U.S. patent application number 17/383634 was filed with the patent office on 2021-12-16 for methods for treating liver disorders using fxr agonists.
The applicant listed for this patent is NOVARTIS AG. Invention is credited to Michael BADMAN, Jin CHEN, Bryan LAFFITTE, Sam LINDGREN.
Application Number | 20210386729 17/383634 |
Document ID | / |
Family ID | 1000005771541 |
Filed Date | 2021-12-16 |
United States Patent
Application |
20210386729 |
Kind Code |
A1 |
BADMAN; Michael ; et
al. |
December 16, 2021 |
METHODS FOR TREATING LIVER DISORDERS USING FXR AGONISTS
Abstract
The invention provides methods for modulating the activity of
farnesoid X receptors (FXRs) using specific FXR agonists, in
particular for treating or preventing liver diseases and disorders.
In one embodiment, the invention provides a pharmaceutical unit
dosage form composition, comprising a compound of Formula (I)
##STR00001## or a stereoisomer, enantiomer or pharmaceutically
acceptable salt thereof.
Inventors: |
BADMAN; Michael; (Newton,
MA) ; CHEN; Jin; (Randolph, NJ) ; LAFFITTE;
Bryan; (Cardiff, CA) ; LINDGREN; Sam;
(Allschwil, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NOVARTIS AG |
Basel |
|
CH |
|
|
Family ID: |
1000005771541 |
Appl. No.: |
17/383634 |
Filed: |
July 23, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16078431 |
Aug 21, 2018 |
11110083 |
|
|
PCT/IB2017/050962 |
Feb 20, 2017 |
|
|
|
17383634 |
|
|
|
|
62298113 |
Feb 22, 2016 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/497 20130101;
A61K 31/506 20130101; A61K 31/46 20130101; A61K 31/4748 20130101;
A61P 1/16 20180101; A61K 9/0053 20130101 |
International
Class: |
A61K 31/46 20060101
A61K031/46; A61K 31/506 20060101 A61K031/506; A61K 31/497 20060101
A61K031/497; A61K 31/4748 20060101 A61K031/4748; A61P 1/16 20060101
A61P001/16 |
Claims
1. A pharmaceutical unit dosage form composition, comprising about
10 .mu.g, about 30 .mu.g, about 60 .mu.g or about 90 .mu.g of a
compound of Formula (I) ##STR00007## or a stereoisomer, enantiomer
or pharmaceutically acceptable salt thereof; suitable for oral
administration up to a maximum total dose of 100 .mu.g per day.
2. The pharmaceutical unit dosage form composition of claim 1,
comprising about 10 .mu.g of said compound of Formula (I).
3. The pharmaceutical unit dosage form composition of claim 1,
comprising about 30 .mu.g of said compound of Formula (I).
4. The pharmaceutical unit dosage form composition of claim 1,
comprising about 60 .mu.g of a compound of Formula (I).
5. The pharmaceutical unit dosage form composition of claim 1,
comprising about 90 .mu.g of a compound of Formula (I).
6. The pharmaceutical unit dosage form composition of claim 1,
wherein said compound of Formula (I) is
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-8-
-carboxylic acid or a pharmaceutically acceptable salt thereof.
7. The pharmaceutical unit dosage form composition of claim 1,
wherein said compound of Formula (I) is
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-8-
-carboxylic acid in free form.
8. The pharmaceutical unit dosage form composition of claim 1,
comprising about 10 .mu.g of
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-8-
-carboxylic acid or a pharmaceutically acceptable salt thereof.
9. The pharmaceutical unit dosage form composition of claim 1,
comprising about 10 .mu.g of
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-8-
-carboxylic acid in free form.
10. The pharmaceutical unit dosage form composition of claim 1,
comprising about 30 .mu.g of
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-8-
-carboxylic acid or a pharmaceutically acceptable salt thereof.
11. The pharmaceutical unit dosage form composition of claim 1,
comprising about 30 .mu.g of
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-8-
-carboxylic acid in free form.
12. The pharmaceutical unit dosage form composition of claim 1,
comprising about 80 .mu.g of
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-8-
-carboxylic acid or a pharmaceutically acceptable salt thereof.
13. The pharmaceutical unit dosage form composition of claim 1,
comprising about 80 .mu.g of
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-8-
-carboxylic acid in free form.
14. The pharmaceutical unit dosage form composition of claim 1,
comprising about 90 .mu.g of
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-8-
-carboxylic acid or a pharmaceutically acceptable salt thereof.
15. The pharmaceutical unit dosage form composition of claim 1,
comprising about 90 .mu.g of
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-8-
-carboxylic acid in free form.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 16/078,431 filed 21 Aug. 2018, which is a 371 national phase
application of international application number PCT/IB2017/050962
filed 20 Feb. 2017; which application claims the benefit of U.S.
provisional application Ser. No. 62/298,113 filed 22 Feb. 2016.
Each of these applications is incorporated by reference herein in
its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to novel regimens for treating
or preventing liver conditions mediated by farnesoid X receptors
(FXRs), by using therapeutically effective amount of a FXR agonist,
as well as methods, uses, compositions involving such regimens.
BACKGROUND OF THE INVENTION
[0003] Farnesoid X Receptor Agonist (FXR) is a nuclear receptor
activated by bile acids, also known as Bile acid Receptor (BAR).
FXR is expressed in principal sites of bile acid metabolism, such
as liver, intestine and kidney, where it mediates effects on
multiple metabolic pathways in a tissue-specific manner.
[0004] The mode of action of FXR in the liver and intestine is well
known, and described e.g. in (Calkin and Tontonoz, (2012), Nature
Reviews Molecular Cell Biology 13, 213-24). FXR is responsible for
modulating bile acid production, conjugation and elimination
through multiple mechanisms in the liver and intestine. In normal
physiology, FXR detects increased levels of bile acids and responds
by decreasing bile acid synthesis and bile acid uptake while
increasing bile acid modification and secretion in the liver. In
the intestine, FXR detects increased bile acid levels and decreases
bile acid absorption and increases secretion of FGF15/19. The net
result is a decrease in the overall levels of bile acids. In the
liver, FXR agonism increases expression of genes involved in
canalicular and basolateral bile acid efflux and bile acid
detoxifying enzymes while inhibiting basolateral bile acid uptake
by hepatocytes and inhibiting bile acid synthesis.
[0005] Furthermore, FXR agonists decrease hepatic triglyceride
synthesis leading to reduced steatosis, inhibit hepatic stellate
cell activation reducing liver fibrosis and stimulate FGF15/FGF19
expression (a key regulator of bile acid metabolism) leading to
improved hepatic insulin sensitivity. Thus, FXR acts as a sensor of
elevated bile acids and initiates homeostatic responses to control
bile acid levels, a feedback mechanism that is believed to be
impaired in cholestasis. FXR agonism has shown clinical benefits in
subjects with cholestatic disorders (Nevens et al., J. Hepatol. 60
(1 SUPPL. 1): 347A-348A (2014)), bile acid malabsorption diarrhea
(Walters et al., Aliment Pharmacol. Ther. 41(1):54-64 (2014)) and
non-alcoholic steatohepatitis (NASH; Neuschwander-Tetri et al
2015).
[0006] Bile acids are normally produced by the organism. At high
dose they can cause different side effects as they have detergent
properties (diarrhea or cellular injury). In addition they can also
cause pruritus.
[0007] Obeticholic acid (6.alpha.-ethyl-chenodeoxycholic acid),
that is abbreviated to OCA and also known as INT-747, is a bile
acid-derived FXR agonist, analogue to the natural bile acid
chenodeoxycholic acid. In clinical studies, OCA showed efficacy in
both Primary Biliary Cirrhosis (PBC) and non-alcoholic
steatohepatitis (NASH) subjects; however OCA treatment may be
associated with increased pruritus. OCA was tested at doses between
5 mg and 50 mg in PBC subjects or NASH subjects.
[0008] There remains a need for new treatments and therapies for
liver conditions mediated by FXR, which could be associated with
more limited side effects.
SUMMARY OF THE INVENTION
[0009] The invention provides methods of treating, preventing, or
ameliorating conditions mediated by farnesoid X receptors (FXR), in
particular liver diseases and disorders, comprising administering
to a subject in need thereof a therapeutically effective amount of
a FXR agonist of formula (I)
##STR00002##
(i.e.
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl-
}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-8-carb-
oxylic acid), a stereoisomer, an enantiomer, a pharmaceutically
acceptable salt or an amino acid conjugate thereof, [0010] e.g. a
FXR agonist of formula (II)
##STR00003##
[0010] (i.e.
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-8-
-carboxylic acid) (as herein defined as Compound A), a
pharmaceutically acceptable salt or an amino acid conjugate
thereof, [0011] e.g. a FXR agonist of formula (III)
##STR00004##
[0011] (i.e.
2-({2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-ox-
azol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazo-
l-6-yl}formamido)acetic acid) (Compound B), [0012] of formula
(IV)
##STR00005##
[0012] (i.e.
2-({2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-ox-
azol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazo-
l-6-yl}formamido)ethane-1-sulfonic acid) (Compound C), [0013] of
formula (V)
##STR00006##
[0013] (i.e.
2S,3S,4S,5R,6S)-6-((2-((1R,3S,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethox-
y)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-4-fluoroben-
zo[d]thiazole-6-carbonyl)oxy)-3,4,5-trhydroxytetrahydro-2H-pyran-2-carboxy-
lic acid (Compound D), or a pharmaceutically acceptable salt
thereof.
[0014] The invention further provides new dosing regimens of FXR
agonists of formula (I), a stereoisomer, an enantiomer, a
pharmaceutically acceptable salt or an amino acid conjugate
thereof, e.g. Compound A or amino acid conjugate thereof, e.g.
glycine conjugate, taurine conjugate or acyl glucuronide conjugate
of Compound A, e.g. Compound A, for treating or preventing liver
diseases and disorders mediated by farnesoid X receptors (FXR), as
well as the use of such new regimens and pharmaceutical
compositions adapted for administering such new regimens.
[0015] The compounds of formula (I) (e.g. Compound A) are non-bile
acid derived FXR agonists. They are described in WO2012/087519.
[0016] Non-bile acid derived FXR agonists have the advantages of
greater potency, greater specificity for the FXR target and
absorption, distribution, metabolism and elimination processes that
are not subject to processes of bile acid metabolism.
[0017] Various (enumerated) embodiments of the disclosure are
described herein. It will be recognized that features specified in
each embodiment may be combined with other specified features to
provide further embodiments of the present disclosure.
[0018] Embodiment 1: Therapeutic regimens for treating or
preventing a condition mediated by Farnesoid X receptor (FXR),
comprising administering the FXR agonist of formula (I), a
stereoisomer, an enantiomer, a pharmaceutically acceptable salt
thereof or an amino acid conjugate thereof, e.g. Compound A or an
amino acid conjugate thereof, at a dose (e.g. daily dose) of about
3 .mu.g to about 100 .mu.g, about 5 .mu.g to about 100 .mu.g, e.g.
about 10 .mu.g to about 100 .mu.g, e.g. about 20 .mu.g to 100
.mu.g, e.g. about 30 .mu.g to about 90 .mu.g, e.g. about 40 .mu.g
to about 60 .mu.g; or at a dose in a range of about 10 .mu.g to
about 60 .mu.g, e.g. about 10 .mu.g to about 40 .mu.g, e.g. about
20 .mu.g to about 40 .mu.g; or at a dose in a range of about 20
.mu.g to about 60 .mu.g, e.g. about 30 .mu.g to about 60 .mu.g; or
at a dose in a range of about 5 .mu.g to about 60 .mu.g, e.g. about
5 .mu.g to about 40 .mu.g, e.g. about 3 .mu.g to about 40 .mu.g.
e.g. about 3 .mu.g to about 30 .mu.g. Such doses may be for daily
or twice daily administration.
[0019] Embodiment 2: Therapeutic regimens for treating or
preventing a condition mediated by Farnesoid X receptor (FXR),
comprising administering the FXR agonist of formula (I), a
stereoisomer, an enantiomer, a pharmaceutically acceptable salt
thereof or an amino acid conjugate thereof, e.g. Compound A or an
amino acid conjugate thereof, at a dose of about 3 .mu.g, about 4
.mu.g, about 5 .mu.g, about 10 .mu.g, about 20 .mu.g, about 25
.mu.g, about 30 .mu.g, about 40 .mu.g, about 60 .mu.g, or about 90
.mu.g. Such doses may be for daily administration (e.g. daily
doses). Such doses may be for twice daily.
[0020] Embodiment 3: Therapeutic regimens for treating or
preventing a condition mediated by Farnesoid X receptor (FXR) such
as a liver or an intestinal disease, comprising administering the
FXR agonist of formula (I), a stereoisomer, an enantiomer, a
pharmaceutically acceptable salt thereof or an amino acid conjugate
thereof, e.g. Compound A or an amino acid conjugate thereof, at a
dose of about 10 .mu.g, e.g. daily or twice daily, e.g. for daily
administration.
[0021] Embodiment 4: Therapeutic regimens for treating or
preventing a condition mediated by Farnesoid X receptor (FXR) such
as a liver or an intestinal disease, comprising administering the
FXR agonist of formula (I), a stereoisomer, an enantiomer, a
pharmaceutically acceptable salt thereof or an amino acid conjugate
thereof, e.g. Compound A or an amino acid conjugate thereof, at a
dose of about 25 .mu.g or about 30 .mu.g, e.g. daily or twice
daily, e.g. for daily administration.
[0022] Embodiment 5: Therapeutic regimens for treating or
preventing a condition mediated by Farnesoid X receptor (FXR) such
as a liver or an intestinal disease, comprising administering the
FXR agonist of formula (I), a stereoisomer, an enantiomer, a
pharmaceutically acceptable salt thereof or an amino acid conjugate
thereof, e.g. Compound A or an amino acid conjugate thereof, at a
daily dose of about 60 .mu.g, e.g. daily or twice daily, e.g. for
daily administration.
[0023] Embodiment 6: Therapeutic regimens for treating or
preventing a condition mediated by Farnesoid X receptor (FXR) such
as a liver or an intestinal disease, comprising administering the
FXR agonist of formula (I), a stereoisomer, an enantiomer, a
pharmaceutically acceptable salt thereof or an amino acid conjugate
thereof, e.g. Compound A or an amino acid conjugate thereof, at a
daily dose of about 90 .mu.g, e.g. daily or twice daily, e.g. for
daily administration.
[0024] Embodiment 7: Use of a FXR agonist of formula (I), a
stereoisomer, an enantiomer, a pharmaceutically acceptable salt
thereof or an amino acid conjugate thereof, e.g. Compound A or an
amino acid conjugate thereof, in the manufacture of a medicament
for treating or preventing a condition mediated by Farnesoid X
receptor (FXR), wherein the FXR agonist is to be administered at a
dose (e.g. daily dose), of about 3 .mu.g to about 100 .mu.g, e.g.
about 5 .mu.g to about 100 .mu.g, e.g. about 10 .mu.g to about 100
.mu.g, e.g. about 20 .mu.g to 100 .mu.g, e.g. about 30 .mu.g to
about 90 .mu.g, e.g. about 40 .mu.g to about 60 .mu.g; or at a dose
of about 10 .mu.g to about 60 .mu.g, e.g. about 10 .mu.g to about
40 .mu.g, e.g. about 20 .mu.g to about 40 .mu.g; or at a dose of
about 20 .mu.g to about 60 .mu.g, e.g. about 30 .mu.g to about 60
.mu.g; or at a dose of about 5 .mu.g to about 60 .mu.g, e.g. about
5 .mu.g to about 40 .mu.g, e.g. about 3 .mu.g to about 40 .mu.g.
e.g. about 3 .mu.g to about 30 .mu.g. Such doses may be for
administration daily (daily doses) or twice daily, e.g. for daily
administration.
[0025] Embodiment 8: Use of a FXR agonist of formula (I), a
stereoisomer, an enantiomer, a pharmaceutically acceptable salt
thereof or an amino acid conjugate thereof, e.g. Compound A or an
amino acid conjugate thereof, in the manufacture of a medicament
for treating or preventing a condition mediated by Farnesoid X
receptor (FXR), wherein the FXR agonist is to be administered at a
dose of about 3 .mu.g, about 4 .mu.g, about 5 .mu.g, about 10
.mu.g, about 20 .mu.g, about 25 .mu.g, about 30 .mu.g, about 40
.mu.g, about 60 .mu.g, or about 90 .mu.g. Such doses may be for
daily administration (e.g. daily doses) or daily or twice daily,
e.g. for daily administration.
[0026] Embodiment 9: Use of a FXR agonist of formula (I), a
stereoisomer, an enantiomer, a pharmaceutically acceptable salt
thereof or an amino acid conjugate thereof, e.g. Compound A or an
amino acid conjugate thereof, in the manufacture of a medicament
for treating or preventing a condition mediated by Farnesoid X
receptor (FXR), wherein the FXR agonist is to be administered at a
dose of about 3 .mu.g/day to about 100 .mu.g/day, about 5 .mu.g/day
to about 100 .mu.g/day, e.g. about 10 .mu.g/day to about 100
.mu.g/day, e.g. about 20 .mu.g/day to 100 .mu.g/day, e.g. about 30
.mu.g/day to about 90 .mu.g/day, e.g. about 40 .mu.g/day to about
60 .mu.g/day; or at a dose of about 10 .mu.g/day to about 60
.mu.g/day, e.g. about 10 .mu.g/day to about 40 .mu.g/day, e.g.
about 20 .mu.g/day to about 40 .mu.g/day; or at a dose of about 20
.mu.g/day to about 60 .mu.g/day, e.g. about 30 .mu.g/day to about
60 .mu.g/day; or at a dose of about 5 .mu.g/day to about 60
.mu.g/day, e.g. about 5 .mu.g/day to about 40 .mu.g/day; or at a
dose of about 3 .mu.g/day to about 40 .mu.g/day, e.g. about 3
.mu.g/day to about 30 .mu.g/day.
[0027] Embodiment 10: Use of a FXR agonist of formula (I), a
stereoisomer, an enantiomer, a pharmaceutically acceptable salt
thereof or an amino acid conjugate thereof, e.g. Compound A or an
amino acid conjugate thereof, in the manufacture of a medicament
for treating or preventing a condition mediated by Farnesoid X
receptor (FXR), wherein the FXR agonist is to be administered at a
dose of about 3 .mu.g, about 4 .mu.g, about 5 .mu.g, about 10
.mu.g, about 20 .mu.g, about 25 .mu.g, about 30 .mu.g, about 40
.mu.g, about 60 .mu.g, or about 90 .mu.g. Such doses may be for
daily administration (e.g. daily doses) or twice daily
administration.
[0028] Embodiment 11: A FXR agonist of formula (I), a stereoisomer,
an enantiomer, a pharmaceutically acceptable salt thereof or an
amino acid conjugate thereof, e.g. Compound A or an amino acid
conjugate thereof, for use in treating or preventing a condition
mediated by FXR; wherein the FXR agonist is to be administered at a
dose (e.g. daily dose) of about 3 .mu.g to about 100 .mu.g, about 5
.mu.g to about 100 .mu.g, e.g. about 10 .mu.g to about 100 .mu.g,
e.g. about 20 .mu.g to 100 .mu.g, e.g. about 30 .mu.g to about 90
.mu.g, e.g. about 40 .mu.g to about 60 .mu.g; or at a dose of about
10 .mu.g to about 60 .mu.g, e.g. about 10 .mu.g to about 40 .mu.g,
e.g. about 20 .mu.g to about 40 .mu.g; or at a dose of about 20
.mu.g to about 60 .mu.g, e.g. about 30 .mu.g to about 60 .mu.g; or
at a dose of about 5 .mu.g to about 60 .mu.g, e.g. about 5 .mu.g to
about 40 .mu.g; or at a dose of about 3 .mu.g to 40 .mu.g, e.g.
about 3 .mu.g to 30 .mu.g, and wherein said condition mediated by
FXR is cholestatic disorders, e.g. cholestasis (e.g. intrahepatic
cholestasis, estrogen-induced cholestasis, drug-induced
cholestasis, cholestasis of pregnancy, parenteral
nutrition-associated cholestasis), primary biliary cholangitis
(PBC; formerly primary biliary cirrhosis), cirrhosis, primary
sclerosing cholangitis (PSC), progressive familiar cholestatis
(PFIC), Alagille syndrome, biliary atresia, ductopenic liver
transplant rejection, cystic fibrosis liver disease.
[0029] Embodiment 12: A FXR agonist of formula (I), a stereoisomer,
an enantiomer, a pharmaceutically acceptable salt thereof or an
amino acid conjugate thereof, e.g. Compound A or an amino acid
conjugate thereof, for use in treating or preventing a condition
mediated by FXR; wherein the FXR agonist is to be administered at a
dose of about 3 .mu.g, about 4 .mu.g, about 5 .mu.g, about 10
.mu.g, about 20 .mu.g, about 25 .mu.g, about 30 .mu.g, about 40
.mu.g, about 60 .mu.g, or about 90 .mu.g. Such doses may be for
daily administration (e.g. daily doses). Such doses may be for
twice daily administration.
[0030] Embodiment 13: The use of a FXR agonist of formula (I), a
stereoisomer, an enantiomer, a pharmaceutically acceptable salt
thereof or an amino acid conjugate thereof, e.g. Compound A or an
amino acid conjugate thereof, according to any one of Embodiments 1
to 12, wherein the condition mediated by FXR is a cholestatic
disorder, e.g. cholestasis (e.g. intrahepatic cholestasis,
estrogen-induced cholestasis, drug-induced cholestasis, cholestasis
of pregnancy, parenteral nutrition-associated cholestasis), primary
biliary cholangitis (PBC), cirrhosis, primary sclerosing
cholangitis (PSC), progressive familiar cholestatis (PFIC),
Alagille syndrome, biliary atresia, ductopenic liver transplant
rejection, fibrosis liver disease, e.g. cystic fibrosis liver
disease.
[0031] Embodiment 14: The use of a FXR agonist of formula (I), a
stereoisomer, an enantiomer, a pharmaceutically acceptable salt
thereof or an amino acid conjugate thereof, e.g. Compound A or an
amino acid conjugate thereof, according to any one of Embodiments 1
to 12, wherein the condition mediated by FXR is cholestasis, PBC,
cirrhosis, fibrosis liver disease or PSC.
[0032] Embodiment 15: The use of a FXR agonist of formula (I), a
stereoisomer, an enantiomer, a pharmaceutically acceptable salt
thereof or an amino acid conjugate thereof, e.g. Compound A or an
amino acid conjugate thereof, according to any one of Embodiments 1
to 12, wherein the condition mediated by FXR is cholestasis, PBC,
cirrhosis or fibrosis liver disease.
[0033] Embodiment 16: A method for treating or preventing a
condition mediated by Farnesoid X receptor (FXR) in a subject
suffering therefrom, comprising administering to the subject a FXR
agonist of formula (I), a stereoisomer, an enantiomer, a
pharmaceutically acceptable salt thereof or an amino acid conjugate
thereof, e.g. Compound A or an amino acid conjugate thereof;
wherein said FXR agonist is to be administered at a daily dose of
about 3 .mu.g to about 100 .mu.g, about 5 .mu.g to about 100 .mu.g,
e.g. about 10 .mu.g to about 100 .mu.g, e.g. about 20 .mu.g to 100
.mu.g, e.g. about 30 .mu.g to about 90 .mu.g, e.g. about 40 .mu.g
to about 60 .mu.g; or at a dose of about 10 .mu.g to about 60
.mu.g, e.g. about 10 .mu.g to about 40 .mu.g, e.g. about 20 .mu.g
to about 40 .mu.g; or at a dose of about 20 .mu.g to about 60
.mu.g, e.g. about 30 .mu.g to about 60 .mu.g; or at a dose of about
5 .mu.g to about 60 .mu.g, e.g. about 5 .mu.g to about 40 .mu.g,
e.g. about 10 .mu.g to about 100 .mu.g, e.g. about 20 .mu.g to
about 100 .mu.g, e.g. about 30 .mu.g to about 90 .mu.g; e.g. about
3 .mu.g to about 40 .mu.g, e.g. about 3 .mu.g to about 30
.mu.g.
[0034] Embodiment 17: A method for treating or preventing a
condition mediated by Farnesoid X receptor (FXR) in a subject
suffering therefrom, comprising administering to the subject a FXR
agonist of formula (I), a stereoisomer, an enantiomer, a
pharmaceutically acceptable salt thereof or an amino acid conjugate
thereof, e.g. Compound A or an amino acid conjugate thereof;
wherein said FXR agonist is to be administered at a dose of about 3
.mu.g/day to 100 .mu.g/day, e.g. about 5 .mu.g/day to 100
.mu.g/day, e.g. about 10 .mu.g to about 100 .mu.g/day, e.g. about
20 .mu.g/day to about 100 .mu.g/day, e.g. about 30 .mu.g/day to
about 90 .mu.g/day, e.g. about 3 .mu.g/day to about 30
.mu.g/day.
[0035] Embodiment 18: A method for treating or preventing a
condition mediated by Farnesoid X receptor (FXR) in a subject
suffering therefrom, comprising administering to the subject a FXR
agonist of formula (I), a stereoisomer, an enantiomer, a
pharmaceutically acceptable salt thereof or an amino acid conjugate
thereof, e.g. Compound A or an amino acid conjugate thereof;
wherein said FXR agonist is to be administered at a dose of about 3
.mu.g/day, about 4 .mu.g/day, about 10 .mu.g/day, about 20
.mu.g/day, about 25 .mu.g/day, about 30 .mu.g/day, about 60
.mu.g/day, or about 90 .mu.g/day.
[0036] Embodiment 19: A method for treating or preventing a
condition mediated by Farnesoid X receptor (FXR) according to any
one of Embodiments 1 to 18, wherein the condition is a cholestatic
disorder, e.g. cholestasis (e.g. intrahepatic cholestasis,
estrogen-induced cholestasis, drug-induced cholestasis, cholestasis
of pregnancy, parenteral nutrition-associated cholestasis), primary
biliary cholangitis (PBC), cirrhosis, primary sclerosing
cholangitis (PSC), progressive familiar cholestatis (PFIC),
Alagille syndrome, biliary atresia, ductopenic liver transplant
rejection, fibrosis liver disease, e.g. cystic fibrosis liver
disease.
[0037] Embodiment 20: A method for treating or preventing a
condition mediated by Farnesoid X receptor (FXR) according to any
one of Embodiments 1 to 18, wherein the condition is cholestasis,
PBC, cirrhosis, fibrosis liver disease or PSC.
[0038] Embodiment 21: A method for treating or preventing a
condition mediated by Farnesoid X receptor (FXR) according to any
one of Embodiments 1 to 18, wherein the condition is cholestasis,
PBC, cirrhosis or fibrosis liver disease.
[0039] Embodiment 22: A method for treating or preventing is a
cholestatic disorder in a subject suffering therefrom, comprising
administering to the subject a FXR agonist of formula (I), a
stereoisomer, an enantiomer, a pharmaceutically acceptable salt
thereof or an amino acid conjugate thereof, e.g. Compound A or an
amino acid conjugate thereof, in a dose (e.g. daily dose) of about
3 .mu.g to about 100 .mu.g, about 5 .mu.g to about 100 .mu.g, e.g.
about 10 .mu.g to about 100 .mu.g, e.g. about 20 .mu.g to 100
.mu.g, e.g. about 30 .mu.g to about 90 .mu.g, e.g. about 40 .mu.g
to about 60 .mu.g; or at a dose of about 10 .mu.g to about 60
.mu.g, e.g. about 10 .mu.g to about 40 .mu.g, e.g. about 20 .mu.g
to about 40 .mu.g; or at a dose of about 20 .mu.g to about 60
.mu.g, e.g. about 30 .mu.g to about 60 .mu.g; or at a dose of about
5 .mu.g to about 60 .mu.g, e.g. about 5 .mu.g to about 40 .mu.g,
e.g. about 10 .mu.g to about 100 .mu.g, e.g. about 20 .mu.g to
about 100 .mu.g, e.g. about 30 .mu.g to about 90 .mu.g.
[0040] Embodiment 23: A method for treating or preventing is a
cholestatic disorder in a subject suffering therefrom, comprising
administering to the subject a FXR agonist of formula (I), a
stereoisomer, an enantiomer, a pharmaceutically acceptable salt
thereof or an amino acid conjugate thereof, e.g. Compound A or an
amino acid conjugate thereof, at a dose of about 3 .mu.g, about 4
.mu.g, about 5 .mu.g, about 10 .mu.g, about 20 .mu.g, about 25
.mu.g, about 30 .mu.g, about 40 .mu.g, about 60 .mu.g, or about 90
.mu.g. Such doses may be for daily administration (e.g. daily
doses). Such doses may be for twice daily administration.
[0041] Embodiment 24: A use, a FXR agonist or a method for treating
or preventing a condition mediated by Farnesoid X receptor (FXR) in
a subject suffering therefrom according to any one of Embodiments 1
to 23, wherein the FXR agonist compound is to be administered for a
period of 3 months to lifelong, e.g. 6 months to lifelong, e.g. 1
year to lifelong, e.g. for a period of 3 months to 1 year, e.g. 6
months to lifelong, e.g. for a period of 3 months, 6 months or 1
year or for lifelong.
[0042] Embodiment 25: A use, a FXR agonist, a FXR agonist regimen,
or a method for treating or preventing a cholestatic disorder in a
subject suffering therefrom according to any one of Embodiments 1
to 23, wherein the FXR agonist compound is to be administered for a
period of 3 months to lifelong, e.g. 6 months to lifelong, e.g. 1
year to lifelong, e.g. for a period of 3 months to 1 year, e.g. 6
months to lifelong, e.g. for a period of 3 months, 6 months or 1
year or for lifelong.
[0043] Embodiment 26: A use, a FXR agonist, a FXR agonist regimen,
or a method for treating or preventing a cholestatic disorder in a
subject suffering therefrom according to any one of Embodiments 1
to 23, wherein the disorder is selected from the group consisting
of cholestasis (e.g. intrahepatic cholestasis, estrogen-induced
cholestasis, drug-induced cholestasis, cholestasis of pregnancy,
parenteral nutrition-associated cholestasis), primary biliary
cholangitis (PBC), cirrhosis, primary sclerosing cholangitis (PSC),
progressive familiar cholestatis (PFIC), Alagille syndrome, biliary
atresia, ductopenic liver transplant rejection and cystic fibrosis
liver disease.
[0044] Embodiment 27: A use, a FXR agonist, a FXR agonist regimen,
or a method for treating or preventing a cholestatic disorder in a
subject suffering therefrom according to any one of Embodiments 1
to 23 or 26, wherein the disorder is primary biliary cholangitis
(PBC) [0045] with at least 2 of the following 3 diagnosis criteria:
[0046] (i)History of ALP elevated above upper limit of normal for
at lease 6 months; [0047] (ii) Positive antimitochondrial
antibodies (AMA) titer OR if AMA negative or in low titer
(<1:80) PBC specific antibodies (anti-GP210 and/or anti-SP100)
and/or antibodies against the major M2 components (PDC-E2,
2-oxo-glutaric acid dehydrogenase complex)) [0048] (iii) Previous
liver biopsy findings consistent with PBC [0049] and at least one
for the following 2 markers of disease severity: ALP
.gtoreq.1.67.times. upper limit of normal (ULN) or Total
bilirubin>ULN but <2.times. ULN.
[0050] Embodiment 28: A use, a FXR agonist, a FXR agonist regimen,
or a method according to any one of Embodiments 1 to 27 wherein the
disorder is primary biliary cholangitis and compound A is to be
used in combination with ursodeoxycholic acid (UDCA) in adults with
an inadequate response to UDCA or as monotherapy in adults unable
to tolerate UDCA.
[0051] Embodiment 29: A pharmaceutical unit dosage form composition
comprising about 10 .mu.g, about 30 .mu.g, about 60 .mu.g, about 90
.mu.g, or about 120 .mu.g of Compound A suitable for oral
administration up to a maximum total dose of 100 .mu.g per day.
Such unit dosage form compositions may be in a form selected from a
liquid, a tablet, a capsule. Also these unit dosage form
compositions are for use in treating a disorder selected from the
group consisting of cholestasis (e.g. intrahepatic cholestasis,
estrogen-induced cholestasis, drug-induced cholestasis, cholestasis
of pregnancy, parenteral nutrition-associated cholestasis), primary
biliary cholangitis (PBC), cirrhosis, primary sclerosing
cholangitis (PSC), progressive familiar cholestatis (PFIC),
Alagille syndrome, biliary atresia, ductopenic liver transplant
rejection and cystic fibrosis liver disease; e.g. primary biliary
cholangitis (PBC).
[0052] Embodiment 30: A use, a FXR agonist or a method according to
any one of Embodiments 1 to 28, a pharmaceutical unit dosage form
of Embodiment 29, wherein Compound A is administered to humans in a
fasting state, e.g. administration in a fasting state, at least 30
minutes prior to first beverage, apart from water, and at least 60
minutes prior to the first meal of the day.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0053] For purposes of interpreting this specification, the
following definitions will apply and whenever appropriate, terms
used in the singular will also include the plural and vice
versa.
[0054] As used herein, the term "about" in relation to a numerical
value x means +/-10%, unless the context dictates otherwise.
[0055] As used herein, the term "FXR agonist" refers to an agent
that directly binds to and upregulates the activity of FXR.
[0056] As used herein, the term "pharmaceutically acceptable" means
a nontoxic material that does not interfere with the effectiveness
of the biological activity of the active ingredient(s).
[0057] As used herein, the term "amino acid conjugate" refers to
conjugates of the compound of Formula (I) with any suitable amino
acid. Preferably, such suitable amino acid conjugates of the
compound of Formula (I) will have the added advantage of enhanced
integrity in bile or intestinal fluids. Suitable amino acids
include but are not limited to glycine, taurine and
acylglucuronide. Thus, the present invention encompasses the
glycine, taurine and acylglucuronide conjugates of the compound of
Formula (I), e.g. glycine, taurine and acylglucuronide conjugates
of Compound A.
[0058] As used herein, the term "subject" or "subject" refers to a
human.
[0059] As used herein, the term "treat", "treating" or "treatment"
of any disease or disorder refers in one embodiment, to
ameliorating the disease or disorder (i.e., slowing or arresting or
reducing the development of the disease or at least one of the
clinical symptoms thereof). In another embodiment "treat",
"treating" or "treatment" refers to alleviating or ameliorating at
least one physical parameter including those which may not be
discernible by the subject. In yet another embodiment, "treat",
"treating" or "treatment" refers to modulating the disease or
disorder, either physically, (e.g., stabilization of a discernible
symptom), physiologically, (e.g., stabilization of a physical
parameter), or both. In yet another embodiment, "treat", "treating"
or "treatment" refers to preventing or delaying the onset or
development or progression of the disease or disorder.
[0060] As used herein, the term "therapeutically effective amount"
refers to an amount of the compound of the invention, e.g. compound
of formula (I) or a pharmaceutically acceptable salt thereof, e.g.
Compound A, which is sufficient to achieve the stated effect.
Accordingly, a therapeutically effective amount of a FXR agonist of
formula (I), a stereoisomer, an enantiomer, a pharmaceutically
acceptable salt thereof or an amino acid conjugate thereof, e.g.
Compound A or an amino acid conjugate thereof, used for the
treatment or prevention of a condition mediated by FXR will be an
amount sufficient for the treatment or prevention of the condition
mediated by FXR.
[0061] By "therapeutic regimen" is meant the pattern of treatment
of an illness, e.g., the pattern of dosing used during the
treatment of the disease or disorder.
[0062] As used herein, a subject is "in need of" a treatment if
such subject would benefit biologically, medically or in quality of
life from such treatment.
[0063] As used herein, a "therapeutically effective amount" refers
to an amount of compound of formula (I), a stereoisomer, an
enantiomer, a pharmaceutically acceptable salt thereof or an amino
acid conjugate thereof, e.g. Compound A or an amino acid conjugate
thereof, e.g. Compound A, that is effective, upon single or
multiple dose administration to a subject (such as a human subject)
at treating, preventing, curing, delaying, reducing the severity
of, ameliorating at least one symptom of a disorder or recurring
disorder, or prolonging the survival of the subject beyond that
expected in the absence of such a treatment.
DESCRIPTION OF THE FIGURES
[0064] FIGS. 1A-1D show the effect of a Compound A on serum markers
of cholestasis and liver damage in the chronic treatment rat ANIT
model.
[0065] FIG. 1E shows serum FGF15 protein levels following treatment
with Compound A in the chronic rat ANIT-induced cholestasis
model.
[0066] FIGS. 2A-2B show the effect of different dosages of Compound
A on mRNA expression of FXR target genes in rat intestine.
MODES OF CARRYING OUT THE INVENTION
[0067] The present invention provides the use of FXR agonists for
treating or preventing liver disease and disorders.
[0068] The disclosed FXR antagonists, e.g. Compound A, are useful
for the treatment, prevention, or amelioration of liver diseases
and disorders.
[0069] The FXR agonists, e.g. Compound A, may be used in vitro, ex
vivo, or incorporated into pharmaceutical compositions and
administered to individuals (e.g. human subjects) in vivo to treat,
ameliorate, or prevent liver diseases and disorders. A
pharmaceutical composition will be formulated to be compatible with
its intended route of administration (e.g., oral compositions
generally include an inert diluent or an edible carrier). Other
nonlimiting examples of routes of administration include parenteral
(e.g., intravenous), intradermal, subcutaneous, oral (e.g.,
inhalation), transdermal (topical), transmucosal, and rectal
administration. The pharmaceutical compositions compatible with
each intended route are well known in the art.
[0070] The frequency of dosing may be twice per day, once per day,
or every two days, e.g. once a day. In some embodiments the
frequency of dosing is twice per day. The dosing frequency will
depend on, inter alia, the phase of the treatment regimen.
[0071] In some embodiments, the dosing regimen comprises
administration of an FXR agonist of formula (I), e.g. Compound A,
about 3 .mu.g-about 100 .mu.g delivered orally, e.g. about 5
.mu.g-about 100 .mu.g delivered orally, e.g. about 10 .mu.g-about
100 .mu.g delivered orally, e.g. about 20 .mu.g-100 .mu.g delivered
orally, e.g. about 30 .mu.g-about 90 .mu.g delivered orally, e.g.
about 40 .mu.g-about 60 .mu.g delivered orally. Such doses may be
for daily administration (daily doses), or twice daily
administration or every two days administration, e.g. for daily
administration.
[0072] In some embodiments, the dosing regimen comprises
administration of an FXR agonist of formula (I), e.g. Compound A,
at a dose in a range of about 20 .mu.g-about 60 .mu.g delivered
orally, e.g. about 30 .mu.g-about 60 .mu.g delivered orally. Such
doses may be for daily administration (daily doses), or twice daily
administration or every two days administration, e.g. for daily
administration.
[0073] In some embodiments, the dosing regimen comprises
administration of an FXR agonist of formula (I), e.g. Compound A,
about 10 .mu.g-60 .mu.g delivered orally, e.g. about 10 .mu.g-about
40 .mu.g delivered orally, e.g. about 20 .mu.g-about 40 .mu.g
delivered orally. Such doses may be for daily administration (daily
doses), or twice daily administration or every two days
administration, e.g. for daily administration.
[0074] In some embodiments, the dosing regimen comprises
administration of an FXR agonist of formula (I), e.g. Compound A,
at a dose in a range of about 5 .mu.g-about 60 .mu.g delivered
orally, e.g. about 5 .mu.g-about 40 .mu.g delivered orally. Such
doses may be for daily administration (daily doses), or twice daily
administration or every two days administration, e.g. for daily
administration.
[0075] In some embodiments, the dosing regimen comprises
administration of an FXR agonist of formula (I), e.g. Compound A,
at a dose in a range of about 3 .mu.g-about 40 .mu.g delivered
orally, e.g. about 3 .mu.g-about 30 .mu.g delivered orally. Such
doses may be for daily administration (daily doses), or twice daily
administration or every two days administration, e.g. for daily
administration.
[0076] In some embodiments, the dosing regimen comprises
administration of an FXR agonist of formula (I), e.g. Compound A,
at a dose of about 3 .mu.g delivered orally, about 4 .mu.g
delivered orally, about 5 .mu.g delivered orally, about 10 .mu.g
delivered orally, about 20 .mu.g delivered orally, about 25 .mu.g
delivered orally, about 30 .mu.g delivered orally, about 40 .mu.g
delivered orally, about 60 .mu.g delivered orally, or about 90
.mu.g delivered orally. Such doses may be for oral
administration.
[0077] In some embodiments, the dosing regimen comprises
administration of an FXR agonist of formula (I), e.g. Compound A,
at a dose in a range of about 3 .mu.g/day to about 100 .mu.g/day,
e.g. about 5 .mu.g/day to about 100 .mu.g/day, e.g. about 10
.mu.g/day to about 100 .mu.g/day, e.g. about 20 .mu.g/day to 100
.mu.g/day, e.g. about 30 .mu.g/day to about 90 .mu.g/day, e.g.
about 40 .mu.g/day to about 60 .mu.g/day, e.g. about 10 .mu.g/day
to 60 .mu.g/day, e.g. about 10 .mu.g/day to about 40 .mu.g/day,
e.g. about 20 .mu.g/day to 40 .mu.g/day, e.g. about 20 .mu.g/day to
about 60 .mu.g/day, e.g. about 30 .mu.g/day to about 60 .mu.g/day,
e.g. about 5 .mu.g/day to 60 .mu.g/day, e.g. about 5 .mu.g/day to
40 .mu.g/day, e.g. about 3 .mu.g/day to about 40 .mu.g/day, about 3
.mu.g/day to about 30 .mu.g/day.
[0078] In some embodiments, the dosing regimen comprises
administration of a FXR agonist of formula (I), e.g. Compound A, at
a dose of about 3 .mu.g/day, about 4 .mu.g/day, about 5 .mu.g/day,
about 10 .mu.g/day, about 25 .mu.g/day, about 30 .mu.g/day, about
60 .mu.g/day, or about 90 .mu.g/day. Such regimens may be delivered
orally.
[0079] In some embodiments, the dosing regimen comprises
administration of a FXR agonist of formula (I), e.g. Compound A, at
a dose of about 3 .mu.g twice daily, about 4 .mu.g twice daily,
about 5 .mu.g twice daily, about 10 .mu.g twice daily, about 25
.mu.g twice daily, about 30 .mu.g twice daily. Such regimens may be
delivered orally.
[0080] In some embodiments, the dosing regimen comprises
administration of a FXR agonist of formula (I), e.g. Compound A, at
a dose of about 5 .mu.g every two days, about 10 .mu.g every two
days, about 40 .mu.g every two days, about 60 .mu.g every two days.
Such regimens may be delivered orally.
[0081] As herein defined, the dosing regimens are adapted to treat
or prevent a cholestatic disorder, e.g. cholestasis (e.g.
intrahepatic cholestasis, estrogen-induced cholestasis,
drug-induced cholestasis, cholestasis of pregnancy, parenteral
nutrition-associated cholestasis), primary biliary cholangitis
(PBC), cirrhosis, primary sclerosing cholangitis (PSC), progressive
familiar cholestatis (PFIC), Alagille syndrome, biliary atresia,
ductopenic liver transplant rejection, cystic fibrosis liver
disease.
[0082] Disclosed herein are methods of treating or preventing a
cholestatic disorder such as e.g. PBC, comprising administering a
subject in need thereof a FXR agonist of formula (I), e.g. Compound
A, at a dose of about 3 .mu.g to about 100 .mu.g, about 5 .mu.g to
about 100 .mu.g, e.g. about 10 .mu.g to about 100 .mu.g, e.g. about
20 .mu.g to 100 .mu.g, e.g. about 30 .mu.g to about 90 .mu.g, e.g.
about 40 .mu.g to about 60 .mu.g, e.g. about 10 .mu.g to 60 .mu.g,
e.g. about 10 .mu.g to about 40 .mu.g, e.g. about 20 .mu.g to about
40 .mu.g; or a dose of about 20 .mu.g to about 60 .mu.g, e.g. about
30 .mu.g to about 60 .mu.g; or a dose of about 5 .mu.g to about 60
.mu.g, e.g. about 5 .mu.g to about 40 .mu.g, e.g. about 3 .mu.g to
about 40 .mu.g, e.g. about 3 .mu.g to about 30 .mu.g.
[0083] Disclosed herein are methods of treating or preventing a
cholestatic disorder such as e.g. PBC comprising administering a
subject in need thereof a FXR agonist of formula (I), e.g. Compound
A, at about 3 .mu.g, e.g. at about 4 .mu.g, e.g. at about 5 .mu.g,
e.g. about 10 .mu.g, e.g. about 20 .mu.g, e.g. about 25 .mu.g, e.g.
about 30 .mu.g, e.g. about 40 .mu.g, e.g. about 60 .mu.g, or e.g.
about 90 .mu.g. In some embodiments such a dose is administered
daily, e.g. orally. In some embodiments such a dose is administered
orally, e.g. daily.
[0084] Disclosed herein are FXR agonists of formula (I), a
stereoisomer, an enantiomer, a pharmaceutically acceptable salt
thereof or an amino acid conjugate thereof, e.g. Compound A or an
amino acid conjugate thereof, e.g. Compound A, for use in treating
or preventing a cholestatic disorder, e.g. PBC, characterized in
that said FXR agonist is to be administered at a dose selected from
the group consisting of about 3 .mu.g, about 4 .mu.g, about 5
.mu.g, about 10 .mu.g, about 20 .mu.g about 25 .mu.g, about 30
.mu.g, about 40 .mu.g, about 60 .mu.g and about 90 .mu.g. Such
doses may be administered daily, twice daily or every two days,
e.g. daily. Such doses may be administered orally.
[0085] In some embodiments, are disclosed FXR agonists of formula
(I), a stereoisomer, an enantiomer, a pharmaceutically acceptable
salt thereof or an amino acid conjugate thereof, e.g. Compound A or
an amino acid conjugate thereof, e.g. Compound A, for use in
treating or preventing a cholestatic disorder such as e.g. PBC,
wherein said FXR agonist is to be administered at a daily dose
selected from the group consisting of about 10 .mu.g, about 20
.mu.g, about 25 .mu.g, about 30 .mu.g, about 60 .mu.g and about 90
.mu.g.
[0086] In some embodiments, are disclosed FXR agonists of formula
(I), a stereoisomer, an enantiomer, a pharmaceutically acceptable
salt thereof or an amino acid conjugate thereof, e.g. Compound A or
an amino acid conjugate thereof, e.g. Compound A, for use in
treating or preventing a cholestatic disorder such as e.g. PBC,
wherein said FXR agonist is to be administered at a daily dose
selected from the group consisting of about 3 .mu.g, about 4 .mu.g,
about 5 .mu.g, about 10 .mu.g, about 30 .mu.g.
[0087] In some embodiments, are disclosed FXR agonists of formula
(I), a stereoisomer, an enantiomer, a pharmaceutically acceptable
salt thereof or an amino acid conjugate thereof, e.g. Compound A or
an amino acid conjugate thereof, e.g. Compound A, for use in
treating or preventing a cholestatic disorder such as e.g. PBC,
wherein said FXR agonist is to be administered twice daily at a
dose selected from the group consisting of about 3 .mu.g, about 4
.mu.g, about 5 .mu.g, about 10 .mu.g, about 25 .mu.g, about 30
.mu.g.
[0088] In some embodiments, are disclosed FXR agonists of formula
(I), a stereoisomer, an enantiomer, a pharmaceutically acceptable
salt thereof or an amino acid conjugate thereof, e.g. Compound A or
an amino acid conjugate thereof, e.g. Compound A, for use in
treating or preventing a cholestatic disorder such as e.g. PBC,
wherein said FXR agonist is to be administered every two days at a
dose selected from the group consisting of about 5 .mu.g, about 10
.mu.g, about 40 .mu.g, about 60 .mu.g.
[0089] In some embodiments, are disclosed FXR agonists of formula
(I), a stereoisomer, an enantiomer, a pharmaceutically acceptable
salt thereof or an amino acid conjugate thereof, e.g. Compound A or
an amino acid conjugate thereof, e.g. Compound A, for use in
treating or preventing a cholestatic disorder such as e.g. PBC,
wherein said FXR agonist is to be administered at a daily dose of
about 3 .mu.g or about 5 .mu.g.
[0090] In some embodiments, are disclosed FXR agonists of formula
(I), a stereoisomer, an enantiomer, a pharmaceutically acceptable
salt thereof or an amino acid conjugate thereof, e.g. Compound A or
an amino acid conjugate thereof, e.g. Compound A, for use in
treating or preventing a cholestatic disorder such as e.g. PBC,
wherein said FXR agonist is to be administered at a daily dose of
about 10 .mu.g.
[0091] In some embodiments, are disclosed formula (I), a
stereoisomer, an enantiomer, a pharmaceutically acceptable salt
thereof or an amino acid conjugate thereof, e.g. Compound A or an
amino acid conjugate thereof, e.g. Compound A, for use in treating
or preventing a cholestatic disorder such as e.g. PBC, wherein said
FXR agonist is to be administered at a daily dose of about 20 .mu.g
or 25 .mu.g.
[0092] In some embodiments, are disclosed FXR agonists of formula
(I), a stereoisomer, an enantiomer, a pharmaceutically acceptable
salt thereof or an amino acid conjugate thereof, e.g. Compound A or
an amino acid conjugate thereof, e.g. Compound A, for use in
treating or preventing a cholestatic disorder such as e.g. PBC,
wherein said FXR agonist is to be administered at a daily dose of
about 30 .mu.g.
[0093] In some embodiments, are disclosed FXR agonists of formula
(I) or pharmaceutically acceptable salts thereof, e.g. Compound A,
for use in treating or preventing a cholestatic disorder such as
e.g. PBC, wherein said FXR agonist is to be administered at a daily
dose of about 40 .mu.g.
[0094] In some embodiments, are disclosed FXR agonists of formula
(I), a stereoisomer, an enantiomer, a pharmaceutically acceptable
salt thereof or an amino acid conjugate thereof, e.g. Compound A or
an amino acid conjugate thereof, e.g. Compound A, for use in
treating or preventing a cholestatic disorder such as e.g. PBC,
wherein said FXR agonist is to be administered at a daily dose of
about 60 .mu.g, of about 90 .mu.g.
[0095] In some embodiments, there is provided dosing regimens that
provide a Cmax of the FXR agonist of formula (I) or
pharmaceutically acceptable salt thereof, e.g. Compound A, of at
least about 0.2 ng/mL, e.g. in a range of about 0.2 to about 2.0
ng/mL, e.g. about 0.2 to about 1.0 ng/mL, e.g. about 0.2 to about
0.5 ng/mL.
Kits for the Treatment of Liver Disease or Disorders
[0096] Provided herein are kits useful for providing FXR agonists
of formula (I), a stereoisomer, an enantiomer, a pharmaceutically
acceptable salt thereof or an amino acid conjugate thereof, e.g.
Compound A or an amino acid conjugate thereof, e.g. Compound A, for
the treatment of liver diseases or disorders, e.g. a cholestatic
disorder, e.g. PBC. Such kits may comprise FXR agonists of formula
(I), a stereoisomer, an enantiomer, a pharmaceutically acceptable
salt thereof or an amino acid conjugate thereof, e.g. Compound A or
an amino acid conjugate thereof, e.g. Compound A, or a
pharmaceutical composition comprising said FXR agonist, e.g.
Compound A. Additionally, such kits may comprise means for
administering the FXR agonist molecule (e.g. solid composition) and
instructions for use.
[0097] Accordingly, disclosed herein are kits comprising: a) a
pharmaceutical composition comprising a therapeutically effective
amount of a FXR agonist formula (I), a stereoisomer, an enantiomer,
a pharmaceutically acceptable salt thereof or an amino acid
conjugate thereof, e.g. Compound A or an amino acid conjugate
thereof, e.g. Compound A; b) means for administering the FXR
agonist molecule (e.g. Compound A) to a subject having a liver
disease or disorder; and c) instructions for use, wherein the
pharmaceutical composition comprises said FXR agonist molecule at
dose (e.g. daily dose) in a range of about 3 .mu.g to about 100
.mu.g, about 5 .mu.g to about 100 .mu.g, e.g. about 10 .mu.g to
about 100 .mu.g, e.g. about 20 .mu.g to 100 .mu.g, e.g. about 30
.mu.g to about 90 .mu.g, e.g. about 40 .mu.g to about 60 .mu.g,
e.g. about 10 .mu.g to 60 .mu.g, e.g. about 10 .mu.g to 40 .mu.g,
e.g. about 20 .mu.g to 40 .mu.g, e.g. about 20 .mu.g to about 60
.mu.g, e.g. about 30 .mu.g to about 60 .mu.g; or at a dose (e.g.
daily dose) in a range of about 5 .mu.g to about 40 .mu.g, e.g.
about 10 .mu.g to about 40 .mu.g, e.g. about 20 .mu.g to about 40
.mu.g, e.g. about 3 .mu.g to about 40 .mu.g, about 3 .mu.g to about
30 .mu.g.
[0098] Are also disclosed kits comprising: a) a pharmaceutical
composition comprising a therapeutically effective amount of a FXR
agonist of formula (I), a stereoisomer, an enantiomer, a
pharmaceutically acceptable salt thereof or an amino acid conjugate
thereof, e.g. Compound A or an amino acid conjugate thereof, e.g.
Compound A; b) means for administering the FXR agonist molecule
(e.g. Compound A) to a subject having a cholestatic disorder; and
c) instructions for use, wherein the pharmaceutical composition
comprises a dose of the FXR agonist molecule selected from the
group consisting of about 3 .mu.g, about 4 .mu.g, about 5 .mu.g,
about 10 .mu.g, about 20 .mu.g, about 25 .mu.g, about 30 .mu.g,
about 40 .mu.g, about 60 .mu.g, and about 90 .mu.g; e.g. wherein
the pharmaceutical composition comprises about 3 .mu.g, about 4
.mu.g, about 5 .mu.g, about 10 .mu.g, about 20 .mu.g, about 25
.mu.g, about 30 .mu.g, about 40 .mu.g, about 60 .mu.g, or about 90
.mu.g of the FXR agonist molecule.
[0099] According to the invention, the above mentioned kits are
adapted t treat or prevent preventing a cholestatic disorder, e.g.
cholestasis (e.g. intrahepatic cholestasis, estrogen-induced
cholestasis, drug-induced cholestasis, cholestasis of pregnancy,
parenteral nutrition-associated cholestasis), primary biliary
cholangitis (PBC), cirrhosis, primary sclerosing cholangitis (PSC),
progressive familiar cholestatis (PFIC), Alagille syndrome, biliary
atresia, ductopenic liver transplant rejection, cystic fibrosis
liver disease.
[0100] In another embodiment, a FXR agonist of formula (I), a
stereoisomer, an enantiomer, a pharmaceutically acceptable salt
thereof or an amino acid conjugate thereof, e.g. Compound A or an
amino acid conjugate thereof, e.g. Compound A, is administered
enterally; and more particularly, orally.
[0101] Unless specified otherwise, a compound for use in the
methods of the invention refers to a FXR agonist of formula (I), a
stereoisomer, an enantiomer, a pharmaceutically acceptable salt
thereof or an amino acid conjugate thereof, e.g. Compound A or an
amino acid conjugate thereof, prodrugs, and inherently formed
moieties (e.g., polymorphs, solvates and/or hydrates). Any formula
given herein is also intended to represent unlabeled forms as well
as isotopically labeled forms of the compounds.
[0102] Treatments using a FXR agonist according to the present
invention, e.g. Compound A achieve at least 30%, 35%, 40%, 50%, 60%
percent of patients having reduction of alkaline phosphatase
<1.67.times. ULN; also following administration of Compound A
changes in liver stiffness as measures by Fibroscan, changes in the
itch domain of PBC40 questionnaire and changes in itch based on 100
mm visual analog score are shown.
EXAMPLES
Example 1
Effect of Test Compound in Chronic Treatment Rat ANIT Model
[0103] Compound A was evaluated in the rat
alpha-naphthyl-isothiocyanate (ANIT) model over a range of doses
from 0.01 to 3 mg/kg. This model was utilized because it
recapitulates many features of cholestasis observed in human PBC.
In rats, ANIT-treatment leads to hepatic inflammatory cell
infiltrate, bile duct hyperplasia, necrosis of bile duct
epithelium, expansion of the hepatic portal region, hepatic
fibrosis, hepatocellular necrosis and elevated levels of
circulating bile acids, bilirubin, ALT, AST and GGT. These features
are similar to subjects with advanced PBC.
[0104] Rats were treated with alpha-naphthyl-isothiocyanate (ANIT)
(0.1% w/w) in food for 3 days prior to treatment with the compound
at the indicated doses or with vehicle control ("Veh"). A
non-cholestatic control group was fed standard chow diet without
ANIT, and serve as the non-cholestatic control animals ("Control").
After 14 days of oral dosing, the indicated analyte was measured in
serum. LLQ, lower limit of quantitation. Mean.+-.SEM; n=5.
[0105] ANIT treatment caused elevation of hepatobiliary injury
indicators, such as elevated levels of circulating aspartate
aminotransferase (AST) (FIG. 1A), alanine aminotransferase (ALT)
(FIG. 1B), bilirubin (FIG. 1C) and bile acids (FIG. 1D) ("Veh" vs
"Control"). These data demonstrate that ANIT exposure induced
profound cholestasis and hepatocellular damage. In contrast,
Compound A improved many of these indicators starting at doses as
low as 0.01 mg/kg. Marked reductions of serum bile acid and
bilirubin concentrations were observed upon treatment with Compound
A. The reduced levels of total bile acids (TBA) levels associated
with treatment of Compound A were consistent with the
pharmacological action of FXR agonist by reducing accumulation of
bile acids in the liver, enhancing bile acid excretion in the
biliary tract and inhibiting bile acid synthesis. The improvement
in the serum conjugated bilirubin (a direct indicator for hepatic
function) by Compound A implies recovery from cholestasis with
improved bile excretion.
[0106] Furthermore, Compound A stimulated serum FGF15 expression in
the chronic treatment rat ANIT model in a dose dependent manner
(FIG. 1E). Serum FGF15 levels were quantified using an FGF15 Meso
Scale Discovery (MSD) assay. Mouse FGF15 antibody from R&D
Systems (AF6755) was used both as capture and detection antibody in
the assay. MSD SULFO-TAG NHS-Ester was used to label the FGF15
antibody. MSD standard 96-well plates were coated with the FGF15
capture antibody and the plates were blocked with MSD Blocker A
(R93AA-2). After washing the plate with PBS+0.05% Tween 20, MSD
diluent 4 was dispensed into each well and incubated for 30 min. 25
.mu.l of calibrator dilutions or samples (serum or EDTA plasma)
were dispensed into each well and incubated with shaking at RT.
After washing, detection antibody was added and incubated with
shaking for 1 h at RT. After washing and the addition of MSD Read
buffer (R92TC-2), the plate was read on an MSD SECTOR Imager 6000.
Plots of the standard curve and unknown samples were calculated
using MSD data analysis software.
[0107] Activation of FXR in the ileum induces the expression of
fibroblast growth factor 15 (FGF15 in rodent; FGF19 in human), a
hormone that is secreted in the portal blood and signals to the
liver to repress Cyp7a1 expression synergistically with SHP. The
direct FXR-dependent induction of FGF15/19 along with FGF15/19's
anti-cholestatic properties makes it a convenient serum biomarker
for detecting target engagement of FXR agonists. Significant
dose-dependent induction of FGF15 observed with treatment of
Compound A demonstrates FXR target engagement by Compound A.
Example 2
[0108] The efficacious concentration of Compound A was determined
by PK/PD modeling from the rat ANIT-induced cholestasis chronic
treatment model.
[0109] Male Wistar rats were treated with ANIT (0.1% ANIT in chow
diet) for 2 weeks. The treatment of Compound A (0.01, 0.05, 0.25, 1
and 3 mg/kg, n=5/group) was initiated 3 days after disease
induction by ANIT. The serum samples were collected on day 14 for
analysis of biomarkers of hepatobiliary injury (including ALT, AST,
bilirubin and bile acids). The PK samples (pre-dose, 0.5, 1, 3, 7,
10 and 24 h, n=3/dose group) were taken on day 13 (at
steady-state). AUC0-24 h was determined using Phoenix WinNonlin 6.3
software and the average concentrations were calculated from mean
of AUC0-24 h at each dose (divided the AUC 0-24 h by 24 h). The
mean biomarker data were compared to the PK data (average
concentration at each dose) for the modeling. The IC80 was
determined using the Inhibitory effect Imax model (effect C=0 at
Imax, C=infinity at E0) built in Phoenix WinNonlin 6.3 software.
Since the biomarkers were markedly lowered at the lowest dose in
the study (0.01 mg/kg), there was variability in the IC80
determination for each biomarker. Therefore, we chose to use a mean
of the IC80 for the four biomarkers (total bilirubin, total bile
acids, ALT and AST) as the IC80 for efficacy in this model. From
these studies, the IC80 of LJN452 was 0.127 ng/ml and the
corresponding AUC0-24 h was 3.05 ng*h/ml (Table 1), and the
corresponding efficacious dose is approximately 0.01 mg/kg (based
on Table 1 and Table 2).
TABLE-US-00001 TABLE 1 Estimation of effective exposure of Compound
A in rat ANIT model by PK/PD modeling IC.sub.80 of LJN452 Serum
biomarkers E.sub.0 I.sub.max (ng/ml) Total bilirubin (mg/dL) 2.3
2.0 0.223 Total bile acids (.mu.mol/L) 147.8 125.5 0.155 ALT (U/L)
138.2 84.2 0.054 AST (U/L) 272.8 140.3 0.076 Mean (IC.sub.80) 0.127
Mean (efficacious 3.05 AUC.sub.0-24 h; ng*h/ml)
[0110] PK/PD modeling of the exposure of Compound A compared to the
serum markers of hepatobiliary injury in the 2-week rat ANIT
chronic treatment model. E0, effect at zero drug concentration;
I.sub.max, maximal drug effect; IC.sub.80, drug concentration
producing 80% of the maximum effect.
TABLE-US-00002 TABLE 2 Pharmacokinetic properties of Compound A in
the chronic 2 week rat ANIT-induced cholestasis model Dose Cmax AUC
0-24 hr mg/kg ng/ml hrs* ng/ml 0.01 0.39 3.49 0.05 2.28 18.25 0.25
15.59 158.28 1.0 52.03 581.62 3.0 ND ND
[0111] Compound A serum exposure in the 2 week chronic ANIT-induced
cholestasis model. Samples were collected on day 13 of the study
shown in Example 1. ND=not determined. Data are presented as mean
(n=3/group).
Example 3
[0112] The efficacious concentration of Compound A was determined
by PK/PD modeling from the rat_ANIT-induced cholestasis chronic
treatment model described in Example 1. The PK samples (pre-dose,
0.5, 1, 3, 7, 10 and 24 h, n=3/dose group) were taken on day 13 (at
steady-state). AUC0-24 h was determined using Phoenix WinNonlin 6.3
software and the average concentrations were calculated from mean
of AUC0-24 h at each dose (divided the AUC0-24 h by 24 h). The
individual biomarker data were compared to the PK data (average
concentration at each dose) for the modeling. Since the lowest dose
(0.01 mg/kg) already approached maximal efficacy, the IC80 was
chosen as the measurement of the efficacious exposure (Table 1).
The IC80 was determined using the Inhibitory effect Imax model
(effect C=0 at Imax, C=infinity at E0) built in Phoenix WinNonlin
6.3 software.
From these calculations, the average efficacious concentration of
Compound A at Cmax can be estimated as 0.127 ng/ml and the AUC0-24
h as 3.05 ng*h/ml (Table 3).
TABLE-US-00003 TABLE 3 Estimation of effective exposure of Compound
A in rat ANIT model by PK/PD modeling IC.sub.80 of Compound Serum
biomarkers E.sub.0 I.sub.max A (ng/ml) Total bilirubin (mg/dL) 2.3
2.0 0.223 Total bile acids (.mu.mol/L) 147.8 125.5 0.155 ALT (U/L)
138.2 84.2 0.054 AST (U/L) 272.8 140.3 0.076 Mean (IC80) 0.127 Mean
(efficacious 3.05 AUC0-24 h; ng*h/ml)
PK/PD modeling of the exposure of Compound A compared to the serum
markers of hepatobiliary injury in the 2-week rat ANIT chronic
treatment model. E.sub.0: effect at zero drug concentration;
I.sub.max: maximal drug effect IC80, drug concentration producing
80% of the maximum effect.
Example 4
[0113] To characterize the dose/exposure/efficacy relationship for
Compound A, regulation of FXR target genes involved in bile acid
synthesis and transport was analyzted in rats.
[0114] Rats were treated for two weeks with a broad range of doses
of Compound A (0.003, 0.01, 0.03, 0.1, 0.3, 1, 3 mg/kg) and
subsequent gene induction (SHP, BSEP, FGF15) or repression (Cyp7a1,
Cyp8b1) was determined by qRT-PCR in liver and ileum on day 14 (at
t=1 and 3 hours). The effective dose (ED) calculations are
described below. Both the mean ED and the median ED indicate an
estimated effective dose of approximately 0.01 mg/kg.
[0115] In the liver treatment with Compound A resulted in
significant, dose-dependent increases in gene expression levels of
both SHP and BSEP and the levels of Cyp8b1 mRNA were potently
repressed. Complete data set representing all time points and doses
evaluated can be found in FIG. 2.
[0116] The results shown in FIG. 1 and FIG. 2 are consistent with
the use of a compound A for the treatment of liver disease or
intestinal disease according to the dosage, e.g. daily dosage, as
herein above defined for humans.
Example 5
[0117] The human efficacy dose was calculated based on the
efficacious exposure in the rat ANIT-induced disease model. Since
the in vitro potency and protein binding between human and rat were
similar, the EC80 exposure in human was assumed to be the same as
that in rat (3.05 ng*h/mL).
Study Protocol:
[0118] A total of 69 healthy subjects received Compound A at doses
ranging from 10 g to 3000 .mu.g in single or 10 .mu.g to 100 g in
multiple daily doses.
[0119] For each subject, Compound A was determined in plasma and
urine using validated LC-MS/MS methods. The lower limit of
quantification (LLOQ) for Compound A was 20 .mu.g/mL in plasma and
100 .mu.g/mL in urine.
[0120] Following a single oral dose, the median Tmax was 4 hours
with a mean apparent terminal elimination half-life ranging from 13
to 22 h. An approximately dose proportional increase was noted for
mean Cmax and AUCinf in the dose range of 10 .mu.g to 3000 .mu.g
fora single dose. Following once daily doses of Compound A for 13
days, median Tmax was at 4 h on Day 13. An approximately
dose-proportional increase in Cmax and AUCtau was observed in the
dose range (Table 4).
TABLE-US-00004 TABLE 4 Summary of Plasma Pharmacokinetic Parameters
under fasting condition Compound: Compound A; Matrix: plasma,
Analyte: Compound A Tmax** Cmax AUClast AUCinf T1/2 CL/F Treatment
(h) (ng/mL) (h * ng/mL) (h * ng/mL) (h) (L/h) Compound A n 5 5 5 4
4 4 10 .mu.g (fasted) Mean (SD) 4.00 0.186 2.79 3.39 14.9 2.98
(3.00-6.00) (0.0310) (0.311) (0.333) (3.22) (0.324) CV % 26.1 16.7
11.1 9.8 21.7 10.9 Compound A n 6 6 6 5 5 5 30 .mu.g (fasted) Mean
(SD) 4.00 0.627 12.7 13.4 13.7 2.26 (3.00-6.00) (0.108) (1.04)
(1.16) (4.74) (0.202) CV % 27.2 17.2 8.2 8.7 34.7 8.9 Compound A n
6 6 6 5 5 5 100 .mu.g (fasted) Mean (SD) 4.00 1.73 34.8 37.9 13.5
3.08 (4.00-4.03) (1.04) (15.6) (17.2) (3.36) (1.25) CV % 0.4 59.8
44.9 45.4 24.9 40.4 Compound A n 6 6 6 6 6 6 300 .mu.g (fasted)
Mean (SD) 4.00 6.41 119 123 15.3 3.21 (3.00-8.00) (3.24) (55.0)
(56.4) (5.55) (2.30) CV % 39.1 50.6 46.4 45.8 36.4 71.6 Compound A
n 6 6 6 5 5 5 1000 .mu.g (fasted) Mean (SD) 4.00 22.1 416 482 21.9
2.43 (3.00-8.00) (9.37) (229) (250) (10.5) (0.917) CV % 39.0 42.4
55.0 51.9 47.8 37.7 Compound A n 6 6 6 6 6 6 3000 .mu.g (fasted)
Mean (SD) 4.00 54.2 888 933 16.5 3.63 (4.00-6.00) (38.2) (341)
(361) (3.53) (1.35) CV % 18.8 70.5 38.4 38.7 21.4 37.3
Multiple Oral Dose Pharmacokinetics:
[0121] With once daily oral dosing of Compound A (10 .mu.g, 30
.mu.g, 60 .mu.g, 100 .mu.g) in the fasted state for 13 days, the
time to reach maximal Compound A plasma concentrations at Day 13
was similar to that of Day 1 across all doses with a median Tmax of
4 hours (range: 3-10 hours) post-dose. Steady-state was reached by
Day 4 as trough levels were comparable from Day 4 and onwards up to
Day 13. Consistent to the relative short t1/2, an accumulation
ratio of less than 2-fold (1.21-1.87) was observed. An
approximately dose proportional increase was noted for mean Cmax
and AUCinf in the dose range of 10 .mu.g to 100 .mu.g. At Day 13,
the inter-subject variability (CV %) ranged from approximately 20%
to 40% for Cmax, and from approximately 25% to 44% for AUCtau
(Table 5).
TABLE-US-00005 TABLE 5 Summary of Plasma Pharmacokinetic parameters
following multipleoral dose administration Compound: Compound A;
Matrix: plasma, Analyte: Compound A Profile AUCtau Cmax Tmax**
Tlast Treatment Day (h * ng/mL) (ng/mL) (h) (h) Racc Compound A 1 n
9 9 9 9 9 10 .mu.g qd Mean (SD) 2.88 0.212 4.00 23.9 1.00 (1.27)
(0.109) (4.00-10.0) (0.00556) (0) CV % 43.9 51.7 37.5 0.0 0.0 13 n
9 9 9 9 9 Mean (SD) 4.88 0.319 4.00 23.6 1.87 (1.47) (0.104)
(4.00-6.00) (0) (0.609) CV % 30.1 32.7 21.4 0.0 32.5 Compound A 1 n
6 6 6 6 6 30 .mu.g qd Mean (SD) 11.7 0.894 6.00 23.9 1.00 (3.31)
(0.305) (6.00-8.00) (0) (0) CV % 28.2 34.1 15.5 0.0 0.0 13 n 6 6 6
6 6 Mean (SD) 14.0 0.943 4.00 23.6 1.21 (4.37) (0.260) (4.00-10.0)
(0.0136) (0.278) CV % 31.2 27.6 45.4 0.1 22.9 Compound A 1 n 6 6 6
6 6 60 .mu.g qd Mean (SD) 16.2 1.22 4.00 23.9 1.00 (5.44) (0.475)
(3.00-6.00) (0) (0) CV % 33.5 39.1 23.6 0.0 0.0 13 n 6 6 6 6 6 Mean
(SD) 25.3 1.61 4.00 22.3 1.66 (6.40) (0.331) (3.00-6.00) (3.07)
(0.560) CV % 25.4 20.5 31.5 13.7 33.7 Compound A 1 n 6 6 6 6 6 100
.mu.g qd Mean (SD) 30.3 2.40 4.00 23.9 1.00 (12.4) (1.09)
(4.00-4.00) (0) (0) CV % 41.0 45.6 0.0 0.0 0.0 13 n 4 4 4 4 4 Mean
(SD) 50.2 3.47 4.00 23.6 1.41 (21.9) (1.38) (3.00-8.00) (0) (0.287)
CV % 43.7 39.8 46.7 0.0 20.4 **Median and range are presented for
Tmax
[0122] The human PK results from this study showed that the plasma
exposure of Compound A was dose-proportional for doses 1-100 .mu.g
on both day 1 and day 13. The average Cmax and AUCtau at day 13 for
a dose level of 10 .mu.g (the exposures for the doses 10-100 .mu.g
were normalized to 10 .mu.g) was calculated to be 0.32 ng/mL and
4.84 ng*h/mL, respectively. With this information, the human
efficacious dose is estimated to be at least .about.6 .mu.g with a
Cmax of .about.0.2 ng/mL (.about.0.3). An approximately
dose-proportional increase in Cmax and AUCtau was observed in the
dose range of 10-100 .mu.g
[0123] Dose-dependent increases in FGF19, a biomarker of FXR target
engagement in the enterocyte, were noted in single dose studies
from 10 .mu.g (median Cmax 438 .mu.g/mL) to 1 mg Compound A (median
Cmax 1820 .mu.g/mL). At 3000 .mu.g Compound A the median FGF19 Cmax
was 1750 .mu.g/mL. Similar dose dependent increases were noted in
repeated daily dosing of Compound A from 10 .mu.g (median Cmax 405
.mu.g/m/L to 100 .mu.g (median Cmax 1054 .mu.g/mL). The
pharmacodynamic marker, FGF19 continues to rise with increasing
Compound A doses beyond 100 .mu.g in the above study.
[0124] Results from this clinical study also showed that when
Compound A was taken with a high-fat meal, median Tmax was delayed
from 4 h to 9 h, and mean Compound A Cmax and AUCinf increased by
approximately 60% compared to the fasted state. Individual Compound
A fed vs. fasted exposure ratios ranged from 1.17 to 2.27-fold for
Cmax and from 1.24 to 1.94-fold for AUCinf. To avoid variability in
drug exposure, it is recommended that throughout the treatment
period, patients will be directed to take study drug at home with
.about.240 mL (8 ounces) of water in the morning in a fasting
state, at least 30 min prior to the first beverage apart from water
and 60 min prior to first meal of the day, preferably at the same
time of the day.
[0125] No safety concerns were identified in single dose studies up
to 3000 .mu.g Compound A. In repeated daily administration doses up
to and including 60 .mu.g Compound A were well tolerated.
[0126] At 100 .mu.g Compound A, elevation of transaminases (ALT and
AST) occurred in 3 subjects, one with ALT >ULN, one with ALT
>3.times.ULN and one with ALT >5.times.ULN. Elevations of AST
were less marked and no elevation in ALP or bilirubin was noted in
any subject. Elevated ALT resolved to within normal levels within
14 days and without intervention.
[0127] No significant findings in physical exam, vital signs or
ECGs have been related to Compound A; no adverse events related to
itch, a common adverse event for bile acid-derived FXR agonists,
have been observed in this clinical study.
[0128] The data from this clinical trial as well as preclinical
evidence presented above show that Compound A at daily doses of 10
.mu.g to 90 .mu.g to be safe and pharmacological active for
treatment of liver disease. Furthermore, FGF19 continues to rise
with increasing Compound A doses even beyond 100 .mu.g, e.g. at 120
.mu.g.
[0129] It is understood that the examples and embodiments described
herein are for illustrative purposes only and that various
modifications or changes in light thereof will be suggested to
persons skilled in the art and are to be included within the spirit
and purview of this application and scope of the appended claims.
All publications, patents, and patent applications cited herein are
hereby incorporated by reference for all purpose.
* * * * *