderately to severely active UC in a subject,
wherein an anti-IL-12 and/or anti-IL-23 antibody for use with IV
administration is in a pharmaceutical composition comprising a
solution comprising 10 mM L-histidine, 8.5% (w/v) sucrose, 0.04%
(w/v) polysorbate 80, 0.4 mg/mL L methionine, and 20 .mu.g/mL EDTA
disodium salt, dehydrate, at pH 6.0.
[0030] In certain embodiments, the present application provides for
a clinically proven safe and clinically proven effective method of
treating moderately to severely active UC in a subject, wherein an
anti-IL-12 and/or anti-IL-23 antibody for use with subcutaneous
administration is in a pharmaceutical composition comprising a
solution comprising 6.7 mM L-histidine, 7.6% (w/v) sucrose, 0.004%
(w/v) polysorbate 80, at pH 6.0.
[0031] In certain embodiments, the present application provides a
method further comprising administering to the subject one or more
additional drugs used to treat UC. In a preferred embodiment, the
additional drug is selected from the group consisting of: oral
5-aminosalicylate (5-ASA) compounds, oral corticosteroids,
immunomodulators, 6-mercaptopurine (6-MP), azathioprine (AZA), or
methotrexate (MTX).
[0032] Other aspects of the application include pharmaceutical
compositions comprising an anti-IL-12 and/or anti-IL-23 antibody
for use in a clinically proven safe and clinically proven effective
method of treating moderately to severely active UC in a subject,
as well as methods of preparing the compositions and kits
comprising the pharmaceutical compositions.
[0033] In certain embodiments, a kit useful for a method of the
invention comprises at least one of a pharmaceutical composition
for intravenous administration of the invention and pharmaceutical
composition for subcutaneous administration of the invention. In
other embodiments, the kit comprises both a pharmaceutical
composition for intravenous administration and a pharmaceutical
composition for subcutaneous administration of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] The foregoing summary, as well as the following detailed
description of the invention, will be better understood when read
in conjunction with the appended drawings. It should be understood
that the invention is not limited to the precise embodiments shown
in the drawings.
[0035] FIG. 1 shows a diagrammatic representation of the study
design. Abbreviations: W8=Week 8; W16=Week 16; LTE=Long-term
Extension.
DETAILED DESCRIPTION OF THE INVENTION
[0036] Various publications, articles and patents are cited or
described in the background and throughout the specification; each
of these references is herein incorporated by reference in its
entirety. Discussion of documents, acts, materials, devices,
articles or the like which has been included in the present
specification is for the purpose of providing context for the
invention. Such discussion is not an admission that any or all of
these matters form part of the prior art with respect to any
inventions disclosed or claimed.
[0037] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood to one of
ordinary skill in the art to which this invention pertains.
Otherwise, certain terms used herein have the meanings as set forth
in the specification. All patents, published patent applications
and publications cited herein are incorporated by reference as if
set forth fully herein.
[0038] It must be noted that as used herein and in the appended
claims, the singular forms "a," "an," and "the" include plural
reference unless the context clearly dictates otherwise. Unless
otherwise indicated, the term "at least" preceding a series of
elements is to be understood to refer to every element in the
series. Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. Such equivalents are intended to be encompassed by the
invention.
[0039] Throughout this specification and the claims which follow,
unless the context requires otherwise, the word "comprise", and
variations such as "comprises" and "comprising", will be understood
to imply the inclusion of a stated integer or step or group of
integers or steps but not the exclusion of any other integer or
step or group of integer or step. When used herein the term
"comprising" can be substituted with the term "containing" or
"including" or sometimes when used herein with the term
"having".
[0040] When used herein "consisting of" excludes any element, step,
or ingredient not specified in the claim element. When used herein,
"consisting essentially of" does not exclude materials or steps
that do not materially affect the basic and novel characteristics
of the claim. Any of the aforementioned terms of "comprising",
"containing", "including", and "having", whenever used herein in
the context of an aspect or embodiment of the invention can be
replaced with the term "consisting of" or "consisting essentially
of" to vary scopes of the disclosure.
[0041] As used herein, the conjunctive term "and/or" between
multiple recited elements is understood as encompassing both
individual and combined options. For instance, where two elements
are conjoined by "and/or", a first option refers to the
applicability of the first element without the second. A second
option refers to the applicability of the second element without
the first. A third option refers to the applicability of the first
and second elements together. Any one of these options is
understood to fall within the meaning, and therefore satisfy the
requirement of the term "and/or" as used herein. Concurrent
applicability of more than one of the options is also understood to
fall within the meaning, and therefore satisfy the requirement of
the term "and/or."
[0042] As used herein, "subject" means any animal, preferably a
mammal, most preferably a human, whom will be or has been treated
by a method according to an embodiment of the invention. The term
"mammal" as used herein, encompasses any mammal. Examples of
mammals include, but are not limited to, cows, horses, sheep, pigs,
cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates
(NHPs) such as monkeys or apes, humans, etc., more preferably a
human.
[0043] As used herein, the term "in combination", in the context of
the administration of two or more therapies to a subject, refers to
the use of more than one therapy. The use of the term "in
combination" does not restrict the order in which therapies are
administered to a subject. For example, a first therapy (e.g., a
composition described herein) can be administered prior to (e.g., 5
minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4
hours, 6 hours, 12 hours, 16 hours, 24 hours, 48 hours, 72 hours,
96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8
weeks, or 12 weeks before), concomitantly with, or subsequent to
(e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2
hours, 4 hours, 6 hours, 12 hours, 16 hours, 24 hours, 48 hours, 72
hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6
weeks, 8 weeks, or 12 weeks after) the administration of a second
therapy to a subject.
[0044] As used herein, an "anti-IL-12 antibody," "anti-IL-23
antibody," "anti-IL-12/23p40 antibody," or "IL-12/23p40 antibody,"
refers to a monoclonal antibody (mAb) or antigen binding fragment
thereof, that binds the 40 kDa (p40) subunit shared by the
cytokines interleukin-12 and interleukin-23 (IL-12/23p40). The
antibody can affect at least one of IL-12/23 activity or function,
such as but not limited to, RNA, DNA or protein synthesis, IL-12/23
release, IL-12/23 receptor signaling, membrane IL-12/23 cleavage,
IL-12/23 activity, IL-12/23 production and/or synthesis.
[0045] The term "antibody" is further intended to encompass
antibodies, digestion fragments, specified portions and variants
thereof, including antibody mimetics or comprising portions of
antibodies that mimic the structure and/or function of an antibody
or specified fragment or portion thereof, including single chain
antibodies and fragments thereof. Functional fragments include
antigen-binding fragments that bind to a mammalian IL-12/23. For
example, antibody fragments capable of binding to IL-12/23 or
portions thereof, including, but not limited to, Fab (e.g., by
papain digestion), Fab' (e.g., by pepsin digestion and partial
reduction) and F(ab')2 (e.g., by pepsin digestion), facb (e.g., by
plasmin digestion), pFc' (e.g., by pepsin or plasmin digestion), Fd
(e.g., by pepsin digestion, partial reduction and reaggregation),
Fv or scFv (e.g., by molecular biology techniques) fragments, are
encompassed by the invention (see, e.g., Colligan, Immunology,
supra).
[0046] Such fragments can be produced by enzymatic cleavage,
synthetic or recombinant techniques, as known in the art and/or as
described herein. Antibodies can also be produced in a variety of
truncated forms using antibody genes in which one or more stop
codons have been introduced upstream of the natural stop site. For
example, a combination gene encoding a F(ab')2 heavy chain portion
can be designed to include DNA sequences encoding the C.sub.H1
domain and/or hinge region of the heavy chain. The various portions
of antibodies can be joined together chemically by conventional
techniques, or can be prepared as a contiguous protein using
genetic engineering techniques.
[0047] As used herein, the term "human antibody" refers to an
antibody in which substantially every part of the protein (e.g.,
CDR, framework, C.sub.L, C.sub.H domains (e.g., C.sub.H1, C.sub.H2,
C.sub.H3), hinge, (V.sub.L, V.sub.H)) is substantially
non-immunogenic in humans, with only minor sequence changes or
variations. A "human antibody" can also be an antibody that is
derived from or closely matches human germline immunoglobulin
sequences. Human antibodies can include amino acid residues not
encoded by germline immunoglobulin sequences (e.g., mutations
introduced by random or site-specific mutagenesis in vitro or by
somatic mutation in vivo). Often, this means that the human
antibody is substantially non-immunogenic in humans. Human
antibodies have been classified into groupings based on their amino
acid sequence similarities. Accordingly, using a sequence
similarity search, an antibody with a similar linear sequence can
be chosen as a template to create a human antibody. Similarly,
antibodies designated primate (monkey, baboon, chimpanzee, etc.),
rodent (mouse, rat, rabbit, guinea pig, hamster, and the like) and
other mammals designate such species, sub-genus, genus, sub-family,
and family specific antibodies. Further, chimeric antibodies can
include any combination of the above. Such changes or variations
optionally and preferably retain or reduce the immunogenicity in
humans or other species relative to non-modified antibodies. Thus,
a human antibody is distinct from a chimeric or humanized
antibody.
[0048] It is pointed out that a human antibody can be produced by a
non-human animal or prokaryotic or eukaryotic cell that is capable
of expressing functionally rearranged human immunoglobulin (e.g.,
heavy chain and/or light chain) genes. Further, when a human
antibody is a single chain antibody, it can comprise a linker
peptide that is not found in native human antibodies. For example,
an Fv can comprise a linker peptide, such as two to about eight
glycine or other amino acid residues, which connects the variable
region of the heavy chain and the variable region of the light
chain. Such linker peptides are considered to be of human
origin.
[0049] Anti-IL-12/23p40 antibodies (also termed IL-12/23p40
antibodies) (or antibodies to IL-23) useful in the methods and
compositions of the present invention can optionally be
characterized by high affinity binding to IL-12/23p40, optionally
and preferably, having low toxicity. In particular, an antibody,
specified fragment or variant of the invention, where the
individual components, such as the variable region, constant region
and framework, individually and/or collectively, optionally and
preferably possess low immunogenicity, is useful in the present
invention. The antibodies that can be used in the invention are
optionally characterized by their ability to treat subjects for
extended periods with measurable alleviation of symptoms and low
and/or acceptable toxicity. Low or acceptable immunogenicity and/or
high affinity, as well as other suitable properties, can contribute
to the therapeutic results achieved. "Low immunogenicity" is
defined herein as raising significant HAHA, HACA or HAMA responses
in less than about 75%, or preferably less than about 50% of the
subjects treated and/or raising low titres in the subject treated
(less than about 300, preferably less than about 100 measured with
a double antigen enzyme immunoassay) (Elliott et al., Lancet
344:1125-1127 (1994), entirely incorporated herein by reference).
"Low immunogenicity" can also be defined as the incidence of
titrable levels of antibodies to the anti-IL-12 antibody in
subjects treated with anti-IL-12 antibody as occurring in less than
25% of subjects treated, preferably, in less than 10% of subjects
treated with the recommended dose for the recommended course of
therapy during the treatment period.
[0050] The terms "clinically proven efficacy" and "clinically
proven effective" as used herein in the context of a dose, dosage
regimen, treatment or method refer to the effectiveness of a
particular dose, dosage or treatment regimen. Efficacy can be
measured based on change in the course of the disease in response
to an agent of the present invention. For example, an
anti-IL12/23p40 of the present invention (e.g., ustekinumab) is
administered to a subject in an amount and for a time sufficient to
induce an improvement, preferably a sustained improvement, in at
least one indicator that reflects the severity of the disorder that
is being treated. Various indicators that reflect the extent of the
subject's illness, disease or condition can be assessed for
determining whether the amount and time of the treatment is
sufficient. Such indicators include, for example, clinically
recognized indicators of disease severity, symptoms, or
manifestations of the disorder in question. The degree of
improvement generally is determined by a physician, who can make
this determination based on signs, symptoms, biopsies, or other
test results, and who can also employ questionnaires that are
administered to the subject, such as quality-of-life questionnaires
developed for a given disease. For example, an anti-IL12/23p40 or
anti-IL23 antibody of the present invention can be administered to
achieve an improvement in a subject's condition related to
ulcerative colitis.
[0051] Improvement can be indicated by an improvement in an index
of disease activity, by amelioration of clinical symptoms or by any
other measure of disease activity. Once such index of disease is
the ulcerative colitis Mayo score. The Mayo score is an
established, validated disease activity index for mild, moderate,
and severe ulcerative colitis (UC) that is calculated as the sum of
the 4 subscores of stool frequency, rectal bleeding, findings of
endoscopy, and physician's global assessment (PGA), and ranges from
0-12. A score of 3 to 5 points indicates mildly active disease, a
score of 6 to 10 points indicates moderately active disease, and a
score of 11 to 12 points indicates severe disease. The partial Mayo
score, which is the Mayo score without the endoscopy subscore, is
calculated as the sum of stool frequency, rectal bleeding, and
physician's global assessment subscores, and ranges from 0 to 9.
The modified Mayo score, which is the Mayo score without the PGA
subscore, is calculated as the sum of the stool frequency, rectal
bleeding, and endoscopy subscores, and ranges from 0 to 9. Other
disease activity indexes for UC include for example, Ulcerative
Colitis Endoscopic Index of Severity (UCEIS) score and the Bristol
Stool Form Scale (B SFS) score. The UCEIS score provides an overall
assessment of endoscopic severity of UC, based on mucosal vascular
pattern, bleeding, and ulceration (Travis et al., Gut. 61:535-542
(2012)). The score ranges from 3 to 11 with a higher score
indicating more severe disease by endoscopy. The BSFS score is used
to classify the form (or consistency) of human feces into 7
categories (Lewis and Heaton, Scand J Gastroenterol. 32(9):920-924
(1997)).
[0052] The term "clinical response" as used herein as it relates to
a subject's response to drug administration, refers to a decrease
from induction baseline in the Mayo score by .gtoreq.30% and
.gtoreq.3 points, with either a decrease from baseline in the
rectal bleeding subscore .gtoreq.1 or a rectal bleeding subscore of
0 or 1.
[0053] The term "clinically proven safe," as it relates to a dose,
dosage regimen, treatment or method with anti-IL-12/IL-23p40
antibody of the present invention (e.g., ustekinumab), refers to a
favorable risk:benefit ratio with an acceptable frequency and/or
acceptable severity of treatment-emergent adverse events (referred
to as AEs or TEAEs) compared to the standard of care or to another
comparator. As used herein, "adverse event," "treatment-emergent
adverse event," and "adverse reaction" mean any harm, unfavorable,
unintended or undesired sign or outcome associated with or caused
by administration of a pharmaceutical composition or therapeutic.
It is an untoward medical occurrence in a subject administered a
medicinal product. However, abnormal values or observations are not
reported as adverse events unless considered clinically significant
by the investigator. As used herein, when referring to an adverse
event, "clinically apparent" means clinically significant as
determined by a medical doctor or an investigator using standard
acceptable to those of ordinary skill in the art. When the harm or
undesired outcome of adverse events reaches such a level of
severity, a regulatory agency can deem the pharmaceutical
composition or therapeutic unacceptable for the proposed use. In
particular, "safe" as it relates to a dose, dosage regimen or
treatment with an anti-IL12/23p40 or anti-IL23 antibody of the
present invention refers to with an acceptable frequency and/or
acceptable severity of adverse events associated with
administration of the antibody if attribution is considered to be
possible, probable, or very likely due to the use of the
anti-IL12/23p40 or anti-IL23 antibody.
[0054] As used herein, unless otherwise noted, the term "clinically
proven" (used independently or to modify the terms "safe" and/or
"effective") shall mean that it has been proven by a clinical trial
wherein the clinical trial has met the approval standards of U.S.
Food and Drug Administration, EMEA or a corresponding national
regulatory agency. For example, the clinical study may be an
adequately sized, randomized, double-blinded study used to
clinically prove the effects of the drug.
[0055] As used herein, a dosage amount of an anti-IL-12/IL-23p40
antibody in "mg/kg" refers to the amount of the anti-IL-12/IL-23p40
antibody in milligrams per kilogram of the body weight of a subject
to be administered with the antibody.
[0056] Antibodies of the Present Invention--Production and
Generation
[0057] At least one anti-IL-12/23p40 (or anti-IL-23) used in the
method of the present invention can be optionally produced by a
cell line, a mixed cell line, an immortalized cell or clonal
population of immortalized cells, as well known in the art. See,
e.g., Ausubel, et al., ed., Current Protocols in Molecular Biology,
John Wiley & Sons, Inc., NY, NY (1987-2001); Sambrook, et al.,
Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring
Harbor, N.Y. (1989); Harlow and Lane, antibodies, a Laboratory
Manual, Cold Spring Harbor, N.Y. (1989); Colligan, et al., eds.,
Current Protocols in Immunology, John Wiley & Sons, Inc., NY
(1994-2001); Colligan et al., Current Protocols in Protein Science,
John Wiley & Sons, NY, N.Y., (1997-2001), each entirely
incorporated herein by reference.
[0058] Human antibodies that are specific for human IL-12/23p40 or
IL-23 proteins or fragments thereof can be raised against an
appropriate immunogenic antigen, such as an isolated IL-12/23p40
protein, IL-23 protein and/or a portion thereof (including
synthetic molecules, such as synthetic peptides). Other specific or
general mammalian antibodies can be similarly raised. Preparation
of immunogenic antigens, and monoclonal antibody production can be
performed using any suitable technique in view of the present
disclosure.
[0059] In one approach, a hybridoma is produced by fusing a
suitable immortal cell line (e.g., a myeloma cell line, such as,
but not limited to, Sp2/0, Sp2/0-AG14, NSO, NS1, NS2, AE-1, L.5,
L243, P3X63Ag8.653, Sp2 SA3, Sp2 MAI, Sp2 SS1, Sp2 SA5, U937, MLA
144, ACT IV, MOLT4, DA-1, JURKAT, WEHI, K-562, COS, RAJI, NIH 3T3,
HL-60, MLA 144, NAMALWA, NEURO 2A, or the like, or heteromylomas,
fusion products thereof, or any cell or fusion cell derived
therefrom, or any other suitable cell line as known in the art)
(see, e.g., www.atcc.org, www.lifetech.com, and the like), with
antibody producing cells, such as, but not limited to, isolated or
cloned spleen, peripheral blood, lymph, tonsil, or other immune or
B cell containing cells, or any other cells expressing heavy or
light chain constant or variable or framework or CDR sequences,
either as endogenous or heterologous nucleic acid, as recombinant
or endogenous, viral, bacterial, algal, prokaryotic, amphibian,
insect, reptilian, fish, mammalian, rodent, equine, ovine, goat,
sheep, primate, eukaryotic, genomic DNA, cDNA, rDNA, mitochondrial
DNA or RNA, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single,
double or triple stranded, hybridized, and the like or any
combination thereof. See, e.g., Ausubel, supra, and Colligan,
Immunology, supra, chapter 2, entirely incorporated herein by
reference.
[0060] Antibody producing cells can also be obtained from the
peripheral blood or, preferably, the spleen or lymph nodes, of
humans or other suitable animals that have been immunized with the
antigen of interest. Any other suitable host cell can also be used
for expressing heterologous or endogenous nucleic acid encoding an
antibody, specified fragment or variant thereof, of the present
invention. The fused cells (hybridomas) or recombinant cells can be
isolated using selective culture conditions or other suitable known
methods, and cloned by limiting dilution or cell sorting, or other
known methods. Cells which produce antibodies with the desired
specificity can be selected by a suitable assay (e.g., ELISA).
[0061] Other suitable methods of producing or isolating antibodies
of the requisite specificity can be used, including, but not
limited to, methods that select recombinant antibody from a peptide
or protein library (e.g., but not limited to, a bacteriophage,
ribosome, oligonucleotide, RNA, cDNA, or the like, display library;
e.g., as available from Cambridge antibody Technologies,
Cambridgeshire, UK; MorphoSys, Martinsreid/Planegg, DE; Biovation,
Aberdeen, Scotland, UK; Biolnvent, Lund, Sweden; Dyax Corp., Enzon,
Affymax/Biosite; Xoma, Berkeley, Calif.; Ixsys. See, e.g., EP
368,684, PCT/GB91/01134; PCT/GB92/01755; PCT/GB92/002240;
PCT/GB92/00883; PCT/GB93/00605; U.S. Ser. No. 08/350,260(5/12/94);
PCT/GB94/01422; PCT/GB94/02662; PCT/GB97/01835; (CAT/MRC);
WO90/14443; WO90/14424; WO90/14430; PCT/US94/1234; WO92/18619;
WO96/07754; (Scripps); WO96/13583, WO97/08320 (MorphoSys);
WO95/16027 (Biolnvent); WO88/06630; WO90/3809 (Dyax); U.S. Pat. No.
4,704,692 (Enzon); PCT/US91/02989 (Affymax); WO89/06283; EP 371
998; EP 550 400; (Xoma); EP 229 046; PCT/US91/07149 (Ixsys); or
stochastically generated peptides or proteins--U.S. Pat. Nos.
5,723,323, 5,763,192, 5,814,476, 5,817,483, 5,824,514, 5,976,862,
WO 86/05803, EP 590 689 (Ixsys, predecessor of Applied Molecular
Evolution (AME), each entirely incorporated herein by reference))
or that rely upon immunization of transgenic animals (e.g., SCID
mice, Nguyen et al., Microbiol. Immunol. 41:901-907 (1997); Sandhu
et al., Crit. Rev. Biotechnol. 16:95-118 (1996); Eren et al.,
Immunol. 93:154-161 (1998), each entirely incorporated by reference
as well as related patents and applications) that are capable of
producing a repertoire of human antibodies, as known in the art
and/or as described herein. Such techniques, include, but are not
limited to, ribosome display (Hanes et al., Proc. Natl. Acad. Sci.
USA, 94:4937-4942 (Can 1997); Hanes et al., Proc. Natl. Acad. Sci.
USA, 95:14130-14135 (November 1998)); single cell antibody
producing technologies (e.g., selected lymphocyte antibody method
("SLAM") (U.S. Pat. No. 5,627,052, Wen et al., J. Immunol.
17:887-892 (1987); Babcook et al., Proc. Natl. Acad. Sci. USA
93:7843-7848 (1996)); gel microdroplet and flow cytometry (Powell
et al., Biotechnol. 8:333-337 (1990); One Cell Systems, Cambridge,
Mass.; Gray et al., J. Imm. Meth. 182:155-163 (1995); Kenny et al.,
Bio/Technol. 13:787-790 (1995)); B-cell selection (Steenbakkers et
al., Molec. Biol. Reports 19:125-134 (1994); Jonak et al., Progress
Biotech, Vol. 5, In Vitro Immunization in Hybridoma Technology,
Borrebaeck, ed., Elsevier Science Publishers B.V., Amsterdam,
Netherlands (1988)).
[0062] Methods for engineering or humanizing non-human or human
antibodies can also be used and are well known in the art.
Generally, a humanized or engineered antibody has one or more amino
acid residues from a source that is non-human, e.g., but not
limited to, mouse, rat, rabbit, non-human primate or other mammal.
These non-human amino acid residues are replaced by residues often
referred to as "import" residues, which are typically taken from an
"import" variable, constant or other domain of a known human
sequence.
[0063] Known human Ig sequences are disclosed, e.g.,
www.ncbi.nlm.nih.gov/entrez/query.fcgi; www.ncbi.nih.gov/igblast;
www.atcc.org/phage/hdb.html; www.mrc-cpe.cam.ac.uk/ALIGNMENTS.php;
www.kabatdatabase.com/top.html; ftp.ncbi.nih.gov/repository/kabat;
www.sciquest.com; www.abcam.com;
www.antibodyresource.com/onlinecomp.html;
www.public.iastate.edu/.about.pedro/research tools.html;
www.whfreeman.com/immunology/CH05/kuby05.htm;
www.hhmi.org/grants/lectures/1996/vlab; www.path. cam.
ac.uk/.about.mrc7/mikeimages.html;
mcb.harvard.edu/BioLinks/Immunology.html; www.immunologylink.com;
pathbox.wustl.edu/.about.hcenter/index.html;
www.appliedbiosystems.com; www.nal.usda.gov/awic/pubs/antibody;
www.m.ehime-u.ac.jp/.about.yasuhito/Elisa.html; www.biodesign.com;
www.cancerresearchuk.org; www.biotech.ufl.edu; www.isac-net.org;
baserv.uci.kun.nl/.about.jraats/linksl.html;
www.recab.uni-hd.de/immuno.bme.nwu.edu; www.mrc-cpe.cam.ac.uk;
www.ibt.unam.mx/vir/V_mice.html; http://www.bioinforg.uk/abs;
antibody.bath.ac.uk; www.unizh.ch;
www.cryst.bbk.ac.uk/.about.ubcg07s;
www.nimr.mrc.ac.uk/CC/ccaewg/ccaewg.html;
www.path.cam.ac.uk/.about.mrc7/humanisation/TAHHP.html;
www.ibt.unam.mx/vir/structure/stat_aim.html;
www.biosci.missouri.edu/smithgp/index.html; www.jerini.de; Kabat et
al., Sequences of Proteins of Immunological Interest, U.S. Dept.
Health (1983), each entirely incorporated herein by reference.
[0064] Such imported sequences can be used to reduce immunogenicity
or reduce, enhance or modify binding, affinity, on-rate, off-rate,
avidity, specificity, half-life, or any other suitable
characteristic, as known in the art. In general, the CDR residues
are directly and most substantially involved in influencing antigen
binding. Accordingly, part or all of the non-human or human CDR
sequences are maintained while the non-human sequences of the
variable and constant regions can be replaced with human or other
amino acids.
[0065] Antibodies can also optionally be humanized or human
antibodies engineered with retention of high affinity for the
antigen and other favorable biological properties. To achieve this
goal, humanized (or human) antibodies can be optionally prepared by
a process of analysis of the parental sequences and various
conceptual humanized products using three-dimensional models of the
parental and humanized sequences. Three-dimensional immunoglobulin
models are commonly available and are familiar to those skilled in
the art. Computer programs are available which illustrate and
display probable three-dimensional conformational structures of
selected candidate immunoglobulin sequences. Inspection of these
displays permits analysis of the likely role of the residues in the
functioning of the candidate immunoglobulin sequence, i.e., the
analysis of residues that influence the ability of the candidate
immunoglobulin to bind its antigen. In this way, framework (FR)
residues can be selected and combined from the consensus and import
sequences so that the desired antibody characteristic, such as
increased affinity for the target antigen(s), is achieved.
[0066] In addition, the human anti-IL-12/23p40 (or anti-IL-23)
specific antibody used in the method of the present invention can
comprise a human germline light chain framework. In particular
embodiments, the light chain germline sequence is selected from
human VK sequences including, but not limited to, A1, A10, A11,
A14, A17, A18, A19, A2, A20, A23, A26, A27, A3, A30, A5, A7, B2,
B3, L1, L10, L11, L12, L14, L15, L16, L18, L19, L2, L20, L22, L23,
L24, L25, L4/18a, L5, L6, L8, L9, O1, O11, O12, O14, O18, O2, O4,
and O8. In certain embodiments, this light chain human germline
framework is selected from V1-11, V1-13, V1-16, V1-17, V1-18,
V1-19, V1-2, V1-20, V1-22, V1-3, V1-4, V1-5, V1-7, V1-9, V2-1,
V2-11, V2-13, V2-14, V2-15, V2-17, V2-19, V2-6, V2-7, V2-8, V3-2,
V3-3, V3-4, V4-1, V4-2, V4-3, V4-4, V4-6, V5-1, V5-2, V5-4, and
V5-6.
[0067] In other embodiments, the human anti-IL-12/23p40 (or
anti-IL-23) specific antibody used in the method of the present
invention can comprise a human germline heavy chain framework. In
particular embodiments, this heavy chain human germline framework
is selected from VH1-18, VH1-2, VH1-24, VH1-3, VH1-45, VH1-46,
VH1-58, VH1-69, VH1-8, VH2-26, VH2-5, VH2-70, VH3-11, VH3-13,
VH3-15, VH3-16, VH3-20, VH3-21, VH3-23, VH3-30, VH3-33, VH3-35,
VH3-38, VH3-43, VH3-48, VH3-49, VH3-53, VH3-64, VH3-66, VH3-7,
VH3-72, VH3-73, VH3-74, VH3-9, VH4-28, VH4-31, VH4-34, VH4-39,
VH4-4, VH4-59, VH4-61, VH5-51, VH6-1, and VH7-81.
[0068] In particular embodiments, the light chain variable region
and/or heavy chain variable region comprises a framework region or
at least a portion of a framework region (e.g., containing 2 or 3
subregions, such as FR2 and FR3). In certain embodiments, at least
FRL1, FRL2, FRL3, or FRL4 is fully human. In other embodiments, at
least FRH1, FRH2, FRH3, or FRH4 is fully human. In some
embodiments, at least FRL1, FRL2, FRL3, or FRL4 is a germline
sequence (e.g., human germline) or comprises human consensus
sequences for the particular framework (readily available at the
sources of known human Ig sequences described above). In other
embodiments, at least FRH1, FRH2, FRH3, or FRH4 is a germline
sequence (e.g., human germline) or comprises human consensus
sequences for the particular framework. In preferred embodiments,
the framework region is a fully human framework region.
[0069] Humanization or engineering of antibodies of the present
invention can be performed using any known method, such as but not
limited to those described in, Winter (Jones et al., Nature 321:522
(1986); Riechmann et al., Nature 332:323 (1988); Verhoeyen et al.,
Science 239:1534 (1988)), Sims et al., J. Immunol. 151: 2296
(1993); Chothia and Lesk, J. Mol. Biol. 196:901 (1987), Carter et
al., Proc. Natl. Acad. Sci. U.S.A. 89:4285 (1992); Presta et al.,
J. Immunol. 151:2623 (1993), U.S. Pat. Nos. 5,723,323, 5,976,862,
5,824,514, 5,817,483, 5,814,476, 5,763,192, 5,723,323, 5,766886,
5714352, 6204023, 6180370, 5693762, 5530101, 5585089, 5225539;
4816567, PCT/:US98/16280, US96/18978, US91/09630, US91/05939,
US94/01234, GB89/01334, GB91/01134, GB92/01755; WO90/14443,
WO90/14424, WO90/14430, EP 229246, each entirely incorporated
herein by reference, included references cited therein.
[0070] In certain embodiments, the antibody comprises an altered
(e.g., mutated) Fc region. For example, in some embodiments, the Fc
region has been altered to reduce or enhance the effector functions
of the antibody. In some embodiments, the Fc region is an isotype
selected from IgM, IgA, IgG, IgE, or other isotype. Alternatively,
or additionally, it can be useful to combine amino acid
modifications with one or more further amino acid modifications
that alter C1q binding and/or the complement dependent cytotoxicity
function of the Fc region of an IL-23 binding molecule. The
starting polypeptide of particular interest can be one that binds
to C1q and displays complement dependent cytotoxicity (CDC).
Polypeptides with pre-existing C1q binding activity, optionally
further having the ability to mediate CDC can be modified such that
one or both of these activities are enhanced. Amino acid
modifications that alter C1q and/or modify its complement dependent
cytotoxicity function are described, for example, in WO0042072,
which is hereby incorporated by reference.
[0071] As disclosed above, one can design an Fc region of the human
anti-IL-12/23p40 (or anti-IL-23) specific antibody of the present
invention with altered effector function, e.g., by modifying C1q
binding and/or Fc.gamma.R binding and thereby changing complement
dependent cytotoxicity (CDC) activity and/or antibody-dependent
cell-mediated cytotoxicity (ADCC) activity. "Effector functions"
are responsible for activating or diminishing a biological activity
(e.g., in a subject). Examples of effector functions include, but
are not limited to: C1q binding; CDC; Fc receptor binding; ADCC;
phagocytosis; down regulation of cell surface receptors (e.g., B
cell receptor; BCR), etc. Such effector functions can require the
Fc region to be combined with a binding domain (e.g., an antibody
variable domain) and can be assessed using various assays (e.g., Fc
binding assays, ADCC assays, CDC assays, etc.).
[0072] For example, one can generate a variant Fc region of the
human anti-IL-12/23p40 (or anti-IL-23) antibody with improved C1q
binding and improved Fc.gamma.RIII binding (e.g., having both
improved ADCC activity and improved CDC activity). Alternatively,
if it is desired that effector function be reduced or ablated, a
variant Fc region can be engineered with reduced CDC activity
and/or reduced ADCC activity. In other embodiments, only one of
these activities can be increased, and, optionally, also the other
activity reduced (e.g., to generate an Fc region variant with
improved ADCC activity, but reduced CDC activity and vice
versa).
[0073] Fc mutations can also be introduced in engineer to alter
their interaction with the neonatal Fc receptor (FcRn) and improve
their pharmacokinetic properties. A collection of human Fc variants
with improved binding to the FcRn have been described (Shields et
al., (2001). High resolution mapping of the binding site on human
IgG1 for Fc.gamma.RI, Fc.gamma.RII, Fc.gamma.RIII, and FcRn and
design of IgG1 variants with improved binding to the Fc.gamma.R, J.
Biol. Chem. 276:6591-6604).
[0074] Another type of amino acid substitution serves to alter the
glycosylation pattern of the Fc region of the human
anti-IL-12/23p40 (or anti-IL-23) specific antibody. Glycosylation
of an Fc region is typically either N-linked or O-linked. N-linked
refers to the attachment of the carbohydrate moiety to the side
chain of an asparagine residue. O-linked glycosylation refers to
the attachment of one of the sugars N-aceylgalactosamine,
galactose, or xylose to a hydroxyamino acid, most commonly serine
or threonine, although 5-hydroxyproline or 5-hydroxylysine can also
be used. The recognition sequences for enzymatic attachment of the
carbohydrate moiety to the asparagine side chain peptide sequences
are asparagine-X-serine and asparagine-X-threonine, where X is any
amino acid except proline. Thus, the presence of either of these
peptide sequences in a polypeptide creates a potential
glycosylation site.
[0075] The glycosylation pattern can be altered, for example, by
deleting one or more glycosylation site(s) found in the
polypeptide, and/or adding one or more glycosylation sites that are
not present in the polypeptide. Addition of glycosylation sites to
the Fc region of a human IL-23 specific antibody is conveniently
accomplished by altering the amino acid sequence such that it
contains one or more of the above-described tripeptide sequences
(for N-linked glycosylation sites). An exemplary glycosylation
variant has an amino acid substitution of residue Asn 297 of the
heavy chain. The alteration can also be made by the addition of, or
substitution by, one or more serine or threonine residues to the
sequence of the original polypeptide (for O-linked glycosylation
sites). Additionally, a change of Asn 297 to Ala can remove one of
the glycosylation sites.
[0076] In certain embodiments, the human anti-IL-12/23p40 (or
anti-IL-23) specific antibody of the present invention is expressed
in cells that express beta (1,4)-N-acetylglucosaminyltransferase
III (GnT III), such that GnT III adds GlcNAc to the human
anti-IL-12/23p40 (or anti-IL-23) antibody. Methods for producing
antibodies in such a fashion are provided in WO/9954342,
WO/03011878, patent publication 20030003097A1, and Umana et al.,
Nature Biotechnology, 17:176-180, February 1999; all of which are
herein specifically incorporated by reference in their
entireties.
[0077] The human anti-IL-12/23p40 (or anti-IL-23) antibody can also
be optionally generated by immunization of a transgenic animal
(e.g., mouse, rat, hamster, non-human primate, and the like)
capable of producing a repertoire of human antibodies, as described
herein and/or as known in the art. Cells that produce a human
anti-IL-12/23p40 (or anti-IL-23) antibody can be isolated from such
animals and immortalized using suitable methods, such as the
methods described herein.
[0078] Transgenic mice that can produce a repertoire of human
antibodies that bind to human antigens can be produced by known
methods (e.g., but not limited to, U.S. Pat. Nos. 5,770,428,
5,569,825, 5,545,806, 5,625,126, 5,625,825, 5,633,425, 5,661,016
and 5,789,650 issued to Lonberg et al.; Jakobovits et al. WO
98/50433, Jakobovits et al. WO 98/24893, Lonberg et al. WO
98/24884, Lonberg et al. WO 97/13852, Lonberg et al. WO 94/25585,
Kucherlapate et al. WO 96/34096, Kucherlapate et al. EP 0463 151
B1, Kucherlapate et al. EP 0710 719 A1, Surani et al. U.S. Pat. No.
5,545,807, Bruggemann et al. WO 90/04036, Bruggemann et al. EP 0438
474 B1, Lonberg et al. EP 0814 259 A2, Lonberg et al. GB 2 272 440
A, Lonberg et al. Nature 368:856-859 (1994), Taylor et al., Int.
Immunol. 6(4)579-591 (1994), Green et al, Nature Genetics 7:13-21
(1994), Mendez et al., Nature Genetics 15:146-156 (1997), Taylor et
al., Nucleic Acids Research 20(23):6287-6295 (1992), Tuaillon et
al., Proc Natl Acad Sci USA 90(8)3720-3724 (1993), Lonberg et al.,
Int Rev Immunol 13(1):65-93 (1995) and Fishwald et al., Nat
Biotechnol 14(7):845-851 (1996), which are each entirely
incorporated herein by reference). Generally, these mice comprise
at least one transgene comprising DNA from at least one human
immunoglobulin locus that is functionally rearranged, or which can
undergo functional rearrangement. The endogenous immunoglobulin
loci in such mice can be disrupted or deleted to eliminate the
capacity of the animal to produce antibodies encoded by endogenous
genes.
[0079] Screening antibodies for specific binding to similar
proteins or fragments can be conveniently achieved using peptide
display libraries. This method involves the screening of large
collections of peptides for individual members having the desired
function or structure. Antibody screening of peptide display
libraries is well known in the art. The displayed peptide sequences
can be from 3 to 5000 or more amino acids in length, frequently
from 5-100 amino acids long, and often from about 8 to 25 amino
acids long. In addition to direct chemical synthetic methods for
generating peptide libraries, several recombinant DNA methods have
been described. One type involves the display of a peptide sequence
on the surface of a bacteriophage or cell. Each bacteriophage or
cell contains the nucleotide sequence encoding the particular
displayed peptide sequence. Such methods are described in PCT
Patent Publication Nos. 91/17271, 91/18980, 91/19818, and
93/08278.
[0080] Other systems for generating libraries of peptides have
aspects of both in vitro chemical synthesis and recombinant
methods. See, PCT Patent Publication Nos. 92/05258, 92/14843, and
96/19256. See also, U.S. Pat. Nos. 5,658,754; and 5,643,768.
Peptide display libraries, vector, and screening kits are
commercially available from such suppliers as Invitrogen (Carlsbad,
Calif.), and Cambridge antibody Technologies (Cambridgeshire, UK).
See, e.g., U.S. Pat. Nos. 4,704,692, 4,939,666, 4,946,778,
5,260,203, 5,455,030, 5,518,889, 5,534,621, 5,656,730, 5,763,733,
5,767,260, 5,856,456, assigned to Enzon; U.S. Pat. Nos. 5,223,409,
5,403,484, 5,571,698, 5,837,500, assigned to Dyax, 5427908,
5580717, assigned to Affymax; 5885793, assigned to Cambridge
antibody Technologies; 5750373, assigned to Genentech, 5618920,
5595898, 5576195, 5698435, 5693493, 5698417, assigned to Xoma,
Colligan, supra; Ausubel, supra; or Sambrook, supra, each of the
above patents and publications entirely incorporated herein by
reference.
[0081] Antibodies used in the method of the present invention can
also be prepared using at least one anti-IL-12/23p40 (or
anti-IL-23) antibody encoding nucleic acid to provide transgenic
animals or mammals, such as goats, cows, horses, sheep, rabbits,
and the like, that produce such antibodies in their milk. Such
animals can be provided using known methods. See, e.g., but not
limited to, U.S. Pat. Nos. 5,827,690; 5,849,992; 4,873,316;
5,849,992; 5,994,616; 5,565,362; 5,304,489, and the like, each of
which is entirely incorporated herein by reference.
[0082] Antibodies used in the method of the present invention can
additionally be prepared using at least one anti-IL-12/23p40 (or
anti-IL-23) antibody encoding nucleic acid to provide transgenic
plants and cultured plant cells (e.g., but not limited to, tobacco
and maize) that produce such antibodies, specified portions or
variants in the plant parts or in cells cultured therefrom. As a
non-limiting example, transgenic tobacco leaves expressing
recombinant proteins have been successfully used to provide large
amounts of recombinant proteins, e.g., using an inducible promoter.
See, e.g., Cramer et al., Curr. Top. Microbol. Immunol. 240:95-118
(1999) and references cited therein. Also, transgenic maize have
been used to express mammalian proteins at commercial production
levels, with biological activities equivalent to those produced in
other recombinant systems or purified from natural sources. See,
e.g., Hood et al., Adv. Exp. Med. Biol. 464:127-147 (1999) and
references cited therein. Antibodies have also been produced in
large amounts from transgenic plant seeds including antibody
fragments, such as single chain antibodies (scFv's), including
tobacco seeds and potato tubers. See, e.g., Conrad et al., Plant
Mol. Biol. 38:101-109 (1998) and references cited therein. Thus,
antibodies of the present invention can also be produced using
transgenic plants, according to known methods. See also, e.g.,
Fischer et al., Biotechnol. Appl. Biochem. 30:99-108 (October,
1999), Ma et al., Trends Biotechnol. 13:522-7 (1995); Ma et al.,
Plant Physiol. 109:341-6 (1995); Whitelam et al., Biochem. Soc.
Trans. 22:940-944 (1994); and references cited therein. Each of the
above references is entirely incorporated herein by reference.
[0083] The antibodies used in the method of the invention can bind
human IL-12/IL-23p40 or IL-23 with a wide range of affinities (KD).
In a preferred embodiment, a human mAb can optionally bind human
IL-12/IL-23p40 or IL-23 with high affinity. For example, a human
mAb can bind human IL-12/IL-23p40 or IL-23 with a KD equal to or
less than about 10-7 M, such as but not limited to, 0.1-9.9 (or any
range or value therein).times.10-7, 10-8, 10-9, 10-10, 10-11,
10-12, 10-13 or any range or value therein.
[0084] The affinity or avidity of an antibody for an antigen can be
determined experimentally using any suitable method. (See, for
example, Berzofsky, et al., "Antibody-Antigen Interactions," In
Fundamental Immunology, Paul, W. E., Ed., Raven Press: New York,
N.Y. (1984); Kuby, Janis Immunology, W. H. Freeman and Company: New
York, N.Y. (1992); and methods described herein). The measured
affinity of a particular antibody-antigen interaction can vary if
measured under different conditions (e.g., salt concentration, pH).
Thus, measurements of affinity and other antigen-binding parameters
(e.g., KD, Ka, Kd) are preferably made with standardized solutions
of antibody and antigen, and a standardized buffer, such as the
buffer described herein.
[0085] Vectors and Host Cells
[0086] The present invention also relates to vectors that include
isolated nucleic acid molecules, host cells that are genetically
engineered with the recombinant vectors, and the production of at
least one anti-IL-12/IL-23p40 antibody by recombinant techniques,
as is well known in the art. See, e.g., Sambrook, et al., supra;
Ausubel, et al., supra, each entirely incorporated herein by
reference.
[0087] The polynucleotides can optionally be joined to a vector
containing a selectable marker for propagation in a host.
Generally, a plasmid vector is introduced in a precipitate, such as
a calcium phosphate precipitate, or in a complex with a charged
lipid. If the vector is a virus, it can be packaged in vitro using
an appropriate packaging cell line and then transduced into host
cells.
[0088] The DNA insert should be operatively linked to an
appropriate promoter. The expression constructs will further
contain sites for transcription initiation, termination and, in the
transcribed region, a ribosome binding site for translation. The
coding portion of the mature transcripts expressed by the
constructs will preferably include a translation initiating at the
beginning and a termination codon (e.g., UAA, UGA or UAG)
appropriately positioned at the end of the mRNA to be translated,
with UAA and UAG preferred for mammalian or eukaryotic cell
expression.
[0089] Expression vectors will preferably but optionally include at
least one selectable marker. Such markers include, e.g., but are
not limited to, methotrexate (MTX), dihydrofolate reductase (DHFR,
U.S. Pat. Nos. 4,399,216; 4,634,665; 4,656,134; 4,956,288;
5,149,636; 5,179,017, ampicillin, neomycin (G418), mycophenolic
acid, or glutamine synthetase (GS, U.S. Pat. Nos. 5,122,464;
5,770,359; 5,827,739) resistance for eukaryotic cell culture, and
tetracycline or ampicillin resistance genes for culturing in E.
coli and other bacteria or prokaryotics (the above patents are
entirely incorporated hereby by reference). Appropriate culture
mediums and conditions for the above-described host cells are known
in the art. Suitable vectors will be readily apparent to the
skilled artisan. Introduction of a vector construct into a host
cell can be effected by calcium phosphate transfection,
DEAE-dextran mediated transfection, cationic lipid-mediated
transfection, electroporation, transduction, infection or other
known methods. Such methods are described in the art, such as
Sambrook, supra, Chapters 1-4 and 16-18; Ausubel, supra, Chapters
1, 9, 13, 15, 16.
[0090] At least one antibody used in the method of the present
invention can be expressed in a modified form, such as a fusion
protein, and can include not only secretion signals, but also
additional heterologous functional regions. For instance, a region
of additional amino acids, particularly charged amino acids, can be
added to the N-terminus of an antibody to improve stability and
persistence in the host cell, during purification, or during
subsequent handling and storage. Also, peptide moieties can be
added to an antibody of the present invention to facilitate
purification. Such regions can be removed prior to final
preparation of an antibody or at least one fragment thereof. Such
methods are described in many standard laboratory manuals, such as
Sambrook, supra, Chapters 17.29-17.42 and 18.1-18.74; Ausubel,
supra, Chapters 16, 17 and 18.
[0091] Those of ordinary skill in the art are knowledgeable in the
numerous expression systems available for expression of a nucleic
acid encoding a protein used in the method of the present
invention. Alternatively, nucleic acids can be expressed in a host
cell by turning on (by manipulation) in a host cell that contains
endogenous DNA encoding an antibody. Such methods are well known in
the art, e.g., as described in U.S. Pat. Nos. 5,580,734, 5,641,670,
5,733,746, and 5,733,761, entirely incorporated herein by
reference.
[0092] Illustrative of cell cultures useful for the production of
the antibodies, specified portions or variants thereof, are
mammalian cells. Mammalian cell systems often will be in the form
of monolayers of cells although mammalian cell suspensions or
bioreactors can also be used. A number of suitable host cell lines
capable of expressing intact glycosylated proteins have been
developed in the art, and include the COS-1 (e.g., ATCC CRL 1650),
COS-7 (e.g., ATCC CRL-1651), HEK293, BHK21 (e.g., ATCC CRL-10), CHO
(e.g., ATCC CRL 1610) and BSC-1 (e.g., ATCC CRL-26) cell lines,
Cos-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653, SP2/0-Ag14, 293
cells, HeLa cells and the like, which are readily available from,
for example, American Type Culture Collection, Manassas, Va.
(www.atcc.org). Preferred host cells include cells of lymphoid
origin, such as myeloma and lymphoma cells. Particularly preferred
host cells are P3X63Ag8.653 cells (ATCC Accession Number CRL-1580)
and SP2/0-Ag14 cells (ATCC Accession Number CRL-1851). In a
particularly preferred embodiment, the recombinant cell is a
P3X63Ab8.653 or a SP2/0-Ag14 cell.
[0093] Expression vectors for these cells can include one or more
of the following expression control sequences, such as, but not
limited to, an origin of replication; a promoter (e.g., late or
early SV40 promoters, the CMV promoter (U.S. Pat. Nos. 5,168,062;
5,385,839), an HSV tk promoter, a pgk (phosphoglycerate kinase)
promoter, an EF-1 alpha promoter (U.S. Pat. No. 5,266,491), at
least one human immunoglobulin promoter; an enhancer, and/or
processing information sites, such as ribosome binding sites, RNA
splice sites, polyadenylation sites (e.g., an SV40 large T Ag poly
A addition site), and transcriptional terminator sequences. See,
e.g., Ausubel et al., supra; Sambrook, et al., supra. Other cells
useful for production of nucleic acids or proteins of the present
invention are known and/or available, for instance, from the
American Type Culture Collection Catalogue of Cell Lines and
Hybridomas (www.atcc.org) or other known or commercial sources.
[0094] When eukaryotic host cells are employed, polyadenlyation or
transcription terminator sequences are typically incorporated into
the vector. An example of a terminator sequence is the
polyadenlyation sequence from the bovine growth hormone gene.
Sequences for accurate splicing of the transcript can also be
included. An example of a splicing sequence is the VP1 intron from
SV40 (Sprague, et al., J. Virol. 45:773-781 (1983)). Additionally,
gene sequences to control replication in the host cell can be
incorporated into the vector, as known in the art.
[0095] Purification of an Antibody
[0096] An anti-IL-12/IL-23p40 or IL-23 antibody can be recovered
and purified from recombinant cell cultures by well-known methods
including, but not limited to, protein A purification, ammonium
sulfate or ethanol precipitation, acid extraction, anion or cation
exchange chromatography, phosphocellulose chromatography,
hydrophobic interaction chromatography, affinity chromatography,
hydroxylapatite chromatography and lectin chromatography. High
performance liquid chromatography ("HPLC") can also be employed for
purification. See, e.g., Colligan, Current Protocols in Immunology,
or Current Protocols in Protein Science, John Wiley & Sons, NY,
N.Y., (1997-2001), e.g., Chapters 1, 4, 6, 8, 9, 10, each entirely
incorporated herein by reference.
[0097] Antibodies used in the method of the present invention
include naturally purified products, products of chemical synthetic
procedures, and products produced by recombinant techniques from a
eukaryotic host, including, for example, yeast, higher plant,
insect and mammalian cells. Depending upon the host employed in a
recombinant production procedure, the antibody can be glycosylated
or can be non-glycosylated, with glycosylated preferred. Such
methods are described in many standard laboratory manuals, such as
Sambrook, supra, Sections 17.37-17.42; Ausubel, supra, Chapters 10,
12, 13, 16, 18 and 20, Colligan, Protein Science, supra, Chapters
12-14, all entirely incorporated herein by reference.
[0098] Anti-IL-12/IL-23p40 or IL-23 Antibodies
[0099] An anti-IL-12/IL-23p40 or IL-23 antibody according to the
present invention includes any protein or peptide containing
molecule that comprises at least a portion of an immunoglobulin
molecule, such as but not limited to, at least one ligand binding
portion (LBP), such as but not limited to, a complementarity
determining region (CDR) of a heavy or light chain or a ligand
binding portion thereof, a heavy chain or light chain variable
region, a framework region (e.g., FR1, FR2, FR3, FR4 or fragment
thereof, further optionally comprising at least one substitution,
insertion or deletion), a heavy chain or light chain constant
region, (e.g., comprising at least one CH1, hinge1, hinge2, hinge3,
hinge4, CH2, or CH3 or fragment thereof, further optionally
comprising at least one substitution, insertion or deletion), or
any portion thereof, that can be incorporated into an antibody. An
antibody can include or be derived from any mammal, such as but not
limited to, a human, a mouse, a rabbit, a rat, a rodent, a primate,
or any combination thereof, and the like.
[0100] Preferably, the human antibody or antigen-binding fragment
binds human IL-12/IL-23p40 or IL-23 and, thereby, partially or
substantially neutralizes at least one biological activity of the
protein. An antibody, or specified portion or variant thereof, that
partially or preferably substantially neutralizes at least one
biological activity of at least one IL-12/IL-23p40 or IL-23 protein
or fragment can bind the protein or fragment and thereby inhibit
activities mediated through the binding of IL-12/IL-23p40 or IL-23
to the IL-12 and/or IL-23 receptor or through other IL-12/IL-23p40
or IL-23-dependent or mediated mechanisms. As used herein, the term
"neutralizing antibody" refers to an antibody that can inhibit an
IL-12/IL-23p40 or IL-23-dependent activity by about 20-120%,
preferably by at least about 10, 20, 30, 40, 50, 55, 60, 65, 70,
75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% or more
depending on the assay. The capacity of an anti-IL-12/IL-23p40 or
IL-23 antibody to inhibit an IL-12/IL-23p40 or IL-23-dependent
activity is preferably assessed by at least one suitable
IL-12/IL-23p40 or IL-23 protein or receptor assay, as described
herein and/or as known in the art. A human antibody can be of any
class (IgG, IgA, IgM, IgE, IgD, etc.) or isotype and can comprise a
kappa or lambda light chain. In one embodiment, the human antibody
comprises an IgG heavy chain or defined fragment, for example, at
least one of isotypes, IgG1, IgG2, IgG3 or IgG4 (e.g., .gamma.1,
.gamma.2, .gamma.3, .gamma.4). Antibodies of this type can be
prepared by employing a transgenic mouse or other trangenic
non-human mammal comprising at least one human light chain (e.g.,
IgG, IgA, and IgM) transgenes as described herein and/or as known
in the art. In another embodiment, the anti-IL-23 human antibody
comprises an IgG1 heavy chain and an IgG1 light chain.
[0101] An antibody binds at least one specified epitope specific to
at least one IL-12/IL-23p40 or IL-23 protein, subunit, fragment,
portion or any combination thereof. The at least one epitope can
comprise at least one antibody binding region that comprises at
least one portion of the protein, which epitope is preferably
comprised of at least one extracellular, soluble, hydrophillic,
external or cytoplasmic portion of the protein.
[0102] Generally, the human antibody or antigen-binding fragment
will comprise an antigen-binding region that comprises at least one
human complementarity determining region (CDR1, CDR2 and CDR3) or
variant of at least one heavy chain variable region and at least
one human complementarity determining region (CDR1, CDR2 and CDR3)
or variant of at least one light chain variable region. The CDR
sequences can be derived from human germline sequences or closely
match the germline sequences. For example, the CDRs from a
synthetic library derived from the original non-human CDRs can be
used. These CDRs can be formed by incorporation of conservative
substitutions from the original non-human sequence. In another
particular embodiment, the antibody or antigen-binding portion or
variant can have an antigen-binding region that comprises at least
a portion of at least one light chain CDR (i.e., CDR1, CDR2 and/or
CDR3) having the amino acid sequence of the corresponding CDRs 1, 2
and/or 3.
[0103] Such antibodies can be prepared by chemically joining
together the various portions (e.g., CDRs, framework) of the
antibody using conventional techniques, by preparing and expressing
a (i.e., one or more) nucleic acid molecule that encodes the
antibody using conventional techniques of recombinant DNA
technology or by using any other suitable method.
[0104] In one embodiment, an anti-IL-12/23p40 antibody useful for
the invention is a monoclonal antibody, preferably a human mAb,
comprising heavy chain complementarity determining regions (CDRs)
HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively;
and light chain CDRs LCDR1, LCDR2, and LCDR3, of SEQ ID NOs: 4, 5,
and 6, respectively.
[0105] The anti-IL-12/IL-23p40 or IL-23 specific antibody can
comprise at least one of a heavy or light chain variable region
having a defined amino acid sequence. For example, in a preferred
embodiment, the anti-IL-12/IL-23p40 or IL-23 antibody comprises an
anti-IL-12/IL-23p40 antibody with a heavy chain variable region
comprising an amino acid sequence at least 85%, preferably at least
90%, more preferably at least 95%, and most preferably 100%
identical to SEQ ID NO:7, and a light chain variable region
comprising an amino acid sequence at least 85%, preferably at least
90%, more preferably at least 95%, and most preferably 100%
identical to SEQ ID NO:8.
[0106] The anti-IL-12/IL-23p40 or IL-23 specific antibody can also
comprise at least one of a heavy or light chain having a defined
amino acid sequence. In another preferred embodiment, the
anti-IL-12/IL-23p40 or IL-23 antibody comprises an
anti-IL-12/IL-23p40 antibody with a heavy chain comprising an amino
acid sequence at least 85%, preferably at least 90%, more
preferably at least 95%, and most preferably 100% identical to SEQ
ID NO:10, and a light chain variable region comprising an amino
acid sequence at least 85%, preferably at least 90%, more
preferably at least 95%, and most preferably 100% identical to SEQ
ID NO:11.
[0107] Preferably, the anti-IL-12/23p40 antibody is ustekinumab
(Stelara.RTM.), comprising a heavy chain having the amino acid
sequence of SEQ ID NO: 10 and a light chain comprising the amino
acid sequence of SEQ ID NO: 11. Other examples of anti-IL12/23p40
antibodies useful for the invention include, but are not limited
to, Briakinumab (ABT-874, Abbott) and other antibodies described in
U.S. Pat. Nos. 6,914,128, 7,247,711, 7,700,739, the entire contents
of which are incorporated herein by reference).
[0108] The invention also relates to antibodies, antigen-binding
fragments, immunoglobulin chains and CDRs comprising amino acids in
a sequence that is substantially the same as an amino acid sequence
described herein. Preferably, such antibodies or antigen-binding
fragments and antibodies comprising such chains or CDRs can bind
human IL-12/IL-23p40 or IL-23 with high affinity (e.g., KD less
than or equal to about 10.sup.-9M). Amino acid sequences that are
substantially the same as the sequences described herein include
sequences comprising conservative amino acid substitutions, as well
as amino acid deletions and/or insertions. A conservative amino
acid substitution refers to the replacement of a first amino acid
by a second amino acid that has chemical and/or physical properties
(e.g., charge, structure, polarity, hydrophobicity/hydrophilicity)
that are similar to those of the first amino acid. Conservative
substitutions include, without limitation, replacement of one amino
acid by another within the following groups: lysine (K), arginine
(R) and histidine (H); aspartate (D) and glutamate (E); asparagine
(N), glutamine (Q), serine (S), threonine (T), tyrosine (Y), K, R,
H, D and E; alanine (A), valine (V), leucine (L), isoleucine (I),
proline (P), phenylalanine (F), tryptophan (W), methionine (M),
cysteine (C) and glycine (G); F, W and Y; C, S and T.
[0109] Antibodies that bind to human IL-12/IL-23p40 or IL-23 and
that comprise a defined heavy or light chain variable region can be
prepared using suitable methods, such as phage display (Katsube,
Y., et al., Int J Mol. Med, 1(5):863-868 (1998)) or methods that
employ transgenic animals, as known in the art and/or as described
herein. For example, a transgenic mouse, comprising a functionally
rearranged human immunoglobulin heavy chain transgene and a
transgene comprising DNA from a human immunoglobulin light chain
locus that can undergo functional rearrangement, can be immunized
with human IL-12/IL-23p40 or IL-23 or a fragment thereof to elicit
the production of antibodies. If desired, the antibody producing
cells can be isolated and hybridomas or other immortalized
antibody-producing cells can be prepared as described herein and/or
as known in the art. Alternatively, the antibody, specified portion
or variant can be expressed using the encoding nucleic acid or
portion thereof in a suitable host cell.
[0110] An anti-IL-12/IL-23p40 or IL-23 antibody used in the method
of the present invention can include one or more amino acid
substitutions, deletions or additions, either from natural
mutations or human manipulation, as specified herein.
[0111] The number of amino acid substitutions a skilled artisan
would make depends on many factors, including those described
above. Generally speaking, the number of amino acid substitutions,
insertions or deletions for any given anti-IL-12/IL-23p40 or IL-23
antibody, fragment or variant will not be more than 40, 30, 20, 19,
18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, such
as 1-30 or any range or value therein, as specified herein.
[0112] Amino acids in an anti-IL-12/IL-23p40 or IL-23 specific
antibody that are essential for function can be identified by
methods known in the art, such as site-directed mutagenesis or
alanine-scanning mutagenesis (e.g., Ausubel, supra, Chapters 8, 15;
Cunningham and Wells, Science 244:1081-1085 (1989)). The latter
procedure introduces single alanine mutations at every residue in
the molecule. The resulting mutant molecules are then tested for
biological activity, such as, but not limited to, at least one
IL-12/IL-23p40 or IL-23 neutralizing activity. Sites that are
critical for antibody binding can also be identified by structural
analysis, such as crystallization, nuclear magnetic resonance or
photoaffinity labeling (Smith, et al., J. Mol. Biol. 224:899-904
(1992) and de Vos, et al., Science 255:306-312 (1992)).
[0113] Anti-IL-12/IL-23p40 or IL-23 antibodies can include, but are
not limited to, at least one portion, sequence or combination
selected from 5 to all of the contiguous amino acids of at least
one of SEQ ID NOs 1, 2, 3, 4, 5, 6, 7, 8, 10, or 11.
[0114] IL-12/IL-23p40 or IL-23 antibodies or specified portions or
variants can include, but are not limited to, at least one portion,
sequence or combination selected from at least 3-5 contiguous amino
acids of the SEQ ID NOs above; 5-17 contiguous amino acids of the
SEQ ID NOs above, 5-10 contiguous amino acids of the SEQ ID NOs
above, 5-11 contiguous amino acids of the SEQ ID NOs above, 5-7
contiguous amino acids of the SEQ ID NOs above; 5-9 contiguous
amino acids of the SEQ ID NOs above.
[0115] An anti-IL-12/IL-23p40 or IL-23 antibody can further
optionally comprise a polypeptide of at least one of 70-100% of 5,
17, 10, 11, 7, 9, 119, 108, 449, or 214 contiguous amino acids of
the SEQ ID NOs above. In one embodiment, the amino acid sequence of
an immunoglobulin chain, or portion thereof (e.g., variable region,
CDR) has about 70-100% identity (e.g., 70, 71, 72, 73, 74, 75, 76,
77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93,
94, 95, 96, 97, 98, 99, 100 or any range or value therein) to the
amino acid sequence of the corresponding chain of at least one of
the SEQ ID NOs above. For example, the amino acid sequence of a
light chain variable region can be compared with the sequence of
the SEQ ID NOs above, or the amino acid sequence of a heavy chain
CDR3 can be compared with the SEQ ID NOs above. Preferably, 70-100%
amino acid identity (i.e., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99,
100 or any range or value therein) is determined using a suitable
computer algorithm, as known in the art.
[0116] "Identity," as known in the art, is a relationship between
two or more polypeptide sequences or two or more polynucleotide
sequences, as determined by comparing the sequences. In the art,
"identity" also means the degree of sequence relatedness between
polypeptide or polynucleotide sequences, as determined by the match
between strings of such sequences. "Identity" and "similarity" can
be readily calculated by known methods, including, but not limited
to, those described in Computational Molecular Biology, Lesk, A.
M., ed., Oxford University Press, New York, 1988;
Biocomputing:Informatics and Genome Projects, Smith, D. W., ed.,
Academic Press, New York, 1993; Computer Analysis of Sequence Data,
Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New
Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje,
G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov,
M. and Devereux, J., eds., M Stockton Press, New York, 1991; and
Carillo, H., and Lipman, D., Siam J. Applied Math., 48:1073 (1988).
In addition, values for percentage identity can be obtained from
amino acid and nucleotide sequence alignments generated using the
default settings for the AlignX component of Vector NTI Suite 8.0
(Informax, Frederick, Md.).
[0117] Preferred methods to determine identity are designed to give
the largest match between the sequences tested. Methods to
determine identity and similarity are codified in publicly
available computer programs. Preferred computer program methods to
determine identity and similarity between two sequences include,
but are not limited to, the GCG program package (Devereux, J., et
al., Nucleic Acids Research 12(1): 387 (1984)), BLASTP, BLASTN, and
FASTA (Atschul, S. F. et al., J. Molec. Biol. 215:403-410 (1990)).
The BLAST X program is publicly available from NCBI and other
sources (BLAST Manual, Altschul, S., et al., NCBINLM NIH Bethesda,
Md. 20894: Altschul, S., et al., J. Mol. Biol. 215:403-410 (1990).
The well-known Smith Waterman algorithm can also be used to
determine identity.
[0118] Exemplary heavy chain and light chain variable regions
sequences and portions thereof are provided in the SEQ ID NOs
above. The antibodies of the present invention, or specified
variants thereof, can comprise any number of contiguous amino acid
residues from an antibody of the present invention, wherein that
number is selected from the group of integers consisting of from
10-100% of the number of contiguous residues in an
anti-IL-12/IL-23p40 or IL-23 antibody. Optionally, this subsequence
of contiguous amino acids is at least about 10, 20, 30, 40, 50, 60,
70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200,
210, 220, 230, 240, 250 or more amino acids in length, or any range
or value therein. Further, the number of such subsequences can be
any integer selected from the group consisting of from 1 to 20,
such as at least 2, 3, 4, or 5.
[0119] As those of skill will appreciate, the present invention
includes at least one biologically active antibody of the present
invention. Biologically active antibodies have a specific activity
at least 20%, 30%, or 40%, and, preferably, at least 50%, 60%, or
70%, and, most preferably, at least 80%, 90%, or 95%-100% or more
(including, without limitation, up to 10 times the specific
activity) of that of the native (non-synthetic), endogenous or
related and known antibody. Methods of assaying and quantifying
measures of enzymatic activity and substrate specificity are well
known to those of skill in the art.
[0120] In another aspect, the invention relates to human antibodies
and antigen-binding fragments, as described herein, which are
modified by the covalent attachment of an organic moiety. Such
modification can produce an antibody or antigen-binding fragment
with improved pharmacokinetic properties (e.g., increased in vivo
serum half-life). The organic moiety can be a linear or branched
hydrophilic polymeric group, fatty acid group, or fatty acid ester
group. In particular embodiments, the hydrophilic polymeric group
can have a molecular weight of about 800 to about 120,000 Daltons
and can be a polyalkane glycol (e.g., polyethylene glycol (PEG),
polypropylene glycol (PPG)), carbohydrate polymer, amino acid
polymer or polyvinyl pyrolidone, and the fatty acid or fatty acid
ester group can comprise from about eight to about forty carbon
atoms.
[0121] The modified antibodies and antigen-binding fragments can
comprise one or more organic moieties that are covalently bonded,
directly or indirectly, to the antibody. Each organic moiety that
is bonded to an antibody or antigen-binding fragment of the
invention can independently be a hydrophilic polymeric group, a
fatty acid group or a fatty acid ester group. As used herein, the
term "fatty acid" encompasses mono-carboxylic acids and
di-carboxylic acids. A "hydrophilic polymeric group," as the term
is used herein, refers to an organic polymer that is more soluble
in water than in octane. For example, polylysine is more soluble in
water than in octane. Thus, an antibody modified by the covalent
attachment of polylysine is encompassed by the invention.
Hydrophilic polymers suitable for modifying antibodies of the
invention can be linear or branched and include, for example,
polyalkane glycols (e.g., PEG, monomethoxy-polyethylene glycol
(mPEG), PPG and the like), carbohydrates (e.g., dextran, cellulose,
oligosaccharides, polysaccharides and the like), polymers of
hydrophilic amino acids (e.g., polylysine, polyarginine,
polyaspartate and the like), polyalkane oxides (e.g., polyethylene
oxide, polypropylene oxide and the like) and polyvinyl pyrolidone.
Preferably, the hydrophilic polymer that modifies the antibody of
the invention has a molecular weight of about 800 to about 150,000
Daltons as a separate molecular entity. For example, PEG5000 and
PEG20,000, wherein the subscript is the average molecular weight of
the polymer in Daltons, can be used. The hydrophilic polymeric
group can be substituted with one to about six alkyl, fatty acid or
fatty acid ester groups. Hydrophilic polymers that are substituted
with a fatty acid or fatty acid ester group can be prepared by
employing suitable methods. For example, a polymer comprising an
amine group can be coupled to a carboxylate of the fatty acid or
fatty acid ester, and an activated carboxylate (e.g., activated
with N, N-carbonyl diimidazole) on a fatty acid or fatty acid ester
can be coupled to a hydroxyl group on a polymer.
[0122] Fatty acids and fatty acid esters suitable for modifying
antibodies of the invention can be saturated or can contain one or
more units of unsaturation. Fatty acids that are suitable for
modifying antibodies of the invention include, for example,
n-dodecanoate (C12, laurate), n-tetradecanoate (C14, myristate),
n-octadecanoate (C18, stearate), n-eicosanoate (C20, arachidate),
n-docosanoate (C22, behenate), n-triacontanoate (C30),
n-tetracontanoate (C40), cis-.DELTA.9-octadecanoate (C18, oleate),
all cis-.DELTA.5,8,11,14-eicosatetraenoate (C20, arachidonate),
octanedioic acid, tetradecanedioic acid, octadecanedioic acid,
docosanedioic acid, and the like. Suitable fatty acid esters
include mono-esters of dicarboxylic acids that comprise a linear or
branched lower alkyl group. The lower alkyl group can comprise from
one to about twelve, preferably, one to about six, carbon
atoms.
[0123] The modified human antibodies and antigen-binding fragments
can be prepared using suitable methods, such as by reaction with
one or more modifying agents. A "modifying agent" as the term is
used herein, refers to a suitable organic group (e.g., hydrophilic
polymer, a fatty acid, a fatty acid ester) that comprises an
activating group. An "activating group" is a chemical moiety or
functional group that can, under appropriate conditions, react with
a second chemical group thereby forming a covalent bond between the
modifying agent and the second chemical group. For example,
amine-reactive activating groups include electrophilic groups, such
as tosylate, mesylate, halo (chloro, bromo, fluoro, iodo),
N-hydroxysuccinimidyl esters (NETS), and the like. Activating
groups that can react with thiols include, for example, maleimide,
iodoacetyl, acrylolyl, pyridyl disulfides, 5-thiol-2-nitrobenzoic
acid thiol (TNB-thiol), and the like. An aldehyde functional group
can be coupled to amine- or hydrazide-containing molecules, and an
azide group can react with a trivalent phosphorous group to form
phosphoramidate or phosphorimide linkages. Suitable methods to
introduce activating groups into molecules are known in the art
(see for example, Hermanson, G. T., Bioconjugate Techniques,
Academic Press: San Diego, Calif. (1996)). An activating group can
be bonded directly to the organic group (e.g., hydrophilic polymer,
fatty acid, fatty acid ester), or through a linker moiety, for
example, a divalent C1-C12 group wherein one or more carbon atoms
can be replaced by a heteroatom, such as oxygen, nitrogen or
sulfur. Suitable linker moieties include, for example,
tetraethylene glycol, --(CH2)3-, --NH--(CH2)6-NH--, --(CH2)2-NH--
and --CH2-O--CH2-CH2-O--CH2-CH2-O--CH--NH--.
[0124] Modifying agents that comprise a linker moiety can be
produced, for example, by reacting a mono-Boc-alkyldiamine (e.g.,
mono-Boc-ethylenediamine, mono-Boc-diaminohexane) with a fatty acid
in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
(EDC) to form an amide bond between the free amine and the fatty
acid carboxylate. The Boc protecting group can be removed from the
product by treatment with trifluoroacetic acid (TFA) to expose a
primary amine that can be coupled to another carboxylate, as
described, or can be reacted with maleic anhydride and the
resulting product cyclized to produce an activated maleimido
derivative of the fatty acid. (See, for example, Thompson, et al.,
WO 92/16221, the entire teachings of which are incorporated herein
by reference.)
[0125] The modified antibodies can be produced by reacting a human
antibody or antigen-binding fragment with a modifying agent. For
example, the organic moieties can be bonded to the antibody in a
non-site specific manner by employing an amine-reactive modifying
agent, for example, an NHS ester of PEG. Modified human antibodies
or antigen-binding fragments can also be prepared by reducing
disulfide bonds (e.g., intra-chain disulfide bonds) of an antibody
or antigen-binding fragment. The reduced antibody or
antigen-binding fragment can then be reacted with a thiol-reactive
modifying agent to produce the modified antibody of the invention.
Modified human antibodies and antigen-binding fragments comprising
an organic moiety that is bonded to specific sites of an antibody
of the present invention can be prepared using suitable methods,
such as reverse proteolysis (Fisch et al., Bioconjugate Chem.,
3:147-153 (1992); Werlen et al., Bioconjugate Chem., 5:411-417
(1994); Kumaran et al., Protein Sci. 6(10):2233-2241 (1997); Itoh
et al., Bioorg. Chem., 24(1): 59-68 (1996); Capellas et al.,
Biotechnol. Bioeng., 56(4):456-463 (1997)), and the methods
described in Hermanson, G. T., Bioconjugate Techniques, Academic
Press: San Diego, Calif. (1996).
[0126] The method of the present invention also uses an
anti-IL-12/IL-23p40 or IL-23 antibody composition comprising at
least one, at least two, at least three, at least four, at least
five, at least six or more anti-IL-12/IL-23p40 or IL-23 antibodies
thereof, as described herein and/or as known in the art that are
provided in a non-naturally occurring composition, mixture or form.
Such compositions comprise non-naturally occurring compositions
comprising at least one or two full length, C- and/or N-terminally
deleted variants, domains, fragments, or specified variants, of the
anti-IL-12/IL-23p40 or IL-23 antibody amino acid sequence selected
from the group consisting of 70-100% of the contiguous amino acids
of the SEQ ID NOs above, or specified fragments, domains or
variants thereof. Preferred anti-IL-12/IL-23p40 or IL-23 antibody
compositions include at least one or two full length, fragments,
domains or variants as at least one CDR or LBP containing portions
of the anti-IL-12/IL-23p40 or IL-23 antibody sequence described
herein, for example, 70-100% of the SEQ ID NOs above, or specified
fragments, domains or variants thereof. Further preferred
compositions comprise, for example, 40-99% of at least one of
70-100% of the SEQ ID NOs above, etc., or specified fragments,
domains or variants thereof. Such composition percentages are by
weight, volume, concentration, molarity, or molality as liquid or
dry solutions, mixtures, suspension, emulsions, particles, powder,
or colloids, as known in the art or as described herein.
[0127] Antibody Compositions Comprising Further Therapeutically
Active Ingredients
[0128] The antibody compositions used in the method of the
invention can optionally further comprise an effective amount of at
least one compound or protein selected from at least one of an
anti-infective drug, a cardiovascular (CV) system drug, a central
nervous system (CNS) drug, an autonomic nervous system (ANS) drug,
a respiratory tract drug, a gastrointestinal (GI) tract drug, a
hormonal drug, a drug for fluid or electrolyte balance, a
hematologic drug, an antineoplastic, an immunomodulation drug, an
ophthalmic, otic or nasal drug, a topical drug, a nutritional drug
or the like. Such drugs are well known in the art, including
formulations, indications, dosing and administration for each
presented herein (see, e.g., Nursing 2001 Handbook of Drugs, 21st
edition, Springhouse Corp., Springhouse, P A, 2001; Health
Professional's Drug Guide 2001, ed., Shannon, Wilson, Stang,
Prentice-Hall, Inc, Upper Saddle River, N.J.; Pharmcotherapy
Handbook, Wells et al., ed., Appleton & Lange, Stamford, Conn.,
each entirely incorporated herein by reference).
[0129] By way of example of the drugs that can be combined with the
antibodies for the method of the present invention, the
anti-infective drug can be at least one selected from amebicides or
at least one antiprotozoals, anthelmintics, antifungals,
antimalarials, antituberculotics or at least one antileprotics,
aminoglycosides, penicillins, cephalosporins, tetracyclines,
sulfonamides, fluoroquinolones, antivirals, macrolide
anti-infectives, and miscellaneous anti-infectives. The hormonal
drug can be at least one selected from corticosteroids, androgens
or at least one anabolic steroid, estrogen or at least one
progestin, gonadotropin, antidiabetic drug or at least one
glucagon, thyroid hormone, thyroid hormone antagonist, pituitary
hormone, and parathyroid-like drug. The at least one cephalosporin
can be at least one selected from cefaclor, cefadroxil, cefazolin
sodium, cefdinir, cefepime hydrochloride, cefixime, cefmetazole
sodium, cefonicid sodium, cefoperazone sodium, cefotaxime sodium,
cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil,
cefprozil, ceftazidime, ceftibuten, ceftizoxime sodium, ceftriaxone
sodium, cefuroxime axetil, cefuroxime sodium, cephalexin
hydrochloride, cephalexin monohydrate, cephradine, and
loracarbef.
[0130] The at least one coricosteroid can be at least one selected
from betamethasone, betamethasone acetate or betamethasone sodium
phosphate, betamethasone sodium phosphate, cortisone acetate,
dexamethasone, dexamethasone acetate, dexamethasone sodium
phosphate, fludrocortisone acetate, hydrocortisone, hydrocortisone
acetate, hydrocortisone cypionate, hydrocortisone sodium phosphate,
hydrocortisone sodium succinate, methylprednisolone,
methylprednisolone acetate, methylprednisolone sodium succinate,
prednisolone, prednisolone acetate, prednisolone sodium phosphate,
prednisolone tebutate, prednisone, triamcinolone, triamcinolone
acetonide, and triamcinolone diacetate. The at least one androgen
or anabolic steroid can be at least one selected from danazol,
fluoxymesterone, methyltestosterone, nandrolone decanoate,
nandrolone phenpropionate, testosterone, testosterone cypionate,
testosterone enanthate, testosterone propionate, and testosterone
transdermal system.
[0131] The at least one immunosuppressant can be at least one
selected from azathioprine, basiliximab, cyclosporine, daclizumab,
lymphocyte immune globulin, muromonab-CD3, mycophenolate mofetil,
mycophenolate mofetil hydrochloride, sirolimus, 6-mercaptopurine,
methotrexate, mizoribine, and tacrolimus.
[0132] The at least one local anti-infective can be at least one
selected from acyclovir, amphotericin B, azelaic acid cream,
bacitracin, butoconazole nitrate, clindamycin phosphate,
clotrimazole, econazole nitrate, erythromycin, gentamicin sulfate,
ketoconazole, mafenide acetate, metronidazole (topical), miconazole
nitrate, mupirocin, naftifine hydrochloride, neomycin sulfate,
nitrofurazone, nystatin, silver sulfadiazine, terbinafine
hydrochloride, terconazole, tetracycline hydrochloride,
tioconazole, and tolnaftate. The at least one scabicide or
pediculicide can be at least one selected from crotamiton, lindane,
permethrin, and pyrethrins. The at least one topical corticosteroid
can be at least one selected from betamethasone dipropionate,
betamethasone valerate, clobetasol propionate, desonide,
desoximetasone, dexamethasone, dexamethasone sodium phosphate,
diflorasone diacetate, fluocinolone acetonide, fluocinonide,
flurandrenolide, fluticasone propionate, halcionide,
hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate,
hydrocorisone valerate, mometasone furoate, and triamcinolone
acetonide. (See, e.g., pp. 1098-1136 of Nursing 2001 Drug
Handbook.)
[0133] Anti-IL-12/IL-23p40 or IL-23 antibody compositions can
further comprise at least one of any suitable and effective amount
of a composition or pharmaceutical composition comprising at least
one anti-IL-12/IL-23p40 or IL-23 antibody contacted or administered
to a cell, tissue, organ, animal or subject in need of such
modulation, treatment or therapy, optionally further comprising at
least one selected from at least one TNF antagonist (e.g., but not
limited to a TNF chemical or protein antagonist, TNF monoclonal or
polyclonal antibody or fragment, a soluble TNF receptor (e.g., p55,
p70 or p85) or fragment, fusion polypeptides thereof, or a small
molecule TNF antagonist, e.g., TNF binding protein I or II (TBP-1
or TBP-II), nerelimonmab, infliximab, eternacept, CDP-571, CDP-870,
afelimomab, lenercept, and the like), an antirheumatic (e.g.,
methotrexate, auranofin, aurothioglucose, azathioprine, etanercept,
gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide,
sulfasalzine), an immunization, an immunoglobulin, an
immunosuppressive (e.g., azathioprine, basiliximab, cyclosporine,
daclizumab), a cytokine or a cytokine antagonist. Non-limiting
examples of such cytokines include, but are not limited to, any of
IL-1 to IL-23 et al. (e.g., IL-1, IL-2, etc.). Suitable dosages are
well known in the art. See, e.g., Wells et al., eds.,
Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange,
Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket
Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma
Linda, Calif. (2000), each of which references are entirely
incorporated herein by reference.
[0134] Anti-IL-12/IL-23p40 or IL-23 antibody compounds,
compositions or combinations used in the method of the present
invention can further comprise at least one of any suitable
auxiliary, such as, but not limited to, diluent, binder,
stabilizer, buffers, salts, lipophilic solvents, preservative,
adjuvant or the like. Pharmaceutically acceptable auxiliaries are
preferred. Non-limiting examples of, and methods of preparing such
sterile solutions are well known in the art, such as, but limited
to, Gennaro, Ed., Remington's Pharmaceutical Sciences, 18th
Edition, Mack Publishing Co. (Easton, Pa.) 1990. Pharmaceutically
acceptable carriers can be routinely selected that are suitable for
the mode of administration, solubility and/or stability of the
anti-IL-12/IL-23p40, fragment or variant composition as well known
in the art or as described herein.
[0135] Pharmaceutical excipients and additives useful in the
present composition include, but are not limited to, proteins,
peptides, amino acids, lipids, and carbohydrates (e.g., sugars,
including monosaccharides, di-, tri-, tetra-, and oligosaccharides;
derivatized sugars, such as alditols, aldonic acids, esterified
sugars and the like; and polysaccharides or sugar polymers), which
can be present singly or in combination, comprising alone or in
combination 1-99.99% by weight or volume. Exemplary protein
excipients include serum albumin, such as human serum albumin
(HSA), recombinant human albumin (rHA), gelatin, casein, and the
like. Representative amino acid/antibody components, which can also
function in a buffering capacity, include alanine, glycine,
arginine, betaine, histidine, glutamic acid, aspartic acid,
cysteine, lysine, leucine, isoleucine, valine, methionine,
phenylalanine, aspartame, and the like. One preferred amino acid is
glycine.
[0136] Carbohydrate excipients suitable for use in the invention
include, for example, monosaccharides, such as fructose, maltose,
galactose, glucose, D-mannose, sorbose, and the like;
disaccharides, such as lactose, sucrose, trehalose, cellobiose, and
the like; polysaccharides, such as raffinose, melezitose,
maltodextrins, dextrans, starches, and the like; and alditols, such
as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol
(glucitol), myoinositol and the like. Preferred carbohydrate
excipients for use in the present invention are mannitol,
trehalose, and raffinose.
[0137] Anti-IL-12/IL-23p40 or IL-23 antibody compositions can also
include a buffer or a pH adjusting agent; typically, the buffer is
a salt prepared from an organic acid or base. Representative
buffers include organic acid salts, such as salts of citric acid,
ascorbic acid, gluconic acid, carbonic acid, tartaric acid,
succinic acid, acetic acid, or phthalic acid; Tris, tromethamine
hydrochloride, or phosphate buffers. Preferred buffers for use in
the present compositions are organic acid salts, such as
citrate.
[0138] Additionally, anti-IL-12/IL-23p40 or IL-23 antibody
compositions can include polymeric excipients/additives, such as
polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates
(e.g., cyclodextrins, such as 2-hydroxypropyl-.beta.-cyclodextrin),
polyethylene glycols, flavoring agents, antimicrobial agents,
sweeteners, antioxidants, antistatic agents, surfactants (e.g.,
polysorbates, such as "TWEEN 20" and "TWEEN 80"), lipids (e.g.,
phospholipids, fatty acids), steroids (e.g., cholesterol), and
chelating agents (e.g., EDTA).
[0139] These and additional known pharmaceutical excipients and/or
additives suitable for use in the anti-IL-12/IL-23p40 or IL-23
antibody, portion or variant compositions according to the
invention are known in the art, e.g., as listed in "Remington: The
Science & Practice of Pharmacy," 19th ed., Williams &
Williams, (1995), and in the "Physician's Desk Reference," 52nd
ed., Medical Economics, Montvale, N.J. (1998), the disclosures of
which are entirely incorporated herein by reference. Preferred
carrier or excipient materials are carbohydrates (e.g., saccharides
and alditols) and buffers (e.g., citrate) or polymeric agents. An
exemplary carrier molecule is the mucopolysaccharide, hyaluronic
acid, which can be useful for intraarticular delivery.
[0140] Formulations
[0141] As noted above, the invention provides for stable
formulations, which preferably comprise a phosphate buffer with
saline or a chosen salt, as well as preserved solutions and
formulations containing a preservative as well as multi-use
preserved formulations suitable for pharmaceutical or veterinary
use, comprising at least one anti-IL-12/IL-23p40 or IL-23 antibody
in a pharmaceutically acceptable formulation. Preserved
formulations contain at least one known preservative or optionally
selected from the group consisting of at least one phenol,
m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol,
phenylmercuric nitrite, phenoxyethanol, formaldehyde,
chlorobutanol, magnesium chloride (e.g., hexahydrate), alkylparaben
(methyl, ethyl, propyl, butyl and the like), benzalkonium chloride,
benzethonium chloride, sodium dehydroacetate and thimerosal, or
mixtures thereof in an aqueous diluent. Any suitable concentration
or mixture can be used as known in the art, such as 0.001-5%, or
any range or value therein, such as, but not limited to 0.001,
0.003, 0.005, 0.009, 0.01, 0.02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3,
0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6,
1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9,
3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.3, 4.5,
4.6, 4.7, 4.8, 4.9, or any range or value therein. Non-limiting
examples include, no preservative, 0.1-2% m-cresol (e.g., 0.2, 0.3.
0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol (e.g., 0.5, 0.9, 1.1,
1.5, 1.9, 2.0, 2.5%), 0.001-0.5% thimerosal (e.g., 0.005, 0.01),
0.001-2.0% phenol (e.g., 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%),
0.0005-1.0% alkylparaben(s) (e.g., 0.00075, 0.0009, 0.001, 0.002,
0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3,
0.5, 0.75, 0.9, 1.0%), and the like.
[0142] As noted above, the method of the invention uses an article
of manufacture, comprising packaging material and at least one vial
comprising a solution of at least one anti-IL-12/IL-23p40 or IL-23
antibody with the prescribed buffers and/or preservatives,
optionally in an aqueous diluent, wherein said packaging material
comprises a label that indicates that such solution can be held
over a period of 1, 2, 3, 4, 5, 6, 9, 12, 18, 20, 24, 30, 36, 40,
48, 54, 60, 66, 72 hours or greater. The invention further uses an
article of manufacture, comprising packaging material, a first vial
comprising lyophilized anti-IL-12/IL-23p40 or IL-23 antibody, and a
second vial comprising an aqueous diluent of prescribed buffer or
preservative, wherein said packaging material comprises a label
that instructs a subject to reconstitute the anti-IL-12/IL-23p40 or
IL-23 antibody in the aqueous diluent to form a solution that can
be held over a period of twenty-four hours or greater.
[0143] The anti-IL-12/IL-23p40 or IL-23 antibody used in accordance
with the present invention can be produced by recombinant means,
including from mammalian cell or transgenic preparations, or can be
purified from other biological sources, as described herein or as
known in the art.
[0144] The range of the anti-IL-12/IL-23p40 or IL-23 antibody
includes amounts yielding upon reconstitution, if in a wet/dry
system, concentrations from about 1.0 .mu.g/ml to about 1000 mg/ml,
although lower and higher concentrations are operable and are
dependent on the intended delivery vehicle, e.g., solution
formulations will differ from transdermal patch, pulmonary,
transmucosal, or osmotic or micro pump methods.
[0145] Preferably, the aqueous diluent optionally further comprises
a pharmaceutically acceptable preservative. Preferred preservatives
include those selected from the group consisting of phenol,
m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol,
alkylparaben (methyl, ethyl, propyl, butyl and the like),
benzalkonium chloride, benzethonium chloride, sodium dehydroacetate
and thimerosal, or mixtures thereof. The concentration of
preservative used in the formulation is a concentration sufficient
to yield an anti-microbial effect. Such concentrations are
dependent on the preservative selected and are readily determined
by the skilled artisan.
[0146] Other excipients, e.g., isotonicity agents, buffers,
antioxidants, and preservative enhancers, can be optionally and
preferably added to the diluent. An isotonicity agent, such as
glycerin, is commonly used at known concentrations. A
physiologically tolerated buffer is preferably added to provide
improved pH control. The formulations can cover a wide range of
pHs, such as from about pH 4 to about pH 10, and preferred ranges
from about pH 5 to about pH 9, and a most preferred range of about
6.0 to about 8.0. Preferably, the formulations of the present
invention have a pH between about 6.8 and about 7.8. Preferred
buffers include phosphate buffers, most preferably, sodium
phosphate, particularly, phosphate buffered saline (PBS).
[0147] Other additives, such as a pharmaceutically acceptable
solubilizers like Tween 20 (polyoxyethylene (20) sorbitan
monolaurate), Tween 40 (polyoxyethylene (20) sorbitan
monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan
monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block
copolymers), and PEG (polyethylene glycol) or non-ionic
surfactants, such as polysorbate 20 or 80 or poloxamer 184 or 188,
Pluronic.RTM. polyls, other block co-polymers, and chelators, such
as EDTA and EGTA, can optionally be added to the formulations or
compositions to reduce aggregation. These additives are
particularly useful if a pump or plastic container is used to
administer the formulation. The presence of pharmaceutically
acceptable surfactant mitigates the propensity for the protein to
aggregate.
[0148] The formulations can be prepared by a process which
comprises mixing at least one anti-IL-12/IL-23p40 or IL-23 antibody
and a preservative selected from the group consisting of phenol,
m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol,
alkylparaben, (methyl, ethyl, propyl, butyl and the like),
benzalkonium chloride, benzethonium chloride, sodium dehydroacetate
and thimerosal or mixtures thereof in an aqueous diluent. Mixing
the at least one anti-IL-12/IL-23p40 or IL-23 specific antibody and
preservative in an aqueous diluent is carried out using
conventional dissolution and mixing procedures. To prepare a
suitable formulation, for example, a measured amount of at least
one anti-IL-12/IL-23p40 or IL-23 antibody in buffered solution is
combined with the desired preservative in a buffered solution in
quantities sufficient to provide the protein and preservative at
the desired concentrations. Variations of this process would be
recognized by one of ordinary skill in the art. For example, the
order the components are added, whether additional additives are
used, the temperature and pH at which the formulation is prepared,
are all factors that can be optimized for the concentration and
means of administration used.
[0149] The formulations can be provided to subjects as clear
solutions or as dual vials comprising a vial of lyophilized
anti-IL-12/IL-23p40 or IL-23 specific antibody that is
reconstituted with a second vial containing water, a preservative
and/or excipients, preferably, a phosphate buffer and/or saline and
a chosen salt, in an aqueous diluent. Either a single solution vial
or dual vial requiring reconstitution can be reused multiple times
and can suffice for a single or multiple cycles of subject
treatment and thus can provide a more convenient treatment regimen
than currently available.
[0150] The present articles of manufacture are useful for
administration over a period ranging from immediate to twenty-four
hours or greater. Accordingly, the presently claimed articles of
manufacture offer significant advantages to the subject.
Formulations of the invention can optionally be safely stored at
temperatures of from about 2.degree. C. to about 40.degree. C. and
retain the biologically activity of the protein for extended
periods of time, thus allowing a package label indicating that the
solution can be held and/or used over a period of 6, 12, 18, 24,
36, 48, 72, or 96 hours or greater. If preserved diluent is used,
such label can include use up to 1-12 months, one-half, one and a
half, and/or two years.
[0151] The solutions of anti-IL-12/IL-23p40 or IL-23 specific
antibody can be prepared by a process that comprises mixing at
least one antibody in an aqueous diluent. Mixing is carried out
using conventional dissolution and mixing procedures. To prepare a
suitable diluent, for example, a measured amount of at least one
antibody in water or buffer is combined in quantities sufficient to
provide the protein and, optionally, a preservative or buffer at
the desired concentrations. Variations of this process would be
recognized by one of ordinary skill in the art. For example, the
order the components are added, whether additional additives are
used, the temperature and pH at which the formulation is prepared,
are all factors that can be optimized for the concentration and
means of administration used.
[0152] The claimed products can be provided to subjects as clear
solutions or as dual vials comprising a vial of lyophilized at
least one anti-IL-12/IL-23p40 or IL-23 specific antibody that is
reconstituted with a second vial containing the aqueous diluent.
Either a single solution vial or dual vial requiring reconstitution
can be reused multiple times and can suffice for a single or
multiple cycles of subject treatment and thus provides a more
convenient treatment regimen than currently available.
[0153] The claimed products can be provided indirectly to subjects
by providing to pharmacies, clinics, or other such institutions and
facilities, clear solutions or dual vials comprising a vial of
lyophilized at least one anti-IL-12/IL-23p40 or IL-23 specific
antibody that is reconstituted with a second vial containing the
aqueous diluent. The clear solution in this case can be up to one
liter or even larger in size, providing a large reservoir from
which smaller portions of the at least one antibody solution can be
retrieved one or multiple times for transfer into smaller vials and
provided by the pharmacy or clinic to their customers and/or
subjects.
[0154] Recognized devices comprising single vial systems include
pen-injector devices for delivery of a solution, such as BD Pens,
BD Autojector.RTM., Humaject.RTM., NovoPen.RTM., B-D.RTM. Pen,
AutoPen.RTM., and OptiPen.RTM., GenotropinPen.RTM., Genotronorm
Pen.RTM., Humatro Pen.RTM., Reco-Pen.RTM., Roferon Pen.RTM.,
Biojector.RTM., Iject.RTM., J-tip Needle-Free Injector.RTM.,
Intraject.RTM., Medi-Ject.RTM., Smartject.RTM. e.g., as made or
developed by Becton Dickensen (Franklin Lakes, N.J.,
www.bectondickenson.com), Disetronic (Burgdorf, Switzerland,
www.disetronic.com; Bioject, Portland, Oreg. (www.bioject.com);
National Medical Products, Weston Medical (Peterborough, UK,
www.weston-medical.com), Medi-Ject Corp (Minneapolis, Minn.,
www.mediject.com), and similarly suitable devices. Recognized
devices comprising a dual vial system include those pen-injector
systems for reconstituting a lyophilized drug in a cartridge for
delivery of the reconstituted solution, such as the
HumatroPen.RTM.. Examples of other devices suitable include
pre-filled syringes, auto-injectors, needle free injectors, and
needle free IV infusion sets.
[0155] The products can include packaging material. The packaging
material provides, in addition to the information required by the
regulatory agencies, the conditions under which the product can be
used. The packaging material of the present invention provides
instructions to the subject, as applicable, to reconstitute the at
least one anti-IL-12/IL-23p40 or IL-23 antibody in the aqueous
diluent to form a solution and to use the solution over a period of
2-24 hours or greater for the two vial, wet/dry, product. For the
single vial, solution product, pre-filled syringe or auto-injector,
the label indicates that such solution can be used over a period of
2-24 hours or greater. The products are useful for human
pharmaceutical product use.
[0156] The formulations used in the method of the present invention
can be prepared by a process that comprises mixing an
anti-IL-12/IL-23p40 and a selected buffer, preferably, a phosphate
buffer containing saline or a chosen salt. Mixing the
anti-IL-12/IL-23p40 antibody and buffer in an aqueous diluent is
carried out using conventional dissolution and mixing procedures.
To prepare a suitable formulation, for example, a measured amount
of at least one antibody in water or buffer is combined with the
desired buffering agent in water in quantities sufficient to
provide the protein and buffer at the desired concentrations.
Variations of this process would be recognized by one of ordinary
skill in the art. For example, the order the components are added,
whether additional additives are used, the temperature and pH at
which the formulation is prepared, are all factors that can be
optimized for the concentration and means of administration
used.
[0157] The method of the invention provides pharmaceutical
compositions comprising various formulations useful and acceptable
for administration to a human or animal subject. Such
pharmaceutical compositions are prepared using water at "standard
state" as the diluent and routine methods well known to those of
ordinary skill in the art. For example, buffering components such
as histidine and histidine monohydrochloride hydrate, can be
provided first followed by the addition of an appropriate,
non-final volume of water diluent, sucrose and polysorbate 80 at
"standard state." Isolated antibody can then be added. Last, the
volume of the pharmaceutical composition is adjusted to the desired
final volume under "standard state" conditions using water as the
diluent. Those skilled in the art will recognize a number of other
methods suitable for the preparation of the pharmaceutical
compositions.
[0158] The pharmaceutical compositions can be aqueous solutions or
suspensions comprising the indicated mass of each constituent per
unit of water volume or having an indicated pH at "standard state."
As used herein, the term "standard state" means a temperature of
25.degree. C.+/-2.degree. C. and a pressure of 1 atmosphere. The
term "standard state" is not used in the art to refer to a single
art recognized set of temperatures or pressure, but is instead a
reference state that specifies temperatures and pressure to be used
to describe a solution or suspension with a particular composition
under the reference "standard state" conditions. This is because
the volume of a solution is, in part, a function of temperature and
pressure. Those skilled in the art will recognize that
pharmaceutical compositions equivalent to those disclosed here can
be produced at other temperatures and pressures. Whether such
pharmaceutical compositions are equivalent to those disclosed here
should be determined under the "standard state" conditions defined
above (e.g. 25.degree. C.+/-2.degree. C. and a pressure of 1
atmosphere).
[0159] Importantly, such pharmaceutical compositions can contain
component masses "about" a certain value (e.g. "about 0.53 mg
L-histidine") per unit volume of the pharmaceutical composition or
have pH values about a certain value. A component mass present in a
pharmaceutical composition or pH value is "about" a given numerical
value if the isolated antibody present in the pharmaceutical
composition is able to bind a peptide chain while the isolated
antibody is present in the pharmaceutical composition or after the
isolated antibody has been removed from the pharmaceutical
composition (e.g., by dilution). Stated differently, a value, such
as a component mass value or pH value, is "about" a given numerical
value when the binding activity of the isolated antibody is
maintained and detectable after placing the isolated antibody in
the pharmaceutical composition.
[0160] Competition binding analysis is performed to determine if
the IL-12/IL-23p40 or IL-23 specific mAbs bind to similar or
different epitopes and/or compete with each other. Abs are
individually coated on ELISA plates. Competing mAbs are added,
followed by the addition of biotinylated hrlL-12 or IL-23. For
positive control, the same mAb for coating can be used as the
competing mAb ("self-competition"). IL-12/IL-23p40 or IL-23 binding
is detected using streptavidin. These results demonstrate whether
the mAbs recognize similar or partially overlapping epitopes on
IL-12/IL-23p40 or IL-23.
[0161] In one embodiment of the pharmaceutical compositions, the
isolated antibody concentration is from about 77 to about 104 mg
per ml of the pharmaceutical composition. In another embodiment of
the pharmaceutical compositions the pH is from about 5.5 to about
6.5.
[0162] The stable or preserved formulations can be provided to
subjects as clear solutions or as dual vials comprising a vial of
lyophilized at least one anti-IL-12/IL-23p40 that is reconstituted
with a second vial containing a preservative or buffer and
excipients in an aqueous diluent. Either a single solution vial or
dual vial requiring reconstitution can be reused multiple times and
can suffice for a single or multiple cycles of subject treatment
and thus provides a more convenient treatment regimen than
currently available.
[0163] Other formulations or methods of stabilizing the
anti-IL-12/IL-23p40 can result in other than a clear solution of
lyophilized powder comprising the antibody. Among non-clear
solutions are formulations comprising particulate suspensions, said
particulates being a composition containing the anti-IL-12/IL-23p40
in a structure of variable dimension and known variously as a
microsphere, microparticle, nanoparticle, nanosphere, or liposome.
Such relatively homogenous, essentially spherical, particulate
formulations containing an active agent can be formed by contacting
an aqueous phase containing the active agent and a polymer and a
nonaqueous phase followed by evaporation of the nonaqueous phase to
cause the coalescence of particles from the aqueous phase as taught
in U.S. Pat. No. 4,589,330. Porous microparticles can be prepared
using a first phase containing active agent and a polymer dispersed
in a continuous solvent and removing said solvent from the
suspension by freeze-drying or dilution-extraction-precipitation as
taught in U.S. Pat. No. 4,818,542. Preferred polymers for such
preparations are natural or synthetic copolymers or polymers
selected from the group consisting of glelatin agar, starch,
arabinogalactan, albumin, collagen, polyglycolic acid, polylactic
aced, glycolide-L(-) lactide poly(episilon-caprolactone,
poly(epsilon-caprolactone-CO-lactic acid),
poly(epsilon-caprolactone-CO-glycolic acid), poly(B-hydroxy butyric
acid), polyethylene oxide, polyethylene,
poly(alkyl-2-cyanoacrylate), poly(hydroxyethyl methacrylate),
polyamides, poly(amino acids), poly(2-hydroxyethyl DL-aspartamide),
poly(ester urea), poly(L-phenylalanine/ethylene
glycol/1,6-diisocyanatohexane) and poly(methyl methacrylate).
Particularly preferred polymers are polyesters, such as
polyglycolic acid, polylactic aced, glycolide-L(-) lactide
poly(episilon-caprolactone, poly(epsilon-caprolactone-CO-lactic
acid), and poly(epsilon-caprolactone-CO-glycolic acid. Solvents
useful for dissolving the polymer and/or the active include: water,
hexafluoroisopropanol, methylenechloride, tetrahydrofuran, hexane,
benzene, or hexafluoroacetone sesquihydrate. The process of
dispersing the active containing phase with a second phase can
include pressure forcing said first phase through an orifice in a
nozzle to affect droplet formation.
[0164] Dry powder formulations can result from processes other than
lyophilization, such as by spray drying or solvent extraction by
evaporation or by precipitation of a crystalline composition
followed by one or more steps to remove aqueous or non-aqueous
solvent. Preparation of a spray-dried antibody preparation is
taught in U.S. Pat. No. 6,019,968. The antibody-based dry powder
compositions can be produced by spray drying solutions or slurries
of the antibody and, optionally, excipients, in a solvent under
conditions to provide a respirable dry powder. Solvents can include
polar compounds, such as water and ethanol, which can be readily
dried. Antibody stability can be enhanced by performing the spray
drying procedures in the absence of oxygen, such as under a
nitrogen blanket or by using nitrogen as the drying gas. Another
relatively dry formulation is a dispersion of a plurality of
perforated microstructures dispersed in a suspension medium that
typically comprises a hydrofluoroalkane propellant as taught in WO
9916419. The stabilized dispersions can be administered to the lung
of a subject using a metered dose inhaler. Equipment useful in the
commercial manufacture of spray dried medicaments are manufactured
by Buchi Ltd. or Niro Corp.
[0165] An anti-IL-12/IL-23p40 in either the stable or preserved
formulations or solutions described herein, can be administered to
a subject in accordance with the present invention via a variety of
delivery methods including SC or IM injection; transdermal,
pulmonary, transmucosal, implant, osmotic pump, cartridge, micro
pump, or other means appreciated by the skilled artisan, as
well-known in the art.
[0166] Therapeutic Applications
[0167] The present invention also provides a method for modulating
or treating ulcerative colitis, in a cell, tissue, organ, animal,
or subject, as known in the art or as described herein, using at
least one IL-23 antibody of the present invention, e.g.,
administering or contacting the cell, tissue, organ, animal, or
subject with a therapeutic effective amount of IL-12/IL-23p40 or
IL-23 specific antibody.
[0168] Any method of the present invention can comprise
administering an effective amount of a composition or
pharmaceutical composition comprising an IL-12/IL-23p40 to a cell,
tissue, organ, animal or subject in need of such modulation,
treatment or therapy. Such a method can optionally further comprise
co-administration or combination therapy for treating such diseases
or disorders, wherein the administering of said at least one
IL-12/IL-23p40, specified portion or variant thereof, further
comprises administering, before concurrently, and/or after, at
least one selected from at least one TNF antagonist (e.g., but not
limited to, a TNF chemical or protein antagonist, TNF monoclonal or
polyclonal antibody or fragment, a soluble TNF receptor (e.g., p55,
p70 or p85) or fragment, fusion polypeptides thereof, or a small
molecule TNF antagonist, e.g., TNF binding protein I or II (TBP-1
or TBP-II), nerelimonmab, infliximab, eternacept (Enbrel.TM.),
adalimulab (Humira.TM.), CDP-571, CDP-870, afelimomab, lenercept,
and the like), an antirheumatic (e.g., methotrexate, auranofin,
aurothioglucose, azathioprine, gold sodium thiomalate,
hydroxychloroquine sulfate, leflunomide, sulfasalzine), a muscle
relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID)
(e.g., 5-aminosalicylate), an analgesic, an anesthetic, a sedative,
a local anesthetic, a neuromuscular blocker, an antimicrobial
(e.g., aminoglycoside, an antifungal, an antiparasitic, an
antiviral, a carbapenem, cephalosporin, a flurorquinolone, a
macrolide, a penicillin, a sulfonamide, a tetracycline, another
antimicrobial), an antipsoriatic, a corticosteriod, an anabolic
steroid, a diabetes related agent, a mineral, a nutritional, a
thyroid agent, a vitamin, a calcium related hormone, an
antidiarrheal, an antitussive, an antiemetic, an antiulcer, a
laxative, an anticoagulant, an erythropoietin (e.g., epoetin
alpha), a filgrastim (e.g., G-CSF, Neupogen), a sargramostim
(GM-CSF, Leukine), an immunization, an immunoglobulin, an
immunosuppressive (e.g., basiliximab, cyclosporine, daclizumab), a
growth hormone, a hormone replacement drug, an estrogen receptor
modulator, a mydriatic, a cycloplegic, an alkylating agent, an
antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an
antidepressant, antimanic agent, an antipsychotic, an anxiolytic, a
hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an
asthma medication, a beta agonist, an inhaled steroid, a
leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine
or analog, dornase alpha (Pulmozyme), a cytokine or a cytokine
antagonist. Suitable dosages are well known in the art. See, e.g.,
Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton
and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon
Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing,
Loma Linda, C A (2000); Nursing 2001 Handbook of Drugs, 21st
edition, Springhouse Corp., Springhouse, P A, 2001; Health
Professional's Drug Guide 2001, ed., Shannon, Wilson, Stang,
Prentice-Hall, Inc, Upper Saddle River, N.J., each of which
references are entirely incorporated herein by reference.
[0169] Therapeutic Treatments
[0170] Treatment of ulcerative colitis is affected by administering
an effective amount or dosage of an anti-IL-12/23p40 composition in
a subject in need thereof. The dosage administered can vary
depending upon known factors, such as the pharmacodynamic
characteristics of the particular agent, and its mode and route of
administration; age, health, and weight of the recipient; nature
and extent of symptoms, kind of concurrent treatment, frequency of
treatment, and the effect desired. In some instances, to achieve
the desired therapeutic amount, it can be necessary to provide for
repeated administration, i.e., repeated individual administrations
of a particular monitored or metered dose, where the individual
administrations are repeated until the desired daily dose or effect
is achieved.
[0171] In one exemplary regimen of providing safe and effective
treatment of severely active UC in a subject in need thereof, a
total dosage of about 130 mg of an anti-IL-12/IL-23p40 antibody is
administered intravenously to the subject per administration. For
example, the total volume of the composition administered is
appropriately adjusted to provide to the subject the target dosage
of the antibody at 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg,
140 mg, 150 mg, 160 mg, 170 mg or 180 mg per administration.
[0172] In another exemplary regimen of providing safe and effective
treatment of severely active UC in a subject in need thereof, a
total dosage of about 6.0 mg/kg.+-.1.5 mg/kg of an
anti-IL-12/IL-23p40 antibody is administered intravenously to the
subject per administration. For example, the total volume of the
composition administered is appropriately adjusted to provide to
the subject the target dosage of the antibody at 3.0 mg/kg, 3.5
mg/kg, 4.0 mg/kg, 4.5 mg/kg, 5.0 mg/kg, 5.5 mg/kg, 6.0 mg/kg, 6.5
mg/kg, 7.0 mg/kg, 7.5 mg/kg, 8.0 mg/kg, 8.5 mg/kg, or 9.0 mg/kg
body weight of the subject per administration.
[0173] The total dosage of an anti-IL-12/IL-23p40 antibody to be
administered to the subject per administration can be administered
by intravenous infusion over a period of about 30 minutes to 180
minutes, preferably 60 minutes to 120 minutes, such as 30 minutes,
60 minutes, 90 minutes, 120 minutes, 150 minutes, or 180
minutes.
[0174] In yet another exemplary regimen of providing safe and
effective treatment of severely active UC in a subject in need
thereof, a total dosage of about 90 mg of an anti-IL-12/IL-23p40
antibody is administered subcutaneously to the subject per
administration. For example, the total volume of the composition
administered is appropriately adjusted to provide to the subject
the target dosage of the antibody at 40 mg, 50 mg, 60 mg, 70 mg, 80
mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg or 140 mg per
administration. The target dosage per administration can be
administered in a single subcutaneous injection or in multiple
subcutaneous injections, such as 1, 2, 3, 4, 5, or more
subcutaneous injections.
[0175] The total dosage of the anti-IL-12/IL-23p40 antibody can be
administered once per day, once per week, once per month, once
every six months, etc. for a period of one day, one week, one
month, six months, 1 year, 2 years or longer. Multiple
administrations of the anti-IL-12/IL-23p40 antibody, each at a
total dosage of described herein, can be administered to a subject
in need thereof.
[0176] Dosage forms (composition) suitable for internal
administration generally contain from about 0.001 milligram to
about 500 milligrams of active ingredient per unit or
container.
[0177] For parenteral administration, the antibody can be
formulated as a solution, suspension, emulsion, particle, powder,
or lyophilized powder in association, or separately provided, with
a pharmaceutically acceptable parenteral vehicle. Examples of such
vehicles are water, saline, Ringer's solution, dextrose solution,
and 1-10% human serum albumin. Liposomes and nonaqueous vehicles,
such as fixed oils, can also be used. The vehicle or lyophilized
powder can contain additives that maintain isotonicity (e.g.,
sodium chloride, mannitol) and chemical stability (e.g., buffers
and preservatives). The formulation is sterilized by known or
suitable techniques.
[0178] Suitable pharmaceutical carriers are described in the most
recent edition of Remington's Pharmaceutical Sciences, A. Osol, a
standard reference text in this field.
[0179] Many known and developed modes can be used according to the
present invention for administering pharmaceutically effective
amounts of an IL-12/IL-23p40 antibody. IL-12/IL-23p40 or IL-23
antibodies of the present invention can be delivered in a carrier,
as a solution, emulsion, colloid, or suspension, or as a dry
powder, using any of a variety of devices and methods suitable for
administration by inhalation or other modes described here within
or known in the art.
[0180] Formulations for parenteral administration can contain as
common excipients sterile water or saline, polyalkylene glycols,
such as polyethylene glycol, oils of vegetable origin, hydrogenated
naphthalenes and the like. Aqueous or oily suspensions for
injection can be prepared by using an appropriate emulsifier or
humidifier and a suspending agent, according to known methods.
Agents for injection can be a non-toxic, non-orally administrable
diluting agent, such as aqueous solution, a sterile injectable
solution or suspension in a solvent. As the usable vehicle or
solvent, water, Ringer's solution, isotonic saline, etc. are
allowed; as an ordinary solvent or suspending solvent, sterile
involatile oil can be used. For these purposes, any kind of
involatile oil and fatty acid can be used, including natural or
synthetic or semisynthetic fatty oils or fatty acids; natural or
synthetic or semisynthtetic mono- or di- or tri-glycerides.
Parental administration is known in the art and includes, but is
not limited to, conventional means of injections, a gas pressured
needle-less injection device as described in U.S. Pat. No.
5,851,198, and a laser perforator device as described in U.S. Pat.
No. 5,839,446 entirely incorporated herein by reference.
[0181] Alternative Delivery
[0182] The invention further relates to the administration of an
anti-IL-12/IL-23p40 or IL-23 antibody by parenteral, subcutaneous,
intramuscular, intravenous, intrarticular, intrabronchial,
intraabdominal, intracapsular, intracartilaginous, intracavitary,
intracelial, intracerebellar, intracerebroventricular, intracolic,
intracervical, intragastric, intrahepatic, intramyocardial,
intraosteal, intrapelvic, intrapericardiac, intraperitoneal,
intrapleural, intraprostatic, intrapulmonary, intrarectal,
intrarenal, intraretinal, intraspinal, intrasynovial,
intrathoracic, intrauterine, intravesical, intralesional, bolus,
vaginal, rectal, buccal, sublingual, intranasal, or transdermal
means. An anti-IL-12/IL-23p40 or IL-23 antibody composition can be
prepared for use for parenteral (subcutaneous, intramuscular or
intravenous) or any other administration particularly in the form
of liquid solutions or suspensions; for use in vaginal or rectal
administration particularly in semisolid forms, such as, but not
limited to, creams and suppositories; for buccal, or sublingual
administration, such as, but not limited to, in the form of tablets
or capsules; or intranasally, such as, but not limited to, the form
of powders, nasal drops or aerosols or certain agents; or
transdermally, such as not limited to a gel, ointment, lotion,
suspension or patch delivery system with chemical enhancers such as
dimethyl sulfoxide to either modify the skin structure or to
increase the drug concentration in the transdermal patch
(Junginger, et al. In "Drug Permeation Enhancement;" Hsieh, D. S.,
Eds., pp. 59-90 (Marcel Dekker, Inc. New York 1994, entirely
incorporated herein by reference), or with oxidizing agents that
enable the application of formulations containing proteins and
peptides onto the skin (WO 98/53847), or applications of electric
fields to create transient transport pathways, such as
electroporation, or to increase the mobility of charged drugs
through the skin, such as iontophoresis, or application of
ultrasound, such as sonophoresis (U.S. Pat. Nos. 4,309,989 and
4,767,402) (the above publications and patents being entirely
incorporated herein by reference).
EMBODIMENTS
[0183] The invention provides also the following non-limiting
embodiments. [0184] 1. A method of treating moderately to severely
active ulcerative colitis (UC) in a subject in need thereof,
comprising administering to the subject a pharmaceutical
composition comprising a clinically proven safe and clinically
proven effective amount of an anti-IL-12/IL-23p40 antibody, wherein
the antibody comprises a heavy chain variable region and a light
chain variable region, the heavy chain variable region comprising:
a complementarity determining region heavy chain 1 (CDRH1) amino
acid sequence of SEQ ID NO:1; a CDRH2 amino acid sequence of SEQ ID
NO:2; and a CDRH3 amino acid sequence of SEQ ID NO:3; and the light
chain variable region comprising: a complementarity determining
region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO:4; a
CDRL2 amino acid sequence of SEQ ID NO:5; and a CDRL3 amino acid
sequence of SEQ ID NO:6. [0185] 2. The method of embodiment 1,
wherein the antibody comprises the heavy chain variable region of
the amino acid sequence of SEQ ID NO:7 and the light chain variable
region of the amino acid sequence of SEQ ID NO:8. [0186] 3. The
method of embodiment 1, wherein the antibody comprises a heavy
chain of the amino acid sequence of SEQ ID NO:10 and a light chain
of the amino acid sequence of SEQ ID NO:11. [0187] 4. The method of
any one of embodiments 1 to 3, wherein the antibody is administered
intravenously to the subject, preferably at week 0 of the
treatment, at a dosage of about 6.0 mg/kg body weight of the
subject or 130 mg per administration. [0188] 5. The method of any
one of embodiments 1 to 4, wherein the antibody is further
administered subcutaneously to the subject, preferably at week 8 of
the treatment, at a dosage of about 90 mg per administration.
[0189] 6. The method of any one of embodiments 1 to 5, wherein the
subject had previously failed or were intolerant of at least one
therapy selected from the group consisting of an anti-TNF,
vedolizumab, corticosteroids, azathioprine (AZA), and 6
mercaptopurine (6 MP), or the subject had demonstrated
corticosteroid dependence. [0190] 7. The method of embodiment 5,
wherein the antibody is administered in a maintenance dose every 8
weeks after the treatment at week 8 or every 12 weeks after the
treatment at week 8. [0191] 8. The method of embodiment 7, wherein
the subject is a responder to the treatment with the antibody and
is identified as having a clinical remission based on at least one
of the global definition and the US definition by week 16,
preferably by week 8, more preferably by week 2, of the treatment
and the clinical remission continues at least 44 weeks after week
0. [0192] 9. The method of embodiment 8, wherein the subject is in
corticosteroid-free clinical remission at least 44 weeks after week
0. [0193] 10. The method of embodiment 7, wherein the subject is a
responder to the treatment with the antibody and is identified as
having an endoscopic healing continuing at least 44 weeks after
week 0. [0194] 11. The method of embodiment 7, wherein the subject
is a responder to the treatment with the antibody and is identified
as achieving a clinical response based on the Mayo endoscopy
subscore continuing at least 44 weeks after week 0. [0195] 12. The
method of embodiment 7, wherein the subject is a responder to the
treatment with the antibody and is identified as having a change
from baseline in Inflammatory Bowel Disease Questionnaire (IBDQ)
score continuing at least 44 weeks after week 0. [0196] 13. The
method of embodiment 7, wherein the subject is a responder to the
treatment with the antibody and is identified as having a mucosal
healing continuing at least 44 weeks after week 0. [0197] 14. The
method of embodiment 7, wherein the subject is a responder to the
treatment with the antibody and is identified as having a decrease
from baseline in Mayo score continuing at least 44 weeks after week
0. [0198] 15. The method of embodiment 7, wherein the subject is a
responder to the treatment with the antibody and is identified as
having a normalization of one or more biomarkers selected from the
group consisting of C-reactive protein, fecal lactoferrin and fecal
calprotectin continuing at least 44 weeks after week 0. [0199] 16.
The method of embodiment 7, wherein the subject is in clinical
response as determined by a decrease from baseline in the Mayo
score by .gtoreq.30% and .gtoreq.3 points and a decrease from
baseline in the rectal bleeding subscore .gtoreq.1 points or a
rectal bleeding subscore of 0 or 1 continuing at least 44 weeks
after week 0. [0200] 17. A method of treating moderately to
severely active ulcerative colitis (UC) in a subject in need
thereof, comprising: [0201] a. intravenously administering to the
subject an anti-IL-12/IL-23p40 antibody in a first pharmaceutical
composition at a dosage of about 6.0 mg/kg body weight of the
subject or 130 mg per administration at week 0 of the treatment,
and [0202] b. subcutaneously administering to the subject the
anti-IL-12/IL-23p40 antibody in a second pharmaceutical composition
at a dosage of 90 mg per administration, preferably at week 8 of
the treatment, [0203] wherein the antibody comprises a heavy chain
variable region and a light chain variable region, the heavy chain
variable region comprising: a complementarity determining region
heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO:1; a CDRH2
amino acid sequence of SEQ ID NO:2; and a CDRH3 amino acid sequence
of SEQ ID NO:3; and the light chain variable region comprising: a
complementarity determining region light chain 1 (CDRL1) amino acid
sequence of SEQ ID NO:4; a CDRL2 amino acid sequence of SEQ ID
NO:5; and a CDRL3 amino acid sequence of SEQ ID NO:6; and [0204]
wherein the subject had previously failed or were intolerant of at
least one therapy selected from the group consisting of: an
anti-TNF, vedolizumab, corticosteroids, azathioprine (AZA), and 6
mercaptopurine (6 MP), or the subject had demonstrated
corticosteroid dependence. [0205] 18. The method of embodiment 17,
wherein the antibody comprises the heavy chain variable region of
the amino acid sequence of SEQ ID NO:7 and the light chain variable
region of the amino acid sequence of SEQ ID NO:8. [0206] 19. The
method of embodiment 17, wherein the antibody comprises a heavy
chain of the amino acid sequence of SEQ ID NO:10 and a light chain
of the amino acid sequence of SEQ ID NO:11. [0207] 20. The method
of any one of embodiments 1-19, wherein the pharmaceutical
composition for intravenous administration further comprises a
solution comprising 10 mM L-histidine, 8.5% (w/v) sucrose, 0.04%
(w/v) polysorbate 80, 0.4 mg/mL L-methionine, and 20 .mu.g/mL EDTA
disodium salt, dehydrate, at pH 6.0. [0208] 21. The method of any
one of embodiments 1-20, wherein the pharmaceutical composition for
subcutaneous administration further comprises a solution comprising
6.7 mM L-histidine, 7.6% (w/v) sucrose, 0.004% (w/v) polysorbate
80, at pH 6.0. [0209] 22. The method of any one of embodiments
1-21, wherein the subject is a responder to the treatment with the
antibody and is identified as having a clinical remission based on
at least one of the global definition and the US definition by week
16, preferably by week 8, more preferably by week 2, of the
treatment. [0210] 23. The method of any one of embodiments 1-22,
wherein the subject is a responder to the treatment with the
antibody and is identified as having an endoscopic healing by week
16, preferably by week 8, more preferably by week 2, of the
treatment. [0211] 24. The method of any one of embodiments 1-23,
wherein the subject is a responder to the treatment with the
antibody and is identified as achieving a clinical response based
on the Mayo endoscopy subscore by week 16, preferably by week 8,
more preferably by week 2, of the treatment. [0212] 25. The method
of any one of embodiments 1-24, wherein the subject is a responder
to the treatment with the antibody and is identified as having a
change from baseline in Inflammatory Bowel Disease Questionnaire
(IBDQ) score by week 16, preferably by week 8, more preferably by
week 2, of the treatment. [0213] 26. The method of any one of
embodiments 1-25, wherein the subject is a responder to the
treatment with the antibody and is identified as having a mucosal
healing by week 16, preferably by week 8, more preferably by week
2, of the treatment. [0214] 27. The method of any one of
embodiments 1-26, wherein the subject is a responder to the
treatment with the antibody and is identified as having a decrease
from baseline in Mayo score by week 16, preferably by week 8, more
preferably by week 2, of the treatment. [0215] 28. The method of
any one of embodiments 1-27, wherein the subject is a responder to
the treatment with the antibody and is identified as having a
normalization of one or more biomarkers selected from the group
consisting of C-reactive protein, fecal lactoferrin and fecal
calprotectin by week 16, preferably by week 8, more preferably by
week 2, of the treatment. [0216] 29. The method of any one of
embodiments 1-28, wherein the subject is in clinical response as
determined by a decrease from baseline in the Mayo score by
.gtoreq.30% and .gtoreq.3 points and a decrease from baseline in
the rectal bleeding subscore .gtoreq.1 points or a rectal bleeding
subscore of 0 or 1 by week 16, preferably by week 8, more
preferably by week 2, of the treatment. [0217] 30. The method of
any one of embodiments 17-21, wherein the subject is not a
responder to the treatment with the antibody by week 8 and is a
responder to the treatment by week 16 of the treatment. [0218] 31.
A method of treating moderately to severely active ulcerative
colitis (UC) in a subject in need thereof, comprising: [0219] a.
intravenously administering to the subject an anti-IL-12/IL-23p40
antibody in a first pharmaceutical composition at a dosage of about
6.0 mg/kg body weight of the subject or 130 mg per administration
at week 0 of the treatment, and [0220] b. subcutaneously
administering to the subject the anti-IL-12/IL-23p40 antibody in a
second pharmaceutical composition at a dosage of 90 mg per
administration, preferably at week 8 of the treatment, [0221]
wherein the antibody comprises a heavy chain variable region and a
light chain variable region, the heavy chain variable region
comprising: a complementarity determining region heavy chain 1
(CDRH1) amino acid sequence of SEQ ID NO:1; a CDRH2 amino acid
sequence of SEQ ID NO:2; and a CDRH3 amino acid sequence of SEQ ID
NO:3; and the light chain variable region comprising: a
complementarity determining region light chain 1 (CDRL1) amino acid
sequence of SEQ ID NO:4; a CDRL2 amino acid sequence of SEQ ID
NO:5; and a CDRL3 amino acid sequence of SEQ ID NO:6 followed by a
maintenance therapy [0222] wherein the maintenance therapy
comprises subcutaneously administering to the subject the
anti-IL-12/IL-23p40 antibody at a dosage of 90 mg per
administration, once every 8 weeks or once every 12 weeks, and
wherein the maintenance therapy is provided for 44 weeks. [0223]
32. A pharmaceutical composition of an anti-IL-12/IL-23p40
antibody, comprising an antibody and packaging comprising one or
more drug product label elements disclosed in Annex I including
data from a randomized, double-blind, placebo-controlled, clinical
study in adult men and women with moderately to severely active
ulcerative colitis (UC), wherein the antibody comprises: (i) a
heavy chain variable region and a light chain variable region, the
heavy chain variable region comprising: a complementarity
determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ
ID NO:1; a CDRH2 amino acid sequence of SEQ ID NO:2; and a CDRH3
amino acid sequence of SEQ ID NO:3; and the light chain variable
region comprising: a complementarity determining region light chain
1 (CDRL1) amino acid sequence of SEQ ID NO:4; a CDRL2 amino acid
sequence of SEQ ID NO:5; and a CDRL3 amino acid sequence of SEQ ID
NO:6; (ii) a heavy chain variable region of the amino acid sequence
of SEQ ID NO:7 and a light chain variable region of the amino acid
sequence of SEQ ID NO:8; or (iii) a heavy chain of the amino acid
sequence of SEQ ID NO:10 and a light chain of the amino acid
sequence of SEQ ID NO:11. [0224] 33. A method of selling a drug
product comprising ustekinumab, comprising: manufacturing
ustekinumab; promoting that a therapy comprising ustekinumab is
safe and effective for treatment of a subject with ulcerative
colitis, wherein performing the steps a) and b) results in a health
care professional (HCP) to purchase the drug product; thereby
selling the drug product.
[0225] Having generally described the invention, the same will be
more readily understood by reference to the following Examples,
which are provided by way of illustration and are not intended as
limiting. Further details of the invention are illustrated by the
following non-limiting Examples. The disclosures of all citations
in the specification are expressly incorporated herein by
reference.
EXAMPLES
Example 1: Induction Study of Ustekinumab in the Treatment of
Ulcerative Colitis in Humans
[0226] The following multicenter, randomized, double-blind,
placebo-controlled, clinical study in adult men and women with
moderately to severely active ulcerative colitis (UC) was
performed: A Phase 3, Randomized, Double-blind, Placebo-controlled,
Parallel-group, Multicenter Study to Evaluate the Safety and
Efficacy of ustekinumab Induction and Maintenance Therapy in
Subjects with Moderately to Severely Active Ulcerative Colitis
[0227] Overall Rationale
[0228] A study was performed to assess the efficacy of intravenous
(IV) administration of ustekinumab in subjects with moderately to
severely active ulcerative colitis who demonstrated inadequate
response or failure to tolerate conventional (corticosteroids or
6-mercaptopurine/azathioprine [6-MP/AZA]) or biologic therapy (TNF
antagonist and/or the integrin antagonist, vedolizumab). Subjects
received a single 130 mg, a single 6 mg/kg IV dose, or placebo at
Week 0. Subjects who demonstrated no clinical response at Week 8
received an additional IV or subcutaneous (SC) dose at Week 8.
[0229] Objectives
[0230] The primary objectives of the study included (1) evaluating
the efficacy of ustekinumab in inducing clinical remission in
subjects with moderately to severely active UC; and (2) evaluating
the safety of the IV ustekinumab in subjects with moderately to
severely active UC.
[0231] The secondary objectives of the study included (1)
evaluating the efficacy of IV ustekinumab in inducing endoscopic
healing (i.e. improvement in the endoscopic appearance of mucosa)
in subjects with moderately to severely active UC; (2) evaluating
the efficacy of IV ustekinumab in inducing clinical response in
subjects with moderately to severely active UC; (3) evaluating the
impact of IV ustekinumab on disease-specific health-related quality
of life; (4) evaluating the efficacy of ustekinumab treatment on
mucosal healing (i.e, endoscopic healing and histologic healing);
(5) evaluating the efficacy of induction therapy with IV
ustekinumab by biologic failure status; and (6) evaluating the
pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of
ustekinumab induction therapy in subjects with moderately to
severely active UC, including changes in C-reactive protein (CRP),
fecal calprotectin, fecal lactoferrin, and other PD biomarkers.
[0232] The exploratory objectives of the study included (1)
evaluating response using the Mayo score without the physician's
global assessment (PGA) subscore and (2) evaluating the performance
of the Bristol Stool Form Scale (BSFS) score.
[0233] Experimental Design
[0234] The Phase 3 development program for ustekinumab comprised 2
separate studies, an induction study and a maintenance study. In
the induction study, subjects were randomized at Week 0 into one of
three treatment groups: placebo, low-dose ustekinumab, and
high-dose ustekinumab. At Week 8, all subjects were evaluated for
the primary endpoint of clinical remission and clinical response.
Subjects who achieved a clinical response at Week 8 were eligible
to enter the maintenance study. Subjects who did not achieve
clinical response at Week 8 received a second dose of ustekinumab
at Week 8 of treatment.
[0235] At Week 16, subjects who did not achieve clinical response
at Week 8 were re-evaluated for clinical response. Subjects who
achieved clinical response at Week 16 were eligible to enter the
maintenance study. Subjects who did not achieve clinical response
at Week 16 were not eligible to enter the maintenance study and had
a safety follow-up visit approximately 20 weeks after their last
dose of study agent (Week 8).
[0236] Subjects who were in clinical response to IV ustekinumab
during induction comprised the primary population in the
maintenance study. The maintenance study is a randomized withdrawal
study designed to evaluate maintenance therapy using SC ustekinumab
and is currently ongoing.
[0237] Dosage and Administration
[0238] Subjects received a single IV dose of ustekinumab or placebo
at Week 0 of the study. The induction study antibodies with the
administered doses are as follows: [0239] Ustekinumab at a low,
fixed does of 130 mg [0240] Ustekinumab at a high, weight-range
based dose of .about.6 mg/kg: [0241] Ustekinumab 260 mg
(body-weight .ltoreq.55 kg) [0242] Ustekinumab 390 mg (body-weight
>55 kg but .ltoreq.85 kg) [0243] Ustekinumab 520 mg (body-weight
>85 kg)
[0244] Subjects who did not present a clinical response received a
second dose of ustekinumab at Week 8. The study antibodies with the
second administered doses are as follows: [0245] Subjects who were
randomized to placebo at Week 0 received 1 dose of ustekinumab
.about.6 mg/kg IV+placebo SC (to maintain the blind) at Week 8.
[0246] Subjects who were randomized to ustekinumab at Week 0
received 1 dose of ustekinumab 90 mg SC+placebo IV (to maintain the
blind) at Week 8.
[0247] Safety Evaluations
[0248] Safety was evaluated based on AEs and clinical laboratory
test results (i.e., hematology and serum chemistry). Adverse events
were either voluntarily reported by the subject or were obtained by
means of interviewing subjects in a non-directed manner at study
visits. Safety evaluations included the following clinical
laboratory tests: [0249] Hematology: Hemoglobin (Hb), hematocrit,
red blood cell count, white blood cell (WBC) count, and platelets.
[0250] Serum Chemistry: Sodium, potassium, chloride, blood urea
nitrogen (BUN), creatinine, aspartate aminotransferase (AST),
alanine aminotransferase (ALT), total and direct bilirubin,
alkaline phosphatase, calcium, phosphate, albumin, total protein.
[0251] Screening: Serology for human immunodeficiency virus
antibody, serology for hepatitis C virus (HCV) antibody, serology
for hepatitis B virus (HBV) antibody, hepatitis B surface antigen,
HBV surface antibody (anti-HBs), and HBV core (anti-HBc) antibody
total, QuantiFERON-TB Gold test, pregnancy (0 human chorionic
gonadotropin [.beta.-HCG]).
[0252] Pharmacokinetics
[0253] Blood samples for the measurement of serum ustekinumab
concentrations were collected at Week 0 (pre- and postinfusion) and
Weeks 2, 4, and 8. Analyses of serum ustekinumab concentrations
were performed using a validated electrochemiluminescent
immunoassay (ECLIA) method on the Meso Scale Discovery (MSD.RTM.)
platform (Gaithersburg, Md., USA). The lowest quantifiable
concentration in a sample for the ECLIA method using the MSD
platform was 0.1688 .mu.g/mL.
[0254] Immunogenicity
[0255] Antibodies to ustekinumab were evaluated using serum samples
collected from all subjects. Analyses of antibodies to ustekinumab
were performed using a validated, drug-tolerant,
electrochemiluminescence immunoassay (ECLIA), in which ustekinumab
was used to capture and detect induced immune responses to
ustekinumab. Antibody titers were determined for all subjects who
had antibodies to ustekinumab and the neutralizing antibody (Nab)
status of anti-drug antibody positive samples were determined.
[0256] Efficacy Evaluation
[0257] Efficacy evaluations were collected throughout the study.
Mayo score and partial Mayo score, Uceraltive Colitis Endoscopic
Index of Severity (UCEIS), Bristol Stool Form Scale (BSFS),
C-reactive protein (CRP), fecal lactoferrin, fecal calprotectin,
Inflammatory Bowel Disease Questionnaire (IBDQ), 36-item Short Form
Health Survey (SF-36), and EuroQoL-5D Health Questionnaire were all
evaluated to determine efficacy. The efficacy criteria were defined
as follows: [0258] Clinical remission (global submissions): Mayo
score .ltoreq.2 points, with no individual subscore >1. [0259]
Clinical remission (US submissions): absolute stool number
.ltoreq.3, rectal bleeding subscore of 0, and Mayo endoscopy
subscore of 0 or 1. [0260] Clinical response: a decrease from
induction baseline in the Mayo score by .gtoreq.30% and .gtoreq.3
points, with either a decrease from baseline in the rectal bleeding
subscore .gtoreq.1 or a rectal bleeding subscore of 0 or 1. [0261]
Endoscopic healing (i.e., improvement in the endoscopic appearance
of the mucosa): Mayo endoscopy subscore of 0 or 1. [0262]
Histologic healing: based on the Geboes score and is defined as 0
to <5% neutrophils in epithelium and no crypt destruction,
erosions, ulcerations, or granulations. [0263] Mucosal healing:
both endoscopic healing and histologic healing. [0264] Normal or
inactive mucosal disease: Mayo endoscopy subscore of 0. [0265]
Symptomatic remission: Mayo stool frequency subscore of 0 or 1 and
a rectal bleeding subscore of 0. [0266] Normalization of CRP
concentration: CRP concentration .ltoreq.3 mg/L. [0267]
Normalization of fecal lactoferrin concentration: fecal lactoferrin
concentration .ltoreq.7.24 .mu.g/g. [0268] Normalization of fecal
calprotectin concentration: fecal calprotectin concentration
.ltoreq.250 mg/kg. [0269] Modified Mayo score response: [0270]
Definition 1: a decrease in the modified Mayo score of .gtoreq.2
points and .gtoreq.35% and either a decrease in the rectal bleeding
subscore of .gtoreq.1 or a rectal bleeding subscore of 0 or 1.
[0271] Definition 2: a decrease in the modified Mayo score of
.gtoreq.2 points and .gtoreq.30% and either a decrease in rectal
bleeding of .gtoreq.1 or a rectal bleeding score of 0 or 1.
Safety Results
[0272] Intravenous ustekinumab doses of both .about.6 mg/kg and 130
mg were generally well-tolerated with a safety profile that was
generally comparable with placebo through Week 8.0f the 960
subjects in the safety analysis set, 1 or more treatment-emergent
AEs was reported through Week 8 for 50.0%, 41.4%, and 48.0% of
subjects in the .about.6 mg/kg, 130 mg, and placebo groups,
respectively. Through Week 8, serious adverse effects (SAEs) were
reported for 3.1%, 3.7%, and 6.6% of subjects in the .about.6
mg/kg, 130 mg, and placebo groups, respectively.
[0273] AEs within 1 hour of infusion were 0.9%, 2.2%, and 1.9% in
the .about.6 mg/kg, 130 mg, and placebo groups, respectively.
[0274] The proportions of subjects with 1 or more infections were
15.3%, 15.9%, and 15.0% in the .about.6 mg/kg, 130 mg, and placebo
groups, respectively. Serious infections were reported for 0.3%,
0.6%, and 1.3% of subjects in the .about.6 mg/kg, 130 mg, and
placebo groups, respectively.
[0275] Pharmacokinetics Results
[0276] Serum samples were collected at Week 0 (preadministration),
Week 0 (1 hr post-administration, Week 2, Week 4, and Week 8. For
subjects randomized to ustekinumab treatment, a single IV infusion
of ustekinumab was given either as a weight-based tiered dose of
.about.6 mg/kg (ie, 260 mg for subjects with body-weight .ltoreq.55
kg, 390 mg for subjects with body-weight >55 kg and .ltoreq.85
kg, or 520 mg for subjects with body-weight >85 kg), or as a
fixed dose of 130 mg. Considering that the median body-weight of
subjects in the 130 mg group was 72 kg, the ustekinumab 130 mg dose
corresponded to .about.2 mg/kg on a per-kg basis. Thus, on average,
ustekinumab exposure in the .about.6 mg/kg group was approximately
3 times that of the 130 mg group. In line with this expectation,
after a single IV administration of ustekinumab .about.6 mg/kg or
130 mg, median serum ustekinumab concentrations were approximately
dose proportional at all sampling timepoints through Week 8. Median
peak serum ustekinumab concentrations, which were observed 1 hour
after the end of the infusion at Week 0, were 127.0 .mu.g/mL and
43.16 .mu.g/mL for the .about.6 mg/kg and 130 mg groups,
respectively. At Week 8, the time of the primary efficacy endpoint,
the median serum ustekinumab concentrations were 8.59 .mu.g/mL and
2.51 .mu.g/mL for the .about.6 mg/kg and 130 mg groups,
respectively.
[0277] Subjects who were not in clinical response at Week 8
following administration of placebo IV at Week 0 received
ustekinumab .about.6 mg/kg IV at Week 8, while subjects who were
not in clinical response at Week 8 following administration of
ustekinumab IV at Week 0 received ustekinumab 90 mg SC at Week 8.
Among subjects who received placebo IV at Week 0 and who
subsequently received ustekinumab .about.6 mg/kg IV at Week 8,
median serum ustekinumab concentration at Week 16 (8 weeks after
the ustekinumab IV dose) was slightly higher than that observed at
Week 8 (among subjects who received ustekinumab .about.6 mg/kg IV
at Week 0 [10.51 .mu.g/mL versus 8.59 .mu.g/mL, respectively]).
Among subjects who received ustekinumab 90 mg SC at Week 8
(following their initial IV ustekinumab dose at Week 0), the median
serum ustekinumab concentration at Week 16 was slightly higher in
subjects who received ustekinumab .about.6 mg/kg IV at Week 0
compared to those who received ustekinumab 130 mg at Week 0 (1.92
.mu.g/mL versus 1.59 .mu.g/mL, respectively)
[0278] Immunogenicity Results
[0279] Of the 635 subjects in the ustekinumab groups with
appropriate samples for the assessment of antibodies to
ustekinumab, 4 (0.6%) subjects were positive for antibodies to
ustekinumab through Week 8. Of these 4 subjects, 2 (50%) were
positive for NAbs.
[0280] Of 822 subjects who received ustekinumab at any time through
Week 16, and had appropriate samples for the assessment of
anti-drug antibodies (ADAs), 18 subjects (2.2%) were positive for
antibodies to ustekinumab through the final safety visit. Of these,
4 of 15 subjects (26.7%) were positive for NAbs among those
evaluable for NAbs through the final safety visit. Among subjects
who received ustekinumab 90 mg SC at Week 8, the incidence of
antibodies to ustekinumab through Week 16 was numerically higher in
the 130 mg IV.fwdarw.90 mg SC group compared to the .about.6 mg/kg
IV.fwdarw.90 mg SC group (4.5% [6 of 132 subjects] vs 1.0% [1 of
101 subjects]).
[0281] Efficacy Results
[0282] Clinical Remission at Week 8--Global Definition
[0283] At Week 8, significantly greater proportions of subjects in
the .about.6 mg/kg and 130 mg groups achieved clinical remission
(15.5% and 15.6%, respectively) compared with subjects in the
placebo group (5.3%; p<0.001 for both comparisons; Table 1).
TABLE-US-00001 TABLE 1 Number of Subjects in Clinical Remission
(Global Definition) at Week 8 Ustekinumab IV Placebo IV 130 mg 6
mg/kg Combined Primary Efficacy Analysis Set 319 320 322 642 Week 8
(N) 319 320 322 642 Subjects in clinical remission 17 (5.3%) 50
(15.6%) 50 (15.5%) 100 (15.6%) Adjusted Treatment difference 10.3
10.2 10.2 (97.5% CI) (5.7, 14.9) (5.6, 14.8) (6.6, 13.9) p-value
<0.001 <0.001 <0.001 N = number of subjects; CI =
confidence interval
[0284] Clinical Remission at Week 8--US Definition
[0285] At Week 8, significantly greater proportions of subjects in
the .about.6 mg/kg and 130 mg groups achieved clinical remission
(18.9% and 16.6%, respectively) compared with subjects in the
placebo group (6.3%; p<0.001 for both comparisons; Table 2).
TABLE-US-00002 TABLE 2 Number of Subjects in Clinical Remission (US
Definition) at Week 8 Ustekinumab IV Placebo IV 130 mg 6 mg/kg
Combined Primary Efficacy Analysis Set 319 320 322 642 Week 8 (N)
319 320 322 642 Subjects in clinical remission 20 (6.3%) 53 (16.6%)
61 (18.9%) 114 (17.8%) Adjusted Treatment difference 10.3 12.7 11.5
(97.5% CI) (4.8, 15.8) (7.0, 18.4) (7.0, 16) p-value <0.001
<0.001 <0.001 N = number of subjects; CI = confidence
interval
[0286] Endoscopic Healing at Week 8
[0287] At Week 8, significantly greater proportions of subjects in
the .about.6 mg/kg and 130 mg groups achieved endoscopic healing
(27.0% and 26.3%, respectively) compared with subjects in the
placebo group (13.8%; p<0.001 for both comparisons; Table
3).
TABLE-US-00003 TABLE 3 Number of Subjects with Endoscopic Healing
at Week 8 Ustekinumab IV Placebo IV 130 mg 6 mg/kg Combined Primary
Efficacy Analysis Set 319 320 322 642 Week 8 (N) 319 320 322 642
Subjects with endoscopic 44 (13.8%) 84 (26.3%) 87 (27.0%) 171
(26.6%) healing Adjusted Treatment difference 12.4 13.3 12.8 (95%
CI) (6.5, 18.4) (7.3, 19.3) (7.9, 17.8) (97.5% CI) (5.2, 19.2)
(6.4, 20.1) (7.2, 18.5) p-value <0.001 <0.001 <0.001 N =
number of subjects; CI = confidence interval
[0288] Clinical Response at Week 8
[0289] At Week 8, significantly greater proportions of subjects in
the .about.6 mg/kg and 130 mg groups achieved clinical response
(61.8% and 51.3%, respectively) compared with subjects in the
placebo group (31.3%; p<0.001 for both comparisons; Table
4).
TABLE-US-00004 TABLE 4 Number of Subjects in Clinical Response
Ustekinumab IV Placebo IV 130 mg 6 mg/kg Combined Primary Efficacy
Analysis Set 319 320 322 642 Week 8 (N) 319 320 322 642 Subjects in
clinical response 100 (31.3%) 164 (51.3%) 199 (61.8%) 363 (56.5%)
Adjusted Treatment difference 19.9 30.5 25.2 (95% CI) (12.8, 27.3)
(23.2, 37.8) (18.9, 31.5) (97.5% CI) (11.4, 28.3) (22.2, 38.8)
(18.0, 32.4) p-value <0.001 <0.001 <0.001 N = number of
subjects; CI = confidence interval
[0290] Change in Baseline in Total IBDQ Score at Week 8
[0291] At baseline, median IBDQ scores were similar across all
treatment groups. At Week 8, the median improvements from baseline
in the IBDQ scores were significantly greater in the .about.6 mg/kg
and 130 mg groups (31.0 and 31.5, respectively) compared with the
placebo group (10.0; p<0.001 for both comparisons).
[0292] Clinical Remission at Week 8
[0293] When remission was assessed as clinical remission (global
definition) with a rectal bleeding subscore of 0 at Week 8, the
proportions of subjects who achieved this endpoint were almost
identical to that observed based on the primary efficacy analysis
(global definition). Significantly greater proportions of subjects
in the .about.6 mg/kg and 130 mg groups achieved this endpoint
(15.2% and 15.3%, respectively) compared with subjects in the
placebo group (5.3%; p<0.001 for both comparisons).
[0294] Symptomatic Remission at Week 8
[0295] At Week 8, significantly greater proportions of subjects in
the .about.6 mg/kg and 130 mg groups achieved symptomatic remission
(44.7% and 41.3%, respectively) compared with subjects in the
placebo group (22.6%; p<0.001 for both comparisons).
[0296] Histologic Healing at Week 8
[0297] Histologic healing was defined as 0 to .ltoreq.5%
neutrophils in epithelium and no crypt destruction, erosions,
ulcerations, or granulations. At Week 8, significantly greater
proportions of subjects in the .about.6 mg/kg and 130 mg groups
achieved histologic healing (35.6% and 37.9%, respectively)
compared with subjects in the placebo group (21.9%; p<0.001 for
both comparisons).
[0298] Change from Baseline in Mayo Score at Week 8
[0299] At baseline, the mean Mayo scores were the same across all
treatment groups (8.9 for all groups). At Week 8, the mean
decreases from baseline in Mayo scores were significantly greater
in the .about.6 mg/kg and 130 mg groups (3.5 and 3.2, respectively)
compared with the placebo group (1.8; p<0.001 for both
comparisons).
[0300] Change from Baseline in Partial Mayo Score Through Week
8
[0301] At baseline, the mean partial Mayo scores were the same
across all treatment groups (6.2 for all groups). As early as Week
2 and continuing for visits through Week 8, the mean decreases in
the partial Mayo score were significantly greater in the .about.6
mg/kg and 130 mg groups compared with the placebo group. At Week 2,
the mean decreases from baseline in the partial Mayo scores were
1.6 and 1.5, in the .about.6 mg/kg and 130 mg, respectively,
compared with 1.0 in the placebo group (p<0.001 for both
comparisons). At Week 8, the mean decreases from baseline in the
partial Mayo scores were 2.9 and 2.6, in the .about.6 mg/kg and 130
mg, respectively, compared with 1.5 in the placebo group
(p<0.001 for both comparisons).
[0302] UCEIS Score at Week 8
[0303] The UCEIS score provides an overall assessment of endoscopic
severity of UC, based on mucosal vascular pattern, bleeding, and
ulceration. The score ranges from 3 to 11 with a higher score
indicating more severe disease by endoscopy. The UCEIS score was
assessed only during the central read of the video of the
endoscopy.
[0304] At baseline, the mean UCEIS scores were similar across all
treatment groups (7.6, 7.5, 7.5 in the .about.6 mg/kg, 130 mg and
placebo groups, respectively). At Week 8, the mean decreases from
baseline in UCEIS scores were significantly greater in the .about.6
mg/kg and 130 mg groups (1.3 and 1.1, respectively) compared with
the placebo group (0.5; p<0.001 for both comparisons).
[0305] At Week 8, significantly greater proportions of subjects in
the .about.6 mg/kg and 130 mg groups had a UCEIS score of .ltoreq.4
(20.2% and 19.1%, respectively) compared with subjects in the
placebo group (11.0%; p<0.001 and p=0.004, respectively). It is
hypothesized that a UCEIS score of .ltoreq.4 is associated with
Mayo endoscopic subscores of 0 or 1 that have defined endoscopic
healing in this study.
[0306] Bristol Stool Form Scale Score
[0307] The BSFS score at a visit was the average of the 3-day daily
average of the BSFS score prior to the visit. The same 3 days used
to calculate the stool frequency and rectal bleeding subscores of
the Mayo score were used to calculate the average BSFS score for
the visit.
[0308] Approximately 40% (370/961) of randomized subjects had BSFS
score collected at baseline. At baseline, 99.2% (367/370) of the
subjects had average BSFS scores of .gtoreq.3 and the majority of
subjects (54.3%) had average B SFS scores of .gtoreq.6, indicating
diarrhea. As early as Week 2 and continuing for visits through Week
8, the proportions of subjects with diarrhea (average BSFS scores
of .gtoreq.6) were smaller in the .about.6 mg/kg and 130 mg groups
compared with the placebo group. At Week 8, 22.8%, 21.1%, and 32.0%
of subjects had diarrhea (average BSFS scores of .gtoreq.6) in the
.about.6 mg/kg, 130 mg and placebo groups, respectively.
Furthermore, at Week 8 the proportion of subjects with normal stool
(.gtoreq.3 and .ltoreq.5) was greater in the .about.6 mg/kg and 130
mg groups compared with placebo (48.3%, 48.9%, and 29.3%,
respectively).
[0309] Normalization of C-reactive Protein
[0310] C-reactive protein (CRP) is used as a marker of inflammation
in subjects with IBD. In
[0311] UC, elevated CRP has been associated with severe clinical
activity, an elevated sedimentation rate, and active disease as
detected by colonoscopy. C-reactive protein was assayed using a
validated, high-sensitivity CRP assay.
[0312] At baseline, the proportion of subjects who had abnormal CRP
(>3 mg/L) was similar across all treatment groups; overall,
59.2% of randomized subjects had abnormal CRP concentrations at
baseline. As early as Week 2 and continuing for visits through Week
8, among subjects who had abnormal values at baseline,
significantly greater proportions of subjects in the .about.6 mg/kg
and 130 mg groups achieved normalization of CRP (.ltoreq.3 mg/L)
compared with the placebo group. At Week 8, 38.7% and 34.1% of
subjects achieved normalization of CRP in the .about.6 mg/kg and
130 mg groups, respectively, compared with 21.1% of subjects in the
placebo group (p<0.001 for both comparisons).
[0313] Normalization of Fecal Lactoferrin
[0314] At baseline, the proportions of subjects with abnormal fecal
lactoferrin (>7.24 .mu.g/g) were similar across all treatment
groups; overall 90.0% of randomized subjects had abnormal fecal
lactoferrin concentrations at baseline. At Week 4 and Week 8, among
subjects who had abnormal values at baseline, significantly greater
proportions of subjects in the .about.6 mg/kg and 130 mg groups
achieved normalization of fecal lactoferrin (.ltoreq.7.24 .mu.g/g)
compared with the placebo group. At Week 8, 14.6% and 17.2% of
subjects in the .about.6 mg/kg and 130 mg groups, respectively,
achieved normalization of fecal lactoferrin compared with 9.3% of
subjects in the placebo group (p=0.042, p=0.006, respectively, for
the ustekinumab groups).
[0315] Normalization of Fecal Calprotectin
[0316] At baseline, the proportions of subjects with abnormal fecal
calprotectin (>250 mg/kg) were slightly greater in the .about.6
mg/kg group (85.1%) compared with the placebo group (78.4%); 82.5%
of subjects in the 130 mg group had abnormal fecal calprotectin at
baseline. At Week 2 and Week 4, among subjects who had abnormal
values at baseline, significantly greater proportions of subjects
in the .about.6 mg/kg and 130 mg groups achieved normalization of
fecal calprotectin (.ltoreq.250 mg/kg). At Week 8, among subjects
with abnormal fecal calprotectin at baseline, the proportions of
subjects with normalized fecal calprotectin, though not
significant, were numerically greater in the ustekinumab .about.6
mg/kg and 130 mg groups (25.5% and 24.2%, respectively), compared
with subjects in the placebo group (20.4%; p=0.148, p=0.301 for
both comparisons, respectively).
Example 2: Maintenance Study of Ustekinumab in the Treatment of
Ulcerative Colitis in Humans
[0317] Methodology
[0318] In this randomized-withdrawal maintenance study, all
subjects enrolled were to be responders to study agent administered
in the induction study. Primary (randomized) population: Subjects
who were in clinical response to IV ustekinumab following induction
comprised the primary population in the maintenance study. This
population included the following: subjects who were randomized to
receive ustekinumab (ie, 130 mg IV or .about.6 mg/kg IV) at Week 0
of the induction study and were in clinical response at induction
Week 8; and subjects who were randomized to receive placebo at Week
0 of the induction study and were not in clinical response at
induction Week 8 but were in clinical response at induction Week 16
after receiving a dose of IV ustekinumab (.about.6 mg/kg) at
induction Week 8 (placebo.fwdarw.ustekinumab .about.6 mg/kg IV).
These subjects were randomized in a 1:1:1 ratio at maintenance Week
0 to receive ustekinumab 90 mg SC every 8 weeks (q8w), ustekinumab
90 mg SC every 12 weeks (q12w), or placebo SC. Nonrandomized
population: Additional subjects entering the maintenance study were
not randomized in the primary population and received maintenance
treatment in this study as follows: ustekinumab induction delayed
responders (ie, subjects who were not in clinical response to IV
ustekinumab at induction Week 8 but were in clinical response at
induction Week 16 after receiving ustekinumab 90 mg SC at induction
Week 8) received ustekinumab 90 mg SC q8w; and placebo induction
responders (ie, subjects who were in clinical response to placebo
IV induction) received placebo SC. Nonrandomized subjects were
followed for both efficacy and safety but were not included in the
key efficacy analyses.
[0319] All subjects received their assigned dose of SC study agent
at the maintenance Week 0 visit. Thereafter, to maintain the blind,
all subjects received study agent at all scheduled study agent
administration visits. Subjects were assessed for clinical flare at
every visit and, if loss of clinical response was confirmed, were
eligible for rescue medication. The main portion of the maintenance
study was through Week 44 and a long-term study extension will
continue through Week 220.
Number of Subjects (Planned and Analyzed):
[0320] 783 subjects who completed the induction study and were in
clinical response to induction study agent were enrolled in this
maintenance study. The numbers of subjects in each treatment group
at maintenance Week 0 were as follows: [0321] Randomized (primary)
population (523 subjects [327 subjects were planned]): [0322] 176
subjects were randomized to ustekinumab 90 mg SC q8w. [0323] 172
subjects were randomized to ustekinumab 90 mg SC q12w. [0324] 175
subjects were randomized to placebo SC. [0325] Nonrandomized
population (260 subjects): [0326] 157 subjects who were ustekinumab
induction delayed responders (ie, were not in clinical response to
ustekinumab at induction Week 8 but were in clinical response at
induction Week 16) received ustekinumab 90 mg SC q8w. [0327] 103
subjects who were in clinical response to placebo IV induction
(placebo induction responders) received placebo SC.
Diagnosis and Main Criteria for Inclusion:
[0328] All subjects enrolled into this randomized-withdrawal
maintenance study were those with moderately to severely active UC
who had an inadequate response or had failed to tolerate
conventional therapy (ie, corticosteroids or immunomodulators) or
biologic therapy (ie, a TNF antagonist and/or vedolizumab), and
demonstrated a clinical response to study agent during the
induction study. This included subjects who were in clinical
response to IV ustekinumab, in clinical response to IV placebo, or
in delayed clinical response to ustekinumab, and had not received a
protocol-prohibited medication change during the induction
study.
Criteria for Evaluation:
[0329] Pharmacokinetics (PK): Serum ustekinumab concentration
[0330] Immunogenicity: Antibodies to ustekinumab [0331]
Pharmacodynamics (PD)/biomarkers: Serum biomarkers; fecal
microbiome; RNA expression and histologic assessment of disease
activity and healing in mucosal biopsies [0332] Genetics and
epigenetics: Whole blood deoxyribonucleic acid (DNA) [0333]
Efficacy: Mayo score and partial Mayo score, UC Endoscopic Index of
Severity (UCEIS), CRP, fecal lactoferrin, and fecal calprotectin
[0334] Health-related Quality of Life: Inflammatory Bowel Disease
Questionnaire (IBDQ), 36-item Short Form Health Survey (SF-36),
EuroQoL-5D Health Questionnaire (EQ-5D) [0335] Health economics: UC
disease-related hospitalizations and surgeries; productivity Visual
Analog Scale (VAS), and Work Productivity and Activity Impairment
Questionnaire-General Health (WPAI-GH) [0336] Safety: Adverse
events (AEs), serious adverse events (SAEs), infections, injection
site reactions, allergic reactions, hematology and chemistry
parameters, vital signs, physical examinations, and early detection
of tuberculosis
[0337] Endpoints [0338] The primary endpoint was clinical remission
at Week 44. The definition of clinical remission (as well as the
testing procedure) is different for submissions in the US and
outside the US to accommodate the global and US preferred
definitions of clinical remission. Each definition of clinical
remission was applied to all subjects in the primary efficacy
analysis set. [0339] The global definition of the primary endpoint
of clinical remission was defined as a Mayo score .ltoreq.2 points,
with no individual subscore >1. [0340] The US definition of
clinical remission was defined as an absolute stool number
.ltoreq.3, a Mayo rectal bleeding subscore of 0, and a Mayo
endoscopy subscore of 0 or 1. [0341] The major secondary endpoints,
listed in the order in which they were tested, were: [0342]
Maintenance of clinical response through Week 44 [0343] Endoscopic
healing at Week 44 [0344] Clinical remission and not receiving
concomitant corticosteroids (corticosteroid-free clinical
remission) at Week 44 [0345] Maintenance of clinical remission
through Week 44 among the subjects who had achieved clinical
remission at maintenance baseline [0346] For the 3rd and 4th major
secondary endpoints, the global definition of clinical remission
was used to support submissions for countries outside the US and
the US definition of clinical remission was used to support the
submission in the United States. Demographic and baseline disease
characteristics were summarized based on the 961 subjects in the
primary efficacy analysis set.
[0347] Analyses of multiplicity-controlled endpoints, except for
the fourth major secondary endpoint related to maintenance of
clinical remission, were conducted using a Cochran-Mantel-Haenszel
(CMH) chi square test stratified by clinical remission (global
definition) status at maintenance baseline (yes/no as determined by
the IWRS) and induction treatment (placebo IV
[I-0].fwdarw.ustekinumab .about.6 mg/kg IV [I-8], ustekinumab 130
mg IV [I-0], or ustekinumab .about.6 mg/kg IV [I-0]). For the
fourth major secondary endpoint (maintenance of clinical
remission), a CMH chi-square test stratified by induction treatment
was used.
Global and US-specific multiple testing procedures were
prespecified to control the overall Type 1 error rate at the 0.05
level over the multiplicity-controlled endpoints in this study
(Section 3.11.2.7.3). All statistical testing was performed at the
2-sided 0.05 significance level. Nominal p-values are
presented.
[0348] Safety was assessed by summarizing the frequency and type of
treatment-emergent adverse events (AEs), laboratory parameters
(hematology and chemistry), and vital signs parameters. Safety
summaries are provided separately for randomized subjects,
nonrandomized subjects, and all treated subjects. Presentation of
the safety data focuses on the randomized population.
Results:
[0349] Study Population
[0350] A total of 783 subjects who completed the induction study
and were in clinical response to induction study agent were
enrolled in this maintenance study. Of these, 523 subjects were in
the targeted primary population for the maintenance study and were
randomized to receive a SC administration of ustekinumab or placebo
at maintenance Week 0 (176, 172, and 175 subjects in the
ustekinumab 90 mg SC q8w, ustekinumab 90 mg SC q12w, and placebo
groups, respectively). The remaining 250 subjects were in the
nonrandomized population, including 157 ustekinumab induction
delayed responders (who received ustekinumab 90 mg SC q8w) and 103
placebo induction responders (who received placebo). All enrolled
subjects who were assigned treatment at maintenance baseline
received their study agent at that time.
[0351] Prior to Week 40 (last dosing visit of the maintenance
study), 85 subjects (16.3%) in the primary population discontinued
study agent. The proportion of subjects who discontinued study
agent was greater in the placebo group (24.6%) than those in the
ustekinumab q8w and q12w groups (10.2% and 14.0%, respectively).
The most common reasons for discontinuation were lack of efficacy
and an adverse event due to worsening of UC. Prior to Week 44, 29
subjects (5.5%) in the primary population terminated study
participation; the most common reason for termination of study
participation was withdrawal of consent.
[0352] Baseline clinical disease characteristics were
representative of a population of subjects with moderately to
severely active UC that was refractory to available therapies and
were generally well-balanced across the 3 treatment groups. The
median duration of disease was 6.05 years and the median baseline
Mayo score was 9.0, with 86.9% and 13.1% presenting with moderate
and severe UC, respectively. At induction baseline, 52.2% of
subjects in the primary population of the maintenance study were
taking corticosteroids, 26.6% were taking immunomodulatory drugs,
and 70.7% were taking aminosalicylates. The majority of subjects
(93.5%) had an inadequate response to, or were intolerant of,
corticosteroids and/or 6-MP/AZA, or demonstrated corticosteroid
dependence at induction baseline. Overall in the primary
population, 47.6% of subjects had a history of documented biologic
failure and 52.4% of subjects did not. Also, 47.2% had failed at
least 1 anti-TNF whereas 13.4% had failed both an anti-TNF and
vedolizumab, and 49.3% were naive to biologic therapy; 2 subjects
were biologic failures to only vedolizumab.
[0353] Efficacy Results
[0354] Ustekinumab maintenance therapy demonstrated efficacy in a
population of subjects with moderately to severely active UC who
had previously failed or were intolerant of conventional or
biologic therapies, including TNF antagonists and/or vedolizumab,
and were in clinical response 8 weeks after receiving a single dose
of ustekinumab IV induction therapy.
Based on the pre-specified global and US-specific multiple testing
procedures, statistical significance can be claimed for both
ustekinumab dose regimens (90 mg q8w and 90 mg q12w) for the
primary endpoint of clinical remission at Week 44 and the three
major secondary endpoints of maintenance of clinical response
through Week 44, endoscopic healing at Week 44, and
corticosteroid-free clinical remission at Week 44. Additionally,
statistical significance can be claimed for maintenance of clinical
remission through Week 44 (among the subjects who had achieved
clinical remission at maintenance baseline) for both ustekinumab
doses based on the US-specific testing procedure, and for the
ustekinumab q12w regimen based on the global testing procedure.
[0355] Clinical Efficacy in the Primary Population (ie, Subjects in
Clinical Response 8 Weeks After Receiving Ustekinumab IV Induction
Therapy) [0356] Primary Endpoint: Clinical Remission [0357] The
proportions of subjects in clinical remission (based on the global
definition) at Week 44 were significantly greater in the
ustekinumab q8w group and ustekinumab q12w group (43.8% and 38.4%,
respectively) compared with subjects in the placebo group (24.0%;
p<0.001 and p=0.002, respectively). [0358] The proportions of
subjects in clinical remission (based on the US-specific
definition) at Week 44 were significantly greater in the
ustekinumab q8w group and ustekinumab q12w group (42.6% and 39.5%,
respectively) compared with subjects in the placebo group (24.6%;
p<0.001 and p=0.002, respectively). [0359] The effect of
ustekinumab on achieving clinical remission (based on both the
global and US specific definitions) was generally consistent across
subgroups (including subjects who were biologic failures and those
who were not biologic failures as well as subjects who were
receiving concomitant immunomodulators or corticosteroids at
induction baseline and those who were not) and was robust to
prespecified changes in data-handling rules. [0360] Major Secondary
Endpoints: Maintenance of Clinical Response, Endoscopic Healing,
Corticosteroid-Free Clinical Remission, and Maintenance of Clinical
Remission [0361] The proportions of subjects who maintained
clinical response through Week 44, achieved endoscopic healing,
achieved corticosteroid-free remission (applying both global and US
specific definitions of clinical remission) were significantly
greater (p<0.01) in the ustekinumab q8w and q12w groups compared
with that in the placebo group. [0362] The proportions of subjects
who maintained clinical remission among the subjects who had
achieved clinical remission at maintenance baseline was numerically
greater for both the ustekinumab q8w and q12w groups compared with
that in the placebo group (applying both the global and US specific
definition of clinical remission). Statistical significance
(p<0.01) was achieved for both comparisons of the q8w and q12w
groups versus placebo using the US-specific definition of clinical
remission; however, statistical significance was only achieved for
the q12w group (p<0.01) compared to placebo using the global
definition of clinical remission. [0363] Other Histologic, Mucosal,
Clinical, and Endoscopic Endpoints [0364] The analyses summarized
below were not adjusted for multiplicity. Statements of statistical
significance are based on nominal p-values. [0365] The proportions
of subjects who achieved histologic healing (ie, neutrophil
infiltration in .ltoreq.5% of crypts, no crypt destruction, and no
erosions, ulcerations, or granulation tissue) at Week 44 were
significantly (p<0.001) greater in the ustekinumab q8w and q12w
groups compared with the placebo group. [0366] The proportions of
subjects who achieved mucosal healing (a combination of endoscopic
healing and histologic healing) at Week 44 were significantly
(p<0.01) greater in the ustekinumab q8w and q12w groups compared
with the placebo group. [0367] Applying both global and US-specific
definitions of clinical remission, the proportions of subjects
achieving corticosteroid-free remission for at least 90 days prior
to Week 44 was significantly greater (p<0.01) in the ustekinumab
q8w and q12w groups compared with that in the placebo group.
Furthermore, among subjects receiving corticosteroids at
maintenance baseline, significantly greater proportions of subjects
(p<0.05) were in clinical remission and not receiving
concomitant corticosteroids for at least 90 days prior to Week 44
in the ustekinumab q8w and q12w groups compared with those in the
placebo group. [0368] The efficacy of ustekinumab maintenance
treatment was also demonstrated in clinical outcomes as measured by
maintained improvement in the partial Mayo score, maintenance of
symptomatic remission as well as maintenance of endoscopic healing.
Further evidence of the efficacy of ustekinumab maintenance
treatment was observed in partial Mayo remission and symptomatic
remission over time as well as symptom control (stool frequency and
rectal bleeding). [0369] Inflammatory Biomarkers [0370] Over time
through Week 44, the ustekinumab treatment groups maintained their
CRP, fecal lactoferrin, and fecal calprotectin concentration levels
observed at maintenance baseline, whereas median CRP, fecal
lactoferrin, and fecal calprotectin concentrations worsened
(increased) in the placebo group. [0371] At Week 44, the proportion
of subjects with normalized CRP, fecal calprotectin and fecal
lactoferrin were generally significantly greater in the ustekinumab
q8w and q12w groups compared with the placebo group. [0372]
Clinical Endpoints by Biologic Failure Status [0373] For subjects
with and subjects without a history of biologic failure, the
proportions of subjects who achieved each of the primary and major
secondary endpoints and mucosal healing were generally greater in
the ustekinumab q8w and q12w groups compared with subjects in the
placebo group. [0374] In some cases, where treatment effects were
similar in the biologic non-failure and failure populations, there
was a consistent trend in the biologic-failure subjects across
endpoints that the treatment effect for the ustekinumab q8w group
was greater than that for the ustekinumab q12w group. This trend
was not observed in the biologic non-failure population. [0375]
Efficacy Based on Inflammatory Biomarker Subgroups [0376] Among
subjects with a higher inflammatory burden (elevated CRP and/or
elevated fecal inflammatory markers) at either induction or
maintenance baseline, while both dosages generally demonstrated
efficacy compared to placebo, the efficacy of ustekinumab q8w
seemed to be better across the range of clinical endpoints than the
ustekinumab q12w group. However, in subjects with low inflammatory
burden at baseline, the ustekinumab q8w and q12w groups
demonstrated similar efficacy over the endpoints. [0377]
Health-Related Quality of Life [0378] Through Week 44, subjects in
the ustekinumab q8w and q12w groups were generally able to maintain
improvement in health-related quality of life as assessed using the
IBDQ, SF 36 and EQ 5D instruments compared to subjects in the
placebo group. [0379] Outcomes for the Ustekinumab 90 mg q8w Dose
and Ustekinumab 90 mg q12w Dose [0380] While both the ustekinumab
q8w and q12w groups demonstrated generally similar efficacy for the
primary and major secondary endpoints, q8w was modestly better than
q12w based on the following more objective and stringent measures
of efficacy, including: [0381] Endoscopic and mucosal healing at
Week 44 [0382] Durable partial Mayo remission at Week 44 [0383]
Corticosteroid-free clinical remission as well as the elimination
of corticosteroids for at least 90 days prior to Week 44 among
subjects receiving corticosteroids at maintenance baseline [0384]
Furthermore, when efficacy was examined over time (for the
following endpoints), the q8w group showed greater efficacy than
the q12w group: [0385] Mayo stool frequency and rectal bleeding
subscores indicating inactive or mild disease (ie, subscores of 0
or 1), as well as an absolute stool number .ltoreq.3 over time
through Week 44. [0386] Partial Mayo remission and symptomatic
remission over time through Week 44 [0387] Median changes from
baseline in fecal lactoferrin and calprotectin concentrations over
time through Week 44. [0388] Efficacy in Ustekinumab Induction
Delayed Responders [0389] Subjects who were delayed responders to
ustekinumab induction therapy were able to maintain clinical
response and achieve clinical remission, endoscopic, histologic,
and mucosal healing (a combination of endoscopic healing and
histologic healing) while receiving ustekinumab 90 mg q8w. [0390]
Efficacy and Pharmacokinetics/Immunogenicity [0391] In general,
during maintenance, a positive association was observed between
serum ustekinumab concentration and the clinical efficacy outcomes
of clinical remission and endoscopic healing. In addition, lower
levels of inflammation, as measured by CRP, were observed in
subjects with higher serum ustekinumab concentrations. [0392] Among
subjects receiving maintenance ustekinumab, the development of
antibodies to ustekinumab did not appear to have an impact on
clinical efficacy as measured by multiple endpoints such as
clinical remission, endoscopic healing, clinical response, and
change from maintenance baseline in Mayo score; however, the
interpretation of the data is limited by the small sample size.
[0393] Pharmacokinetic and Immunogenicity Results [0394] Following
maintenance treatment with ustekinumab 90 mg SC q8w or q12w,
steady-state was reached at approximately 8 or 12 weeks after
subjects began receiving ustekinumab 90 mg SC q8w, or ustekinumab
90 mg SC q12w maintenance dose regimens, respectively. Median
steady state trough serum ustekinumab concentrations over time were
approximately 3-fold greater the concentrations in the ustekinumab
q8w group (2.69 .mu.g/mL to 3.09 .mu.g/mL) than in the q12w group
(0.92 .mu.g/mL to 1.19 .mu.g/mL). [0395] Following maintenance dose
regimens of ustekinumab 90 mg SC q8w or q12w, serum ustekinumab
concentrations were sustained through Week 44 in almost all
subjects, with a smaller proportion of subjects with undetectable
trough concentrations over time in the 90 mg q8w group (0.7% to
2.4%) compared to those in the 90 mg q12w group (4.9% to 7.1%). The
median ustekinumab concentration in subjects in the placebo group
was below detectable levels by Week 16. [0396] The impact of the
different ustekinumab IV induction doses on serum ustekinumab
concentrations during maintenance continued to diminish over time,
as expected. [0397] Median trough serum ustekinumab concentrations
tended to be lower in subjects with higher body weight. [0398]
Nonrandomized subjects in the ustekinumab induction delayed
responders group tended to have lower serum ustekinumab
concentrations over time compared to randomized subjects in the
ustekinumab q8w group following SC administration of the same
ustekinumab dose regimen of 90 mg q8w. [0399] Among 680 treated
subjects with appropriate samples for the assessment of antibodies
to ustekinumab, 39 (5.7%) were positive for antibodies to
ustekinumab through 52 weeks of treatment, the majority with
antibody titers .ltoreq.1:800. Of the 39 treated subjects who were
positive for antibodies to ustekinumab in this maintenance study,
11 (28.2%) were positive for neutralizing antibodies. [0400] In all
randomized treatment groups, median serum ustekinumab
concentrations were lower over time in subjects who were positive
for antibodies to ustekinumab compared with levels in subjects who
were negative for antibodies to ustekinumab.
[0401] Safety Results
[0402] Subcutaneous maintenance regimens of ustekinumab 90 mg
administered q12w or q8w through Week 44 were generally well
tolerated and consistent with the known safety profile of
ustekinumab. [0403] AEs were reported in 77.3%, 69.2%, and 78.9% of
subjects in the ustekinumab q8w, ustekinumab q12w, and placebo
groups, respectively. [0404] Reasonably related AEs were reported
in 26.1%, 17.4%, and 28.6% of subjects in the ustekinumab q8w,
ustekinumab q12w, and placebo groups, respectively. [0405]
Infections (as identified by the investigator) were reported in
48.9%, 33.7%, and 46.3% of subjects in the ustekinumab q8w,
ustekinumab q12w, and placebo groups, respectively. [0406]
Infections requiring oral or parenteral antibiotic treatment were
reported in 22.7%, 15.7%, and 19.4% of subjects in the ustekinumab
q8w, ustekinumab q12w, and placebo groups, respectively. [0407]
Serious infections were infrequent among randomized subjects and
were reported in 1.7%, 3.5%, and 2.3% in the ustekinumab q8w,
ustekinumab q12w, and placebo groups, respectively. Opportunistic
infections were identified in 3 subjects (all in the randomized
population); cytomegalovirus colitis was diagnosed for 2 subjects
in the ustekinumab q12w group and 1 subject was diagnosed with
concurrent moderate AEs of ophthalmic and labial herpes. No cases
of active TB were reported among ustekinumab-treated subjects
through Week 44. [0408] The proportion of randomized subjects with
AEs leading to discontinuation of study agent was higher in the
placebo group than in the q12w and q8w groups and the most frequent
AEs leading to discontinuation in the placebo group was worsening
UC. [0409] Among all treated subjects, including delayed
ustekinumab induction responders, the overall safety profile was
consistent with that observed in the randomized population. [0410]
There was 1 death reported for a subject who was a delayed
ustekinumab induction responder and was receiving ustekinumab q8w.
The cause of death was attributed to acute respiratory failure that
occurred during thyroid surgery for a multinodular goiter. [0411]
Among all treated subjects, 2 subjects (1 subject in the
ustekinumab induction delayed-responders group [receiving
ustekinumab q8w] and 1 subject randomized to the placebo group who
had received ustekinumab IV during induction) reported serious
major adverse cardiovascular events; both events were associated
with perioperative complications. [0412] Among all treated
subjects, there were 6 subjects for whom malignancies were reported
(5 ustekinumab-treated subjects and 1 placebo-only subject). [0413]
Three ustekinumab-treated subjects reported non-melanoma skin
cancers (NMSCs); all had either a prior history of azathioprine or
6-MP treatment and 2 were on concomitant immunomodulator therapy at
the time of the diagnosis. [0414] Two ustekinumab-treated subjects
were reported to have solid tumors; one subject with a papillary
renal cell carcinoma (q12w) and one subject with colon cancer
(q8w); both tumors were detected early during the subject's
participation in this maintenance study. [0415] There were no cases
of anaphylaxis or delayed hypersensitivity reactions identified
among ustekinumab treated subjects. [0416] There were no notable
differences in the proportions of subjects with post-baseline
maximum toxicity Grade .gtoreq.1 chemistry and hematology
laboratory between the placebo and respective ustekinumab groups.
Grade 3 and Grade 4 chemistry and hematology laboratory values were
infrequent.
[0417] Health Economics and Medical Resource Utilization Results
[0418] Through Week 44, fewer subjects in the combined ustekinumab
group had a UC disease-related hospitalization or surgery compared
with the placebo group. [0419] At Week 44, change from maintenance
baseline in productivity visual analog scores (VAS) demonstrated
improvement in subjects in the ustekinumab treatment groups and
worsening in subjects in the placebo group. [0420] At Week 44,
percentages within each of the 4 WPAI-GH domains were maintained
from maintenance baseline for the ustekinumab treatment groups,
with additional improvement observed in subjects in the ustekinumab
q8w group for percent impairment while working due to health,
percent overall work impairment due to health, and percent activity
impairment due to health. For subjects in the placebo group,
percentages for all 4 WPAI-GH domains worsened (ie, increased).
[0421] Conclusions [0422] The ustekinumab maintenance study
provided consistent and definitive evidence that the ustekinumab 90
mg SC q12w and q8w dose regimens were both effective in adult
subjects with moderately to severely active UC who had responded to
a single IV ustekinumab induction dose. [0423] The efficacy of
ustekinumab was observed in subjects who were biologic failures as
well as those who failed conventional but not biologic therapy (ie,
biology-naive). [0424] Of note, while both doses of ustekinumab
were effective, the q8w dose regimen demonstrated modestly better
efficacy across several objective and/or more stringent endpoints
(eg, endoscopic healing and durable partial Mayo remission) as well
as in overtime analyses of symptomatic and partial Mayo remission.
[0425] Maintenance dosing with ustekinumab SC dose regimens of 90
mg q12w and 90 mg q8w was generally well-tolerated over 44 weeks in
this population of adult subjects with moderate to severe
ulcerative colitis. [0426] The safety and efficacy data from this
study support a positive benefit/risk profile for ustekinumab SC
maintenance therapy.
[0427] The European Commission has approved STELARA.RTM.
(ustekinumab) for the treatment of ulcerative colitis (UC) in
Europe as of Sep. 4, 2019. The approved label is shown in Annex I
below describing the intravenous preparation (Sections 1-10) and
subcutaneous preparation (Sections 1-10).
[0428] The present invention comprises a pharmaceutical composition
of an anti-IL-12/IL-23p40 antibody and packaging comprising one or
more label elements disclosed in Annex I, wherein the antibody
comprises: (i) a heavy chain variable region and a light chain
variable region, the heavy chain variable region comprising: a
complementarity determining region heavy chain 1 (CDRH1) amino acid
sequence of SEQ ID NO:1; a CDRH2 amino acid sequence of SEQ ID
NO:2; and a CDRH3 amino acid sequence of SEQ ID NO:3; and the light
chain variable region comprising: a complementarity determining
region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO:4; a
CDRL2 amino acid sequence of SEQ ID NO:5; and a CDRL3 amino acid
sequence of SEQ ID NO:6; (ii) a heavy chain variable region of the
amino acid sequence of SEQ ID NO:7 and a light chain variable
region of the amino acid sequence of SEQ ID NO:8; or (iii) a heavy
chain of the amino acid sequence of SEQ ID NO:10 and a light chain
of the amino acid sequence of SEQ ID NO:11.
Annex I
Summary of Product Characteristics
1. Name of the Medicinal Product
[0429] STELARA 130 mg concentrate for solution for infusion
2. Qualitative and Quantitative Composition
[0430] Each vial contains 130 mg ustekinumab in 26 mL (5
mg/mL).
[0431] Ustekinumab is a fully human IgG1K monoclonal antibody to
interleukin (IL)-12/23 produced in a murine myeloma cell line using
recombinant DNA technology.
[0432] For the full list of excipients, see section 6.1.
3. Pharmaceutical Form
[0433] Concentrate for solution for infusion.
[0434] The solution is clear, colourless to light yellow.
4. Clinical Particulars
[0435] 4.1 Therapeutic indications
Crohn's Disease
[0436] STELARA is indicated for the treatment of adult patients
with moderately to severely active Crohn's disease who have had an
inadequate response with, lost response to, or were intolerant to
either conventional therapy or a TNF.alpha. antagonist or have
medical contraindications to such therapies.
Ulcerative Colitis
[0437] STELARA is indicated for the treatment of adult patients
with moderately to severely active ulcerative colitis who have had
an inadequate response with, lost response to, or were intolerant
to either conventional therapy or a biologic or have medical
contraindications to such therapies (see section 5.1).
4.2 Posology and Method of Administration
[0438] STELARA concentrate for solution for infusion is intended
for use under the guidance and supervision of physicians
experienced in the diagnosis and treatment of Crohn's disease or
ulcerative colitis. STELARA concentrate for solution for infusion
should only be used for the intravenous induction dose.
Posology
Crohn's Disease and Ulcerative Colitis
[0439] STELARA treatment is to be initiated with a single
intravenous dose based on body weight. The infusion solution is to
be composed of the number of vials of STELARA 130 mg as specified
in Label Table 1 (see section 6.6 for preparation).
TABLE-US-00005 Label Table 1 Initial intravenous dosing of STELARA
Number of Body weight of patient at Recommended 130 mg the time of
dosing dose.sup.a STELARA Vials .ltoreq.55 kg 260 mg 2 >55 kg to
.ltoreq.85 kg 390 mg 3 >85 kg 520 mg 4 .sup.aApproximately 6
mg/kg
[0440] The first subcutaneous dose should be given at week 8
following the intravenous dose. For the posology of the subsequent
subcutaneous dosing regimen, see section 4.2 of the STELARA
solution for injection (vial) and solution for injection in
pre-filled syringe SmPC.
Elderly (.gtoreq.65 Years)
[0441] No dose adjustment is needed for elderly patients (see
section 4.4).
Renal and Hepatic Impairment
[0442] STELARA has not been studied in these patient populations.
No dose recommendations can be made.
Paediatric Population
[0443] The safety and efficacy of STELARA for the treatment of
Crohn's disease or ulcerative colitis in children less than 18
years have not yet been established. No data are available.
Method of Administration
[0444] STELARA 130 mg is for intravenous use only. It should be
administered over at least one hour. For instructions on dilution
of the medicinal product before administration, see section
6.6.
4.3 Contraindications
[0445] Hypersensitivity to the active substance or to any of the
excipients listed in section 6.1.
[0446] Clinically important, active infection (e.g. active
tuberculosis; see section 4.4).
4.4 Special Warnings and Precautions for Use
Traceability
[0447] In order to improve the traceability of biological medicinal
products, the tradename and the batch number of the administered
product should be clearly recorded.
Infections
[0448] Ustekinumab may have the potential to increase the risk of
infections and reactivate latent infections. In clinical studies,
serious bacterial, fungal, and viral infections have been observed
in patients receiving STELARA (see section 4.8).
[0449] Caution should be exercised when considering the use of
STELARA in patients with a chronic infection or a history of
recurrent infection (see section 4.3).
[0450] Prior to initiating treatment with STELARA, patients should
be evaluated for tuberculosis infection. STELARA must not be given
to patients with active tuberculosis (see section 4.3). Treatment
of latent tuberculosis infection should be initiated prior to
administering STELARA. Anti-tuberculosis therapy should also be
considered prior to initiation of STELARA in patients with a
history of latent or active tuberculosis in whom an adequate course
of treatment cannot be confirmed. Patients receiving STELARA should
be monitored closely for signs and symptoms of active tuberculosis
during and after treatment.
[0451] Patients should be instructed to seek medical advice if
signs or symptoms suggestive of an infection occur. If a patient
develops a serious infection, the patient should be closely
monitored and STELARA should not be administered until the
infection resolves.
Malignancies
[0452] Immunosuppressants like ustekinumab have the potential to
increase the risk of malignancy. Some patients who received STELARA
in clinical studies developed cutaneous and non-cutaneous
malignancies (see section 4.8).
[0453] No studies have been conducted that include patients with a
history of malignancy or that continue treatment in patients who
develop malignancy while receiving STELARA. Thus, caution should be
exercised when considering the use of STELARA in these
patients.
[0454] All patients, in particular those greater than 60 years of
age, patients with a medical history of prolonged immunosuppressant
therapy or those with a history of PUVA treatment, should be
monitored for the appearance of non-melanoma skin cancer (see
section 4.8).
Systemic and Respiratory Hypersensitivity Reactions
Systemic
[0455] Serious hypersensitivity reactions have been reported in the
postmarketing setting, in some cases several days after treatment.
Anaphylaxis and angioedema have occurred. If an anaphylactic or
other serious hypersensitivity reaction occurs, appropriate therapy
should be instituted and administration of STELARA should be
discontinued (see section 4.8).
Respiratory
[0456] Cases of allergic alveolitis and eosinophilic pneumonia have
been reported during post-approval use of ustekinumab. Clinical
presentations included cough, dyspnoea, and interstitial
infiltrates following one to three doses. Serious outcomes have
included respiratory failure and prolonged hospitalisation.
Improvement has been reported after discontinuation of ustekinumab
and also, in some cases, administration of corticosteroids. If
infection has been excluded and diagnosis is confirmed, discontinue
ustekinumab and institute appropriate treatment (see section
4.8).
Vaccinations
[0457] It is recommended that live viral or live bacterial vaccines
(such as Bacillus of Calmette and Guerin (BCG)) should not be given
concurrently with STELARA. Specific studies have not been conducted
in patients who had recently received live viral or live bacterial
vaccines. No data are available on the secondary transmission of
infection by live vaccines in patients receiving STELARA. Before
live viral or live bacterial vaccination, treatment with STELARA
should be withheld for at least 15 weeks after the last dose and
can be resumed at least 2 weeks after vaccination. Prescribers
should consult the Summary of Product Characteristics for the
specific vaccine for additional information and guidance on
concomitant use of immunosuppressive agents post-vaccination.
[0458] Patients receiving STELARA may receive concurrent
inactivated or non-live vaccinations.
[0459] Long term treatment with STELARA does not suppress the
humoral immune response to pneumococcal polysaccharide or tetanus
vaccines (see section 5.1).
Concomitant Immunosuppressive Therapy
[0460] In psoriasis studies, the safety and efficacy of STELARA in
combination with immunosuppressants, including biologics, or
phototherapy have not been evaluated. In psoriatic arthritis
studies, concomitant MTX use did not appear to influence the safety
or efficacy of STELARA. In Crohn's disease and ulcerative colitis
studies, concomitant use of immunosuppressants or corticosteroids
did not appear to influence the safety or efficacy of STELARA.
Caution should be exercised when considering concomitant use of
other immunosuppressants and STELARA or when transitioning from
other immunosuppressive biologics (see section 4.5).
Immunotherapy
[0461] STELARA has not been evaluated in patients who have
undergone allergy immunotherapy. It is not known whether STELARA
may affect allergy immunotherapy.
Serious Skin Conditions
[0462] In patients with psoriasis, exfoliative dermatitis has been
reported following ustekinumab treatment (see section 4.8).
Patients with plaque psoriasis may develop erythrodermic psoriasis,
with symptoms that may be clinically indistinguishable from
exfoliative dermatitis, as part of the natural course of their
disease. As part of the monitoring of the patient's psoriasis,
physicians should be alert for symptoms of erythrodermic psoriasis
or exfoliative dermatitis. If these symptoms occur, appropriate
therapy should be instituted. STELARA should be discontinued if a
drug reaction is suspected.
Special Populations
Elderly (.gtoreq.65 Years)
[0463] No overall differences in efficacy or safety in patients age
65 and older who received STELARA were observed compared to younger
patients in clinical studies in approved indications, however the
number of patients aged 65 and older is not sufficient to determine
whether they respond differently from younger patients. Because
there is a higher incidence of infections in the elderly population
in general, caution should be used in treating the elderly.
Sodium Content
[0464] STELARA contains less than 1 mmol sodium (23 mg) per dose,
i.e. essentially `sodium-free`.
[0465] STELARA is however, diluted in sodium chloride 9 mg/ml
(0.9%) solution for infusion. This should be taken into
consideration for patients on a controlled sodium diet (see section
6.6).
4.5 Interaction with Other Medicinal Products and Other Forms of
Interaction
[0466] Live vaccines should not be given concurrently with STELARA
(see section 4.4).
[0467] No interaction studies have been performed in humans. In the
population pharmacokinetic analyses of the phase III studies, the
effect of the most frequently used concomitant medicinal products
in patients with psoriasis (including paracetamol, ibuprofen,
acetylsalicylic acid, metformin, atorvastatin, levothyroxine) on
pharmacokinetics of ustekinumab was explored. There were no
indications of an interaction with these concomitantly administered
medicinal products. The basis for this analysis was that at least
100 patients (>5% of the studied population) were treated
concomitantly with these medicinal products for at least 90% of the
study period. The pharmacokinetics of ustekinumab was not impacted
by concomitant use of MTX, NSAIDs, 6-mercaptopurine, azathioprine
and oral corticosteroids in patients with psoriatic arthritis,
Crohn's disease or ulcerative colitis, or prior exposure to
anti-TNF.alpha. agents, in patients with psoriatic arthritis or
Crohn's disease or by prior exposure to biologics (i.e.
anti-TNF.alpha. agents and/or vedolizumab) in patients with
ulcerative colitis.
[0468] The results of an in vitro study do not suggest the need for
dose adjustments in patients who are receiving concomitant CYP450
substrates (see section 5.2).
[0469] In psoriasis studies, the safety and efficacy of STELARA in
combination with immunosuppressants, including biologics, or
phototherapy have not been evaluated. In psoriatic arthritis
studies, concomitant MTX use did not appear to influence the safety
or efficacy of STELARA. In Crohn's disease and ulcerative colitis
studies, concomitant use of immunosuppressants or corticosteroids
did not appear to influence the safety or efficacy of STELARA. (see
section 4.4).
4.6 Fertility, Pregnancy and Lactation
Women of Childbearing Potential
[0470] Women of childbearing potential should use effective methods
of contraception during treatment and for at least 15 weeks after
treatment.
Pregnancy
[0471] There are no adequate data from the use of ustekinumab in
pregnant women. Animal studies do not indicate direct or indirect
harmful effects with respect to pregnancy, embryonic/foetal
development, parturition or postnatal development (see section
5.3). As a precautionary measure, it is preferable to avoid the use
of STELARA in pregnancy.
Breast-Feeding
[0472] It is unknown whether ustekinumab is excreted in human
breast milk. Animal studies have shown excretion of ustekinumab at
low levels in breast milk. It is not known if ustekinumab is
absorbed systemically after ingestion. Because of the potential for
adverse reactions in nursing infants from ustekinumab, a decision
on whether to discontinue breast-feeding during treatment and up to
15 weeks after treatment or to discontinue therapy with STELARA
must be made taking into account the benefit of breast-feeding to
the child and the benefit of STELARA therapy to the woman.
Fertility
[0473] The effect of ustekinumab on human fertility has not been
evaluated (see section 5.3).
4.7 Effects on Ability to Drive and Use Machines
[0474] STELARA has no or negligible influence on the ability to
drive and use machines.
4.8 Undesirable Effects
Summary of the Safety Profile
[0475] The most common adverse reactions (>5%) in controlled
periods of the adult psoriasis, psoriatic arthritis, Crohn's
disease and ulcerative colitis clinical studies with ustekinumab
were nasopharyngitis and headache. Most were considered to be mild
and did not necessitate discontinuation of study treatment. The
most serious adverse reaction that has been reported for STELARA is
serious hypersensitivity reactions including anaphylaxis (see
section 4.4). The overall safety profile was similar for patients
with psoriasis, psoriatic arthritis, Crohn's disease and ulcerative
colitis.
Tabulated List of Adverse Reactions
[0476] The safety data described below reflect exposure in adults
to ustekinumab in 14 phase 2 and phase 3 studies in 6,709 patients
(4,135 with psoriasis and/or psoriatic arthritis, 1,749 with
Crohn's disease and 825 patients with ulcerative colitis). This
includes exposure to STELARA in the controlled and non-controlled
periods of the clinical studies for at least 6 months or 1 year
(4,577 and 3,253 patients respectively with psoriasis, psoriatic
arthritis, Crohn's disease or ulcerative colitis) and exposure for
at least 4 or 5 years (1,482 and 838 patients with psoriasis
respectively).
[0477] Label Table 2 provides a list of adverse reactions from
adult psoriasis, psoriatic arthritis, Crohn's disease and
ulcerative colitis clinical studies as well as adverse reactions
reported from post-marketing experience. The adverse reactions are
classified by System Organ Class and frequency, using the following
convention: Very common (.gtoreq.1/10), Common (.gtoreq.1/100 to
<1/10), Uncommon (.gtoreq.1/1,000 to <1/100), Rare
(.gtoreq.1/10,000 to <1/1,000), Very rare (<1/10,000), not
known (cannot be estimated from the available data). Within each
frequency grouping, adverse reactions are presented in order of
decreasing seriousness.
TABLE-US-00006 Label Table 2 List of adverse reactions System Organ
Class Frequency: Adverse reaction Infections and infestations
Common: Upper respiratory tract infection, nasopharyngitis,
sinusitis Uncommon: Cellulitis, dental infections, herpes zoster,
lower respiratory tract infection, viral upper respiratory tract
infection, vulvovaginal mycotic infection Immune system disorders
Uncommon: Hypersensitivity reactions (including rash, urticaria)
Rare: Serious hypersensitivity reactions (including anaphylaxis,
angioedema) Psychiatric disorders Uncommon: Depression Nervous
system disorders Common: Dizziness, headache Uncommon: Facial palsy
Respiratory, thoracic and Common: Oropharyngeal pain mediastinal
disorders Uncommon: Nasal congestion Rare: Allergic alveolitis,
eosinophilic pneumonia Gastrointestinal disorders Common:
Diarrhoea, nausea, vomiting Skin and subcutaneous Common: Pruritus
tissue disorders Uncommon: Pustular psoriasis, skin exfoliation,
acne Rare: Exfoliative dermatitis Musculoskeletal and Common: Back
pain, myalgia, arthralgia connective tissue disorders General
disorders and Common: Fatigue, injection site erythema,
administration site injection site pain conditions Uncommon:
Injection site reactions (including haemorrhage, haematoma,
induration, swelling and pruritus), asthenia
Description of Selected Adverse Reactions
Infections
[0478] In the placebo-controlled studies of patients with
psoriasis, psoriatic arthritis, Crohn's disease and ulcerative
colitis, the rates of infection or serious infection were similar
between ustekinumab-treated patients and those treated with
placebo. In the placebo-controlled period of these clinical
studies, the rate of infection was 1.36 per patient-year of
follow-up in ustekinumab-treated patients, and 1.34 in
placebo-treated patients. Serious infections occurred at the rate
of 0.03 per patient-year of follow-up in ustekinumab-treated
patients (30 serious infections in 930 patient-years of follow-up)
and 0.03 in placebo-treated patients (15 serious infections in 434
patient-years of follow-up) (see section 4.4).
[0479] In the controlled and non-controlled periods of psoriasis,
psoriatic arthritis, Crohn's disease and ulcerative colitis
clinical studies, representing 11,581 patient-years of exposure in
6,709 patients, the median follow up was 1.0 years; 1.1 years for
psoriatic disease studies, 0.6 year for Crohn's disease studies and
1.0 years for ulcerative colitis studies. The rate of infection was
0.91 per patient-year of follow-up in ustekinumab-treated patients,
and the rate of serious infections was 0.02 per patient-year of
follow-up in ustekinumab-treated patients (199 serious infections
in 11,581 patient-years of follow-up) and serious infections
reported included pneumonia, anal abscess, cellulitis,
diverticulitis, gastroenteritis and viral infections.
[0480] In clinical studies, patients with latent tuberculosis who
were concurrently treated with isoniazid did not develop
tuberculosis.
Malignancies
[0481] In the placebo-controlled period of the psoriasis, psoriatic
arthritis, Crohn's disease and ulcerative colitis clinical studies,
the incidence of malignancies excluding non-melanoma skin cancer
was 0.11 per 100 patient-years of follow-up for ustekinumab-treated
patients (1 patient in 929 patient-years of follow-up) compared
with 0.23 for placebo-treated patients (1 patient in 434
patient-years of follow-up). The incidence of non-melanoma skin
cancer was 0.43 per 100 patient-years of follow-up for
ustekinumab-treated patients (4 patients in 929 patient-years of
follow-up) compared to 0.46 for placebo-treated patients (2
patients in 433 patient-years of follow-up).
[0482] In the controlled and non-controlled periods of psoriasis,
psoriatic arthritis, Crohn's disease and ulcerative colitis
clinical studies, representing 11,561 patient-years of exposure in
6,709 patients, the median follow-up was 1.0 years; 1.1 years for
psoriatic disease studies, 0.6 year for Crohn's disease studies and
1.0 years for ulcerative colitis studies. Malignancies excluding
non-melanoma skin cancers were reported in 62 patients in 11,561
patient-years of follow-up (incidence of 0.54 per 100 patient-years
of follow-up for ustekinumab-treated patients). The incidence of
malignancies reported in ustekinumab-treated patients was
comparable to the incidence expected in the general population
(standardised incidence ratio=0.93 [95% confidence interval: 0.71,
1.20], adjusted for age, gender and race). The most frequently
observed malignancies, other than non-melanoma skin cancer, were
prostate, colorectal, melanoma and breast cancers. The incidence of
non-melanoma skin cancer was 0.49 per 100 patient-years of
follow-up for ustekinumab-treated patients (56 patients in 11,545
patient-years of follow-up). The ratio of patients with basal
versus squamous cell skin cancers (3:1) is comparable with the
ratio expected in the general population (see section 4.4).
Hypersensitivity and Infusion Reactions
[0483] In Crohn's disease and ulcerative colitis intravenous
induction studies, no events of anaphylaxis or other serious
infusion reactions were reported following the single intravenous
dose. In these studies, 2.2% of 785 placebo treated patients and
1.9% of 790 patients treated with the recommended dose of
ustekinumab reported adverse events occurring during or within an
hour of the infusion.
Paediatric Population
[0484] Undesirable effects in pediatric patients 12 years and older
with plaque psoriasis The safety of ustekinumab has been studied in
a phase 3 study of 110 patients from 12 to 17 years of age for up
to 60 weeks. In this study, the adverse events reported were
similar to those seen in previous studies in adults with plaque
psoriasis.
Reporting of Suspected Adverse Reactions
[0485] Reporting suspected adverse reactions after authorisation of
the medicinal product is important. It allows continued monitoring
of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions
via the national reporting system listed in Appendix V.
4.9 Overdose
[0486] Single doses up to 6 mg/kg have been administered
intravenously in clinical studies without dose-limiting toxicity.
In case of overdose, it is recommended that the patient be
monitored for any signs or symptoms of adverse reactions and
appropriate symptomatic treatment be instituted immediately.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
[0487] Pharmacotherapeutic group: Immunosuppressants, interleukin
inhibitors, ATC code: L04AC05.
Mechanism of Action
[0488] Ustekinumab is a fully human IgG1.kappa. monoclonal antibody
that binds with specificity to the shared p40 protein subunit of
human cytokines interleukin (IL)-12 and IL-23. Ustekinumab inhibits
the bioactivity of human IL-12 and IL-23 by preventing p40 from
binding to the IL-12R.beta.1 receptor protein expressed on the
surface of immune cells. Ustekinumab cannot bind to IL-12 or IL-23
that is already bound to IL-12R.beta.1 cell surface receptors.
Thus, ustekinumab is not likely to contribute to complement- or
antibody-mediated cytotoxicity of cells with IL-12 and/or IL-23
receptors. IL-12 and IL-23 are heterodimeric cytokines secreted by
activated antigen presenting cells, such as macrophages and
dendritic cells, and both cytokines participate in immune
functions; IL-12 stimulates natural killer (NK) cells and drives
the differentiation of CD4+ T cells toward the T helper 1 (Th1)
phenotype, IL-23 induces the T helper 17 (Th17) pathway. However,
abnormal regulation of IL 12 and IL 23 has been associated with
immune mediated diseases, such as psoriasis, psoriatic arthritis,
Crohn's disease and ulcerative colitis.
[0489] By binding the shared p40 subunit of IL-12 and IL-23,
ustekinumab may exert its clinical effects in psoriasis, psoriatic
arthritis, Crohn's disease and ulcerative colitis through
interruption of the Th1 and Th17 cytokine pathways, which are
central to the pathology of these diseases.
[0490] In patients with Crohn's disease and ulcerative colitis,
treatment with ustekinumab resulted in a decrease in inflammatory
markers including C-Reactive Protein (CRP) and fecal calprotectin
during the induction phase, which were then maintained throughout
the maintenance phase.
Immunisation
[0491] During the long term extension of Psoriasis Study 2 (PHOENIX
2), adult patients treated with STELARA for at least 3.5 years
mounted similar antibody responses to both pneumococcal
polysaccharide and tetanus vaccines as a non-systemically treated
psoriasis control group. Similar proportions of adult patients
developed protective levels of anti-pneumococcal and anti-tetanus
antibodies and antibody titers were similar among STELARA-treated
and control patients.
Clinical Efficacy
Crohn's Disease
[0492] The safety and efficacy of ustekinumab was assessed in three
randomized, double-blind, placebo-controlled, multicenter studies
in adult patients with moderately to severely active Crohn's
disease (Crohn's Disease Activity Index [CDAI] score of .gtoreq.220
and .ltoreq.450). The clinical development program consisted of two
8-week intravenous induction studies (UNITI-1 and UNITI-2) followed
by a 44 week subcutaneous randomized withdrawal maintenance study
(IM-UNITI) representing 52 weeks of therapy.
[0493] The induction studies included 1409 (UNITI-1, n=769; UNITI-2
n=640) patients. The primary endpoint for both induction studies
was the proportion of subjects in clinical response (defined as a
reduction in CDAI score of .gtoreq.100 points) at week 6. Efficacy
data were collected and analyzed through week 8 for both studies.
Concomitant doses of oral corticosteroids, immunomodulators,
aminosalicylates and antibiotics were permitted and 75% of patients
continued to receive at least one of these medications. In both
studies, patients were randomised to receive a single intravenous
administration of either the recommended tiered dose of
approximately 6 mg/kg (see Table 1, section 4.2), a fixed dose of
130 mg ustekinumab, or placebo at week 0.
[0494] Patients in UNITI-1 had failed or were intolerant to prior
anti-TNF.alpha. therapy. Approximately 48% of the patients had
failed 1 prior anti-TNF.alpha. therapy and 52% had failed 2 or 3
prior anti-TNF.alpha. therapies. In this study, 29.1% of the
patients had an inadequate initial response (primary
non-responders), 69.4% responded but lost response (secondary
non-responders), and 36.4% were intolerant to anti-TNF.alpha.
therapies.
[0495] Patients in UNITI-2 had failed at least one conventional
therapy, including corticosteroids or immunomodulators, and were
either anti-TNF-.alpha. naive (68.6%) or had previously received
but not failed anti-TNF.alpha. therapy (31.4%).
[0496] In both UNITI-1 and UNITI-2, a significantly greater
proportion of patients were in clinical response and remission in
the ustekinumab treated group compared to placebo (Label Table 3).
Clinical response and remission were significant as early as week 3
in ustekinumab treated patients and continued to improve through
week 8. In these induction studies, efficacy was higher and better
sustained in the tiered dose group compared to the 130 mg dose
group, and tiered dosing is therefore the recommended intravenous
induction dose.
TABLE-US-00007 Label Table 3: Induction of Clinical Response and
Remission in UNITI-1 and UNITI 2 UNITI-1* UNITI-2** Recommended
Recommended dose of dose of Placebo ustekinumab Placebo ustekinumab
N = 247 N = 249 N = 209 N = 209 Clinical 18 (7.3%) 52 (20.9%).sup.a
41 (19.6%) 84 (40.2%).sup.a Remission, week 8 Clinical 53 (21.5%)
84 (33.7%).sup.b 60 (28.7%) 116 (55.5%).sup.a Response (100 point),
week 6 Clinical 50 (20.2%) 94 (37.8%).sup.a 67 (32.1%) 121
(57.9%).sup.a Response (100 point), week 8 70 Point 67 (27.1%) 101
(40.6%).sup.b 66 (31.6%) 106 (50.7%).sup.a Response, week 3 70
Point 75 (30.4%) 109 (43.8%).sup.b 81 (38.8%) 135 (64.6%).sup.a
Response, week 6 Clinical remission is defined as CDAI score <
150; Clinical response is defined as reduction in CDAI score by at
least 100 points or being in clinical remission 70 point response
is defined as reduction in CDAI score by at least 70 points
*Anti-TNF.alpha. failures **Conventional therapy failures .sup.ap
< 0.001 .sup.bp < 0.01
[0497] The maintenance study (IM-UNITI), evaluated 388 patients who
achieved 100 point clinical response at week 8 of induction with
ustekinumab in studies UNITI-1 and UNITI-2. Patients were
randomized to receive a subcutaneous maintenance regimen of either
90 mg ustekinumab every 8 weeks, 90 mg ustekinumab every 12 weeks
or placebo for 44 weeks (for recommended maintenance posology, see
section 4.2 of the STELARA Solution for injection (vial) and
Solution for injection in pre filled syringe SmPC).
[0498] Significantly higher proportions of patients maintained
clinical remission and response in the ustekinumab treated groups
compared to the placebo group at week 44 (see Label Table 4).
TABLE-US-00008 Label Table 4: Maintenance of Clinical Response and
Remission in IM-UNITI (week 44; 52 weeks from initiation of the
induction dose) 90 mg 90 mg ustekinumab ustekinumab every every
Placebo* 8 weeks 12 weeks N = 131.sup..dagger. N = 128.sup..dagger.
N = 129.sup..dagger. Clinical Remission 36% 53%.sup.a 49%.sup.b
Clinical Response 44% 59%.sup.b 58%.sup.b Corticosteroid-Free 30%
47%.sup.a 43%.sup.c Clinical Remission Clinical Remission in
patients: in remission at the start 46% (36/79) 67% (52/78).sup.a
56% (44/78) of maintenance therapy who entered from study 44%
(31/70) 63% (45/72).sup.c 57% (41/72) CRD3002.sup..dagger-dbl. who
are Anti-TNF.alpha. 49% (25/51) 65% (34/52).sup.c 57% (30/53) naive
who entered from study 26% (16/61) 41% (23/56) 39% (22/57)
CRD3001.sup..sctn. Clinical remission is defined as CDAI score <
150; Clinical response is defined as reduction in CDAI of at least
100 points or being in clinical remission *The placebo group
consisted of patients who were in response to ustekimumab and were
randomized to receive placebo at the start of maintenance therapy.
.sup..dagger.Patients who were in 100 point clinical response to
ustekimumab at start of maintenance therapy
.sup..dagger-dbl.Patients who failed conventional therapy but not
anti-TNF.alpha. therapy .sup..sctn.Patients who are anti-TNF.alpha.
refractory/intolerant .sup.ap < 0.01 .sup.bp < 0.05
.sup.cnominally significant (p < 0.05)
[0499] In IM-UNITI, 29 of 129 patients did not maintain response to
ustekinumab when treated every 12 weeks and were allowed to dose
adjust to receive ustekinumab every 8 weeks. Loss of response was
defined as a CDAI score .gtoreq.220 points and a .gtoreq.100 point
increase from the CDAI score at baseline. In these patients,
clinical remission was achieved in 41.4% of patients 16 weeks after
dose adjustment.
[0500] Patients who were not in clinical response to ustekinumab
induction at week 8 of the UNITI-1 and UNITI-2 induction studies
(476 patients) entered into the non-randomized portion of the
maintenance study (IM-UNITI) and received a 90 mg subcutaneous
injection of ustekinumab at that time. Eight weeks later, 50.5% of
the patients achieved clinical response and continued to receive
maintenance dosing every 8 weeks; among these patients with
continued maintenance dosing, a majority maintained response
(68.1%) and achieved remission (50.2%) at week 44, at proportions
that were similar to the patients who initially responded to
ustekinumab induction.
[0501] Of 131 patients who responded to ustekinumab induction, and
were randomized to the placebo group at the start of the
maintenance study, 51 subsequently lost response and received 90 mg
ustekinumab subcutaneously every 8 weeks. The majority of patients
who lost response and resumed ustekinumab did so within 24 weeks of
the induction infusion. Of these 51 patients, 70.6% achieved
clinical response and 39.2% percent achieved clinical remission 16
weeks after receiving the first subcutaneous dose of
ustekinumab.
[0502] In IM-UNITI, patients who completed the study through week
44 were eligible to continue treatment in a study extension. Among
patients who entered the study extension, clinical remission and
response were generally maintained through week 92 for both
patients who failed TNF-therapies and those who failed conventional
therapies.
[0503] No new safety concerns were identified in this study
extension with up to 2 years of treatment in patients with Crohn's
Disease.
Endoscopy
[0504] Endoscopic appearance of the mucosa was evaluated in 252
patients with eligible baseline endoscopic disease activity in a
substudy. The primary endpoint was change from baseline in
Simplified Endoscopic Disease Severity Score for Crohn's Disease
(SES-CD), a composite score across 5 ileo-colonic segments of
presence/size of ulcers, proportion of mucosal surface covered by
ulcers, proportion of mucosal surface affected by any other lesions
and presence/type of narrowing/strictures. At week 8, after a
single intravenous induction dose, the change in SES-CD score was
greater in the ustekinumab group (n=155, mean change=-2.8) than in
the placebo group (n=97, mean change=-0.7, p=0.012).
Fistula Response
[0505] In a subgroup of patients with draining fistulas at baseline
(8.8%; n=26), 12/15 (80%) of ustekinumab-treated patients achieved
a fistula response over 44 weeks (defined as .gtoreq.50% reduction
from baseline of the induction study in the number of draining
fistulas) compared to 5/11 (45.5%) exposed to placebo.
Health-Related Quality of Life
[0506] Health-related quality of life was assessed by Inflammatory
Bowel Disease Questionnaire (IBDQ) and SF-36 questionnaires. At
week 8, patients receiving ustekinumab showed statistically
significantly greater and clinically meaningful improvements on
IBDQ total score and SF-36 Mental Component Summary Score in both
UNITI-1 and UNITI-2, and SF-36 Physical Component Summary Score in
UNITI-2, when compared to placebo. These improvements were
generally better maintained in ustekinumab-treated patients in the
IM-UNITI study through week 44 when compared to placebo.
Improvement in health-related quality of life was generally
maintained during the extension through week 92.
Ulcerative Colitis
[0507] The safety and efficacy of ustekinumab was assessed in two
randomized, double-blind, placebo-controlled, multicenter studies
in adult patients with moderately to severely active ulcerative
colitis (Mayo score 6 to 12; Endoscopy subscore .gtoreq.2). The
clinical development program consisted of one intravenous induction
study (referred to as UNIFI-I) with treatment of up to 16 weeks
followed by a 44 week subcutaneous randomized withdrawal
maintenance study (referred to as UNIFI-M) representing at least 52
weeks of therapy.
[0508] Efficacy results presented for UNIFI-I and UNIFI-M were
based on central review of endoscopies.
[0509] UNIFI-I included 961 patients. The primary endpoint for the
induction study was the proportion of subjects in clinical
remission at week 8. Patients were randomised to receive a single
intravenous administration of either the recommended tiered dose of
approximately 6 mg/kg (see Label Table 1, section 4.2), a fixed
dose of 130 mg ustekinumab, or placebo at week 0.
[0510] Concomitant doses of oral corticosteroids, immunomodulators,
and aminosalicylates were permitted and 90% of patients continued
to receive at least one of these medications. Enrolled patients had
to have failed conventional therapy (corticosteroids or
immunomodulators) or at least one biologic (a TNF.alpha. antagonist
and/or vedolizumab). 49% of patients had failed conventional
therapy, but not a biologic (of which 94% where biological-naive).
51% of patients had failed or were intolerant to a biologic.
Approximately 50% of the patients had failed at least 1 prior
anti-TNF.alpha. therapy (of which 48% were primary non-responders)
and 17% had failed at least 1 anti-TNF.alpha. therapy and
vedolizumab.
[0511] In UNIFI-I a significantly greater proportion of patients
were in clinical remission in the ustekinumab treated group
compared to placebo at week 8 (Label Table 5). As early as Week 2,
the earliest scheduled study visit, and at each visit thereafter, a
higher proportion of ustekinumab patients had no rectal bleeding or
achieved normal stool frequency as compared with placebo patients.
Significant differences in partial Mayo score and symptomatic
remission were observed between ustekinumab and placebo as early as
Week 2.
[0512] Efficacy was higher in the tiered dose group (6 mg/kg)
compared to the 130 mg dose group in select endpoints, and tiered
dosing is therefore the recommended intravenous induction dose.
TABLE-US-00009 Label Table 5: Summary of Key Efficacy Outcomes in
UNIFI-I (Week 8) Recommended dose of Placebo
ustekinumab.sup..English Pound. N = 319 N = 322 Clinical Remission*
5% 16%.sup.a In patients who failed 9% (15/158) 19% (29/156).sup.c
conventional therapy, but not a biologic In patients who failed 1%
(2/161) 13% (21/166).sup.b biological therapy.sup. In patients who
failed both 0% (0/47) 10% (6/58).sup.c a TNF and vedolizumab
Clinical Response.sup..sctn. 31% 62%.sup.a In patients who failed
35% (56/158) 67% (104/156).sup.b conventional therapy, but not a
biologic In patients who failed 27% (44/161) 57% (95/166).sup.b
biological therapy.sup. In patients who failed both 28% (13/47) 52%
(30/58).sup.c a TNF and vedolizumab Mucosal Healing.sup..dagger.
14% 27%.sup.a In patients who failed 21% (33/158) 33%
(52/156).sup.c conventional therapy, but not a biologic In patients
who failed 7% (11/161) 21% (35/166).sup.b biological therapy
Symptomatic Remission.sup..dagger-dbl. 23% 45%.sup.b Combined
Symptomatic 8% 21%.sup.b Remission and Mucosal Healing
.sup..English Pound.Infusion dose of ustekimunab using the
weight-based dosage regimen specified in Label Table 1. *Clinical
remission is defined as Mayo score .ltoreq.2 points, with no
individual subscore > 1. .sup..sctn.Clinical response is defined
as a decrease from baseline in the Mayo score by .gtoreq.30% and
.gtoreq.3 points, with either a decrease from baseline in the
rectal bleeding subscore .gtoreq.1 ora rectal bleeding subscore of
0 or 1. .sup. A TNF.alpha. antagonist and/or vedolizumab.
.sup..dagger.Mucosal healing is defined as a Mayo endoscopic
subscore of 0 or 1. .sup..dagger-dbl.Symptomatic remission is
defined as a Mayo stool frequency subscore of 0 or 1 and a rectal
bleeding subscore of 0. Combined symptomatic remission and mucosal
healing is defined as a stool frequency subscore of 0 or 1, a
rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1.
.sup.ap < 0.001 .sup.bNominally significant (p < 0.001)
.sup.cNominally significant (p < 0.05)
[0513] UNIFI-M, evaluated 523 patients who achieved clinical
response with single IV administration of ustekinumab in UNIFI-I.
Patients were randomized to receive a subcutaneous maintenance
regimen of either 90 mg ustekinumab every 8 weeks, 90 mg
ustekinumab every 12 weeks or placebo for 44 weeks (for recommended
maintenance posology, see section 4.2 of the STELARA Solution for
injection (vial) and Solution for injection in pre filled syringe
SmPC).
[0514] Significantly greater proportions of patients were in
clinical remission in both ustekinumab treated groups compared to
the placebo group at week 44 (see Label Table 6).
TABLE-US-00010 Label Table 6: Summary of Key Efficacy Measures in
UNIFI-M (week 44; 52 weeks from initiation of the induction dose)
90 mg 90 mg ustekinumab ustekinumab every every Placebo* 8 Weeks 12
Weeks N = 175 N = 176 N = 172 Clinical 24% 44% .sup.a 38% .sup.b
Remission** In patients 31% (27/87) 48% (41/85).sup.d 49% (50/102)
.sup.d who failed conventional therapy, but not a biologic In
patients 17% (15/88) 40% (36/91) .sup.c 23% (16/70) .sup.d who
failed biological therapy.sup. In patients 15% (4/27) 33%
(7/21).sup.e 23% (5/22).sup.e who failed both a TNF and vedolizumab
Maintenance 45% 71% .sup.a 68% .sup.a of Clinical Response through
week 44.sup..sctn. In patients 51% (44/87) 78% (66/85) .sup.c 77%
(78/102) .sup.c who failed conventional therapy, but not a biologic
In patients 39% (34/88) 65% (59/91) .sup.c 56% (39/70) .sup.d who
failed biological therapy.sup. In patients 41% (11/27) 67%
(14/21).sup.e 50% (11/22).sup.e who failed both a TNF and
vedolizumab Mucosal 29% 51% .sup.a 44% .sup.b Healing.sup..dagger.
Maintenance 38% (17/45) 58% (22/38) 65% (26/40) .sup.c of Clinical
Remission through week 44.sup..English Pound. Corticosteroid 23%
42% .sup.a 38% .sup.b Free Clinical Remission.sup. Durable 35% 57%
.sup.c 48% .sup.d Remission.sup..parallel. Symptomatic 45% 68%
.sup.c 62% .sup.d Remission.sup..dagger-dbl. Combined 28% 48%
.sup.c 41% .sup.d Symptomatic Remission and Mucosal Healing
*Following response to IV ustekinumab. **Clinical remission is
defined as Mayo score .ltoreq.2 points, with no individual subscore
> 1. .sup..sctn.Clinical response is defined as a decrease from
baseline in the Mayo score by .gtoreq.30% and .gtoreq.3 points,
with either a decrease from baseline in the rectal bleeding
subscore .gtoreq.1 or a rectal bleeding subscore of 0 or 1. .sup. A
TNF.alpha. antagonist and/or vedolizumab. .sup..dagger.Mucosal
healing is defined as a Mayo endoscopic sub-score of 0 or 1.
.sup..English Pound.Maintenance of clinical remission through Week
44 is defined as patients in clinical remission through Week 44
among patients in clinical remission at maintenance baseline. .sup.
Corticosteroid-free clinical remission is defined as patients in
clinical remission and not receiving corticosteroids at Week 44.
.sup..parallel.Durable Remission is defined as partial Mayo
remission at .gtoreq.80% of all visits prior to Week 44 and in
partial Mayo remission at last visit (Week 44).
.sup..dagger-dbl.Symptomatic remission is defined as a Mayo stool
frequency subscore of 0 or 1 and a rectal bleeding subscore of 0.
Combined symptomatic remission and mucosal healing is defined as a
stool frequency subscore of 0 or 1, a rectal bleeding subscore of
0, and an endoscopy subscore of 0 or 1. .sup.a p < 0.001 .sup.b
p < 0.05 .sup.c Nominally significant (p < 0.001) .sup.d
Nominally significant (p < 0.05) .sup.eNot statistically
significant
[0515] The beneficial effect of ustekinumab on clinical response,
mucosal healing and clinical remission was observed in induction
and in maintenance both in patients who failed conventional therapy
but not a biologic therapy, as well as in those who had failed at
least one prior TNF.alpha. antagonist therapy including in patients
with a primary non-response to TNF.alpha. antagonist therapy. A
beneficial effect was also observed in induction in patients who
failed at least one prior TNF.alpha. antagonist therapy and
vedolizumab, however the number of patients in this subgroup was
too small to draw definitive conclusions about the beneficial
effect in this group during maintenance.
Week 16 Responders to Ustekinumab Induction
[0516] Ustekinumab treated patients who were not in response at
week 8 of UNIFI-I received an administration of 90 mg SC
ustekinumab at week 8 (36% of patients). Of those patients, 9% of
patients who were initially randomized to the recommended induction
dose achieved clinical remission and 58% achieved clinical response
at Week 16.
[0517] Patients who were not in clinical response to ustekinumab
induction at week 8 of the UNFI-I study but were in response at
week 16 (157 patients) entered into the non-randomized portion of
UNIFI-M and continued to receive maintenance dosing every 8 weeks;
among these patients, a majority (62%) maintained response and 30%
achieved remission at week 44.
Endoscopic Normalization
[0518] Endoscopic normalization was defined as a Mayo endoscopic
subscore of 0 and was observed as early as week 8 of UNIFI-I. At
week 44 of UNIFI-M, it was achieved in 24% and 29% of patients
treated with ustekinumab every 12 or 8 weeks, respectively, as
compared to 18% of patients in the placebo group.
Histologic & Histo Endoscopic Mucosal Healing
[0519] Histologic healing (defined as neutrophil infiltration in
<5% of crypts, no crypt destruction, and no erosions,
ulcerations, or granulation tissue) was assessed at week 8 of
UNIFI-I and Week 44 of UNIFI-M. At week 8, after a single
intravenous induction dose, significantly greater proportions of
patients in the recommended dose group achieved histologic healing
(36%) compared with patients in the placebo group (22%). At Week 44
maintenance of this effect was observed with significantly more
patients in histologic healing in the every 12 week (54%) and every
8 week (59%) ustekinumab groups as compared to placebo (33%).
[0520] A combined endpoint of histo-endoscopic mucosal healing
defined as subjects having both mucosal healing and histologic
healing was evaluated at week 8 of UNIFI-I and week 44 of UNIFI-M.
Patients receiving ustekinumab at the recommended dose showed
significant improvements on the histo-endoscopic mucosal healing
endpoint at week 8 in the ustekinumab group (18%) as compared to
the placebo group (9%). At week 44, maintenance of this effect was
observed with significantly more patients in histo-endoscopic
mucosal healing in the every 12 week (39%) and every 8 week (46%)
ustekinumab groups compared to placebo (24%).
Health-Related Quality of Life
[0521] Health-related quality of life was assessed by Inflammatory
Bowel Disease Questionnaire (IBDQ), SF-36 and EuroQoL-5D (EQ-5D)
questionnaires.
[0522] At week 8 of UNIFI-I, patients receiving ustekinumab showed
significantly greater and clinically meaningful improvements on
IBDQ total score, EQ-5D and EQ-5D VAS, and SF-36 Mental Component
Summary Score and SF-36 Physical Component Summary Score when
compared to placebo. These improvements were maintained in
ustekinumab-treated patients in UNIFI-M through week 44.
[0523] Patients receiving ustekinumab experienced significantly
more improvements in work productivity as assessed by greater
reductions in overall work impairment and in activity impairment as
assessed by the WPAI-GH questionnaire than patients receiving
placebo.
Hospitalizations and Ulcerative Colits (UC) Related Surgeries
[0524] Through week 8 of UNIFI-I, the proportions of subjects with
UC disease related hospitalizations were significantly lower for
subjects in the ustekinumab recommended dose group (1.6%, 5/322)
compared with subjects in the placebo group (4.4%, 14/319) and no
subjects underwent UC disease related surgeries in subjects
receiving ustekinumab at the recommended induction dose compared to
0.6% (2/319) subjects in the placebo group.
[0525] Through week 44 of UNIFI-M, a significantly lower number of
UC-related hospitalizations was observed in subjects in the
combined ustekinumab group (2.0%, 7/348) as compared with subjects
in the placebo group (5.7%, 10/175). A numerically lower number of
subjects in the ustekinumab group (0.6%, 2/348) underwent UC
disease related surgeries compared with subjects in the placebo
group (1.7%, 3/175) through week 44.
Immunogenicity
[0526] Antibodies to ustekinumab may develop during ustekinumab
treatment and most are neutralising. The formation of
anti-ustekinumab antibodies is associated with increased clearance
of ustekinumab in patients with Crohn's disease or ulcerative
colitis. No reduced efficacy was observed. There is no apparent
correlation between the presence of anti-ustekinumab antibodies and
the occurrence of injection site reactions.
Paediatric Population
[0527] The European Medicines Agency has deferred the obligation to
submit the results of studies with ustekinumab in one or more
subsets of the paediatric population in Crohn's Disease and
ulcerative colitis (see section 4.2 for information on paediatric
use).
5.2 Pharmacokinetic Properties
[0528] Following the recommended intravenous induction dose, median
peak serum ustekinumab concentration, observed 1 hour after the
infusion, was 126.1 .mu.g/mL in patients with Crohn's disease and
127.0 pg/mL in patients with ulcerative colitis.
Distribution
[0529] Median volume of distribution during the terminal phase (Vz)
following a single intravenous administration to patients with
psoriasis ranged from 57 to 83 mL/kg.
Biotransformation
[0530] The exact metabolic pathway for ustekinumab is unknown.
Elimination
[0531] Median systemic clearance (CL) following a single
intravenous administration to patients with psoriasis ranged from
1.99 to 2.34 mL/day/kg. Median half-life (t.sub.1/2) of ustekinumab
was approximately 3 weeks in patients with ulcerative colitis,
Crohn's disease, psoriasis and/or psoriatic arthritis, ranging from
15 to 32 days across all psoriasis and psoriatic arthritis
studies.
Dose Linearity
[0532] The systemic exposure of ustekinumab (C.sub.max and AUC)
increased in an approximately dose-proportional manner after a
single intravenous administration at doses ranging from 0.09 mg/kg
to 4.5 mg/kg.
Special Populations
[0533] No pharmacokinetic data are available in patients with
impaired renal or hepatic function.
[0534] No specific studies have been conducted with intravenous
ustekinumab in elderly or paediatric patients.
[0535] In patients with Crohn's disease and ulcerative colitis,
variability in ustekinumab clearance was affected by body weight,
serum albumin level, sex, and antibody to ustekinumab status while
body weight was the main covariate affecting the volume of
distribution. Additionally in Crohn's disease, clearance was
affected by C-reactive protein, TNF antagonist failure status and
race
[0536] (Asian versus non-Asian). The impact of these covariates was
within .+-.20% of the typical or reference value of the respective
PK parameter, thus dose adjustment is not warranted for these
covariates. Concomitant use of immunomodulators did not have a
significant impact on ustekinumab disposition.
Regulation of CYP450 Enzymes
[0537] The effects of IL-12 or IL-23 on the regulation of CYP450
enzymes were evaluated in an in vitro study using human
hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10
ng/mL did not alter human CYP450 enzyme activities (CYP1A2, 2B6,
2C9, 2C19, 2D6, or 3A4; see section 4.5).
5.3 Preclinical Safety Data
[0538] Non-clinical data reveal no special hazard (e.g. organ
toxicity) for humans based on studies of repeated-dose toxicity and
developmental and reproductive toxicity, including safety
pharmacology evaluations. In developmental and reproductive
toxicity studies in cynomolgus monkeys, neither adverse effects on
male fertility indices nor birth defects or developmental toxicity
were observed. No adverse effects on female fertility indices were
observed using an analogous antibody to IL-12/23 in mice.
[0539] Dose levels in animal studies were up to approximately
45-fold higher than the highest equivalent dose intended to be
administered to psoriasis patients and resulted in peak serum
concentrations in monkeys that were more than 100-fold higher than
observed in humans.
[0540] Carcinogenicity studies were not performed with ustekinumab
due to the lack of appropriate models for an antibody with no
cross-reactivity to rodent IL-12/23 p40.
6. Pharmaceutical Particulars
6.1 List of Excipients
[0541] EDTA disodium salt dihydrate
[0542] L-histidine
[0543] L-histidine monohydrochloride monohydrate
[0544] L-methionine
[0545] Polysorbate 80
[0546] Sucrose
[0547] Water for injection
6.2 Incompatibilities
[0548] In the absence of compatibility studies, this medicinal
product must not be mixed with other medicinal products. STELARA
should only be diluted with sodium chloride 9 mg/mL (0.9%)
solution. STELARA should not be administered concomitantly in the
same intravenous line with other medicinal products.
6.3 Shelf life
[0549] 3 years.
[0550] Do not freeze.
[0551] Chemical and physical in-use stability has been demonstrated
for 8 hours at 15-25.degree. C.
[0552] From a microbiological point of view, unless the method of
dilution precludes the risk of microbial contamination, the product
should be used immediately. If not used immediately, in-use storage
times and conditions are the responsibility of user.
6.4 Special Precautions for Storage
[0553] Store in a refrigerator (2.degree. C.-8.degree. C.). Do not
freeze.
[0554] Keep the vial in the outer carton in order to protect from
light.
[0555] For storage conditions after dilution of the medicinal
product, see section 6.3
6.5 Nature and Contents of Container
[0556] 26 mL solution in a type I glass 30 mL vial closed with a
coated butyl rubber stopper. STELARA is available in a 1 vial
pack.
6.6 Special Precautions for Disposal and Other Handling
[0557] The solution in the STELARA vial should not be shaken. The
solution should be visually inspected for particulate matter or
discoloration prior to administration. The solution is clear,
colourless to light yellow. The medicinal product should not be
used if the solution is discolored or cloudy, or if foreign
particulate matter is present.
Dilution
[0558] STELARA concentrate for solution for infusion must be
diluted and prepared by a healthcare professional using aseptic
technique. [0559] 1. Calculate the dose and the number of STELARA
vials needed based on patient weight (see section 4.2, Label Table
1). Each 26 mL vial of STELARA contains 130 mg of ustekinumab. Only
use complete vials of STELARA. [0560] 2. Withdraw and discard a
volume of the sodium chloride 9 mg/mL (0.9%) solution from the 250
mL infusion bag equal to the volume of STELARA to be added.
(discard 26 mL sodium chloride for each vial of STELARA needed, for
2 vials-discard 52 mL, for 3 vials-discard 78 mL, for 4
vials-discard 104 mL) [0561] 3. Withdraw 26 mL of STELARA from each
vial needed and add it to the 250 mL infusion bag. The final volume
in the infusion bag should be 250 mL. Gently mix. [0562] 4.
Visually inspect the diluted solution before administration. Do not
use if visibly opaque particles, discoloration or foreign particles
are observed. [0563] 5. Administer the diluted solution over a
period of at least one hour. Once diluted, the infusion should be
completed within eight hours of the dilution in the infusion bag.
[0564] 6. Use only an infusion set with an in-line, sterile,
non-pyrogenic, low protein-binding filter (pore size 0.2
micrometer). [0565] 7. Each vial is for single use only and any
unused medicinal product should be disposed of in accordance with
local requirements.
7. Marketing Authorisation Holder
[0566] Janssen-Cilag International NV
[0567] Turnhoutseweg 30
[0568] 2340 Beerse
[0569] Belgium
8. Marketing Authorisation Number(s)
[0570] EU/1/08/494/005
9. Date of First Authorisation/Renewal of the Authorisation
[0571] Date of first authorisation: 16 Jan. 2009
[0572] Date of latest renewal: 19 Sep. 2013
10. Date of Revision of the Text
[0573] Detailed information on this medicinal product is available
on the website of the European Medicines Agency
http://www.ema.europa.eu/.
1. Name of the Medicinal Product
[0574] STELARA 45 mg solution for injection
[0575] STELARA 90 mg solution for injection
[0576] STELARA 45 mg solution for injection in pre-filled
syringe
[0577] STELARA 90 mg solution for injection in pre-filled
syringe
2. Qualitative and Quantitative Composition
STELARA 45 mg Solution for Injection
[0578] Each vial contains 45 mg ustekinumab in 0.5 mL.
STELARA 90 mg Solution for Injection
[0579] Each vial contains 90 mg ustekinumab in 1 mL.
STELARA 45 mg Solution for Injection in Pre-Filled Syringe
[0580] Each pre-filled syringe contains 45 mg ustekinumab in 0.5
mL.
STELARA 90 mg Solution for Injection in Pre-Filled Syringe
[0581] Each pre-filled syringe contains 90 mg ustekinumab in 1
mL.
[0582] Ustekinumab is a fully human IgG1.kappa. monoclonal antibody
to interleukin (IL)-12/23 produced in a murine myeloma cell line
using recombinant DNA technology.
[0583] For the full list of excipients, see section 6.1.
3. Pharmaceutical Form
STELARA 45 mg Solution for Injection
[0584] Solution for injection.
STELARA 90 mg Solution for Injection
[0585] Solution for injection.
STELARA 45 mg Solution for Injection in Pre-Filled Syringe
[0586] Solution for injection.
STELARA 90 mg Solution for Injection in Pre-Filled Syringe
[0587] Solution for injection.
[0588] The solution is clear to slightly opalescent, colourless to
light yellow.
4. Clinical Particulars
4.1 Therapeutic Indications
Plaque Psoriasis
[0589] STELARA is indicated for the treatment of moderate to severe
plaque psoriasis in adults who failed to respond to, or who have a
contraindication to, or are intolerant to other systemic therapies
including ciclosporin, methotrexate (MTX) or PUVA (psoralen and
ultraviolet A) (see section 5.1).
Paediatric Plaque Psoriasis
[0590] STELARA is indicated for the treatment of moderate to severe
plaque psoriasis in adolescent patients from the age of 12 years
and older, who are inadequately controlled by, or are intolerant
to, other systemic therapies or phototherapies (see section
5.1).
Psoriatic Arthritis (PsA)
[0591] STELARA, alone or in combination with MTX, is indicated for
the treatment of active psoriatic arthritis in adult patients when
the response to previous non-biological disease-modifying
anti-rheumatic drug (DMARD) therapy has been inadequate (see
section 5.1).
Crohn's Disease
[0592] STELARA is indicated for the treatment of adult patients
with moderately to severely active Crohn's disease who have had an
inadequate response with, lost response to, or were intolerant to
either conventional therapy or a TNF.alpha. antagonist or have
medical contraindications to such therapies.
Ulcerative Colitis
[0593] STELARA is indicated for the treatment of adult patients
with moderately to severely active ulcerative colitis who have had
an inadequate response with, lost response to, or were intolerant
to either conventional therapy or a biologic or have medical
contraindications to such therapies (see section 5.1).
4.2 Posology and Method of Administration
[0594] STELARA is intended for use under the guidance and
supervision of physicians experienced in the diagnosis and
treatment of conditions for which STELARA is indicated.
Posology
Plaque Psoriasis
[0595] The recommended posology of STELARA is an initial dose of 45
mg administered subcutaneously, followed by a 45 mg dose 4 weeks
later, and then every 12 weeks thereafter.
[0596] Consideration should be given to discontinuing treatment in
patients who have shown no response up to 28 weeks of
treatment.
Patients with Body Weight >100 kg
[0597] For patients with a body weight >100 kg the initial dose
is 90 mg administered subcutaneously, followed by a 90 mg dose 4
weeks later, and then every 12 weeks thereafter. In these patients,
45 mg was also shown to be efficacious. However, 90 mg resulted in
greater efficacy. (see section 5.1, Label Table 4)
Psoriatic Arthritis (PsA)
[0598] The recommended posology of STELARA is an initial dose of 45
mg administered subcutaneously, followed by a 45 mg dose 4 weeks
later, and then every 12 weeks thereafter. Alternatively, 90 mg may
be used in patients with a body weight .gtoreq.100 kg.
[0599] Consideration should be given to discontinuing treatment in
patients who have shown no response up to 28 weeks of
treatment.
Elderly (.gtoreq.65 Years)
[0600] No dose adjustment is needed for elderly patients (see
section 4.4).
Renal and Hepatic Impairment
[0601] STELARA has not been studied in these patient populations.
No dose recommendations can be made.
Paediatric Population
[0602] The safety and efficacy of STELARA in children with
psoriasis less than 12 years of age or in children with psoriatic
arthritis less than 18 years of age have not yet been
established.
Paediatric Plaque Psoriasis (12 Years and Older)
[0603] The recommended dose of STELARA based on body weight is
shown below (Label Tables 1 and 2). STELARA should be administered
at Weeks 0 and 4, then every 12 weeks thereafter.
TABLE-US-00011 Label Table 1 Recommended dose of STELARA for
paediatric psoriasis Body weight at the time of dosing Recommended
Dose <60 kg 0.75 mg/kg.sup.a .gtoreq.60-.ltoreq.100 kg 45 mg
>100 kg 90 mg .sup.aTo calculate the volume of injection (mL)
for patients <60 kg, use the following formula: body weight (kg)
.times. 0.0083 (mL/kg) or see Label Table 2. The calculated volume
should be rounded to the nearest 0.01 mL and administered using a 1
mL graduated syringe. A 45 mg vial is available for paediatric
patients who need to receive less than the full 45 mg dose.
TABLE-US-00012 Label Table 2 Injection volumes of STELARA for
paediatric psoriasis patients <60 kg Body weight at time of
dosing Dose Volume of injection (kg) (mg) (mL) 30 22.5 0.25 31 23.3
0.26 32 24.0 0.27 33 24.8 0.27 34 25.5 0.28 35 26.3 0.29 36 27.0
0.30 37 27.8 0.31 38 28.5 0.32 39 29.3 0.32 40 30.0 0.33 41 30.8
0.34 42 31.5 0.35 43 32.3 0.36 44 33.0 0.37 45 33.8 0.37 46 34.5
0.38 47 35.3 0.39 48 36.0 0.40 49 36.8 0.41 50 37.5 0.42 51 38.3
0.42 52 39.0 0.43 53 39.8 0.44 54 40.5 0.45 55 41.3 0.46 56 42.0
0.46 57 42.8 0.47 58 43.5 0.48 59 44.3 0.49
[0604] Consideration should be given to discontinuing treatment in
patients who have shown no response up to 28 weeks of
treatment.
Crohn's Disease and Ulcerative Colitis
[0605] In the treatment regimen, the first dose of STELARA is
administered intravenously. For the posology of the intravenous
dosing regimen, see section 4.2 of the STELARA 130 mg Concentrate
for solution for infusion SmPC.
[0606] The first subcutaneous administration of 90 mg STELARA
should take place at week 8 after the intravenous dose. After this,
dosing every 12 weeks is recommended.
[0607] Patients who have not shown adequate response at 8 weeks
after the first subcutaneous dose, may receive a second
subcutaneous dose at this time (see section 5.1).
[0608] Patients who lose response on dosing every 12 weeks may
benefit from an increase in dosing frequency to every 8 weeks (see
section 5.1, section 5.2).
[0609] Patients may subsequently be dosed every 8 weeks or every 12
weeks according to clinical judgment (see section 5.1).
[0610] Consideration should be given to discontinuing treatment in
patients who show no evidence of therapeutic benefit 16 weeks after
the IV induction dose or 16 weeks after switching to the 8-weekly
maintenance dose.
[0611] Immunomodulators and/or corticosteroids may be continued
during treatment with STELARA. In patients who have responded to
treatment with STELARA, corticosteroids may be reduced or
discontinued in accordance with standard of care.
[0612] In Crohn's disease, if therapy is interrupted, resumption of
treatment with subcutaneous dosing every 8 weeks is safe and
effective.
Elderly (.gtoreq.65 Years)
[0613] No dose adjustment is needed for elderly patients (see
section 4.4).
Renal and Hepatic Impairment
[0614] STELARA has not been studied in these patient populations.
No dose recommendations can be made.
Paediatric Population
[0615] The safety and efficacy of STELARA in treatment of Crohn's
disease or ulcerative colitis in children less than 18 years have
not yet been established. No data are available.
Method of Administration
[0616] STELARA 45 mg and 90 mg vials or pre-filled syringes are for
subcutaneous injection only. If possible, areas of the skin that
show psoriasis should be avoided as injection sites.
[0617] After proper training in subcutaneous injection technique,
patients or their caregivers may inject STELARA if a physician
determines that it is appropriate. However, the physician should
ensure appropriate follow-up of patients. Patients or their
caregivers should be instructed to inject the prescribed amount of
STELARA according to the directions provided in the package
leaflet.
[0618] Comprehensive instructions for administration are given in
the package leaflet.
[0619] For further instructions on preparation and special
precautions for handling, see section 6.6.
4.3 Contraindications
[0620] Hypersensitivity to the active substance or to any of the
excipients listed in section 6.1.
[0621] Clinically important, active infection (e.g. active
tuberculosis; see section 4.4).
4.4 Special Warnings and Precautions for Use
Traceability
[0622] In order to improve the traceability of biological medicinal
products, the tradename and the batch number of the administered
product should be clearly recorded.
Infections
[0623] Ustekinumab may have the potential to increase the risk of
infections and reactivate latent infections. In clinical studies,
serious bacterial, fungal, and viral infections have been observed
in patients receiving STELARA (see section 4.8).
[0624] Caution should be exercised when considering the use of
STELARA in patients with a chronic infection or a history of
recurrent infection (see section 4.3).
[0625] Prior to initiating treatment with STELARA, patients should
be evaluated for tuberculosis infection. STELARA must not be given
to patients with active tuberculosis (see section 4.3). Treatment
of latent tuberculosis infection should be initiated prior to
administering STELARA. Anti-tuberculosis therapy should also be
considered prior to initiation of STELARA in patients with a
history of latent or active tuberculosis in whom an adequate course
of treatment cannot be confirmed. Patients receiving STELARA should
be monitored closely for signs and symptoms of active tuberculosis
during and after treatment.
[0626] Patients should be instructed to seek medical advice if
signs or symptoms suggestive of an infection occur. If a patient
develops a serious infection, the patient should be closely
monitored and STELARA should not be administered until the
infection resolves.
Malignancies
[0627] Immunosuppressants like ustekinumab have the potential to
increase the risk of malignancy. Some patients who received STELARA
in clinical studies developed cutaneous and non-cutaneous
malignancies (see section 4.8).
[0628] No studies have been conducted that include patients with a
history of malignancy or that continue treatment in patients who
develop malignancy while receiving STELARA. Thus, caution should be
exercised when considering the use of STELARA in these
patients.
[0629] All patients, in particular those greater than 60 years of
age, patients with a medical history of prolonged immunosuppressant
therapy or those with a history of PUVA treatment, should be
monitored for the appearance of non-melanoma skin cancer (see
section 4.8).
Systemic and Respiratory Hypersensitivity Reactions
Systemic
[0630] Serious hypersensitivity reactions have been reported in the
postmarketing setting, in some cases several days after treatment.
Anaphylaxis and angioedema have occurred. If an anaphylactic or
other serious hypersensitivity reaction occurs, appropriate therapy
should be instituted and administration of STELARA should be
discontinued (see section 4.8).
Respiratory
[0631] Cases of allergic alveolitis and eosinophilic pneumonia have
been reported during post-approval use of ustekinumab. Clinical
presentations included cough, dyspnoea, and interstitial
infiltrates following one to three doses. Serious outcomes have
included respiratory failure and prolonged hospitalisation.
Improvement has been reported after discontinuation of ustekinumab
and also, in some cases, administration of corticosteroids. If
infection has been excluded and diagnosis is confirmed, discontinue
ustekinumab and institute appropriate treatment (see section
4.8).
Latex Sensitivity
[0632] The needle cover on the syringe in the STELARA pre-filled
syringe is manufactured from dry natural rubber (a derivative of
latex), which may cause allergic reactions in individuals sensitive
to latex.
Vaccinations
[0633] It is recommended that live viral or live bacterial vaccines
(such as Bacillus of Calmette and Guerin (BCG)) should not be given
concurrently with STELARA. Specific studies have not been conducted
in patients who had recently received live viral or live bacterial
vaccines. No data are available on the secondary transmission of
infection by live vaccines in patients receiving STELARA. Before
live viral or live bacterial vaccination, treatment with STELARA
should be withheld for at least 15 weeks after the last dose and
can be resumed at least 2 weeks after vaccination. Prescribers
should consult the Summary of Product Characteristics for the
specific vaccine for additional information and guidance on
concomitant use of immunosuppressive agents post-vaccination.
[0634] Patients receiving STELARA may receive concurrent
inactivated or non-live vaccinations.
[0635] Long term treatment with STELARA does not suppress the
humoral immune response to pneumococcal polysaccharide or tetanus
vaccines (see section 5.1).
Concomitant Immunosuppressive Therapy
[0636] In psoriasis studies, the safety and efficacy of STELARA in
combination with immunosuppressants, including biologics, or
phototherapy have not been evaluated. In psoriatic arthritis
studies, concomitant MTX use did not appear to influence the safety
or efficacy of STELARA. In Crohn's disease and ulcerative colitis
studies, concomitant use of immunosuppressants or corticosteroids
did not appear to influence the safety or efficacy of STELARA.
Caution should be exercised when considering concomitant use of
other immunosuppressants and STELARA or when transitioning from
other immunosuppressive biologics (see section 4.5).
Immunotherapy
[0637] STELARA has not been evaluated in patients who have
undergone allergy immunotherapy. It is not known whether STELARA
may affect allergy immunotherapy.
Serious Skin Conditions
[0638] In patients with psoriasis, exfoliative dermatitis has been
reported following ustekinumab treatment (see section 4.8).
Patients with plaque psoriasis may develop erythrodermic psoriasis,
with symptoms that may be clinically indistinguishable from
exfoliative dermatitis, as part of the natural course of their
disease. As part of the monitoring of the patient's psoriasis,
physicians should be alert for symptoms of erythrodermic psoriasis
or exfoliative dermatitis. If these symptoms occur, appropriate
therapy should be instituted. STELARA should be discontinued if a
drug reaction is suspected.
Special Populations
Elderly (.gtoreq.65 Years)
[0639] No overall differences in efficacy or safety in patients age
65 and older who received STELARA were observed compared to younger
patients in clinical studies in approved indications, however the
number of patients aged 65 and older is not sufficient to determine
whether they respond differently from younger patients. Because
there is a higher incidence of infections in the elderly population
in general, caution should be used in treating the elderly.
4.5 Interaction with Other Medicinal Products and Other Forms of
Interaction
[0640] Live vaccines should not be given concurrently with STELARA
(see section 4.4).
[0641] No interaction studies have been performed in humans. In the
population pharmacokinetic analyses of the phase III studies, the
effect of the most frequently used concomitant medicinal products
in patients with psoriasis (including paracetamol, ibuprofen,
acetylsalicylic acid, metformin, atorvastatin, levothyroxine) on
pharmacokinetics of ustekinumab was explored. There were no
indications of an interaction with these concomitantly administered
medicinal products. The basis for this analysis was that at least
100 patients (>5% of the studied population) were treated
concomitantly with these medicinal products for at least 90% of the
study period. The pharmacokinetics of ustekinumab was not impacted
by concomitant use of MTX, NSAIDs, 6-mercaptopurine, azathioprine
and oral corticosteroids in patients with psoriatic arthritis,
Crohn's disease or ulcerative colitis, or prior exposure to
anti-TNF.alpha. agents, in patients with psoriatic arthritis or
Crohn's disease or by prior exposure to biologics (i.e.
anti-TNF.alpha. agents and/or vedolizumab) in patients with
ulcerative colitis.
[0642] The results of an in vitro study do not suggest the need for
dose adjustments in patients who are receiving concomitant CYP450
substrates (see section 5.2).
[0643] In psoriasis studies, the safety and efficacy of STELARA in
combination with immunosuppressants, including biologics, or
phototherapy have not been evaluated. In psoriatic arthritis
studies, concomitant MTX use did not appear to influence the safety
or efficacy of STELARA. In Crohn's disease and ulcerative colitis
studies, concomitant use of immunosuppressants or corticosteroids
did not appear to influence the safety or efficacy of STELARA. (see
section 4.4).
4.6 Fertility, Pregnancy and Lactation
Women of Childbearing Potential
[0644] Women of childbearing potential should use effective methods
of contraception during treatment and for at least 15 weeks after
treatment.
Pregnancy
[0645] There are no adequate data from the use of ustekinumab in
pregnant women. Animal studies do not indicate direct or indirect
harmful effects with respect to pregnancy, embryonic/foetal
development, parturition or postnatal development (see section
5.3). As a precautionary measure, it is preferable to avoid the use
of STELARA in pregnancy.
Breast-Feeding
[0646] It is unknown whether ustekinumab is excreted in human
breast milk. Animal studies have shown excretion of ustekinumab at
low levels in breast milk. It is not known if ustekinumab is
absorbed systemically after ingestion. Because of the potential for
adverse reactions in nursing infants from ustekinumab, a decision
on whether to discontinue breast-feeding during treatment and up to
15 weeks after treatment or to discontinue therapy with STELARA
must be made taking into account the benefit of breast-feeding to
the child and the benefit of STELARA therapy to the woman.
Fertility
[0647] The effect of ustekinumab on human fertility has not been
evaluated (see section 5.3).
4.7 Effects on Ability to Drive and Use Machines
[0648] STELARA has no or negligible influence on the ability to
drive and use machines.
4.8 Undesirable Effects
Summary of the Safety Profile
[0649] The most common adverse reactions (>5%) in controlled
periods of the adult psoriasis, psoriatic arthritis, Crohn's
disease and ulcerative colitis clinical studies with ustekinumab
were nasopharyngitis and headache. Most were considered to be mild
and did not necessitate discontinuation of study treatment. The
most serious adverse reaction that has been reported for STELARA is
serious hypersensitivity reactions including anaphylaxis (see
section 4.4). The overall safety profile was similar for patients
with psoriasis, psoriatic arthritis, Crohn's disease and ulcerative
colitis.
Tabulated List of Adverse Reactions
[0650] The safety data described below reflect exposure in adults
to ustekinumab in 14 phase 2 and phase 3 studies in 6,709 patients
(4,135 with psoriasis and/or psoriatic arthritis, 1,749 with
Crohn's disease and 825 patients with ulcerative colitis). This
includes exposure to STELARA in the controlled and non-controlled
periods of the clinical studies for at least 6 months or 1 year
(4,577 and 3,253 patients respectively with psoriasis, psoriatic
arthritis, Crohn's disease or ulcerative colitis) and exposure for
at least 4 or 5 years (1,482 and 838 patients with psoriasis
respectively).
[0651] Table 3 provides a list of adverse reactions from adult
psoriasis, psoriatic arthritis, Crohn's disease and ulcerative
colitis clinical studies as well as adverse reactions reported from
post-marketing experience. The adverse reactions are classified by
System Organ Class and frequency, using the following convention:
Very common (.gtoreq. 1/10), Common (.gtoreq. 1/100 to < 1/10),
Uncommon (.gtoreq. 1/1,000 to .ltoreq. 1/100), Rare (.gtoreq.
1/10,000 to < 1/1,000), Very rare (< 1/10,000), not known
(cannot be estimated from the available data). Within each
frequency grouping, adverse reactions are presented in order of
decreasing seriousness.
TABLE-US-00013 Label Table 3 List of adverse reactions System Organ
Class Frequency: Adverse reaction Infections and infestations
Common: Upper respiratory tract infection, nasopharyngitis,
sinusitis Uncommon: Cellulitis, dental infections, herpes zoster,
lower respiratory tract infection, viral upper respiratory tract
infection, vulvovaginal mycotic infection Immune system disorders
Uncommon: Hypersensitivity reactions (including rash, urticaria)
Rare: Serious hypersensitivity reactions (including anaphylaxis,
angioedema) Psychiatric disorders Uncommon: Depression Nervous
system disorders Common: Dizziness, headache Uncommon: Facial palsy
Respiratory, thoracic and Common: Oropharyngeal pain mediastinal
disorders Uncommon: Nasal congestion Rare: Allergic alveolitis,
eosinophilic pneumonia Gastrointestinal disorders Common:
Diarrhoea, nausea, vomiting Skin and subcutaneous Common: Pruritus
tissue disorders Uncommon: Pustular psoriasis, skin exfoliation,
acne Rare: Exfoliative dermatitis Musculoskeletal and Common: Back
pain, myalgia, arthralgia connective tissue disorders General
disorders and Common: Fatigue, injection site erythema,
administration site injection site pain conditions Uncommon:
Injection site reactions (including haemorrhage, haematoma,
induration, swelling and pruritus), asthenia
Description of Selected Adverse Reactions
Infections
[0652] In the placebo-controlled studies of patients with
psoriasis, psoriatic arthritis, Crohn's disease and ulcerative
colitis, the rates of infection or serious infection were similar
between ustekinumab-treated patients and those treated with
placebo. In the placebo-controlled period of these clinical
studies, the rate of infection was 1.36 per patient-year of
follow-up in ustekinumab-treated patients, and 1.34 in
placebo-treated patients. Serious infections occurred at the rate
of 0.03 per patient-year of follow-up in ustekinumab-treated
patients (30 serious infections in 930 patient-years of follow-up)
and 0.03 in placebo-treated patients (15 serious infections in 434
patient-years of follow-up) (see section 4.4).
[0653] In the controlled and non-controlled periods of psoriasis,
psoriatic arthritis, Crohn's disease and ulcerative colitis
clinical studies, representing 11,581 patient-years of exposure in
6,709 patients, the median follow up was 1.0 years; 1.1 years for
psoriatic disease studies, 0.6 year for Crohn's disease studies,
and 1.0 years for ulcerative colitis studies. The rate of infection
was 0.91 per patient-year of follow-up in ustekinumab-treated
patients, and the rate of serious infections was 0.02 per
patient-year of follow-up in ustekinumab-treated patients (199
serious infections in 11,581 patient-years of follow-up) and
serious infections reported included pneumonia, anal abscess,
cellulitis, diverticulitis, gastroenteritis and viral
infections.
[0654] In clinical studies, patients with latent tuberculosis who
were concurrently treated with isoniazid did not develop
tuberculosis.
Malignancies
[0655] In the placebo-controlled period of the psoriasis, psoriatic
arthritis, Crohn's disease and ulcerative colitis clinical studies,
the incidence of malignancies excluding non-melanoma skin cancer
was 0.11 per 100 patient-years of follow-up for ustekinumab-treated
patients (1 patient in 929 patient-years of follow-up) compared
with 0.23 for placebo-treated patients (1 patient in 434
patient-years of follow-up). The incidence of non-melanoma skin
cancer was 0.43 per 100 patient-years of follow-up for
ustekinumab-treated patients (4 patients in 929 patient-years of
follow-up) compared to 0.46 for placebo-treated patients (2
patients in 433 patient-years of follow-up).
[0656] In the controlled and non-controlled periods of psoriasis,
psoriatic arthritis, Crohn's disease and ulcerative colitis
clinical studies, representing 11,561 patient-years of exposure in
6,709 patients, the median follow-up was 1.0 years; 1.1 years for
psoriatic disease studies, 0.6 year for Crohn's disease studies and
1.0 years for ulcerative colitis studies. Malignancies excluding
non-melanoma skin cancers were reported in 62 patients in 11,561
patient-years of follow-up (incidence of 0.54 per 100 patient-years
of follow-up for ustekinumab-treated patients). The incidence of
malignancies reported in ustekinumab-treated patients was
comparable to the incidence expected in the general population
(standardised incidence ratio=0.93 [95% confidence interval: 0.71,
1.20], adjusted for age, gender and race). The most frequently
observed malignancies, other than non-melanoma skin cancer, were
prostate, colorectal, melanoma and breast cancers. The incidence of
non-melanoma skin cancer was 0.49 per 100 patient-years of
follow-up for ustekinumab-treated patients (56 patients in 11,545
patient-years of follow-up). The ratio of patients with basal
versus squamous cell skin cancers (3:1) is comparable with the
ratio expected in the general population (see section 4.4).
Hypersensitivity Reactions
[0657] During the controlled periods of the psoriasis and psoriatic
arthritis clinical studies of ustekinumab, rash and urticaria have
each been observed in .ltoreq.1% of patients (see section 4.4).
Paediatric Population
[0658] Undesirable effects in paediatric patients 12 years and
older with plaque psoriasis The safety of ustekinumab has been
studied in a phase 3 study of 110 patients from 12 to 17 years of
age for up to 60 weeks. In this study, the adverse events reported
were similar to those seen in previous studies in adults with
plaque psoriasis.
Reporting of Suspected Adverse Reactions
[0659] Reporting suspected adverse reactions after authorisation of
the medicinal product is important. It allows continued monitoring
of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions
via the national reporting system listed in Appendix V.
4.9 Overdose
[0660] Single doses up to 6 mg/kg have been administered
intravenously in clinical studies without dose-limiting toxicity.
In case of overdose, it is recommended that the patient be
monitored for any signs or symptoms of adverse reactions and
appropriate symptomatic treatment be instituted immediately.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
[0661] Pharmacotherapeutic group: Immunosuppressants, interleukin
inhibitors, ATC code: L04AC05.
Mechanism of Action
[0662] Ustekinumab is a fully human IgG1.kappa. monoclonal antibody
that binds with specificity to the shared p40 protein subunit of
human cytokines interleukin (IL)-12 and IL-23. Ustekinumab inhibits
the bioactivity of human IL-12 and IL-23 by preventing p40 from
binding to the IL-12R.beta.1 receptor protein expressed on the
surface of immune cells. Ustekinumab cannot bind to IL-12 or IL-23
that is already bound to IL-12R.beta.1 cell surface receptors.
Thus, ustekinumab is not likely to contribute to complement- or
antibody-mediated cytotoxicity of cells with IL-12 and/or IL-23
receptors. IL-12 and IL-23 are heterodimeric cytokines secreted by
activated antigen presenting cells, such as macrophages and
dendritic cells, and both cytokines participate in immune
functions; IL-12 stimulates natural killer (NK) cells and drives
the differentiation of CD4+ T cells toward the T helper 1 (Th1)
phenotype, IL-23 induces the T helper 17 (Th17) pathway. However,
abnormal regulation of IL 12 and IL 23 has been associated with
immune mediated diseases, such as psoriasis, psoriatic arthritis,
Crohn's disease and ulcerative colitis.
[0663] By binding the shared p40 subunit of IL-12 and IL-23,
ustekinumab may exert its clinical effects in psoriasis, psoriatic
arthritis, Crohn's disease and ulcerative colitis through
interruption of the Th1 and Th17 cytokine pathways, which are
central to the pathology of these diseases.
[0664] In patients with Crohn's disease and ulcerative colitis,
treatment with ustekinumab resulted in a decrease in inflammatory
markers including C-Reactive Protein (CRP) and fecal calprotectin
during the induction phase, which were then maintained throughout
the maintenance phase.
Immunisation
[0665] During the long term extension of Psoriasis Study 2 (PHOENIX
2), adult patients treated with STELARA for at least 3.5 years
mounted similar antibody responses to both pneumococcal
polysaccharide and tetanus vaccines as a non-systemically treated
psoriasis control group. Similar proportions of adult patients
developed protective levels of anti-pneumococcal and anti-tetanus
antibodies and antibody titers were similar among STELARA-treated
and control patients.
Clinical Efficacy
Plaque Psoriasis (Adults)
[0666] The safety and efficacy of ustekinumab was assessed in 1,996
patients in two randomised, double-blind, placebo-controlled
studies in patients with moderate to severe plaque psoriasis and
who were candidates for phototherapy or systemic therapy. In
addition, a randomised, blinded assessor, active-controlled study
compared ustekinumab and etanercept in patients with moderate to
severe plaque psoriasis who had had an inadequate response to,
intolerance to, or contraindication to ciclosporin, MTX, or
PUVA.
[0667] Psoriasis Study 1 (PHOENIX 1) evaluated 766 patients. 53% of
these patients were either non-responsive, intolerant, or had a
contraindication to other systemic therapy. Patients randomised to
ustekinumab received 45 mg or 90 mg doses at Weeks 0 and 4 and
followed by the same dose every 12 weeks. Patients randomised to
receive placebo at Weeks 0 and 4 crossed over to receive
ustekinumab (either 45 mg or 90 mg) at Weeks 12 and 16 followed by
dosing every 12 weeks. Patients originally randomised to
ustekinumab who achieved Psoriasis Area and Severity Index 75
response (PASI improvement of at least 75% relative to baseline) at
both
[0668] Weeks 28 and 40 were re-randomised to receive ustekinumab
every 12 weeks or to placebo (i.e., withdrawal of therapy).
Patients who were re-randomised to placebo at week 40 reinitiated
ustekinumab at their original dosing regimen when they experienced
at least a 50% loss of their PASI improvement obtained at week 40.
All patients were followed for up to 76 weeks following first
administration of study treatment.
[0669] Psoriasis Study 2 (PHOENIX 2) evaluated 1,230 patients. 61%
of these patients were either non-responsive, intolerant, or had a
contraindication to other systemic therapy. Patients randomised to
ustekinumab received 45 mg or 90 mg doses at Weeks 0 and 4 followed
by an additional dose at 16 weeks. Patients randomised to receive
placebo at Weeks 0 and 4 crossed over to receive ustekinumab
(either 45 mg or 90 mg) at Weeks 12 and 16. All patients were
followed for up to 52 weeks following first administration of study
treatment.
[0670] Psoriasis Study 3 (ACCEPT) evaluated 903 patients with
moderate to severe psoriasis who inadequately responded to, were
intolerant to, or had a contraindication to other systemic therapy
and compared the efficacy of ustekinumab to etanercept and
evaluated the safety of ustekinumab and etanercept. During the
12-week active-controlled portion of the study, patients were
randomised to receive etanercept (50 mg twice a week), ustekinumab
45 mg at Weeks 0 and 4, or ustekinumab 90 mg at Weeks 0 and 4.
[0671] Baseline disease characteristics were generally consistent
across all treatment groups in Psoriasis Studies 1 and 2 with a
median baseline PASI score from 17 to 18, median baseline Body
Surface Area (BSA).gtoreq.20, and median Dermatology Life Quality
Index (DLQI) range from 10 to 12. Approximately one third
(Psoriasis Study 1) and one quarter (Psoriasis Study 2) of subjects
had Psoriatic Arthritis (PsA). Similar disease severity was also
seen in Psoriasis Study 3.
[0672] The primary endpoint in these studies was the proportion of
patients who achieved PASI 75 response from baseline at week 12
(see Label Tables 4 and 5).
TABLE-US-00014 Label Table 4 Summary of clinical response in
Psoriasis Study 1 (PHOENIX 1) and Psoriasis Study 2 (PHOENIX 2)
Week 28 Week 12 3 doses (week 0, 2 doses (week 0 and week 4) week 4
and week 16) PBO 45 mg 90 mg 45 mg 90 mg Psoriasis Study 1 Number
of patients 255 255 256 250 243 randomised PASI 50 response N (%)
26 (10%) 213 (84%).sup.a 220 (86%).sup.a 228 (91%) 234 (96%) PASI
75 response N (%) 8 (3%) 171 (67%).sup.a 170 (66%).sup.a 178 (71%)
191 (79%) PASI 90 response N (%) 5 (2%) 106 (42%).sup.a 94
(37%).sup.a 123 (49%) 135 (56%) PGA.sup.b of cleared or 10 (4%) 151
(59%).sup.a 156 (61%).sup.a 146 (58%) 160 (66%) minimal N (%)
Number of patients 166 168 164 164 153 .ltoreq.100 kg PASI 75
response N 6 (4%) 124 (74%) 107 (65%) 130 (79%) 124 (81%) (%)
Number of patients 89 87 92 86 90 >100 kg PASI 75 response N 2
(2%) 47 (54%) 63 (68%) 48 (56%) 67 (74%) (%) Psoriasis Study 2
Number of patients 410 409 411 397 400 randomised PASI 50 response
N (%) 41 (10%) 342 (84%).sup.a 367 (89%).sup.a 369 (93%) 380 (95%)
PASI 75 response N (%) 15 (4%) 273 (67%).sup.a 311 (76%).sup.a 276
(70%) 314 (79%) PASI 90 response N (%) 3 (1%) 173 (42%).sup.a 209
(51%).sup.a 178 (45%) 217 (54%) PGA.sup.b of cleared or 18 (4%) 277
(68%).sup.a 300 (73%).sup.a 241 (61%) 279 (70%) minimal N (%)
Number of patients 290 297 289 287 280 .ltoreq.100 kg PASI 75
response N 12 (4%) 218 (73%) 225 (78%) 217 (76%) 226 (81%) (%)
Number of patients 120 112 121 110 119 >100 kg PASI 75 response
N 3 (3%) 55 (49%) 86 (71%) 59 (54%) 88 (74%) (%) .sup.ap < 0.001
for ustekinumab 45 mg or 90 mg in comparison with placebo (PBO).
.sup.bPGA = Physician Global Assessment
TABLE-US-00015 Label Table 5 Summary of clinical response at week
12 in Psoriasis Study 3 (ACCEPT) Psoriasis Study 3 Etanercept
Ustekinumab 24 doses 2 doses (50 mg twice (week 0 and week 4) a
week) 45 mg 90 mg Number of patients 347 209 347 randomised PASI 50
response 286 (82%) 181 (87%) 320 (92%).sup.a N (%) PASI 75 response
197 (57%) 141 (67%).sup.b 256 (74%).sup.a N (%) PASI 90 response 80
(23%) 76 (36%).sup.a 155 (45%).sup.a N (%) PGA of cleared or 170
(49%) 136 (65%).sup.a 245 (71%).sup.a minimal N (%) Number of
patients 251 151 244 .ltoreq.100 kg PASI 75 response 154 (61%) 109
(72%) 189 (77%) N (%) Number of patients 96 58 103 >100 kg PASI
75 response 43 (45%) 32 (55%) 67 (65%) N (%) .sup.ap < 0.001 for
ustekinumab 45 mg or 90 mg in comparison with etanercept. .sup.bp =
0.012 for ustekinumab 45 mg in comparison with etanercept.
[0673] In Psoriasis Study 1 maintenance of PASI 75 was
significantly superior with continuous treatment compared with
treatment withdrawal (p<0.001). Similar results were seen with
each dose of ustekinumab. At 1 year (week 52), 89% of patients
re-randomised to maintenance treatment were PASI 75 responders
compared with 63% of patients re-randomised to placebo (treatment
withdrawal) (p<0.001). At 18 months (week 76), 84% of patients
re-randomised to maintenance treatment were PASI 75 responders
compared with 19% of patients re-randomised to placebo (treatment
withdrawal). At 3 years (week 148), 82% of patients re-randomised
to maintenance treatment were PASI 75 responders. At 5 years (week
244), 80% of patients re-randomised to maintenance treatment were
PASI 75 responders.
[0674] In patients re-randomised to placebo, and who reinitiated
their original ustekinumab treatment regimen after loss of
.gtoreq.50% of PASI improvement 85% regained PASI 75 response
within 12 weeks after re-initiating therapy.
[0675] In Psoriasis Study 1, at week 2 and week 12, significantly
greater improvements from baseline were demonstrated in the DLQI in
each ustekinumab treatment group compared with placebo. The
improvement was sustained through week 28. Similarly, significant
improvements were seen in Psoriasis Study 2 at week 4 and 12, which
were sustained through week 24. In Psoriasis Study 1, improvements
in nail psoriasis (Nail Psoriasis Severity Index), in the physical
and mental component summary scores of the SF-36 and in the Itch
Visual Analogue Scale (VAS) were also significant in each
ustekinumab treatment group compared with placebo. In Psoriasis
Study 2, the Hospital Anxiety and Depression Scale (HADS) and Work
Limitations Questionnaire (WLQ) were also significantly improved in
each ustekinumab treatment group compared with placebo.
[0676] Psoriatic arthritis (PsA) (Adults) Ustekinumab has been
shown to improve signs and symptoms, physical function and
health-related quality of life, and reduce the rate of progression
of peripheral joint damage in adult patients with active PsA.
[0677] The safety and efficacy of ustekinumab was assessed in 927
patients in two randomised, double-blind, placebo-controlled
studies in patients with active PsA (.gtoreq.5 swollen joints and
.gtoreq.5 tender joints) despite non-steroidal anti-inflammatory
(NSAID) or disease modifying antirheumatic (DMARD) therapy.
Patients in these studies had a diagnosis of PsA for at least 6
months. Patients with each subtype of PsA were enrolled, including
polyarticular arthritis with no evidence of rheumatoid nodules
(39%), spondylitis with peripheral arthritis (28%), asymmetric
peripheral arthritis (21%), distal interphalangeal involvement
(12%) and arthritis mutilans (0.5%). Over 70% and 40% of the
patients in both studies had enthesitis and dactylitis at baseline,
respectively. Patients were randomised to receive treatment with
ustekinumab 45 mg, 90 mg, or placebo subcutaneously at Weeks 0 and
4 followed by every 12 weeks (q12w) dosing. Approximately 50% of
patients continued on stable doses of MTX (.ltoreq.25 mg/week).
[0678] In PsA Study 1 (PSUMMIT I) and PsA Study 2 (PSUMMIT II), 80%
and 86% of the patients, respectively, had been previously treated
with DMARDs. In Study 1 previous treatment with anti-tumour
necrosis factor (TNF).alpha. agent was not allowed. In Study 2, the
majority of patients (58%, n=180) had been previously treated with
one or more anti-TNF.alpha. agent(s), of whom over 70% had
discontinued their anti-TNF.alpha. treatment for lack of efficacy
or intolerance at any time.
Signs and Symptoms
[0679] Treatment with ustekinumab resulted in significant
improvements in the measures of disease activity compared to
placebo at week 24. The primary endpoint was the percentage of
patients who achieved American College of Rheumatology (ACR) 20
response at week 24. The key efficacy results are shown in Label
Table 6 below.
TABLE-US-00016 Label Table 6 Number of patients who achieved
clinical response in Psoriatic arthritis Study 1 (PSUMMIT I) and
Study 2 (PSUMMIT II) at week 24 Psoriatic arthritis Study 1
Psoriatic arthritis Study 2 PBO 45 mg 90 mg PBO 45 mg 90 mg Number
of 206 205 204 104 103 105 patients randomised ACR 20 47 (23%) 87
(42%).sup.a 101 (50%).sup.a 21 (20%) 45 (44%).sup.a 46 (44%).sup.a
response, N (%) ACR 50 18 (9%) 51 (25%).sup.a 57 (28%).sup.a 7 (7%)
18 (17%).sup.b 24 (23%).sup.a response, N (%) ACR 70 5 (2%) 25
(12%).sup.a 29 (14%).sup.a 3 (3%) 7 (7%).sup.c 9 (9%).sup.c
response, N (%) Number of patients 146 145 149 80 80 81 with
.gtoreq.3% BSA.sup.d PASI 75 16 (11%) 83 (57%).sup.a 93 (62%).sup.a
4 (5%) 41 (51%).sup.a 45 (56%).sup.a response, N (%) PASI 90 4 (3%)
60 (41%).sup.a 65 (44%).sup.a 3 (4%) 24 (30%).sup.a 36 (44%).sup.a
response, N (%) Combined 8 (5%) 40 (28%).sup.a 62 (42%).sup.a 2
(3%) 24 (30%).sup.a 31 (38%).sup.a PASI 75 and ACR 20 response, N
(%) Number of 154 153 154 74 74 73 patients .ltoreq.100 kg ACR 20
39 (25%) 67 (44%) 78 (51%) 17 (23%) 32 (43%) 34 (47%) response, N
(%) Number of patients 105 105 111 54 58 57 with .gtoreq.3%
BSA.sup.d PASI 75 14 (13%) 64 (61%) 73 (66%) 4 (7%) 31 (53%) 32
(56%) response, N (%) Number of 52 52 50 30 29 31 patients >100
kg ACR 20 8 (15%) 20 (38%) 23 (46%) 4 (13%) 13 (45%) 12 (39%)
response, N (%) Number of patients 41 40 38 26 22 24 with
.gtoreq.3% BSA.sup.d PASI 75 2 (5%) 19 (48%) 20 (53%) 0 10 (45%) 13
(54%) response, N (%) .sup.ap <0.001 .sup.bp <0.05 .sup.cp =
NS .sup.dNumber of patients with .gtoreq.3% BSA psoriasis skin
involvement at baseline
[0680] ACR 20, 50 and 70 responses continued to improve or were
maintained through week 52 (PsA Study 1 and 2) and week 100 (PsA
Study 1). In PsA Study 1, ACR 20 responses at week 100 were
achieved by 57% and 64%, for 45 mg and 90 mg, respectively. In PsA
Study 2, ACR 20 responses at week 52 were achieved by 47% and 48%,
for 45 mg and 90 mg, respectively.
[0681] The proportion of patients achieving a modified PsA response
criteria (PsARC) response was also significantly greater in the
ustekinumab groups compared to placebo at week 24. PsARC responses
were maintained through weeks 52 and 100. A higher proportion of
patients treated with ustekinumab who had spondylitis with
peripheral arthritis as their primary presentation, demonstrated 50
and 70 percent improvement in Bath Ankylosing Spondylitis Disease
Activity Index (BASDAI) scores compared with placebo at week
24.
[0682] Responses observed in the ustekinumab treated groups were
similar in patients receiving and not receiving concomitant MTX,
and were maintained through weeks 52 and 100. Patients previously
treated with anti-TNF.alpha. agents who received ustekinumab
achieved a greater response at week 24 than patients receiving
placebo (ACR 20 response at week 24 for 45 mg and 90 mg was 37% and
34%, respectively, compared with placebo 15%; p<0.05), and
responses were maintained through week 52.
[0683] For patients with enthesitis and/or dactylitis at baseline,
in PsA Study 1 significant improvement in enthesitis and dactylitis
score was observed in the ustekinumab groups compared with placebo
at week 24. In PsA Study 2 significant improvement in enthesitis
score and numerical improvement (not statistically significant) in
dactylitis score was observed in the ustekinumab 90 mg group
compared with placebo at week 24. Improvements in enthesitis score
and dactylitis score were maintained through weeks 52 and 100.
Radiographic Response
[0684] Structural damage in both hands and feet was expressed as
change in total van der Heijde-Sharp score (vdH-S score), modified
for PsA by addition of hand distal interphalangeal joints, compared
to baseline. A pre-specified integrated analysis combining data
from 927 subjects in both PsA Study 1 and 2 was performed.
Ustekinumab demonstrated a statistically significant decrease in
the rate of progression of structural damage compared to placebo,
as measured by change from baseline to week 24 in the total
modified vdH-S score (mean.+-.SD score was 0.97.+-.3.85 in the
placebo group compared with 0.40.+-.2.11 and 0.39.+-.2.40 in the
ustekinumab 45 mg (p<0.05) and 90 mg (p<0.001) groups,
respectively). This effect was driven by PsA Study 1. The effect is
considered demonstrated irrespective of concomitant MTX use, and
was maintained through Weeks 52 (integrated analysis) and 100 (PsA
Study 1).
Physical Function and Health-Related Quality of Life
[0685] Ustekinumab-treated patients showed significant improvement
in physical function as assessed by the Disability Index of the
Health Assessment Questionnaire (HAQ-DI) at week 24. The proportion
of patients achieving a clinically meaningful .gtoreq.0.3
improvement in HAQ-DI score from baseline was also significantly
greater in the ustekinumab groups when compared with placebo.
Improvement in HAQ-DI score from baseline was maintained through
Weeks 52 and 100.
[0686] There was significant improvement in DLQI scores in the
ustekinumab groups as compared with placebo at week 24, which was
maintained through weeks 52 and 100. In PsA Study 2 there was a
significant improvement in Functional Assessment of Chronic Illness
Therapy-Fatigue (FACIT-F) scores in the ustekinumab groups when
compared with placebo at week 24. The proportion of patients
achieving a clinically significant improvement in fatigue (4 points
in FACIT-F) was also significantly greater in the ustekinumab
groups compared with placebo. Improvements in FACIT scores were
maintained through week 52.
Paediatric Population
[0687] The European Medicines Agency has deferred the obligation to
submit the results of studies with ustekinumab in one or more
subsets of the paediatric population aged 6 to 11 years in moderate
to severe plaque psoriasis and juvenile idiopathic arthritis (see
section 4.2 for information on paediatric use).
Paediatric Plaque Psoriasis
[0688] Ustekinumab has been shown to improve signs and symptoms,
and health related quality of life in paediatric patients 12 years
and older with plaque psoriasis.
[0689] The efficacy of ustekinumab was studied in 110 paediatric
patients aged 12 to 17 years with moderate to severe plaque
psoriasis in a multicenter, Phase 3, randomised, double blind,
placebo controlled study (CADMUS). Patients were randomised to
receive either placebo (n=37), or the recommended dose of
ustekinumab (see section 4.2; n=36) or half of the recommended dose
of ustekinumab (n=37) by subcutaneous injection at Weeks 0 and 4
followed by every 12 week (q12w) dosing. At week 12, placebo
treated patients crossed over to receive ustekinumab.
[0690] Patients with PASI .gtoreq.12, PGA .gtoreq.3 and BSA
involvement of at least 10%, who were candidates for systemic
therapy or phototherapy, were eligible for the study. Approximately
60% of the patients had prior exposure to conventional systemic
therapy or phototherapy. Approximately 11% of the patients had
prior exposure to biologics.
[0691] The primary endpoint was the proportion of patients who
achieve a PGA score of cleared (0) or minimal (1) at week 12.
Secondary endpoints included PASI 75, PASI 90, change from baseline
in Children's Dermatology Life Quality Index (CDLQI), change from
baseline in the total scale score of PedsQL (Paediatric Quality of
Life Inventory) at week 12. At week 12, subjects treated with
ustekinumab showed significantly greater improvement in their
psoriasis and health related quality of life compared with placebo
(Table 7).
[0692] All patients were followed for efficacy for up to 52 weeks
following first administration of study agent. The proportion of
patients with a PGA score of cleared (0) or minimal (1) and the
proportion achieving PASI 75 showed separation between the
ustekinumab treated group and placebo at the first post-baseline
visit at week 4, reaching a maximum by week 12.
[0693] Improvements in PGA, PASI, CDLQI and PedsQL were maintained
through week 52 (Label Table 7).
TABLE-US-00017 Label Table 7 Summary of primary and secondary
endpoints at week 12 and week 52 Paediatric Dsoriasis studv
(CADMUS) Week 12 Week 52 Recommended Recommended dose of dose of
Placebo Ustekinumab Ustekinumab N (%) N (%) N (%) Patients 37 36 35
randomised PGA PGA of 2 (5.4%) 25 (69.4%).sup.a 20 (57.1%) cleared
(0) or minimal (1) PGA of 1 (2.7%) 17 (47.2%).sup.a 13 (37.1%)
Cleared (0) PASI PASI 75 4 (10.8%) 29 (80.6%).sup.a 28 (80.0%)
responders PASI 90 2 (5.4%) 22 (61.1%).sup.a 23 (65.7%) responders
PASI 100 1 (2.7%) 14 (38.9%).sup.a 13 (37.1%) responders CDLQI
CDLQI of 6 (16.2%) 18 (50.0%).sup.c 20 (57.1%) 0 or 1.sup.b PedsQL
Change from 3.35 (10.04) 8.03 (10.44).sup.e 7.26 (10.92) baseline
Mean (SD).sup.d .sup.ap < 0.001 .sup.bCDLQI: The CDLQI is a
dermatology instrument to assess the effect of a skin problem on
the health-related quality of life in the paediatric population.
CDLQI of 0 or 1 indicates no effect on child's quality of life.
.sup.cp = 0.002 .sup.dPedsQL: The PedsQL Total Scale Score is a
general health-related quality of life measure developed for use in
children and adolescent populations. For the placebo group at week
12, N = 36 .sup.cp = 0.028
[0694] During the placebo controlled period through week 12, the
efficacy of both the recommended and half of the recommended dose
groups were generally comparable at the primary endpoint (69.4% and
67.6% respectively) although there was evidence of a dose response
for higher level efficacy criteria (e.g. PGA of cleared (0), PASI
90). Beyond week 12, efficacy was generally higher and better
sustained in the recommended dose group compared with half of the
recommended dosage group in which a modest loss of efficacy was
more frequently observed toward the end of each 12 week dosing
interval. The safety profiles of the recommended dose and half of
the recommended dose were comparable.
Crohn's Disease
[0695] The safety and efficacy of ustekinumab was assessed in three
randomized, double-blind, placebo-controlled, multicenter studies
in adult patients with moderately to severely active Crohn's
disease (Crohn's Disease Activity Index [CDAI] score of .gtoreq.220
and .ltoreq.450). The clinical development program consisted of two
8-week intravenous induction studies (UNITI-1 and UNITI-2) followed
by a 44 week subcutaneous randomized withdrawal maintenance study
(IM-UNITI) representing 52 weeks of therapy.
[0696] The induction studies included 1409 (UNITI-1, n=769; UNITI-2
n=640) patients. The primary endpoint for both induction studies
was the proportion of subjects in clinical response (defined as a
reduction in CDAI score of .gtoreq.100 points) at week 6. Efficacy
data were collected and analyzed through week 8 for both studies.
Concomitant doses of oral corticosteroids, immunomodulators,
aminosalicylates and antibiotics were permitted and 75% of patients
continued to receive at least one of these medications. In both
studies, patients were randomised to receive a single intravenous
administration of either the recommended tiered dose of
approximately 6 mg/kg (see section 4.2 of the STELARA 130 mg
Concentrate for solution for infusion SmPC), a fixed dose of 130 mg
ustekinumab, or placebo at week 0.
[0697] Patients in UNITI-1 had failed or were intolerant to prior
anti-TNF.alpha. therapy. Approximately 48% of the patients had
failed 1 prior anti-TNF.alpha. therapy and 52% had failed 2 or 3
prior anti-TNF.alpha. therapies. In this study, 29.1% of the
patients had an inadequate initial response (primary
non-responders), 69.4% responded but lost response (secondary
non-responders), and 36.4% were intolerant to anti-TNF.alpha.
therapies.
[0698] Patients in UNITI-2 had failed at least one conventional
therapy, including corticosteroids or immunomodulators, and were
either anti-TNF-.alpha. naive (68.6%) or had previously received
but not failed anti-TNF.alpha. therapy (31.4%).
[0699] In both UNITI-1 and UNITI-2, a significantly greater
proportion of patients were in clinical response and remission in
the ustekinumab treated group compared to placebo (Label Table 8).
Clinical response and remission were significant as early as week 3
in ustekinumab treated patients and continued to improve through
week 8. In these induction studies, efficacy was higher and better
sustained in the tiered dose group compared to the 130 mg dose
group, and tiered dosing is therefore the recommended intravenous
induction dose.
TABLE-US-00018 Label Table 8: Induction of Clinical Response and
Remission in UNITI-1 and UNITI 2 UNITI-1* UNITI-2** Recommended
Recommended dose of dose of Placebo ustekinumab Placebo ustekinumab
N = 247 N = 249 N = 209 N = 209 Clinical Remission, 18 (7.3%) 52
(20.9%).sup.a 41 (19.6%) 84 (40.2%).sup.a week 8 Clinical Response
53 (21.5%) 84 (33.7%).sup.b 60 (28.7%) 116 (55.5%).sup.a (100
point), week 6 Clinical Response 50 (20.2%) 94 (37.8%).sup.a 67
(32.1%) 121 (57.9%).sup.a (100 point), week 8 70 Point Response, 67
(27.1%) 101 (40.6%).sup.b 66 (31.6%) 106 (50.7%).sup.a week 3 70
Point Response, 75 (30.4%) 109 (43.8%).sup.b 81 (38.8%) 135
(64.6%).sup.a week 6 Clinical remission is defined as CDAI score
< 150; Clinical response is defined as reduction in CDAI score
by at least 100 points or being in clinical remission 70 point
response is defined as reduction in CDAI score by at least 70
points *Anti-TNF.alpha. failures **Conventional therapy failures
.sup.ap < 0.001 .sup.bp < 0.01
[0700] The maintenance study (IM-UNITI), evaluated 388 patients who
achieved 100 point clinical response at week 8 of induction with
ustekinumab in studies UNITI-1 and UNITI-2. Patients were
randomized to receive a subcutaneous maintenance regimen of either
90 mg ustekinumab every 8 weeks, 90 mg ustekinumab every 12 weeks
or placebo for 44 weeks (for recommended maintenance posology, see
section 4.2).
[0701] Significantly higher proportions of patients maintained
clinical remission and response in the ustekinumab treated groups
compared to the placebo group at week 44 (see Label Table 9).
TABLE-US-00019 Label Table 9: Maintenance of Clinical Response and
Remission in IM-UNITI (week 44; 52 weeks from initiation of the
induction dose) 90 mg 90 mg ustekinumab ustekinumab every every
Placebo* 8 weeks 12 weeks N = 131.sup..dagger. N = 128.sup..dagger.
N = 129.sup..dagger. Clinical Remission 36% 53%.sup.a 49%.sup.b
Clinical Response 44% 59%.sup.b 58%.sup.b Corticosteroid-Free 30%
47%.sup.a 43%.sup.c Clinical Remission Clinical Remission in
patients: in remission at the 46% (36/79) 67% (52/78).sup.a 56%
(44/78) start of maintenance therapy who entered from 44% (31/70)
63% (45/72).sup.c 57% (41/72) study CRD3002.sup..dagger-dbl. who
are Anti-TNF.alpha. 49% (25/51) 65% (34/52).sup.c 57% (30/53) naive
who entered from 26% (16/61) 41% (23/56) 39% (22/57) study
CRD3001.sup..sctn. Clinical remission is defined as CDAI score <
150; Clinical response is defined as reduction in CDAI of at least
100 points or being in clinical remission *The placebo group
consisted of patients who were in response to ustekinumab and were
randomized to receive placebo at the start of maintenance therapy.
.sup..dagger.Patients who were in 100 point clinical response to
ustekinumab at start of maintenance therapy
.sup..dagger-dbl.Patients who failed conventional therapy but not
anti-TNF.alpha. therapy .sup..sctn.Patients who are anti-TNF.alpha.
refractory/intolerant .sup.ap < 0.01 .sup.bp < 0.05
.sup.cnominally significant (p < 0.05)
[0702] In IM-UNITI, 29 of 129 patients did not maintain response to
ustekinumab when treated every 12 weeks and were allowed to dose
adjust to receive ustekinumab every 8 weeks. Loss of response was
defined as a CDAI score .gtoreq.220 points and a .gtoreq.100 point
increase from the CDAI score at baseline. In these patients,
clinical remission was achieved in 41.4% of patients 16 weeks after
dose adjustment.
[0703] Patients who were not in clinical response to ustekinumab
induction at week 8 of the UNITI-1 and UNITI-2 induction studies
(476 patients) entered into the non-randomized portion of the
maintenance study (IM-UNITI) and received a 90 mg subcutaneous
injection of ustekinumab at that time. Eight weeks later, 50.5% of
the patients achieved clinical response and continued to receive
maintenance dosing every 8 weeks; among these patients with
continued maintenance dosing, a majority maintained response
(68.1%) and achieved remission (50.2%) at week 44, at proportions
that were similar to the patients who initially responded to
ustekinumab induction.
[0704] Of 131 patients who responded to ustekinumab induction, and
were randomized to the placebo group at the start of the
maintenance study, 51 subsequently lost response and received 90 mg
ustekinumab subcutaneously every 8 weeks. The majority of patients
who lost response and resumed ustekinumab did so within 24 weeks of
the induction infusion. Of these 51 patients, 70.6% achieved
clinical response and 39.2% percent achieved clinical remission 16
weeks after receiving the first subcutaneous dose of
ustekinumab.
[0705] In IM-UNITI, patients who completed the study through week
44 were eligible to continue treatment in a study extension. Among
patients who entered the study extension, clinical remission and
response were generally maintained through week 92 for both
patients who failed TNF-therapies and those who failed conventional
therapies.
[0706] No new safety concerns were identified in this study
extension with up to 2 years of treatment in patients with Crohn's
Disease.
Endoscopy
[0707] Endoscopic appearance of the mucosa was evaluated in 252
patients with eligible baseline endoscopic disease activity in a
substudy. The primary endpoint was change from baseline in
Simplified Endoscopic Disease Severity Score for Crohn's Disease
(SES-CD), a composite score across 5 ileo-colonic segments of
presence/size of ulcers, proportion of mucosal surface covered by
ulcers, proportion of mucosal surface affected by any other lesions
and presence/type of narrowing/strictures. At week 8, after a
single intravenous induction dose, the change in SES-CD score was
greater in the ustekinumab group (n=155, mean change=-2.8) than in
the placebo group (n=97, mean change=-0.7, p=0.012).
Fistula Response
[0708] In a subgroup of patients with draining fistulas at baseline
(8.8%; n=26), 12/15 (80%) of ustekinumab-treated patients achieved
a fistula response over 44 weeks (defined as .gtoreq.50% reduction
from baseline of the induction study in the number of draining
fistulas) compared to 5/11 (45.5%) exposed to placebo.
Health-Related Quality of Life
[0709] Health-related quality of life was assessed by Inflammatory
Bowel Disease Questionnaire (IBDQ) and SF-36 questionnaires. At
week 8, patients receiving ustekinumab showed statistically
significantly greater and clinically meaningful improvements on
IBDQ total score and SF-36 Mental Component Summary Score in both
UNITI-1 and UNITI-2, and SF-36 Physical Component Summary Score in
UNITI-2, when compared to placebo. These improvements were
generally better maintained in ustekinumab-treated patients in the
IM-UNITI study through week 44 when compared to placebo.
Improvement in health-related quality of life was generally
maintained during the extension through week 92.
Ulcerative Colitis
[0710] The safety and efficacy of ustekinumab was assessed in two
randomized, double-blind, placebo-controlled, multicenter studies
in adult patients with moderately to severely active ulcerative
colitis (Mayo score 6 to 12; Endoscopy subscore .gtoreq.2). The
clinical development program consisted of one intravenous induction
study (referred to as UNIFI-I) with treatment of up to 16 weeks
followed by a 44 week subcutaneous randomized withdrawal
maintenance study (referred to as UNIFI-M) representing at least 52
weeks of therapy.
[0711] Efficacy results presented for UNIFI-I and UNIFI-M were
based on central review of endoscopies.
[0712] UNIFI-I included 961 patients. The primary endpoint for the
induction study was the proportion of subjects in clinical
remission at week 8. Patients were randomised to receive a single
intravenous administration of either the recommended tiered dose of
approximately 6 mg/kg (see Label Table 1, section 4.2), a fixed
dose of 130 mg ustekinumab, or placebo at week 0.
[0713] Concomitant doses of oral corticosteroids, immunomodulators,
and aminosalicylates were permitted and 90% of patients continued
to receive at least one of these medications. Enrolled patients had
to have failed conventional therapy (corticosteroids or
immunomodulators) or at least one biologic (a TNF.alpha. antagonist
and/or vedolizumab). 49% of patients had failed conventional
therapy, but not a biologic (of which 94% where biological-naive).
51% of patients had failed or were intolerant to a biologic.
Approximately 50% of the patients had failed at least 1 prior
anti-TNF.alpha. therapy (of which 48% were primary non-responders)
and 17% had failed at least 1 anti-TNF.alpha. therapy and
vedolizumab.
[0714] In UNIFI-I a significantly greater proportion of patients
were in clinical remission in the ustekinumab treated group
compared to placebo at week 8 (Label Table 10). As early as Week 2,
the earliest scheduled study visit, and at each visit thereafter, a
higher proportion of ustekinumab patients had no rectal bleeding or
achieved normal stool frequency as compared with placebo patients.
Significant differences in partial Mayo score and symptomatic
remission were observed between ustekinumab and placebo as early as
Week 2.
[0715] Efficacy was higher in the tiered dose group (6 mg/kg)
compared to the 130 mg dose group in select endpoints, and tiered
dosing is therefore the recommended intravenous induction dose.
TABLE-US-00020 Label Table 10: Summary of Key Efficacy Outcomes in
UNIFI-1 (Week 8) Recommended dose of Placebo
ustekinumab.sup..English Pound. N = 319 N = 322 Clinical Remission*
5% 16%.sup.a In patients who failed 9% (15/158) 19% (29/156).sup.c
conventional therapy, but not a biologic In patients who failed 1%
(2/161) 13% (21/166).sup.b biological therapy.sup. In patients who
failed 0% (0/47) 10% (6/58%).sup.c both a TNF and vedolizumab
Clinical Response.sup..sctn. 31% 62%.sup.a In patients who failed
35% (56/158) 67% (104/156).sup.b conventional therapy, but not a
biologic In patients who failed 27% (44/161) 57% (95/166).sup.b
biological therapy.sup. In patients who failed 28% (13/47) 52%
(30/58).sup.c both a TNF and vedolizumab Mucosal
Healing.sup..dagger. 14% 27%.sup.a In patients who failed 21%
(33/158) 33% (52/156).sup.c conventional therapy, but not a
biologic In patients who failed 7% (11/161) 21% (35/166).sup.b
biological therapy Symptomatic Remission.sup..dagger-dbl. 23%
45%.sup.b Combined Symptomatic 8% 21%.sup.b Remission and Mucosal
Healing .sup..English Pound.Infusion dose of ustekinuinab using the
weight-based dosage regimen specified in Table 1. .sup.*Clinical
remission is defined as Mayo score .ltoreq.2 points, with no
individual subscore >1. .sup..sctn.Clinical response is defined
as a decrease from baseline in the Mayo score by .gtoreq.30% and
.gtoreq.3 points, with either a decrease from baseline in the
rectal bleeding subscore .gtoreq.1 or a rectal bleeding subscore of
0 or 1. .sup. A TNF.alpha. antagonist and/or vedolizumab.
.sup..dagger.Mucosal healing is defined as a Mayo endoscopic
subscore of 0 or 1. .sup..dagger-dbl.Symptomatic remission is
defined as a Mayo stool frequency subscore of 0 or 1 and a rectal
bleeding subscore of 0. Combined symptomatic remission and mucosal
healing is defined as a stool frequency subscore of 0 or 1, a
rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1.
.sup.ap < 0.001 .sup.bNominally significant (p < 0.001)
.sup.cNominally significant (p < 0.05)
[0716] UNIFI-M, evaluated 523 patients who achieved clinical
response with single IV administration of ustekinumab in UNIFI-I.
Patients were randomized to receive a subcutaneous maintenance
regimen of either 90 mg ustekinumab every 8 weeks, 90 mg
ustekinumab every 12 weeks or placebo for 44 weeks (for recommended
maintenance posology, see section 4.2 of the STELARA Solution for
injection (vial) and Solution for injection in pre filled syringe
SmPC).
[0717] Significantly greater proportions of patients were in
clinical remission in both ustekinumab treated groups compared to
the placebo group at week 44 (see Label Table 11).
TABLE-US-00021 Label Table 11: Summary of Key Efficacy Measures in
UNIFI-M (week 44; 52 weeks from initiation of the induction dose)
90 mg 90 mg ustekinumab ustekinumab every every Placebo* 8 Weeks 12
Weeks N = 175 N = 176 N = 172 Clinical 24% 44% .sup.a 38% .sup.b
Remission** In patients 31% (27/87) 48% (41/85).sup.d 49% (50/102)
.sup.d who failed conventional therapy, but not a biologic In
patients 17% (15/88) 40% (36/91) .sup.c 23% (16/70) .sup.d who
failed biological therapy.sup. In patients 15% (4/27) 33%
(7/21).sup.e 23% (5/22).sup.e who failed both a TNF and vedolizumab
Maintenance 45% 71% .sup.a 68% .sup.a of Clinical Response through
week 44.sup..sctn. In patients 51% (44/87) 78% (66/85) .sup.c 77%
(78/102) .sup.c who failed conventional therapy, but not a biologic
In patients 39% (34/88) 65% (59/91) .sup.c 56% (39/70) .sup.d who
failed biological therapy.sup. In patients 41% (11/27) 67%
(14/21).sup.e 50% (11/22).sup.e who failed both a TNF and
vedolizumab Mucosal 29% 51% .sup.a 44% .sup.b Healing.sup..dagger.
Maintenance 38% (17/45) 58% (22/38) 65% (26/40) .sup.c of Clinical
Remission through week 44.sup..English Pound. Corticosteroid 23%
42% .sup.a 38% .sup.b Free Clinical Remission.sup. Durable 35% 57%
.sup.c 48% .sup.d Remission.sup..parallel. Symptomatic 45% 68%
.sup.c 62% .sup.d Remission .sup..dagger-dbl. Combined 28% 48%
.sup.c 41% .sup.d Symptomatic Remission and Mucosal Healing
*Following response to IV ustekinumab. **Clinical remission is
defined as Mayo score .ltoreq.2 points, with no individual subscore
>1. .sup..sctn.Clinical response is defined as a decrease from
baseline in the Mayo score by .gtoreq.30% and .gtoreq.3 points,
with either a decrease from baseline in the rectal bleeding
subscore .gtoreq.1 or a rectal bleeding subscore of 0 or 1. .sup. A
TNF.alpha. antagonist and/or vedolizumab. .sup..dagger.Mucosal
healing is defined as a Mayo endoscopic sub-score of 0 or 1.
.sup..English Pound.Maintenance of clinical remission through Week
44 is defined as patients in clinical remission through Week 44
among patients in clinical remission at maintenance baseline. .sup.
Corticosteroid-free clinical remission is defined as patients in
clinical remission and not receiving corticosteroids at Week 44.
.sup..parallel.Durable Remission is defined as partial Mayo
remission at .gtoreq.80% of all visits prior to Week 44 and in
partial Mayo remission at last visit (Week 44).
.sup..dagger-dbl.Symptomatic remission is defined as a Mayo stool
frequency subscore of 0 or 1 and a rectal bleeding subscore of 0.
Combined symptomatic remission and mucosal healing is defined as a
stool frequency subscore of 0 or 1, a rectal bleeding subscore of
0, and an endoscopy subscore of 0 or 1. .sup.a p < 0.001 .sup.b
p < 0.05 .sup.c Nominally significant (p < 0.001) .sup.d
Nominally significant (p < 0.05) .sup.eNot statistically
significant
[0718] The beneficial effect of ustekinumab on clinical response,
mucosal healing and clinical remission was observed in induction
and in maintenance both in patients who failed conventional therapy
but not a biologic therapy, as well as in those who had failed at
least one prior TNF.alpha. antagonist therapy including in patients
with a primary non-response to TNF.alpha. antagonist therapy. A
beneficial effect was also observed in induction in patients who
failed at least one prior TNF.alpha. antagonist therapy and
vedolizumab, however the number of patients in this subgroup was
too small to draw definitive conclusions about the beneficial
effect in this group during maintenance.
Week 16 Responders to Ustekinumab Induction
[0719] Ustekinumab treated patients who were not in response at
week 8 of UNIFI-I received an administration of 90 mg SC
ustekinumab at week 8 (36% of patients). Of those patients, 9% of
patients who were initially randomized to the recommended induction
dose achieved clinical remission and 58% achieved clinical response
at Week 16.
[0720] Patients who were not in clinical response to ustekinumab
induction at week 8 of the UNFI-I study but were in response at
week 16 (157 patients) entered into the non-randomized portion of
UNIFI-M and continued to receive maintenance dosing every 8 weeks;
among these patients, a majority (62%) maintained response and 30%
achieved remission at week 44.
Endoscopic Normalization
[0721] Endoscopic normalization was defined as a Mayo endoscopic
subscore of 0 and was observed as early as week 8 of UNIFI-I. At
week 44 of UNIFI-M, it was achieved in 24% and 29% of patients
treated with ustekinumab every 12 or 8 weeks, respectively, as
compared to 18% of patients in the placebo group.
Histologic & Histo Endoscopic Mucosal Healing
[0722] Histologic healing (defined as neutrophil infiltration in
<5% of crypts, no crypt destruction, and no erosions,
ulcerations, or granulation tissue) was assessed at week 8 of
UNIFI-I and Week 44 of UNIFI-M. At week 8, after a single
intravenous induction dose, significantly greater proportions of
patients in the recommended dose group achieved histologic healing
(36%) compared with patients in the placebo group (22%). At Week 44
maintenance of this effect was observed with significantly more
patients in histologic healing in the every 12 week (54%) and every
8 week (59%) ustekinumab groups as compared to placebo (33%).
[0723] A combined endpoint of histo-endoscopic mucosal healing
defined as subjects having both mucosal healing and histologic
healing was evaluated at week 8 of UNIFI-I and week 44 of UNIFI-M.
Patients receiving ustekinumab at the recommended dose showed
significant improvements on the histo-endoscopic mucosal healing
endpoint at week 8 in the ustekinumab group (18%) as compared to
the placebo group (9%). At week 44, maintenance of this effect was
observed with significantly more patients in histo-endoscopic
mucosal healing in the every 12 week (39%) and every 8 week (46%)
ustekinumab groups as compared to placebo (24%).
Health-Related Quality of Life
[0724] Health-related quality of life was assessed by Inflammatory
Bowel Disease Questionnaire (IBDQ), SF-36 and EuroQoL-5D (EQ-5D)
questionnaires.
[0725] At week 8 of UNIFI-I, patients receiving ustekinumab showed
significantly greater and clinically meaningful improvements on
IBDQ total score, EQ-5D and EQ-5D VAS, and SF-36 Mental Component
Summary Score and SF-36 Physical Component Summary Score when
compared to placebo. These improvements were maintained in
ustekinumab-treated patients in UNIFI-M through week 44.
[0726] Patients receiving ustekinumab experienced significantly
more improvements in work productivity as assessed by greater
reductions in overall work impairment and in activity impairment as
assessed by the WPAI-GH questionnaire than patients receiving
placebo.
Hospitalizations and Ulcerative Colitis (UC) Related Surgeries
[0727] Through week 8 of UNIFI-I, the proportions of subjects with
UC disease related hospitalizations were significantly lower for
subjects in the ustekinumab recommended dose group (1.6%, 5/322)
compared with subjects in the placebo group (4.4%, 14/319) and no
subjects underwent UC disease related surgeries in subjects
receiving ustekinumab at the recommended induction dose compared to
0.6% (2/319) subjects in the placebo group.
[0728] Through week 44 of UNIFI-M, a significantly lower number of
UC-related hospitalizations was observed in subjects in the
combined ustekinumab group (2.0%, 7/348) as compared with subjects
in the placebo group (5.7%, 10/175). A numerically lower number of
subjects in the ustekinumab group (0.6%, 2/348) underwent UC
disease related surgeries compared with subjects in the placebo
group (1.7%, 3/175) through week 44.
Immunogenicity
[0729] Antibodies to ustekinumab may develop during ustekinumab
treatment and most are neutralising. The formation of
anti-ustekinumab antibodies is associated with both increased
clearance and reduced efficacy of ustekinumab, except in patients
with Crohn's disease or ulcerative colitis where no reduced
efficacy was observed. There is no apparent correlation between the
presence of anti-ustekinumab antibodies and the occurrence of
injection site reactions.
Paediatric Population
[0730] The European Medicines Agency has deferred the obligation to
submit the results of studies with ustekinumab in one or more
subsets of the paediatric population in Crohn's Disease and
ulcerative colitis (see section 4.2 for information on paediatric
use).
5.2 Pharmacokinetic Properties
Absorption
[0731] The median time to reach the maximum serum concentration
(t.sub.max) was 8.5 days after a single 90 mg subcutaneous
administration in healthy subjects. The median t.sub.max values of
ustekinumab following a single subcutaneous administration of
either 45 mg or 90 mg in patients with psoriasis were comparable to
those observed in healthy subjects.
[0732] The absolute bioavailability of ustekinumab following a
single subcutaneous administration was estimated to be 57.2% in
patients with psoriasis.
Distribution
[0733] Median volume of distribution during the terminal phase (Vz)
following a single intravenous administration to patients with
psoriasis ranged from 57 to 83 mL/kg.
Biotransformation
[0734] The exact metabolic pathway for ustekinumab is unknown.
Elimination
[0735] Median systemic clearance (CL) following a single
intravenous administration to patients with psoriasis ranged from
1.99 to 2.34 mL/day/kg. Median half-life (t.sub.1/2) of ustekinumab
was approximately 3 weeks in patients with psoriasis, psoriatic
arthritis, Crohn's disease or ulcerative colitis, ranging from 15
to 32 days across all psoriasis and psoriatic arthritis studies. In
a population pharmacokinetic analysis, the apparent clearance
(CL/F) and apparent volume of distribution (V/F) were 0.465 l/day
and 15.7 l, respectively, in patients with psoriasis. The CL/F of
ustekinumab was not impacted by gender. Population pharmacokinetic
analysis showed that there was a trend towards a higher clearance
of ustekinumab in patients who tested positive for antibodies to
ustekinumab.
Dose Linearity
[0736] The systemic exposure of ustekinumab (C.sub.max and AUC)
increased in an approximately dose-proportional manner after a
single intravenous administration at doses ranging from 0.09 mg/kg
to 4.5 mg/kg or following a single subcutaneous administration at
doses ranging from approximately 24 mg to 240 mg in patients with
psoriasis.
Single Dose Versus Multiple Doses
[0737] Serum concentration-time profiles of ustekinumab were
generally predictable after single or multiple subcutaneous dose
administrations. In patients with psoriasis, steady-state serum
concentrations of ustekinumab were achieved by week 28 after
initial subcutaneous doses at Weeks 0 and 4 followed by doses every
12 weeks. The median steady-state trough concentration ranged from
0.21 .mu.g/mL to 0.26 .mu.g/mL (45 mg) and from 0.47 .mu.g/mL to
0.49 .mu.g/mL (90 mg). There was no apparent accumulation in serum
ustekinumab concentration over time when given subcutaneously every
12 weeks.
[0738] In patients with Crohn's disease and ulcerative colitis,
following an intravenous dose of .about.6 mg/kg, starting at week
8, subcutaneous maintenance dosing of 90 mg ustekinumab was
administered every 8 or 12 weeks. Steady state ustekinumab
concentration was achieved by the start of the second maintenance
dose. In patients with Crohn's disease, median steady-state trough
concentrations ranged from 1.97 .mu.g/mL to 2.24 .mu.g/mL and from
0.61 .mu.g/mL to 0.76 .mu.g/mL for 90 mg ustekinumab every 8 weeks
or every 12 weeks respectively. In patients with ulcerative
colitis, median steady-state trough concentrations ranged from 2.69
.mu.g/mL to 3.09 .mu.g/mL and from 0.92 .mu.g/mL to 1.19 .mu.g/mL
for 90 mg ustekinumab every 8 weeks or every 12 weeks. The
steady-state trough ustekinumab levels resulting from 90 mg
ustekinumab every 8 weeks were associated with higher clinical
remission rates as compared to the steady-state trough levels
following 90 mg every 12 weeks.
Impact of Weight on Pharmacokinetics
[0739] In a population pharmacokinetic analysis using data from
patients with psoriasis, body weight was found to be the most
significant covariate affecting the clearance of ustekinumab. The
median CL/F in patients with weight .gtoreq.100 kg was
approximately 55% higher compared to patients with weight
.ltoreq.100 kg. The median V/F in patients with weight .gtoreq.100
kg was approximately 37% higher as compared to patients with weight
.ltoreq.100 kg. The median trough serum concentrations of
ustekinumab in patients with higher weight (.gtoreq.100 kg) in the
90 mg group were comparable to those in patients with lower weight
(.ltoreq.100 kg) in the 45 mg group. Similar results were obtained
from a confirmatory population pharmacokinetic analysis using data
from patients with psoriatic arthritis.
Dosing Frequency Adjustment
[0740] In patients with Crohn's disease and ulcerative colitis,
based on observed data and population PK analyses, randomized
subjects who lost response to treatment had lower serum ustekinumab
concentrations over time compared with subjects who did not lose
response. In Crohn's disease, dose adjustment from 90 mg every 12
weeks to 90 mg every 8 weeks was associated with an increase in
trough serum ustekinumab concentrations and an accompanying
increase in efficacy. In ulcerative colitis, population PK model
based simulations demonstrated that adjusting dosing from 90 mg
every 12 weeks to every 8 weeks would be expected to result in a
3-fold increase in steady-state trough ustekinumab concentrations.
Additionally on the basis of clinical trial data in patients with
ulcerative colitis, a positive exposure-response relationship was
established between trough concentrations, and clinical remission
and mucosal healing.
Special Populations
[0741] No pharmacokinetic data are available in patients with
impaired renal or hepatic function. No specific studies have been
conducted in elderly patients.
[0742] The pharmacokinetics of ustekinumab were generally
comparable between Asian and non-Asian patients with psoriasis and
ulcerative colitis.
[0743] In patients with Crohn's disease and ulcerative colitis,
variability in ustekinumab clearance was affected by body weight,
serum albumin level, sex, and antibody to ustekinumab status while
body weight was the main covariate affecting the volume of
distribution. Additionally in Crohn's disease, clearance was
affected by C-reactive protein, TNF antagonist failure status and
race (Asian versus non-Asian). The impact of these covariates was
within .+-.20% of the typical or reference value of the respective
PK parameter, thus dose adjustment is not warranted for these
covariates. Concomitant use of immunomodulators did not have a
significant impact on ustekinumab disposition.
[0744] In the population pharmacokinetic analysis, there were no
indications of an effect of tobacco or alcohol on the
pharmacokinetics of ustekinumab.
[0745] Serum ustekinumab concentrations in paediatric psoriasis
patients 12 to 17 years of age, treated with the recommended
weight-based dose were generally comparable to those in the adult
psoriasis population treated with the adult dose, while serum
ustekinumab concentrations in paediatric psoriasis patients treated
with half of the recommended weight-based dose were generally lower
than those in adults.
Regulation of CYP450 Enzymes
[0746] The effects of IL-12 or IL-23 on the regulation of CYP450
enzymes were evaluated in an in vitro study using human
hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10
ng/mL did not alter human CYP450 enzyme activities (CYP1A2, 2B6,
2C9, 2C19, 2D6, or 3A4; see section 4.5).
5.3 Preclinical Safety Data
[0747] Non-clinical data reveal no special hazard (e.g. organ
toxicity) for humans based on studies of repeated-dose toxicity and
developmental and reproductive toxicity, including safety
pharmacology evaluations. In developmental and reproductive
toxicity studies in cynomolgus monkeys, neither adverse effects on
male fertility indices nor birth defects or developmental toxicity
were observed. No adverse effects on female fertility indices were
observed using an analogous antibody to IL-12/23 in mice.
[0748] Dose levels in animal studies were up to approximately
45-fold higher than the highest equivalent dose intended to be
administered to psoriasis patients and resulted in peak serum
concentrations in monkeys that were more than 100-fold higher than
observed in humans.
[0749] Carcinogenicity studies were not performed with ustekinumab
due to the lack of appropriate models for an antibody with no
cross-reactivity to rodent IL-12/23 p40.
6. Pharmaceutical Particulars
6.1 List of Excipients
[0750] L-histidine
[0751] L-histidine monohydrochloride monohydrate
[0752] Polysorbate 80
[0753] Sucrose
[0754] Water for injections
6.2 Incompatibilities
[0755] In the absence of compatibility studies, this medicinal
product must not be mixed with other medicinal products.
6.3 Shelf Life
STELARA 45 mg Solution for Injection
[0756] 2 years
STELARA 90 mg Solution for Injection
[0757] 2 years
STELARA 45 mg Solution for Injection in Pre-Filled Syringe
[0758] 3 years
STELARA 90 mg Solution for Injection in Pre-Filled Syringe
[0759] 3 years
6.4 Special Precautions for Storage
[0760] Store in a refrigerator (2.degree. C.-8.degree. C.). Do not
freeze.
[0761] Keep the vial or pre-filled syringe in the outer carton in
order to protect from light.
6.5 Nature and Contents of Container
STELARA 45 mg Solution for Injection
[0762] 0.5 mL solution in a type I glass 2 mL vial closed with a
coated butyl rubber stopper.
STELARA 90 mg Solution for Injection
[0763] 1 mL solution in a type I glass 2 mL vial closed with a
coated butyl rubber stopper.
STELARA 45 mg Solution for Injection in Pre-Filled Syringe
[0764] 0.5 mL solution in a type I glass 1 mL syringe with a fixed
stainless steel needle and a needle cover containing dry natural
rubber (a derivative of latex). The syringe is fitted with a
passive safety guard.
STELARA 90 mg Solution for Injection in Pre-Filled Syringe
[0765] 1 mL solution in a type I glass 1 mL syringe with a fixed
stainless steel needle and a needle cover containing dry natural
rubber (a derivative of latex). The syringe is fitted with a
passive safety guard.
[0766] STELARA is available in a 1 vial pack or a pack of 1
pre-filled syringe.
6.6 Special Precautions for Disposal and Other Handling
[0767] The solution in the STELARA vial or pre-filled syringe
should not be shaken. The solution should be visually inspected for
particulate matter or discoloration prior to subcutaneous
administration. The solution is clear to slightly opalescent,
colourless to light yellow and may contain a few small translucent
or white particles of protein. This appearance is not unusual for
proteinaceous solutions. The medicinal product should not be used
if the solution is discoloured or cloudy, or if foreign particulate
matter is present. Before administration, STELARA should be allowed
to reach room temperature (approximately half an hour). Detailed
instructions for use are provided in the package leaflet.
[0768] STELARA does not contain preservatives; therefore any unused
medicinal product remaining in the vial and the syringe should not
be used. STELARA is supplied as a sterile, single-use vial or
single-use pre-filled syringe. The syringe, needle and vial must
never be re-used. Any unused medicinal product or waste material
should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
[0769] Janssen-Cilag International NV
[0770] Turnhoutseweg 30
[0771] 2340 Beerse
[0772] Belgium
8. Marketing Authorisation Number(S)
STELARA 45 mg Solution for Injection
[0773] EU/1/08/494/001
STELARA 90 mg Solution for Injection
[0774] EU/1/08/494/002
STELARA 45 mg Solution for Injection in Pre-Filled Syringe
[0775] EU/1/08/494/003
STELARA 90 mg Solution for Injection in Pre-Filled Syringe
[0776] EU/1/08/494/004
9. Date of First Authorisation/Renewal of the Authorisation
[0777] Date of first authorisation: 16 Jan. 2009
[0778] Date of latest renewal: 19 Sep. 2013
10. Date of Revision of the Text
[0779] Detailed information on this medicinal product is available
on the website of the European
[0780] Medicines Agency http://www.ema.europa.eu/
Sequence CWU 1
1
1115PRTArtificial Sequenceanti-IL-12/IL-23p40 antibody
complementarity determining region heavy chain 1 1Thr Tyr Trp Leu
Gly1 5217PRTArtificial Sequenceanti-IL-12/IL-23p40 antibody
complementarity determining region heavy chain 2 2Ile Met Ser Pro
Val Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe Gln1 5 10
15Gly310PRTArtificial Sequenceanti-IL-12/IL-23p40 antibody
complementarity determining region heavy chain 3 3Arg Arg Pro Gly
Gln Gly Tyr Phe Asp Phe1 5 10411PRTArtificial
Sequenceanti-IL-12/IL-23p40 antibody complementarity determining
region light chain 1 4Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala1
5 1057PRTArtificial Sequenceanti-IL-12/IL-23p40 antibody
complementarity determining region light chain 2 5Ala Ala Ser Ser
Leu Gln Ser1 569PRTArtificial Sequenceanti-IL-12/IL-23p40 antibody
complementarity determining region light chain 3 6Gln Gln Tyr Asn
Ile Tyr Pro Tyr Thr1 57119PRTArtificial Sequenceanti-IL-12/IL-23p40
antibody variable heavy chain region 7Glu Val Gln Leu Val Gln Ser
Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys
Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30Trp Leu Gly Trp Val
Arg Gln Met Pro Gly Lys Gly Leu Asp Trp Ile 35 40 45Gly Ile Met Ser
Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln
Val Thr Met Ser Val Asp Lys Ser Ile Thr Thr Ala Tyr65 70 75 80Leu
Gln Trp Asn Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90
95Ala Arg Arg Arg Pro Gly Gln Gly Tyr Phe Asp Phe Trp Gly Gln Gly
100 105 110Thr Leu Val Thr Val Ser Ser 1158108PRTArtificial
Sequenceanti-IL-12/IL-23p40 antibody variable light chain region
8Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5
10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser
Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser
Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg
Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
Tyr Asn Ile Tyr Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu
Ile Lys Arg 100 1059503PRTArtificial SequenceHuman IL-12 with alpha
and beta subunits 9Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met
Phe Pro Cys Leu1 5 10 15His His Ser Gln Asn Leu Leu Arg Ala Val Ser
Asn Met Leu Gln Lys 20 25 30Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys
Thr Ser Glu Glu Ile Asp 35 40 45His Glu Asp Ile Thr Lys Asp Lys Thr
Ser Thr Val Glu Ala Cys Leu 50 55 60Pro Leu Glu Leu Thr Lys Asn Glu
Ser Cys Leu Asn Ser Arg Glu Thr65 70 75 80Ser Phe Ile Thr Asn Gly
Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe 85 90 95Met Met Ala Leu Cys
Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr 100 105 110Gln Val Glu
Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys 115 120 125Arg
Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu 130 135
140Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
Ser145 150 155 160Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys
Leu Cys Ile Leu 165 170 175Leu His Ala Phe Arg Ile Arg Ala Val Thr
Ile Asp Arg Val Met Ser 180 185 190Tyr Leu Asn Ala Ser Ile Trp Glu
Leu Lys Lys Asp Val Tyr Val Val 195 200 205Glu Leu Asp Trp Tyr Pro
Asp Ala Pro Gly Glu Met Val Val Leu Thr 210 215 220Cys Asp Thr Pro
Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser225 230 235 240Ser
Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu 245 250
255Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu
260 265 270Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile
Trp Ser 275 280 285Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn
Lys Thr Phe Leu 290 295 300Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg
Phe Thr Cys Trp Trp Leu305 310 315 320Thr Thr Ile Ser Thr Asp Leu
Thr Phe Ser Val Lys Ser Ser Arg Gly 325 330 335Ser Ser Asp Pro Gln
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala 340 345 350Glu Arg Val
Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys 355 360 365Gln
Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu 370 375
380Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr
Ser385 390 395 400Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro
Pro Lys Asn Leu 405 410 415Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln
Val Glu Val Ser Trp Glu 420 425 430Tyr Pro Asp Thr Trp Ser Thr Pro
His Ser Tyr Phe Ser Leu Thr Phe 435 440 445Cys Val Gln Val Gln Gly
Lys Ser Lys Arg Glu Lys Lys Asp Arg Val 450 455 460Phe Thr Asp Lys
Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser465 470 475 480Ile
Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu 485 490
495Trp Ala Ser Val Pro Cys Ser 50010449PRTArtificial
Sequenceanti-IL-12/IL-23p40 antibody heavy chain 10Glu Val Gln Leu
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys
Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30Trp Leu
Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Asp Trp Ile 35 40 45Gly
Ile Met Ser Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe 50 55
60Gln Gly Gln Val Thr Met Ser Val Asp Lys Ser Ile Thr Thr Ala Tyr65
70 75 80Leu Gln Trp Asn Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr
Cys 85 90 95Ala Arg Arg Arg Pro Gly Gln Gly Tyr Phe Asp Phe Trp Gly
Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ser Ser Thr Lys Gly
Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe
Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200
205Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val
Val Asp Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp
Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315
320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
Tyr Thr 340 345 350Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440
445Lys11214PRTArtificial Sequenceanti-IL-12/IL-23p40 antibody light
chain 11Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser
Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys
Ser Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser
Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
Gln Tyr Asn Ile Tyr Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu
Glu Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe
Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val
Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val
Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155
160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210
* * * * *
References