Novel compositions

Abstract

The present disclosure is directed to bilayer tablet pharmaceutical compositions comprising a first layer comprising obeticholic acid (OCA) or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof; and a second layer comprising bezafibrate or a pharmaceutically acceptable salt or ester thereof. Related compositions and methods of making and using the compositions are disclosed.

Description

Novel CompositionsFIELD OF THE DISCLOSURE

[0001] The present invention relates to fixed-dose combination pharmaceutical compositions comprising an FXR agonist and a fibrate. Also disclosed is use of the combination for the treatment, amelioration or prevention of an FXR mediated disease or condition, such as primary biliary cholangitis (PBC).BACKGROUND OF THE DISCLOSURE

[0002] Primary biliary cholangitis (PBC) is a serious, life-threatening, cholestatic liver disease of unknown etiology that, without treatment, frequently progresses to hepatic fibrosis and eventual cirrhosis, hepatic decompensation, and necessitates liver transplantation or results in death. Subjects with advanced PBC disease are also predisposed to hepatocellular carcinoma. PBC is a rare disease with reported prevalence in the United States (US) of about 40.2 / 100 000. PBC disproportionately affects women more than men by approximately 10: 1 and is typically diagnosed in patients between 40 and 60 years of age.

[0003] Historically, the only approved drug therapy for PBC had been the bile acid ursodeoxycholic acid (UDCA), a physiological constituent of human bile. While UDCA therapy had a marked effect on the treatment of PBC, up to 50% of patients showed a suboptimal response or no response to UDCA. Such patients were at significantly increased risk of a poor clinical outcome due to PBC disease progression.

[0004] Fibrates have anticholestatic, anti-inflammatory, and antifibrotic effects and have recently shown the potential to further improve the biochemical markers of PBC. The mechanisms that underlie these effects are complementary, and largely mediated through activation of peroxisome proliferator activated receptors. Fibrate treatment has been found promising in ameliorating liver biochemical tests in UDCA unresponsive patients, either as monotherapy or in combination with UDCA. Bezafibrate (BZF) has been identified as a potential anticholestatic agent for the treatment of PBC with an inadequate response to UDCA.

[0005] Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist and modified bile acid derived from the primary human bile acid chenodeoxycholic acid (CDCA), was developed forthe treatment of PBC and to provide patients who have an inadequate response to or poor tolerance of UDCA, a novel treatment option that was safe and effective. OCA is approved under the tradename OCALIVA by the US Food and Drug Administration (FDA), European Medicines Agency (EMA; conditional approval), Health Canada, and other regulatory agencies for the treatment of PBC in combination with UDCA in adults with inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA.

[0006] There is a need for an improved therapy for the treatment of cholestatic diseases and conditions, e.g., PBC, especially in patients who have an inadequate response to or cannot tolerate existing therapies.SUMMARY OF THE DISCLOSURE

[0007] The present disclosure relates to fixed dose combination (FDC) pharmaceutical compositions comprising: a first layer comprising obeticholic acid (OCA) or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof, e.g., in an amount of from about 1 mg to about 5 mg; and a second layer comprising a fibrate of the present disclosure, e.g. bezafibrate or a pharmaceutically acceptable salt or ester thereof, e g., in an amount of from about 100 mg to about 600 mg, e.g. 400 mg; wherein the composition is a bilayer tablet. The compositions of the present disclosure are capable of being efficiently and safely manufactured, and do not contain significant amounts of impurities. The compositions of the present disclosure are also capable of providing immediate release of OCA and extended or sustained release of bezafibrate.

[0008] The present disclosure relates to a fixed dose combination (FDC) pharmaceutical composition comprising: a first layer comprising obeticholic acid (OCA), i.e., a compound of formula (1):or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof, e.g., in an amount of from about 1 mg to about 5 mg; and a second layer comprising a fibrate, for example bezafibrate or a pharmaceutically acceptable salt or ester thereof, e g. in an amount of from about 100 mg to about 600 mg, e.g. 400 mg; wherein the composition is a bilayer tablet.

[0009] In one aspect, the amino acid conjugate of OCA is a glycine conjugate. In one aspect, the amino acid conjugate of OCA is a taurine conjugate.

[0010] In a further aspect, the present disclosure describes pharmaceutical compositions, packs or kits, and therapeutic uses of the combination.

[0011] In a further aspect, the present invention relates to methods of treating or preventing FXR mediated diseases, reducing the level of one or more liver enzymes, or inhibiting or reversing fibrosis, comprising administering a therapeutically effective amount of a pharmaceutical composition of the present invention to a subject in need thereof. In certain instances, the FXR mediated disease or condition is primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, primary sclerosing cholangitis (PSC), chronic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis C infection, alcoholic liver disease, liver damage due to progressive fibrosis, or liver fibrosis. In some instances, the FXR mediated disease or condition is portal hypertension, bile acid diarrhea, drug-induced cholestasis, hereditary cholestasis, biliary atresia, or intrahepatic cholestasis of pregnancy.

[0012] In a further aspect, the present invention relates to methods for preparing a bilayer tablet pharmaceutical composition according to the present disclosure.

[0013] In a further aspect, the present relates to use of a pharmaceutical composition of the present invention in the manufacture of a medicament for treating or preventing an FXR mediated disease or condition, reducing the level of a one or more liver enzymes, or inhibiting or reversing fibrosis.

[0014] The compositions and methods of the present invention address unmet needs in the treatment or prevention of an FXR mediated disease or disorder (e.g., PBC).DETAILED DESCRIPTION OF THE DISCLOSURE

[0015] The present disclosure relates to the treatment of FXR mediated diseases or conditions. FXR is a nuclear receptor which acts as a key regulator of cholesterol homeostasis, triglyceride synthesis and lipogenesis (Crawley, Expert Opinion Ther. Patents 2010, 20, 1047-1057). This receptor is expressed in various organs and shown to be involved in many diseases and conditions, including liver diseases, lung diseases, renal diseases, intestinal diseases, and heart diseases, and biological processes, such as glucose metabolism, insulin metabolism, and lipid metabolism.

[0016] In a first aspect, the present disclosure provides a fixed dose combination (FDC) pharmaceutical composition (Composition 1) comprising: a first layer comprising obeticholic acid (OCA), i.e., a compound of formula (1):(1)or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof; and a second layer comprising a fibrate, e.g., bezafibrate, or a pharmaceutically acceptable salt or ester thereof;wherein the composition is a bilayer tablet.The present disclosure further provides the following embodiments of the present FDC bilayer tablet pharmaceutical composition:1.1 Composition 1, wherein the first layer comprises OCA in an amount of about 1 mg to about 10 mg.1.2 Composition 1, wherein the first layer comprises OCA in an amount of about 1 mg, or about 1.5 mg, or about 2 mg, or about 2.5 mg, or about 3 mg, or about 3.5 mg, or about4 mg, or about 4.5 mg, or about 5 mg, or about 5.5 mg, or about 6 mg, or about 6.5 mg, or about 7 mg, or about 7.5 mg, or about 8 mg, or about 8.5 mg, or about 9 mg, or about 9.5 mg, or about 10 mg.1.3 Composition 1, wherein the first layer comprises OCA in an amount of about 2 mg, or about 2.5 mg, or about 3 mg, or about 3.5 mg, or about 4 mg, or about 4.5 mg, or about5 mg.1.4 Composition 1, wherein the first layer comprises OCA in an amount of about 2.5 mg or about 3 mg, or about 4 mg, or about 5 mg.1.5 Composition 1, wherein the first layer comprises OCA in an amount of about 2.5 mg or about 3 mg, or about 5 mg.1.6 Composition 1, wherein the first layer comprises OCA in an amount of about 2.5 mg.1.7 Composition 1, wherein the first layer comprises OCA in an amount of about 3 mg.1.8 Composition 1, wherein the first layer comprises OCA in an amount of about 5 mg.1.9 Any preceding Composition 1 and 1.1 et seq., wherein the second layer comprises bezafibrate in an amount of about 200 mg to about 400 mg.1.10 Any preceding Composition 1 and 1. 1 et seq., wherein the second layer comprises bezafibrate in an amount of about 300 mg.1.11 Any preceding Composition 1 and 1.1 et seq., wherein the second layer comprises bezafibrate in an amount of about 400 mg.1.12 Any preceding Composition 1 and 1.1 et seq., wherein the first layer comprises OCA in an amount of about 2 mg, or about 2.5 mg, or about 3 mg, or about 4 mg, or about 5 mg; and the second layer comprises bezafibrate in an amount of about 400 mg.Any preceding Composition 1 and 1.1 et seq., wherein the first layer comprises OCA in an amount of about 2.5 mg; and the second layer comprises bezafibrate in an amount of about 400 mg. Any preceding Composition 1 and 1. 1 et seq., wherein the first layer comprises OCA in an amount of about 3 mg; and the second layer comprises bezafibrate in an amount of about 400 mg. Any preceding Composition 1 and 1. 1 et seq., wherein the first layer comprises OCA in an amount of about 3.5 mg; and the second layer comprises bezafibrate in an amount of about 400 mg. Any preceding Composition 1 and 1. 1 et seq., wherein the first layer comprises OCA in an amount of about 4 mg; and the second layer comprises bezafibrate in an amount of about 400 mg. Any preceding Composition 1 and 1.1 et seq., wherein the first layer comprises OCA in an amount of about 4.5 mg; and the second layer comprises bezafibrate in an amount of about 400 mg. Composition 1, wherein the first layer comprises OCA in an amount of about 5 mg; and the second layer comprises bezafibrate in an amount of about 400 mg. Any preceding Composition 1 and 1. 1 et seq., wherein the first layer comprises OCA in an amount of about 5 mg; and the second layer comprises bezafibrate in an amount of about 400 mg. Any preceding Composition 1 and 1.1 et seq., wherein the first layer comprises OCA in an amount of about 7.5 mg; and the second layer comprises bezafibrate in an amount of about 400 mg. Any preceding Composition 1 and 1.1 et seq., wherein the second layer is a sustained release layer. Any preceding Composition 1 and 1. 1 et seq., wherein the first layer is an immediate release layer. Any preceding Composition 1 and 1.1 et seq., wherein the first layer is an immediate release layer and the second layer is a sustained release layer.Any preceding Composition 1 and 1.1 et seq., wherein the second layer comprises a release-controlling agent. Composition 1.24, wherein the release-controlling agent comprises hypromellose, hydroxypropylcellulose, Carbopol 71G®, PolyOx™ N60K, PolyOx™ WSR301, a Methocel™, or a combination thereof. Composition 1.24, wherein the release-controlling agent comprises hypromellose, or hydroxypropylcellulose, or a combination thereof. Composition 1.24, wherein the release-controlling agent comprises Methocel™ K100LV. Any preceding Composition 1.24 to 1.27, wherein the release-controlling agent is present in the form of particles having a particle size distribution wherein: NLT 99.0% of the particles pass through a 40 U.S. Standard Sieve; NLT 90.0% of the particles pass through a 100 U.S. Standard Sieve; and between 50.0% and 80.0% of the particles pass through a 230 U.S. Standard Sieve. Any preceding Composition 1 and 1.1 et seq., wherein the first layer further comprises one or more of a filler / binder, a disintegrant, a lubricant and a glidant; and the second layer further comprises one or more of a filler / binder, a release controlling agent, a second binder, a glidant and a lubricant. Composition 1.29, wherein: in the first layer: the filler / binder, when present, is present in an amount of from about 85% to about 92% by weight of the first layer, or from about 88% to about 91% by weight of the first layer; or from about 89% to about 90% by weight of the first layer; or about 89.5% by weight of the first layer; the disintegrant, when present, is present in an amount of from about 4.0% to about 8.0% by weight of the first layer, or from about 5.0% to about 7.0% by weight of the first layer; or about 6.0% by weight of the first layer; the lubricant, when present, is present in an amount of from about 0.1% to about 2.0% by weight of the first layer, or from about 0.5% to about 1.5% by weight of the first layer; or about 1.0% by weight of the first layer;the glidant, when present, is present in an amount of from about 0.1% to about 2.0% by weight of the first layer, or from about 0.5% to about 1.5% by weight of the first layer; or about 1% by weight of the first layer; and in the second layer: the release-controlling agent, when present, is present in an amount of from about 12% to about 25% by weight of the second layer, or from about 15% to about 21% by weight of the second layer; or from about 16% to about 20% by weight of the second layer; or from about 17% to about 19% by weight of the second layer; or about 18% by weight of the second layer; the filler / binder, when present, is present in an amount of from about 10% to about 25% by weight of the second layer, or from about 12% to about 20% by weight of the second layer; or from about 14% to about 18% by weight of the second layer; or from about 16% to about 17% by weight of the second layer; or about 16.4% by weight of the second layer; the second binder, when present, is present in an amount of from about 0.5% to about 5% by weight of the second layer, or from about 1% to about 3% by weight of the second layer; or from about 1% to about 2.5% by weight of the second layer; or from about 1% to about 2% by weight of the second layer; or about 1.5% to about 2% by weight of the second layer; or about 1.75% by weight of the second layer; the lubricant, when present, is present in an amount of from about 0.5% to about 5% by weight of the second layer, or from about 1% to about 3% by weight of the second layer; or from about 1.0% to about 2.5% by weight of the second layer; or from about 1.5% to about 2.0% by weight of the second layer; or about 1.75% by weight of the second layer; and the glidant, when present, is present in an amount of from about 0.1% to about 3.0% by weight of the second layer, or from about 0.1% to about 2.5% by weight of the second layer; or from about 1% to about 2.5% by weight of the second layer; or from about 1.0% to about 2.0% by weight of the second layer; or about 1.47% or about 1.5% by weight of the second layer.Any preceding Composition 1 and 1.1 et seq., wherein the composition further comprises a coating. Composition 1.31, wherein the coating is present in an amount of from about 0.5% to about 5.0% by weight of the total weight of the composition; or from about 1.0% to about 5.0 % by weight of the total weight of the composition; or from about 2.0% to about 4.0 % by weight of the total weight of the composition; or about 3.0 % by weight of the total weight of the composition. Composition 1.29, wherein the Composition has the following composition:Composition 1.29, wherein the Composition has the following composition:Any preceding Composition 1.29-1.34, wherein: in the first layer: the filler / binder comprises microcrystalline cellulose; the disintegrant comprises sodium starch glycolate; the lubricant comprises magnesium stearate; the glidant comprises colloidal silicon dioxide; and in the second layer: the release-controlling agent comprises hydroxypropyl methylcellulose (HPMC or hypromellose); e.g., Methocel™; e.g. Methocel™ KI 00LV; the filler / binder comprises microcrystalline cellulose; the second binder comprises hydroxypropyl cellulose; the lubricant comprises magnesium stearate; the glidant comprises colloidal silicon dioxide; and the coating comprises Opadry® AMB II White. Any preceding Composition 1.29 to 1.35, wherein the first layer comprises OCA in an amount of about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg or about 5 mg; and the second layer comprises bezafibrate in an amount of about 300 to about 400 mg. Composition 1.36, wherein the first layer comprises OCA in an amount of about 5 mg; and the second layer comprises bezafibrate in an amount of about 400 mg.Any preceding Composition 1.33-1.37, wherein the Composition has the following composition:Any preceding Composition 1.33-1.37, wherein the Composition has the following composition:Any preceding Composition 1 and 1.1 et seq., wherein the composition comprises OCA dimer in an amount of <1.0% w / w; e.g. <0.5% w / w; e.g., <0.2% w / w; e.g., <0.1% w / w; e.g., < 0.09% w / w, < 0.075% w / w, < 0.05% w / w, < 0.025% w / w, < 0.01% w / w, or < 0.001% w / w. Any preceding Composition 1 and 1.1 et seq., wherein the composition comprises N-(4- chlorobenzoyl)tyramine in an amount of <1.0% w / w; e.g. <0.5% w / w; e.g., <0.2% w / w; e.g., <0.1% w / w; e.g., < 0.09% w / w, < 0.07% w / w, < 0.06% w / w, < 0.05% w / w, < 0.025% w / w, < 0.01% w / w, or < 0.001% w / w. Any preceding Composition 1 and 1.1 et seq., wherein the composition comprises BZF ethyl ester in an amount of <1.0% w / w; e.g. <0.75% w / w; e.g. <0.5% w / w; e.g., <0.2% w / w; e.g., <0.1% w / w; e.g., < 0.08% w / w, < 0.07% w / w, < 0.06% w / w, < 0.05% w / w, < 0.04% w / w, < 0.025% w / w, < 0.01% w / w, or < 0.001% w / w. Any preceding Composition 1 and 1.1 et seq., wherein the composition comprises OCA / BZF conjugate in an amount of <1.0% w / w; e.g. <0.5% w / w; e.g., <0.2% w / w; e.g., <0.1% w / w; e.g., < 0.09% w / w, < 0.075% w / w, < 0.05% w / w, < 0.025% w / w, < 0.01% w / w, or < 0.001% w / w. Any preceding Composition 1 and 1.1 et seq., wherein the combined amount of total impurities present in the composition is <5% w / w; e.g., <4% w / w; e.g. <3% w / w; e.g. <2% w / w; e.g., <1% w / w; e.g. <0.5% w / w; e.g., <0.4% w / w; e.g., <0.3% w / w; e.g., < 0.25% w / w, e.g., < 0.2% w / w, e.g., < 0.1% w / w, e.g., < 0.025% w / w, e.g., < 0.01% w / w. Any preceding Composition 1 and 1.1 et seq., wherein the amino acid conjugate of OCA is a glycine conjugate. Any preceding Composition 1 and 1.1 et seq., wherein the amino acid conjugate of OCA is a taurine conjugate.1.47 Any preceding Composition 1 and 1.1 et seq., wherein the composition is for use in the treatment of an FXR mediated disease or condition.1.48 Composition 1.47, wherein the FXR mediated disease or condition is selected from primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), portal hypertension, bile acid diarrhea, a chronic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis C infection, an alcoholic liver disease, liver damage due to progressive fibrosis, liver fibrosis, drug-induced cholestasis, hereditary cholestasis, biliary atresia, and intrahepatic cholestasis of pregnancy.1.49 Composition 1.47, wherein the FXR mediated disease or condition is chronic liver disease.1.50 Composition 1.47, wherein the FXR mediated disease or condition is cholestatic liver disease.1.51 Composition 1.47, wherein the FXR mediated disease or condition is PBC.1.52 Composition 1.47, wherein the FXR mediated disease or condition is NASH.1.53 Composition 1.47, wherein the FXR mediated disease or condition is liver fibrosis.1.54 Composition 1.47, wherein the FXR mediated disease or condition is liver fibrosis associated with NASH.1.55 Any preceding Composition 1 and 1.1 et seq., wherein the composition is for administration once daily (QD).1.56 Any preceding Composition 1 and 1.1 et seq., wherein the first layer comprises OCA in an amount of about 5 mg; and the second layer comprises bezafibrate in an amount of about 400 mg.

[0017] In a further aspect, the present disclosure provides a method [Method 1] for treating or preventing an FXR mediated disease or condition, reducing the level of one or more liver enzymes, or inhibiting or reversing fibrosis in a subject in need thereof, comprising administering to the subject a composition according to any of Composition 1 or 1.1 et seq.

[0018] The present disclosure further provides the following embodiments of Method 1:1.1 Method 1, wherein the FXR mediated disease or condition is selected from primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), portal hypertension, bile aciddiarrhea, a chronic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis C infection, an alcoholic liver disease, liver damage due to progressive fibrosis, liver fibrosis, drug-induced cholestasis, hereditary cholestasis, biliary atresia, and intrahepatic cholestasis of pregnancy. Method 1 or 1.1, wherein the FXR mediated disease or condition is chronic liver disease. Method 1 or 1.1, wherein the FXR mediated disease or condition is a cholestatic liver disease. Method 1 or 1.1, wherein the FXR mediated disease or condition is PBC. Method 1 or 1.1, wherein the FXR mediated disease or condition is NASH. Method 1 or 1.1, wherein the FXR mediated disease or condition is liver fibrosis. Method 1 or 1.1, wherein the FXR mediated disease or condition is liver fibrosis associated with NASH. Method 1 or 1.1, wherein the FXR mediated disease or condition is nonalcoholic fatty liver disease (NAFLD). Method 1 or 1.1, wherein the subject is not suffering from a cholestatic condition. Method 1 or 1.1, wherein the subject is suffering from a cholestatic condition. Any preceding Method 1 and 1.1 et seq., wherein the composition is administered once daily (QD). Any preceding Method 1 and 1.1 et seq., wherein the composition is administered for a period of at least 4 weeks. Any preceding Method 1 and 1.1 et seq., wherein the composition is administered for a period of at least 12 weeks. Any preceding Method 1 and 1.1 et seq., wherein the composition is administered for a period of 1-12 weeks. Any preceding Method 1 and 1.1 et seq., wherein the composition is administered for a period of 12-48 weeks. Any preceding Method 1 or 1.1;. et seq., further comprising the step of assessing, monitoring, measuring, or otherwise detecting liver function. Method 1.11, wherein the step of assessing, monitoring, measuring, or otherwise detecting liver function comprises a non-invasive assay.Method 1.12, wherein the non-invasive assay is a HepQuant SHUNT assay. Method 1.13, wherein the HepQuant SHUNT assay comprises measuring clearance of cholate from both the systemic circulation and portal circulation. Method 1.13, wherein the cholate is labeled, for example wherein the cholate is isotopically labeled, for example wherein the cholate is isotopically labeled with a carbon isotope or a hydrogen isotope, for example wherein the cholate is isotopically labeled with13C or deuterium. Method 1.15, wherein the HepQuant SHUNT assay comprises intravenously administering (e g., injecting) 13C labeled cholate. M eth o d 1 . 1 5 , wh erei n the HepQuant SHUNT assay comprises orally administering deuterium labeled cholate. M eth o d 1 . 1 5 , wh erei n the HepQuant SHUNT assay comprises intravenously administering13C labeled cholate, and orally administering deuterium labeled cholate. Method 1.13, wherein the HepQuant SHUNT assay comprises collecting a blood sample from the subject before the subject is administered with the cholate. Method 1.13, wherein the HepQuant SHUNT assay comprises collecting a blood sample from the subject after cholate has been administered to the subject. Method 1.13, wherein the HepQuant SHUNT assay comprises taking a blood sample from the subject 5, 20, 45, 60, and / or 90 minutes after administration of the cholate. Any preceding Method 1.13-1.21, wherein the HepQuant SHUNT assay comprises analyzing the blood samples to generate a Disease Severity Index (Index). Method 1.13, wherein the HepQuant SHUNT assay comprises:(a) collecting a blood sample from a subject (e.g., a patient in need of treatment described herein) before the subject is administered with cholate;(b) intravenously administering13C labeled cholate, and orally administering deuterium labeled cholate, to the subject;(c) collecting a blood sample from the subject; and(d) analyzing the blood samples from Steps (a) and (c) to generate a Disease Severity Index.29 Any preceding Method 1 and 1.1-1.28, wherein Composition 1 or 1.1 et seq. is administered as a first-line treatment for the FXR mediated disease or condition. 30 Any preceding Method 1 and 1.1-1.28, wherein Composition 1 or 1.1 et seq. is administered in combination with UDCA for the treatment of the FXR mediated disease or condition. 31 Any preceding Method 1 and 1.1-1.28, wherein Composition 1 or 1.1 et seq. is administered in place of UDCA for the treatment of the FXR mediated disease or condition. 32 Any preceding Method 1 and 1.1-1.31, wherein the method results in ALP normalization or ALP reduction of >60% from baseline at month 12 of treatment; and / or normalization of Total Bilirubin (<0.6 x ULN) and / or Total Bilirubin Reduction of >20% from baseline at month 12 of treatment. 33 Any preceding Method 1 and 1.1-1.31, wherein the method results in ALP normalization or ALP reduction of >60% from baseline at month 12 of treatment; and normalization of Total Bilirubin (<0.6 x ULN), and Total Bilirubin Reduction of >20% from baseline at month 12 of treatment. 34 Any preceding Method 1 and 1.1-1.31, wherein the method results in one or more of an ALP of <1.67 x ULN, a >15% reduction in ALP, and total bilirubin <ULN. 35 Any preceding Method 1 and 1.1-1.31, wherein the method results in an ALP of <1.67 x ULN, a >15% reduction in ALP, and total bilirubin < ULN. 36 Any preceding Method 1 and 1.1-1.31, wherein the method results in a normalization rate achieved for one or more of the biochemical disease markers of < about 0.8 x ULN, < about 0.9 x ULN, < about 1.0 x ULN, < about 1.1 x ULN, or < about 1.2 x ULN at month 12 after commencement of treatment; for example where the biochemical disease markers include one or more of ALP, total bilirubin (TB), ALT, GGT, and AST. 37 Any preceding Method 1 and 1. 1-1.31, wherein the method results in one or more of:• Normalization of ALP or a reduction >50% of ALP; and a total bilirubin of <0.6 X ULN at month 12;• >50% reduction in ALP at month 12; total bilirubin of <0.6 X ULN at month 12;40% reduction of ALT and normalization of ALT at month 12;• 18% reduction of AST at month 12 with 90% of patients normalizing AST at month 12;• 76% reduction of GGT at month 12 with 75% of patients normalizing GGT at month 12;• 30% reduction in pruritus from baseline NRS score;• 18% reduction in mean baseline total cholesterol. 38 Any preceding Method 1 and 1.1-1.31, wherein the method results in one or more of:• Normalization rates (all <1.Ox ULN) at Month 12 of individual biochemical disease markers; e.g., one or more of ALP, TB, ALT, GGT, AST• Change from baseline to Month 12 in one or more of ALP, TB, GGT, ALT, AST• Incidence of treatment emergent adverse events (TEAEs)• Change from baseline to Month 12 in cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol.• Incidence and time to adjudicated events of hepatic injury.• Change from baseline in pruritus numerical rating scale (NRS) at Month 6. Weekly averaged pruritus NRS in subjects with baseline NRS >4, where NRS is a scale of 0 (no itching) to 10 (worst imaginable itching).• Change from baseline in FIS at Month 12• Change from baseline in FIS >1 to Month 6 39 Any preceding Method 1 and 1.1-1.38, wherein the Composition of the present disclosure is administered for the treatment or prevention of a disease or condition as described herein, in place of UDCA, to a subject who has an inadequate therapeutic response to UDCA (used alone or in combination with another active), or who is unable to tolerate UDCA. 40 Any preceding Method 1 and 1.1-1.38, wherein the Composition of the present disclosure is administered as a first-line treatment for the treatment or prevention of a disease or condition as described herein.1.41 Any preceding Method 1 and 1.1-1.38, wherein the Composition of the present disclosure is administered as a first-line treatment for the treatment or prevention of a disease or condition as described herein, in combination with UDCA.1.42 Any preceding Method 1 and 1.1-1.38, wherein the Composition of the present disclosure is administered for the treatment or prevention of a disease or condition as described herein, e.g., for the treatment of adult patients with primary biliary cholangitis (PBC): without cirrhosis; or with compensated cirrhosis who do not have evidence of portal hypertension, either in combination with ursodeoxycholic acid (UDCA) with an inadequate response to UDCA or as monotherapy in patients unable to tolerate UDCA.1.43 Any preceding Method 1 or 1.1-1.42, wherein the Composition of the present disclosure is a Composition according to any of Composition 1 or 1.1-1.57.1.44 Any preceding Method 1 or 1.1-1.43, further comprising stratifying the subject for the risk of hepatocellular carcinoma (HCC).1.45 Method 1.44, wherein the FXR mediated disease or condition is PBC.

[0019] In a further aspect, the present disclosure relates to a combinational therapy for the treatment of an FXR mediated disease or condition, comprising administration to a subject in need thereof a composition according to any of Compositions 1 and 1.1 et seq.

[0020] In a further aspect of each of the methods of treatment disclosed herein, the Composition of the present disclosure is administered for the treatment or prevention of a disease or condition as described herein, in place of UDCA, to a subject who has an inadequate therapeutic response to UDCA (used alone or in combination with another active), or who is unable to tolerate UDCA.In one aspect the disease or condition is PBC.

[0021] In a further aspect of each of the methods of treatment disclosed herein, the Composition of the present disclosure is administered as a first-line treatment for the treatment or prevention of a disease or condition as described herein, either as a first-line monotherapy or as a first-line combination therapy in combination with one or more additional agents, e.g. UDCA. In one aspect the disease or condition is PBC.

[0022] In a further aspect of each of the methods of treatment disclosed herein, the Composition of the present disclosure is administered as a first-line treatment for the treatment or prevention of adisease or condition as described herein, in combination with UIDCA. In one aspect the disease or condition is PBC.

[0023] In a further aspect of each of the methods of treatment disclosed herein, the Composition of the present disclosure is administered for the treatment or prevention of a disease or condition as described herein, e.g., for the treatment of adult patients with primary biliary cholangitis (PBC): without cirrhosis; or with compensated cirrhosis who do not have evidence of portal hypertension, either in combination with ursodeoxycholic acid (UDCA) in patients with an inadequate response to UDCA or as monotherapy in patients unable to tolerate UDCA.

[0024] In a further aspect of each of the methods of treatment disclosed herein, the Composition of the present disclosure is administered for the treatment or prevention of a disease or condition as described herein, e.g., for the treatment of adult patients with primary biliary cholangitis (PBC): without cirrhosis; or with compensated cirrhosis who do not have evidence of portal hypertension, as a first line monotherapy.

[0025] In a further aspect, the present disclosure also relates to a method [Method 2] of treating of a FXR mediated disease or a liver disease or condition, e.g., PBC, with a decreased incidence of side-effects, e.g., pruritus, comprising administering to a subject in need thereof, a composition according to any of Composition 1 or 1.1 et seq. In one aspect, the method results in the subject having decreased incidence, or decreased severity, of side effects (e.g., pruritus) compared to a subject treated with OCA monotherapy.

[0026] In a further aspect, the present disclosure also provides a method [Method 3] for decreasing one or more liver enzymes, comprising administering to a subject in need thereof, a composition according to any of Composition 1 or 1.1 et seq.. In some embodiments, the liver enzyme is selected from alkaline phosphatase (ALP, AP, or Aik Phos), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), and 5’ nucleotidase. In some embodiments, Method 3 is used to reduce the amount of one or more of the liver enzymes by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, as compared to a control subject (e.g., a subject not treated according to the methods of the present disclosure).

[0027] In a further aspect, the present disclosure also provides a method [Method 4] for normalizing one or more biochemical disease markers, including ALP, total bilirubin (TB), ALT,GGT, and AST in a subject suffering from a FXR mediated disease or condition as described herein, for example PBC. In one aspect of Method 4, the method results in ALP normalization or ALP decrease of >60% from baseline at month 12 of treatment; and / or normalization of Total Bilirubin ( <0.6x ULN) and / or Total Bilirubin Reduction of >20% from baseline at month 12 of treatment.

[0028] In some aspects of the present disclosure, for example Method 4, the Normalization rate achieved for one or more of the biochemical disease markers is < about 0.8 x ULN, < about 0.9 x ULN, < about 1.0 x ULN, < about 1.1 x ULN, or < about 1.2 x ULN at month 12 after commencement of treatment.

[0029] In some aspects of the Methods of the present disclosure, for example Method 4, the method results in ALP normalization or ALP reduction of >60% from baseline at month 12 of treatment; and / or normalization of Total Bilirubin (<0.6 x ULN) and / or Total Bilirubin Reduction of >20% from baseline at month 12 of treatment.

[0030] In some further aspects of the Methods of the present disclosure, for example Method 4, the method results in ALP normalization or ALP reduction of >60% from baseline at month 12 of treatment; and normalization of Total Bilirubin (<0.6 x ULN), and Total Bilirubin Reduction of >20% from baseline at month 12 of treatment.

[0031] In some aspects of the Methods of the present disclosure, for example Method 4, the method results in normalization of Total Bilirubin (<0.6 x ULN) and / or Total Bilirubin Reduction of >20% from baseline at month 12 of treatment.

[0032] In some aspects of the Methods of the present disclosure, for example Method 4, the method results in ALP normalization or ALP decrease of >60% from baseline at month 12 of treatment.

[0033] In some further aspects of the Methods of the present disclosure, for example Method 4, the method results in one or more of an ALP of <1.67 x ULN, a >15% reduction in ALP, and total bilirubin <ULN. In some further aspects of the Methods of the present disclosure, for example Method 4, the method results in an ALP of <1.67 x ULN, a >15% reduction in ALP, and total bilirubin < ULN.

[0034] In some further aspects of the Methods of the present disclosure, the method results in a normalization rate achieved for one or more of the biochemical disease markers of < about 0.8 xULN, < about 0.9 x ULN, < about 1.0 x ULN, < about 1.1 x ULN, or < about 1.2 x ULN at month 12 after commencement of treatment; for example where the biochemical disease markers include one or more of ALP, total bilirubin (TB), ALT, GGT, and AST.

[0035] In a further aspect, the present disclosure provides a method [Method 5] to reduce or eliminate rejection failure of a liver transplant by administering the treatment described herein; e.g., by administering a composition according to any of Compositions 1 or 1.1 et seq.

[0036] In certain instances, administration of the Composition described herein reduces expression or levels of ALP and / or bilirubin. In some embodiments, administration of the Composition described herein reduces ALP and bilirubin levels, thereby reducing transplant complications or rejection. In another embodiment, administration of an effective amount of the Composition described herein increases post-transplantation survival rate of a liver transplantee.

[0037] The present disclosure also provides a method [Method 6] for inhibiting or reversing fibrosis associated with a disease or condition described herein, comprising administering a therapeutically effective amount of a composition of the present disclosure (i.e., a composition according to any of Compositions 1 and 1.1 et seq.) to a subject in need thereof. In some embodiments, the fibrosis to be inhibited or reversed occurs in an organ where FXR is expressed. In some embodiments, the subject is suffering from a cholestatic condition. In some embodiments, the subject is not suffering from a cholestatic condition.

[0038] In some embodiments, a cholestatic condition is defined as having an abnormally elevated serum level of alkaline phosphatase, y-glutamyl transpeptidase (GGT), and / or 5’ nucleotidase. In another embodiment, a cholestatic condition is further defined as presenting with at least one clinical symptom. In some embodiments, the symptom is itching (pruritus). In another embodiment, a cholestatic condition is selected from the group consisting of primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), drug-induced cholestasis, hereditary cholestasis, biliary atresia, and intrahepatic cholestasis of pregnancy.

[0039] The present disclosure also provides a method [Method 7] for reducing lipid levels (i.e., amount of lipid), such as in the blood, comprising administering a therapeutically effective amount of a composition of the present disclosure to a subject in need thereof.

[0040] In some embodiments, the method of the present disclosure reduces the lipid levels by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, as compared to a control subject(e.g., a subject not treated according to the methods of the present disclosure). In some embodiments, the subject has elevated levels of lipid, as compared to a healthy subject (e.g., an individual without a disease or condition, such as those described herein). In some embodiments, the method of the present disclosure reduces the levels of lipid to normal levels e.g., similar to the lipid levels in an individual without a disease or condition, such as those described herein).

[0041] In some embodiments, the lipid is cholesterol. In some embodiments, the method of the present disclosure reduces cholesterol levels by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, as compared to a control subject (e.g., a subject not treated according to the methods of the present disclosure). In some embodiments, the subject has elevated levels of cholesterol, as compared to a healthy subject (e.g., an individual without a disease or condition, such as those described herein). In some embodiments, the method of the present disclosure reduces cholesterol levels below 400 mg / L, 350 mg / L, 300 mg / L, 250 mg / L, 240 mg / L, 230 mg / L, 220 mg / L, 210 mg / L, 200 mg / L, 190 mg / L, 180 mg / L, 170 mg / L, 160 mg / L, or 150 mg / L. In some embodiments, the method of the present disclosure reduces cholesterol levels below 200 mg / L, 190 mg / L, 180 mg / L, 170 mg / L, 160 mg / L, or 150 mg / L.

[0042] In some embodiments, the cholesterol is LDL. In some embodiments, the method of the present disclosure reduces LDL levels by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, as compared to a control subject (e.g., a subject not treated according to the methods of the present disclosure). In some embodiments, the subject has elevated levels of LDL, as compared to a healthy subject (e.g., an individual without a disease or condition, such as those described herein). In some embodiments, the method of the present disclosure reduces LDL levels below 300 mg / L, 200 mg / L, 190 mg / L, 180 mg / L, 170 mg / L, 160 mg / L, 150 mg / L, 140 mg / L, 130 mg / L, 120 mg / L, 110 mg / L, 100 mg / L, 90 mg / L, 80 mg / L, 70 mg / L, 60 mg / L, or 50 mg / L. In some embodiments, the method of the present disclosure reduces LDL levels below 160 mg / L, 150 mg / L, 140 mg / L, 130 mg / L, 120 mg / L, 110 mg / L, 100 mg / L, 90 mg / L, 80 mg / L, 70 mg / L, 60 mg / L, or 50 mg / L. In some embodiments, the method of the present disclosure reduces LDL levels below 130 mg / L, 120 mg / L, 110 mg / L, 100 mg / L, 90 mg / L, 80 mg / L, 70 mg / L, 60 mg / L, or 50 mg / L. In some embodiments, the method of the present disclosure reduces LDL levels below 100 mg / L, 90 mg / L, 80 mg / L, 70 mg / L, 60 mg / L, or 50 mg / L. In someembodiments, the method of the present disclosure reduces LDL levels below 70 mg / L, 60 mg / L, or 50 mg / L.

[0043] In some embodiments, the lipid is triglyceride. In some embodiments, the method of the present disclosure reduces triglyceride levels by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, as compared to a control subject (e.g., a subject not treated according to the methods of the present disclosure). In some embodiments, the subject has elevated levels of triglyceride, as compared to a healthy subject (e.g., an individual without a disease or condition, such as those described herein). In some embodiments, the method of the present disclosure reduces triglyceride levels below 800 mg / L, 700 mg / L, 600 mg / L, 500 mg / L, 400 mg / L, 300 mg / L, 200 mg / L, 190 mg / L, 180 mg / L, 170 mg / L, 160 mg / L, 150 mg / L, 140 mg / L, 130 mg / L, 120 mg / L, 110 mg / L, or 100 mg / L. In some embodiments, the method of the present disclosure reduces triglyceride levels below 200 mg / L, 190 mg / L, 180 mg / L, 170 mg / L, 160 mg / L, 150 mg / L, 140 mg / L, 130 mg / L, 120 mg / L, 110 mg / L, or 100 mg / L. In some embodiments, the method of the present disclosure reduces triglyceride levels below 150 mg / L, 140 mg / L, 130 mg / L, 120 mg / L, 110 mg / L, or 100 mg / L.

[0044] The present disclosure also provides a method [Method 8] for reducing the amount of bilirubin, and / or the amount and / or activity one or more liver enzymes, comprising administering a therapeutically effective amount of a Composition of the present disclosure to a subject in need thereof.

[0045] In some embodiments, the method of the present disclosure reduces the amount of bilirubin by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, as compared to a control subject (e.g., a subject not treated according to the methods of the present disclosure). In some embodiments, the subject has an elevated level of bilirubin, as compared to a healthy subject (e.g., an individual without a disease or condition, such as those described herein). In some embodiments, the method of the present disclosure reduces the level of bilirubin to a normal level (e.g., similar to the level of bilirubin in an individual without a disease or condition, such as those described herein). In a further embodiment, the method of the present disclosure reduces the level of bilirubin below 10 mg / L, 9 mg / L, 8 mg / L, 7 mg / L, 6 mg / L, 5 mg / L, 4 mg / L, 3 mg / L, 2 mg / L, 1.5 mg / L, 1.2 mg / L, or 1 mg / L. In a further embodiment, the method of the present disclosure reduces the level of bilirubin below 2 mg / L, 1.5 mg / L, 1.2 mg / L, or 1 mg / L.

[0046] In. some embodiments, the method of the present disclosure normalizes Total Bilirubin (e.g., <0.6x ULN) and / or reduces total bilirubin Reduction >20% from baseline at month 12 of treatment.

[0047] In some aspects of Method 8, the reduction or normalization rate achieved for bilirubin and / or one or more of the liver enzymes is < about 0.8 x ULN, < about 0.9 x ULN, < about 1.0 x ULN, < about 1.1 x ULN, or < about 1.2 .x ULN at month 12 after commencement of treatment.

[0048] In some aspects of Method 9, the one or more liver enzymes include ALP, TB, ALT, GGT and AST.

[0049] In some embodiments of the methods described herein, the one or more liver enzymes are selected from the group consisting of alkaline phosphatase (ALP, AP, or Aik Phos), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), and 5’ nucleotidase. In some embodiments, the method of the present disclosure reduces the amount of one or more liver enzymes by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, as compared to a control subject (e.g., a subject not treated according to the methods of the present disclosure). In some embodiments, the subject has elevated levels of one or more liver enzymes, as compared to a healthy subject (e.g., an individual without a disease or condition, such as those described herein). In some embodiments, the method of the present disclosure reduces the levels of one or more liver enzymes (e.g., ALP, ALT, AST, GGT, LDH, and 5’ nucleotidase) to normal levels (e.g., similar to the levels of liver enzymes in an individual without a disease or condition, such as those described herein).

[0050] In a further embodiment, the methods of the present disclosure reduces the level of ALP below 500 IU / L (international units per liter), 400 IU / L, 300 IU / L, 200 IU / L, 180 IU / L, 160 IU / L, or 150 IU / L. In a further embodiment, the method of the present disclosure reduces the level of ALP to from about 40 IU / L to about 150 IU / L.

[0051] In a further embodiment, the methods of the present disclosure reduces the level of ALT below 200 IU / L (international units per liter), 150 IU / L, 100 IU / L, 80 IU / L, 60 IU / L, or 50 IU / L. In a further embodiment, the method of the present disclosure reduces the level of ALT to from about 5 IU / L to about 50 IU / L.

[0052] In a further embodiment, the methods of the present disclosure reduces the level of AST below 200 IU / L (international units per liter), 150 IU / L, 100 IU / L, 80 IU / L, 60 IU / L, 50 IU / L, or40 IU / L. In a further embodiment, the method of the present disclosure reduces the level of AST to from about 10 IU / L to about 50 IU / L.

[0053] In a further embodiment, the methods of the present disclosure reduces the level of GGT below 200 IU / L (international units per liter), 150 IU / L, 100 IU / L, 90 IU / L, 80 IU / L, 70 IU / L, or 60 IU / L. In a further embodiment, the methods of the present disclosure reduces the level of GGT to from about 15 IU / L to about 50 IU / L or from about 5 IU / L to about 30 IU / L.

[0054] In a further embodiment, the methods of the present disclosure reduces the level of LDH below 500 IU / L (international units per liter), 400 IU / L, 300 IU / L, 200 IU / L, 180 IU / L, 160 IU / L, 150 IU / L, 140 IU / L, or 130 IU / L. In a further embodiment, the methods of the present disclosure reduces the level of LDH to from about 120 IU / L to about 220 IU / L.

[0055] In a further embodiment, the methods of the present disclosure reduces the level of 5’ nucleotidase below 50 IU / L (international units per liter), 40 IU / L, 30 IU / L, 20 IU / L, 18 IU / L, 17 IU / L, 16 IU / L, 15 IU / L, 14 IU / L, 13 IU / L, 12 IU / L, 11 IU / L, 10 IU / L, 9 IU / L, 8 IU / L, 7 IU / L, 6 IU / L, or 5 IU / L. In a further embodiment, the method of the present disclosure reduces the level of 5’ nucleotidase to from about 2 IU / L to about 15 IU / L.

[0056] In a further aspect, the present disclosure relates to a method [Method 9] for extending the transplant-free survival of a patient having a FXR mediated disease or condition, or a cholestatic disease or condition, comprising administering a therapeutically effective amount of a pharmaceutical composition of the present disclosure to a subject in need thereof.

[0057] The present disclosure further provides the following embodiments of Method 9:9.1 Method 9, wherein the FXR mediated disease or condition is selected from primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), portal hypertension, bile acid diarrhea, a chronic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis C infection, an alcoholic liver disease, liver damage due to progressive fibrosis, liver fibrosis, drug-induced cholestasis, hereditary cholestasis, biliary atresia, and intrahepatic cholestasis of pregnancy.9.2 Method 9 or 9.1, wherein the FXR mediated disease or condition is chronic liver disease.9.3 Method 9 or 9.1, wherein the FXR mediated disease or condition is a cholestatic liver disease.9.4 Method 9 or 9.1, wherein the FXR mediated disease or condition is PBC.Method 9 or 9.1, wherein the FXR mediated disease or condition is NASH. Method 9 or 9.1, wherein the FXR mediated disease or condition is liver fibrosis. Method 9 or 9.1, wherein the FXR mediated disease or condition is liver fibrosis associated with NASH. Method 9 or 9.1, wherein the FXR mediated disease or condition is nonalcoholic fatty liver disease (NAFLD). Method 9 or 9.1, wherein the subject is not suffering from a cholestatic condition. Method 9 or 9.1, wherein the subject is suffering from a cholestatic condition. Any preceding Method 9 and 9.1 et seq., wherein the composition is administered once daily (QD). Any preceding Method 9 and 9.1 et seq., wherein the composition is administered for a period of at least 4 weeks. Any preceding Method 9 and 9.1 et seq., wherein the composition is administered for a period of at least 12 weeks. Any preceding Method 9 and 9.1 et seq., wherein the composition is administered for a period of 1-12 weeks. Any preceding Method 9 and 9.1 et seq., wherein the composition is administered for a period of 12-48 weeks. Any preceding Method 9 or 9.1;. et seq., further comprising the step of assessing, monitoring, measuring, or otherwise detecting liver function. Method 9.16, wherein the step of assessing, monitoring, measuring, or otherwise detecting liver function comprises a non-invasive assay. Method 9.17, wherein the non-invasive assay is a HepQuant SHUNT assay. Method 9.18, wherein the HepQuant SHUNT assay comprises measuring clearance of cholate from both the systemic circulation and portal circulation. Method 9.19, wherein the cholate is labeled, for example wherein the cholate is isotopically labeled, for example wherein the cholate is isotopically labeled with a carbon isotope or a hydrogen isotope, for example wherein the cholate is isotopically labeled with13C or deuterium.Method 9.20, wherein the HepQuant SHUNT assay comprises intravenously administering (e.g., injecting) 13C labeled cholate. M eth o d 9.20 , wh erei n the HepQuant SHUNT assay comprises orally administering deuterium labeled cholate. M eth o d 1 .20 , wh erei n the HepQuant SHUNT assay comprises intravenously administering13C labeled cholate, and orally administering deuterium labeled cholate. Method 9.18, wherein the HepQuant SHUNT assay comprises collecting a blood sample from the subject before the subject is administered with the cholate. Method 9.18, wherein the HepQuant SHUNT assay comprises collecting a blood sample from the subject after cholate has been administered to the subject. Method 9.18, wherein the HepQuant SHUNT assay comprises taking a blood sample from the subject 5, 20, 45, 60, and / or 90 minutes after administration of the cholate. Any preceding Method 9.18-1.26, wherein the HepQuant SHUNT assay comprises analyzing the blood samples to generate a Disease Severity Index (Index). Method 9.18, wherein the HepQuant SHUNT assay comprises:(a) collecting a blood sample from a subject (e g., a patient in need of treatment described herein) before the subject is administered with cholate;(b) intravenously administering13C labeled cholate, and orally administering deuterium labeled cholate, to the subject;(c) collecting a blood sample from the subject; and(d) analyzing the blood samples from Steps (a) and (c) to generate a Disease Severity Index. Any preceding Method 9 and 9.1-9.28, wherein Composition 1 or 1.1 et seq. is administered as a first-line treatment for the FXR mediated disease or condition. Any preceding Method 9 and 9.1-9.28, wherein Composition 1 or 1.1 et seq. is administered in combination with UDCA for the treatment of the FXR mediated disease or condition. Any preceding Method 9 and 9.1-9.28, wherein Composition 1 or 1.1 et seq. is administered in place of UDCA for the treatment of the FXR mediated disease or condition.Any preceding Method 9 and 9.1-9.31, wherein the method results in ALP normalization or ALP reduction of >60% from baseline at month 12 of treatment; and / or normalization of Total Bilirubin (<0.6 x ULN) and / or Total Bilirubin Reduction of >20% from baseline at month 12 of treatment. Any preceding Method 9 and 9.1-9.31, wherein the method results in ALP normalization or ALP reduction of >60% from baseline at month 12 of treatment; and normalization of Total Bilirubin (<0.6 x ULN), and Total Bilirubin Reduction of >20% from baseline at month 12 of treatment. Any preceding Method 9 and 9.1-9.31, wherein the method results in one or more of an ALP of <1.67 x ULN, a >15% reduction in ALP, and total bilirubin <ULN. Any preceding Method 9 and 9.1-9.31, wherein the method results in an ALP of <1.67 x ULN, a >15% reduction in ALP, and total bilirubin < ULN. Any preceding Method 9 and 9.1-9.31, wherein the method results in a normalization rate achieved for one or more of the biochemical disease markers of < about 0.8 x ULN, < about 0.9 x ULN, < about 1.0 x ULN, < about 1.1 x ULN, or < about 1.2 x ULN at month 12 after commencement of treatment; for example where the biochemical disease markers include one or more of ALP, total bilirubin (TB), ALT, GGT, and AST. Any preceding Method 9 and 9.1-9.31, wherein the method results in one or more of:• Normalization of ALP or a reduction >50% of ALP; and a total bilirubin of <0.6 X ULN at month 12;• >50% reduction in ALP at month 12;• total bilirubin of <0.6 X ULN at month 12;• 40% reduction of ALT and normalization of ALT at month 12;• 18% reduction of AST at month 12 with 90% of patients normalizing AST at month 12;• 76% reduction of GGT at month 12 with 75% of patients normalizing GGT at month 12;• 30% reduction in pruritus from baseline NRS score;• 18% reduction in mean baseline total cholesterol. Any preceding Method 9 and 9.1-9.31, wherein the method results in one or more of:• Normalization rates (all <1.Ox ULN) at Month 12 of individual biochemical disease markers; e.g., one or more of ALP, TB, ALT, GGT, AST• Change from baseline to Month 12 in one or more of ALP, TB, GGT, ALT, AST• Incidence of treatment emergent adverse events (TEAEs)• Change from baseline to Month 12 in cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol.• Incidence and time to adjudicated events of hepatic injury.• Change from baseline in pruritus numerical rating scale (NRS) at Month 6. Weekly averaged pruritus NRS in subjects with baseline NRS >4, where NRS is a scale of 0 (no itching) to 10 (worst imaginable itching).• Change from baseline in FIS at Month 12• Change from baseline in FIS >1 to Month 6 Any preceding Method 9 and 9.1-9.38, wherein the Composition of the present disclosure is administered for the treatment or prevention of a disease or condition as described herein, in place of UDCA, to a subject who has an inadequate therapeutic response to UDCA (used alone or in combination with another active), or who is unable to tolerate UDCA. Any preceding Method 9 and 9.1-9.38, wherein the Composition of the present disclosure is administered as a first-line treatment for the treatment or prevention of a disease or condition as described herein. Any preceding Method 9 and 9.1-9.38, wherein the Composition of the present disclosure is administered as a first-line treatment for the treatment or prevention of a disease or condition as described herein, in combination with UDCA. Any preceding Method 9 and 9.1-9.38, wherein the Composition of the present disclosure is administered for the treatment or prevention of a disease or condition as described herein, e.g., for the treatment of adult patients with primary biliary cholangitis (PBC): without cirrhosis; or with compensated cirrhosis who do not have evidence of portal hypertension, either in combination with ursodeoxycholic acid (UDCA) with an inadequate response to UDCA or as monotherapy in patients unable to tolerate UDCA. Any preceding Method 9 and 9.1-9.38, wherein the Composition of the present disclosure is a Composition according to Composition 1 or 1.1 et seq.

[0058] In some embodiments, the methods of the present disclosure comprise administering to a subject in need thereof an effective amount of a fixed dose combination (FDC) bilayer tablet comprising an immediate release layer containing about 0.5 mg to about 30 mg of OCA, and a sustained release layer containing a about 200 to about 600 mg, e.g. 400 mg, of a fibrate, e.g., bezafibrate.

[0059] In the compositions, packs or kits, methods and uses of the present disclosure, OCA may be in a free form (e.g., acid) or it may be a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof. In some embodiments, OCA is in the form of a pharmaceutically acceptable salt or amino acid conjugate e.g., glycine or taurine conjugate).

[0060] The disclosure also encompasses isotopically-labeled OCA or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof, which has a structure that is identical to that of the FXR agonist of the present disclosure of the present disclosure except that one or more atoms is replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into the FXR agonist of the present disclosure or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof, include isotopes of hydrogen, carbon, nitrogen, fluorine, such as3H,nC,14C and18F.

[0061] OCA or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof that contains the aforementioned isotopes and / or other isotopes of other atoms is within the scope of the present disclosure. Isotopically labeled OCA or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof, for example, OCA into which a radioactive isotope(s) such as3H and / or14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are used for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be used in some circumstances. Isotopically labeled OCA or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronideconjugate, or prodrug thereof can be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples of the present disclosure, and substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0062] In some embodiments of the Methods and Compositions disclosed herein, the subject is a mammal. In some embodiments, the mammal is a human.

[0063] It has been discovered in accordance with the present disclosure that coadministration of OCA and bezafibrate in the bilayer tablet compositions described herein provide significant advantages over prior modes of administration in regard to both minimizing formation of impurities, and clinical efficacy.

[0064] Impurities

[0065] Impurities in the OCA / BZF sustained release bilayer fixed dose combination (FDC) tablets of the present disclosure can be categorized in 3 areas: OCA impurities, BZF impurities, and OCA / BZF impurities. Six OCA impurities have been identified in OCA drug substance that can also be observed in the OCA / BZF SR bilayer FDC tablets of the present disclosure.However, five of these impurities are synthetic process impurities that do not form in the drug product, and are controlled at the process for preparing the OCA drug substance. The sixth OCA impurity, 3a-(3a,7a-dihydroxy-6a-ethyl-5p-cholan-24-oyloxy)-7a-hydroxy-6a-ethyl-5p-cholan- 24-oic acid (also referred to herein as "the OCA dimer") is a degradation product of the OCA drug substance, and is also observed to form in the OCA / BZF SR bilayer FDC tablets of the present disclosure. While not wishing to be bound by any particular theory, it is believed the content of the OCA dimer can increase through thermal degradation of the drug substance.

[0066] Five impurities have been observed in the BZF drug substance. Two of these impurities can also be observed in the OCA / BZF SR bilayer FDC tablets of the present disclosure. These are ethyl 2-[4-[2-[(4-chlorobenzoyl)amino]ethyl]phenoxy]-2-methylpropanoate, which is the ethyl ester of BZF, referred to herein as "the BZF ethyl ester," and N-(4-chlorobenzoyl)tyramine.

[0067] In some preferred embodiments, the disintegrant in the immediate release layer comprises or consists of sodium starch glycolate. While not wishing to be bound by a particular theory, it is believed that use of sodium starch glycolate that has a low alcohol content minimizes formation of the BZF ethyl ester impurity.

[0068] There is one impurity that can potentially form in the OCA / BZF SR bilayer FDC tablets of the present disclosure by an interaction between OCA and BZF. This is an OCA / BZF conjugate which would be considered a degradation product. Although the OCA / BZF conjugate has not been detected in the OCA / BZF SR bilayer FDC tablets of the present disclosure, it can nevertheless potentially form by an esterification of OCA by BZF.

[0069] While not wishing to be bound by a particular theory, it is believed that the present compositions, which contain the OCA and bezafibrate in separate layers, minimize the potential interaction between the actives, thus minimizing formation of the aforementioned impurities, e.g., the OCA / BZF conjugate, and also provides increased stability to the compositions.

[0070] The structures of the aforementioned impurities are shown in Table 1 below:Table 1 - Impurities

[0071] In some embodiments, the amount of OCA dimer present in the OCA / BZF SR bilayer FDC tablets of the present disclosure is <1.0% w / w; e.g. <0.5% w / w; e.g., <0.2% w / w; e.g., <0.1% w / w; e.g., < 0.09% w / w, < 0.075% w / w, < 0.05% w / w, < 0.025% w / w, < 0.01% w / w, or < 0.001% w / w.

[0072] In some embodiments, the amount of A-(4-chlorobenzoyl)tyramine present in the OCA / BZF SR bilayer FDC tablets of the present disclosure is <1.0% w / w; e.g. <0.5% w / w; e.g., <0.2% w / w; e.g., <0.1% w / w; e.g., < 0.09% w / w, < 0.07% w / w, < 0.06% w / w, < 0.05% w / w, < 0.025% w / w, < 0.01% w / w, or < 0.001% w / w.

[0073] In some embodiments, the amount of BZF ethyl ester present in the OCA / BZF SR bilayer FDC tablets of the present disclosure is <1.0% w / w; e.g. <0.75% w / w; e.g. <0.5% w / w; e.g., <0.2% w / w; e.g., <0.1% w / w; e.g., < 0.08% w / w, < 0.07% w / w, < 0.06% w / w, < 0.05% w / w, < 0.04% w / w, < 0.025% w / w, < 0.01% w / w, or < 0.001% w / w.

[0074] In some embodiments, the amount of OCA / BZF conjugate present in the OCA / BZF SR bilayer FDC tablets of the present disclosure is <1.0% w / w; e.g. <0.5% w / w; e.g., <0.2% w / w; e.g., <0.1% w / w; e.g., < 0.09% w / w, < 0.075% w / w, < 0.05% w / w, < 0.025% w / w, < 0.01% w / w, or < 0.001% w / w.

[0075] In some embodiments, the combined amount of total impurities present in the OCA / BZF SR bilayer FDC tablets of the present disclosure is <5% w / w; e.g., <4% w / w; e.g. <3% w / w; e.g. <2% w / w; e.g., <1% TN / W, e.g. <0.5% w / w; e.g., <0.4% w / w; e.g., <0.3% w / w; e.g., < 0.25% w / w, e.g., < 0.2% w / w, e.g., < 0.1% w / w, e.g., < 0.025% w / w, e.g., < 0.01% w / w.

[0076] Sustained release

[0077] The presence of OCA in a separate immediate release layer and bezafibrate in a separate sustained release layer provides the ability to release the two components at different rates, to maximize their effects. BZF has a relatively short half-life in vivo. Because bezafibrate has a relatively short duration in the blood relative to OCA, providing sustained release of bezafibrate in accordance with the present disclosure is believed to afford maintenance of clinically effective levels of both agents for a greater time, thus increasing the efficacy of the combination. Further, as discussed above, maintaining the OCA and bezafibrate in separate layers is expected to hinder formation of the OCA dimer impurity, thus increasing stability of the composition. Similarly,the extended-release excipients (e.g., hypromellose) included in the BZF layer could potentially have a similar effect on OCA by extending the release of the product. Again, the present bilayer tablet maintains the OCA and release control agent in separate layers, thus minimalizing potential extended release of OCA.

[0078] In some embodiments, the OCA / BZF SR bilayer FDC tablets of the present disclosure the OCA layer of the bilayer tablet has a dissolution profile (USP <711>) of Q (OCA) = 80% at 30 minutes. In some embodiments, the OCA dissolution profiles has the following mean % values: 10 minutes: about 94%; 15 minutes: about 95%; 30 minutes: about 98%; 45 minutes: about 99%; 60 minutes: about 102%.; where Q (OCA) is the amount of dissolved OCA, expressed as a percentage of the amount of OCA in the bilayer tablet.

[0079] In some embodiments of the OCA / BZF SR bilayer FDC tablets of the present disclosure, the BZF layer of the bilayer tablet has a dissolution profile (USP <711>) of Q (BZF) as shown below in Table 2:Table 2In some embodiments, the BZF dissolution profile has the mean % values shown below inTable 3:Table 3where Q (BZF) is the amount of dissolved BZF, expressed as a percentage of the amount of BZF in the bilayer tablet.

[0080] Particle Size

[0081] The dry granulation process that is used to produce both the OCA immediate release layer and the BZF SR layer produces granules with a desired particle size distribution. Theparticle size distribution of the granules allows for proper flow creating a homogeneous blend that flows well and allows for accurate filling of compression dies. Additionally, the particle distribution that is generated produces an OCA layer of the bilayer tablet that is immediate release as desired, and for the BZF layer a granulation with a particle size distribution that consistently releases and produces the desired sustained release dissolution profile.

[0082] In some embodiments, both the OCA immediate release layer and the BZF SR layer of the bilayer tablet of the present disclosure are prepared by a dry granulation process with roller compaction. Dry granulation avoids the addition of water, which can affect the water content of the final composition, and also the presence of impurities. In addition, dry granulation does not require a drying process, which also adds the inherent risk that accompanies the application of heat. Moreover, OCA tends to be very sticky and not flow well. Dry granulation by roller compaction avoids problems relating to the stickiness of OCA. It also improves the flowability of the blend, and ensures a homogeneous mixture.

[0083] In a further aspect, the present disclosure relates to a method [Method 11] for preparing a bilayer tablet pharmaceutical composition according to any of Compositions 1 and 1.1 et seq, comprising:(a) preparing an OCA blend layer, said layer comprising OCA, one or more fillers / binders, a glidant and a lubricant;(b) preparing a fibrate blend layer, said layer comprising a fibrate, a release-control agent, one or more fillers / binders, a glidant and a lubricant;(c) compressing the layers to form a compressed tablet; and(d) coating the tablet with a coating agent.

[0084] Liver biomarkers can be used to ascertain and quantify the efficacy of the course of treatment of the present disclosure. In other instances, liver biomarkers described herein can be used to ascertain and quantify liver function during the course of treatment of the present disclosure. Liver biomarkers can also be used to predict whether a patient or patient population is susceptible to treatment described herein. In some embodiments, the liver biomarkers include assessing, monitoring, measuring or otherwise detecting an amount or level of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), bilirubin, glycine conjugated obeticholic acid, taurine conjugated obeticholic acid, a bile acid, a bile acid glycineconjugate, or a bile acid taurine conjugate. For example, the liver biomarker assessed, monitored, measured, or detected can be ALP.

[0085] The ALP level can be a measure of ULN. In some embodiments, a patient before treatment can have an ALP level of at least 1.1 x ULN to at least 20 x ULN; at least 1.1 x ULN to at least 15 x ULN; at least 1.1 x ULN to at least 12 x ULN; at least 1.1 x ULN to at least 10 x ULN; at least 1.1 x ULN to at least 8 x ULN; at least 1.1 x ULN to at least 6 x ULN; at least 1.1 x ULN to at least 5 x ULN; at least 1. 1 x ULN to at least 4 x ULN; at least 1.1 x ULN to at least 3 x ULN; or at least 1.1 x ULN to at least 2 x ULN.

[0086] A patient before a treatment described herein can have an ALP level of about 1.5 x ULN to about 20 x ULN; about 1.5 x ULN to about 15 x ULN; about 1.5 x ULN to about 10 ULN; about 1.5 x ULN to about 5 x ULN; or about 1.5 x ULN to about 3 x ULN. A patient before treatment can have an ALP level of about 1.5x, 2x, 3x, 4x, 5x, 8x, lOx, 15x, or 20x ULN.

[0087] A patient before a treatment described herein can have an ALP level of greater than about 1.5x, 2x, 3x, 4x, 5x, 8x, lOx, 15x, or 20x ULN. In some embodiments, a patient has an ALP level of about 1.5 x ULN. In some embodiments, a patient has an ALP level of about 2 x ULN. In some embodiments, a patient has a ALP level of about 5 x ULN. In some embodiments, a patient has an ALP level of about 10 x ULN. In some embodiments, a patient has an ALP level of about 15 x ULN. In some embodiments, a patient has an ALP level greater than about 1.5 x ULN. In some embodiments, a patient has an ALP level greater than about 2 x ULN. In some embodiments, a patient has a ALP level greater than about 5 x ULN. In some embodiments, a patient has an ALP level greater than about 10 x ULN. In some embodiments, a patient has an ALP level greater than about 15 x ULN.

[0088] In another example, the liver biomarker assessed, monitored, measured, or detected can be bilirubin. The bilirubin level can be a measure of ULN. In some embodiments, a patient before treatment can have a bilirubin level of at least 1.1 x ULN to at least 20 x ULN; at least 1.1 x ULN to at least 15 x ULN; at least 1.1 x ULN to at least 12 x ULN; at least 1.1 x ULN to at least 10 x ULN; at least 1.1 x ULN to at least 8 x ULN; at least 1.1 x ULN to at least 6 x ULN; at least 1.1 x ULN to at least 5 x ULN; at least 1.1 x ULN to at least 4 x ULN; at least 1.1 x ULN to at least 3 x ULN; or at least 1.1 x ULN to at least 2 x ULN.

[0089] A patient before a treatment described herein can have a bilirubin level of about 1.5 x ULN to about 20 x ULN; about 1.5 x ULN to about 15 x ULN; about 1.5 x ULN to about 10 ULN; about 1.5 x ULN to about 5 x ULN; or about 1.5 x ULN to about 3 x ULN. In another example a patient before a treatment described herein can have a bilirubin level of about 2 x ULN to about 20 x ULN; about 2 x ULN to about 15 x ULN; about 2 x ULN to about 10 ULN; about 2 x ULN to about 5 x ULN; or about 2 x ULN to about 3 x ULN. In another example a patient before a treatment described herein can have a bilirubin level of greater than about 2 x ULN to greater than about 20 x ULN; greater than about 2 x ULN to greater than about 15 x ULN; greater than about 2 x ULN to greater than about 10 ULN; greater than about 2 x ULN to greater than about 5 x ULN; or greater than about 2 x ULN to greater than about 3 x ULN.

[0090] A patient before a treatment described herein can have a bilirubin level of about 1.5x, 2x, 3x, 4x, 5x, 8x, lOx, 15x, or 20x ULN. A patient before treatment can have a bilirubin level of greater than about 1.5x, 2x, 3x, 4x, 5x, 8x, lOx, 15x, or 20x ULN. In some embodiments, a patient has a bilirubin level greater than about 2 x ULN. In some embodiments, a patient has a bilirubin level greater than about 5 x ULN. In some embodiments, a patient has a bilirubin level greater than about 10 x ULN. In some embodiments, a patient has a bilirubin level greater than about 15 x ULN. In some embodiments, a patient has a bilirubin level less than about 2 x ULN. In some embodiments, a patient has a bilirubin level less than about 5 x ULN. In some embodiments, a patient has a bilirubin level less than about 10 x ULN. In some embodiments, a patient has a bilirubin level less than about 15 x ULN.

[0091] In some instances, it can be useful to assess, monitor, measure, or detect ALP and bilirubin to assess, monitor, measure, or otherwise detect liver function or changes in liver function during treatment described herein. In certain instances, a patient has an ALP level as provided above (e.g., about 1.5 x ULN to about 10 x ULN) and a bilirubin level as provided above (e.g., less than about 5 x ULN). In some embodiments, the patient has an ALP level between about 1.5 x ULN to about 10 x ULN and a bilirubin level less than about 2 x ULN.

[0092] Treatment described herein can reduce the levels of ALP and / or bilirubin in a patient described herein. For example, treatment of an FXR mediated disease or condition described herein can reduce the level of ALP by 2, 4, 5, 6, 8, 9, 10, 12, 15, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 88, 90, 92, 94, 96, 97, 98, 99, 99.2, 99.4,99.6, 99.7, 99.8, 99.9, or 100%. In another example, the level of ALP can be reduced by at least 60%, at least 70%, at least 80%, at least 90%, 100%, at least 125%, at least 150%, at least 175%, at least 200%, at least 225%, at least 250% or at least 300%. In some embodiments, the FXR mediated disease or condition is PBC.

[0093] In another example, the level of ALP can be reduced by about 5% to about 50%; about 10% to about 55%; about 10% to about 45%; about 10% to about 40%; about 10%; about 33%, about 10% to about 30%; about 15% to about 30%; about 15% to about 25%; about 20% to about 50%, about 20% to about 40%; about 20% to about 35%; about 20% to about 30%; 20% to about 27%; or about 20% to about 27%. In another example, the level of ALP can be reduced by at least 50%. The level of ALP can be reduced by at least 40%. The level of ALP can be reduced by at least 35%. The level of ALP can be reduced by at least 30%. The level of ALP can be reduced by at least 27%. The level of ALP can be reduced by at least 25%. The level of ALP can be reduced by at least 20%.

[0094] The reduction of ALP levels can be represented by the fold change over ULN. For example, treatment described herein can reduce the ALP level of a patient described herein to less than about 5 x ULN; less than about 4 x ULN, less than about 3 x ULN, less than about 2 x ULN, less than about 1.7 x ULN, less than about 1.5 x ULN, less than about 1.25 x ULN, or less than about ULN.

[0095] In another example, the ALP level is reduced by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, or 5-fold compared to a baseline value. For example, the ALP level after treatment described herein can be reduced by 1, 1.2, 1.4, 1.6, 1.8, or 2-fold, including intervening values therein, compared to a baseline value. In another example, the ALP level can be reduced by 2, 2.2, 2.4, 2.6, 2.8, or 3-fold, including intervening values therein, compared to a baseline value. In another example, the ALP level can be reduced 3, 4, or 5- fold, including intervening values therein, compared to a baseline value. In another example, the ALP level can be reduced 5, 7, 9, or 10-fold, including intervening values therein, compared to a baseline value. In another example, the ALP level can be reduced 10, 12, 15, or 20-fold, including intervening values therein, compared to a baseline value.

[0096] In a further example, the ALP level is normalized, or is decreased by >40% from baseline at month 12 from the commencement of treatment, >45% from baseline at month 12 from thecommencement of treatment, >50% from baseline at month 12 from the commencement of treatment, >55% from baseline at month 12 from the commencement of treatment, >60% from baseline at month 12 from the commencement of treatment, >65% from baseline at month 12 from the commencement of treatment, >70% from baseline at month 12 from the commencement of treatment, or >75% from baseline at month 12 from the commencement of treatment.

[0097] Treatment of a disease or condition described herein can reduce the level of bilirubin by 2, 4, 5, 6, 8, 9, 10, 12, 15, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 88, 90, 92, 94, 96, 97, 98, 99, 99.2, 99.4, 99.6, 99.7, 99.8, 99.9, or 100%. In another example, the level of bilirubin can be reduced by at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, at least 225%, at least 250% or at least 300%.

[0098] In another example, the level of bilirubin (e.g., Total Bilirubin Reduction) can be reduced by about 5% to about 50%; about 10% to about 55%; about 10% to about 45%; about 10% to about 40%; about 10% to about 33%, about 10% to about 30%; about 15% to about 30%; about 15% to about 25%; about 20% to about 50%, about 20% to about 40%; about 20% to about 35%; about 20% to about 30%; 20% to about 27%; or about 20% to about 27%. In another example, the level of bilirubin can be reduced by at least 50%. The level of bilirubin can be reduced by at least 40%. The level of bilirubin can be reduced by at least 35%. The level of bilirubin can be reduced by at least 30%. The level of bilirubin can be reduced by at least 27%. The level of bilirubin can be reduced by at least 25%. The level of bilirubin can be reduced by at least 20%.

[0099] The reduction of bilirubin levels can be represented by the fold change over ULN. For example, treatment described herein can reduce the bilirubin level of a patient described herein to less than about 5 x ULN; less than about 4 x ULN, less than about 3 x ULN, less than about 2 x ULN, less than about 1.7 x ULN, less than about 1.5 x ULN, less than about 1.25 x ULN, or less than about ULN; < about 0.9 x ULN, < about 0.8 x ULN, < about 0.7 ULN, < about 0.6 ULN, < about 0.5 ULN. or < about 0.3 ULN.

[0100] In another example, the bilirubin level is reduced by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, or 50-fold compared to a baseline value. For example, the bilirubin level after treatment described herein can be reduced by 1, 1.2, 1.4, 1.6, 1.8, or 2-fold, including intervening values therein, compared to a baseline value. In another example, the bilirubin level can be reduced by 2, 2.2, 2.4, 2.6, 2.8, or 3-fold, including intervening values therein, comparedto a baseline value. In another example, the bilirubin level can be reduced 3, 4, or 5-fold, including intervening values therein, compared to a baseline value. In another example, the bilirubin level can be reduced 5, 7, 9, or 10-fold, including intervening values therein, compared to a baseline value. In another example, the bilirubin level can be reduced 10, 12, 15, or 20-fold, including intervening values therein, compared to a baseline value.

[0101] In another embodiment, one or more biomarkers can stratify a patient population undergoing treatment described herein. For example, a PBC patient can be stratified for the risk of hepatocellular carcinoma (HCC).

[0102] In another embodiment, liver biomarkers useful for detection can include metabolites and bile acids. For example, assessing, monitoring, measuring, or otherwise detecting levels of glycine and taurine conjugates of obeticholic acid can be useful for measuring efficacy of a treatment regimen described herein. For example, assessing, monitoring, measuring, or otherwise detecting levels or detecting plasma levels of bile acids including cholic acid, chenodeoxycholic acid, deoxycholic acid, lithocholic acid, and ursodeoxycholic acid, including glycine and taurine conjugates thereof, and optionally comparing the levels to a control, can be useful for measuring efficacy of a treatment regimen described herein.

[0103] In still other embodiments, calculating an AST to platelet index (APRI) can be useful for assessing, monitoring, measuring, or otherwise detecting liver function (including changes therein). The methods described herein can reduce the APRI of a patient described herein. In certain instances, monitoring or measuring the APRI can be used to determine efficacy of the treatment described herein. In some embodiments, a reduction in APRI is observed in a patient (e.g., a PBC patient) after treatment described herein. For example, the APRI may be reduced by about 5 % to about 50 % in patients treated according to the methods of the present disclosure relative to baseline levels measured before dose administration. The reduction may be up to about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%.

[0104] In some embodiments, a pharmaceutical compositions of the present disclosure can be used lifelong by the patient, prolonging survival and delaying liver transplantation. The reduction of hyperlipidemia and liver enzymes ensures reduction in the development of associated vascular disease.

[0105] Because of the simplified dosing, the combined therapy of the present disclosure can be used in adjusting (increasing or decreasing) doses, depending on a patient’s weight and clinical response. In one aspect, the combined therapy provides reduced side effect profile.

[0106] In various embodiments, the particles referred to herein are irregular in shape. However, a proportion of the particles may be spherical or polyhedral in shape. Thus, as used herein, the term “particle size” is generally used to refer to one or more of the following: (a) the diameter of a spherical particle, (b) the length of the longest axis of the particle, (c) the length of the shortest axis of the particle, (d) any measure between the length of the long axis and the length of the short axis, including the mean between the two. In various embodiments, particle size is determined according to the length of the longest axis of the particle. Diameter is generally expressed in micrometers (pm or micron). Diameter may be determined by any appropriate means known in the art, e.g., via optical measurement.

[0107] In some embodiments, the immediate release layer of the FDC bilayer tablet pharmaceutical composition of the present disclosure includes OCA and one or more excipients selected from filler / binders, disintegrants, lubricants and glidants. In some embodiments, the sustained release layer of the FDC bilayer tablet pharmaceutical composition of the present disclosure includes the fibrate, e.g., bezafibrate, and one or more excipients selected from filler / binders, release-controlling agents, binders, lubricants and glidants.

[0108] Filler / Binders

[0109] Various compounds are known in the art to function as both a filler and a binder in pharmaceutical compositions. Examples of suitable binders and filler / binders for use in the immediate release and sustained release layers of the present compositions include microcrystalline cellulose, cellulose derivatives, acrylic derivatives, starch, gelatin, sugars, natural and synthetic gums, polyethylene glycol, ethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, waxes, and polyvinyl pyrrolidone. The filler / binder both the immediate release and sustained release layers can be the same or different. In some embodiments, filler / binder in both the immediate release and sustained release layers is the same, and comprises or consists of microcrystalline cellulose.

[0110] In some embodiments, either or both of the immediate release and sustained release layers can include more than one binder and / or filler / binder. In some embodiments, thesustained release layer includes microcrystalline cellulose, and a second binder, e.g. hydroxypropyl cellulose.

[0111] Disintegrants

[0112] The compositions of the present disclosure may include a disintegrants to facilitate breakup or disintegration after administration. Suitable disintegrants for use in the immediate release layer of the present compositions include sodium starch glycolate, com starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid, agar, starches, clays, celluloses, aligns, gums, and cross-linked polymers. In some preferred embodiments, the disintegrant is or comprises sodium starch glycolate, and in particular low-ethanol sodium starch glycolate, to avoid potential formation of a OCA-ethyl ester.

[0113] Release-controlling agents

[0114] In some embodiments, the release-controlling agent in the BZF layer has a particle size distribution wherein: NLT 99.0% of the particles pass through a 40 U.S. Standard Sieve (420 micron sieve opening); NLT 90.0% of the particles pass through a 100 U.S. Standard Sieve (149 micron sieve opening); and between 50.0% and 80.0% of the particles pass through a 230 U.S. Standard Sieve (63 micron sieve opening).

[0115] Suitable release-controlling agents for use in the sustained release layer of the present compositions include hydroxypropyl methylcellulose ("HPMC" or "hypromellose"), e.g., Methocel™, e.g. Methocel™ K100LV (available from, inter alia, Colorcon, Harleysville, Pennsylvania, USA), glyceryl monostearate, glyceryl distearate, a 2-Propenic Acid Homopolymer, e.g., Carbopol 71G®, or a polyethylene oxide polymer, e.g., PolyOx™ N60K or PolyOx™ WSR301. In some embodiments, the release-controlling agent comprises or consists of a hydroxypropyl methylcellulose, for example Methocel™ KI 00LV, which is a low- molecular weight hydroxypropyl methylcellulose (HPMC) that yields a viscosity of 80-120 cPs, e.g., 100 cPs, for a 2% solution in water, and has 19.0%-24.0% methoxyl substitution and 7.0%- 12.0% hydroxy propyl substitution.

[0116] Lubricants

[0117] Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.

[0118] Glidants

[0119] Suitable glidants include colloidal silicon dioxide, corn starch, and talc.

[0120] Coating Agents

[0121] In some embodiments, the coating material is preferably devoid of materials (e.g., polyethylene glycol) that can potentially form an ester with OCA. One example of such a coating material is Opadry® AMB II which does not contain polyethylene glycol. Other suitable coating agents include other Opadry® coatings, e.g., Opadry® II and Opadry® TF.

[0122] Definitions

[0123] For convenience, certain terms used in the specification, examples and appended claims are collected here.

[0124] The term “fibrate of the present disclosure” refers to bezafibrate and pharmaceutically acceptable salts or esters thereof.

[0125] Bezafibrate (BZF), a pan-peroxisome proliferator-activated receptor (PPAR) [a, o, y] agonist, was originally developed for treatment of hyperlipidemia and used for the prevention of cardiovascular disease. BZF also decreases serum hepatobiliary enzyme activity in individuals with and without cardiovascular disease and thus has been identified as a potential anticholestatic agent for the treatment of PBC with an inadequate response to UDCA.

[0126] OCA is a selective FXR agonist that has been shown to effect significant reductions in ALP in patients with PBC who demonstrated no or partial response to UDCA. As such, OCA has been conditionally approved for patients with PBC in combination with UDCA for those with an inadequate response to UDCA or who are intolerant to UDCA.

[0127] Without being bound to any theory, this disclosure relates to concomitant use of OCA and BZF which results in improved efficacy and tolerability compared to the previous PBC therapies and treatment with OCA alone.

[0128] The term “FXR agonist of the present disclosure” refers to OCA and pharmaceutically acceptable salts, solvates, or amino acid, sulfate or glucuronide conjugates, and prodrugs thereof.

[0129] As used herein, the term “obeticholic acid” or “OCA” refers to a compound having the chemical structure:

[0130] Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist and modified bile acid derived from the primary human bile acid chenodeoxycholic acid (CDCA), was developed for the treatment of PBC and to provide patients who have an inadequate response to or poor tolerance of UDCA, a novel treatment option that was safe and effective (Pellicciari R, Fiorucci S, Camaioni E, et al. 6alpha-ethyl -ch enodeoxy cholic acid (6 ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002;45:3569- 3572).

[0131] Obeticholic acid is also referred to as 3a,7a-dihydroxy-6a-ethyl-5B-cholan-24-oic acid, 6a-ethyl-chenodeoxycholic acid, 6-ethyl-CDCA, 6ECDCA, cholan-24-oic acid, 6-ethyl- 3,7-dihydroxy-(3a,5B, 6a, 7a), and can be prepared by the methods described in U.S. Publication No. 2009 / 0062526 Al, U.S. Patent No. 7,138,390, and WO2006 / 122977. The CAS registry number for obeticholic acid is 459789-99-2.

[0132] The term “the compound” means OCA, or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof. Whenever the term is used in the context of the present disclosure it is to be understood that the reference is being made to a free form, an i sotopi cal ly -lab eled compound, a crystalline compound, a noncrystalline compound or a corresponding pharmaceutically acceptable salt or amino acid conjugates thereof, provided that such is possible and / or appropriate under the circumstances.

[0133] As used herein, the term “amino acid conjugates” refers to conjugates of OCA with any suitable amino acid. For example, such a suitable amino acid conjugate of OCA has the added advantage of enhanced integrity in bile or intestinal fluids. Suitable amino acids include but are not limited to glycine, taurine and sarcosine. Thus, the present disclosure encompasses the glycine, taurine and sarcosine conjugates of OCA.

[0134] “Treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc. “Treating” or “treatment” of a disease state includes inhibiting the existing disease state, i.e., arresting the development of the disease state or its clinical symptoms, or relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.

[0135] “Preventing” a disease state includes causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state but does not yet experience or display symptoms of the disease state.

[0136] The term “inhibiting” or “inhibition” as used herein refers to any detectable positive effect on the progression of a disease or condition. Such a positive effect may include the delay in progression of at least one symptom or sign of the disease or condition, alleviation or reversal of the symptom(s) or sign(s) and slowing of the further worsening of the symptom(s) or sign(s).

[0137] “Disease state” means any disease, disorder, condition, symptom, or indication.

[0138] The term “effective amount” or “therapeutically effective amount” as used herein refers to an amount of an FXR agonist of the present disclosure or a fibrate of the present disclosure that produces an acute or chronic therapeutic effect upon appropriate dose administration, alone or in combination. In some embodiments, an effective amount or therapeutically effective amount of an FXR-activating ligand produces an acute or chronic therapeutic effect upon appropriate dose administration in combination with a fibrate of the present disclosure. The effect includes the prevention, correction, inhibition, or reversal of the symptoms, signs and underlying pathology of a disease / condition (e.g., fibrosis of the liver, kidney, or intestine) and related complications to any detectable extent. An “effective amount” or “therapeutically effective amount” varies depending on the FXR agonist of the present disclosure, the fibrate of the present disclosure, the disease and its severity, and the age, weight, etc., of the subject to be treated.

[0139] “Pharmacological effect” as used herein encompasses effects produced in the subject that achieve the intended purpose of a therapy. In some embodiments, a pharmacological effect means that primary indications of the subject being treated are prevented, alleviated, or reduced. For example, a pharmacological effect would be one that results in the prevention,alleviation or reduction of primary indications in a treated subject. In another embodiment, a pharmacological effect means that disorders or symptoms of the primary indications of the subject being treated are prevented, alleviated, or reduced. For example, a pharmacological effect would be one that results in the prevention, alleviation or reduction of the disorders or symptoms in a treated subject.

[0140] It is to be understood that the isomers arising from asymmetric carbon atoms (e.g., all enantiomers and diastereomers) are included within the scope of the disclosure, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis.

[0141] A “pharmaceutical composition” is a formulation containing therapeutic agents such as an FXR agonist of the present disclosure and / or a fibrate of the present disclosure, in a form suitable for administration to a subject. In some embodiments, a pharmaceutical composition is in bulk or in unit dosage form. It can be advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage.

[0142] Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active reagent calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure is dictated by and directly dependent on the unique characteristics of the active agents and the particular therapeutic effect to be achieved, and the limitations in the art of compounding such an active agent for the treatment of individuals.

[0143] The term “unit dosage form” refers to physically discrete units suitable as unitary dosages for humans and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient as described herein.

[0144] The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The quantity OCA or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof in a unit dose of composition is an effective amount and is varied according to the particular treatment involved and / or the fibrate used for the treatment. One skilled in the artwill appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage also depends on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In some embodiments, the FXR agonist of the present disclosure and / or fibrate of the present disclosure is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0145] The term “flash dose” refers to formulations that are rapidly dispersing dosage forms.

[0146] The term “immediate release” is defined as a release of a therapeutic agent (such as an FXR agonist of the present disclosure or a fibrate of the present disclosure) from a dosage form in a relatively brief period of time, generally up to about 60 minutes. For example, in some embodiments of the OCA / BZF SR bilayer FDC tablets of the present disclosure, the OCA layer of the bilayer tablet has a dissolution profile (USP <711>) of Q (OCA) = 80% at 30 minutes; and / or mean % values of: 10 minutes: about 94%; 15 minutes: about 95%; 30 minutes: about 98%; 45 minutes: about 99%; 60 minutes: about 100%; e.g. about 102%. The term “modified release” is defined to include delayed release, sustained release or extended release, and pulsed release. The term “pulsed release” is defined as a series of releases of drug from a dosage form. The term “sustained release” or “extended release” is defined as continuous release of a therapeutic agent from a dosage form over a prolonged period. For example, in some embodiments, of the OCA / BZF SR bilayer FDC tablets of the present disclosure, the BZF layer of the bilayer tablet has a dissolution profile (USP <711>) of Q (BZF) of 10-33% after one hour; 22-46% after two hours; 34-57% after three hours; 44-67% after four hours; and 51-78% after five hours.

[0147] A “subject” includes mammals, e.g., humans, companion animals (e.g., dogs, cats, birds, and the like), farm animals (e.g., cows, sheep, pigs, horses, fowl, and the like), and laboratory animals (e.g., rats, mice, guinea pigs, birds, and the like). In some embodiments, the subject is a human. In one aspect, the subject is female. In one aspect, the subject is male.

[0148] As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, carriers, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0149] “Pharmaceutically acceptable carrier or excipient” means a carrier or excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes any excipient that is acceptable for veterinary use and / or human pharmaceutical use. A “pharmaceutically acceptable excipient” as used herein includes both one and more than one such excipient

[0150] “Fibrosis” refers to a condition involving the development of excessive fibrous connective tissue, e.g., scar tissue, in a tissue or organ. Such generation of scar tissue may occur in response to infection, inflammation, or injury of the organ due to a disease, trauma, chemical toxicity, and so on. Fibrosis may develop in a variety of different tissues and organs, including the liver, kidney, intestine, lung, heart, etc.

[0151] As used herein, a “cholestatic condition” refers to any disease or condition in which bile excretion from the liver is impaired or blocked, which can occur either in the liver or in the bile ducts. Intrahepatic cholestasis (which occurs inside the liver) and extrahepatic cholestasis (which occurs outside the liver) are the two types of cholestatic conditions.

[0152] Clinical symptoms and signs of a cholestatic condition include itching (pruritus), fatigue, jaundiced skin or eyes, inability to digest certain foods, nausea, vomiting, pale stools, dark urine, and right upper quadrant abdominal pain. A patient with a cholestatic condition can be diagnosed and followed clinically based on a set of standard clinical laboratory tests, including measurement of levels of alkaline phosphatase, y-glutamyl transpeptidase (GGT), 5’ nucleotidase, bilirubin, bile acids, and cholesterol in a patient’s blood serum. Generally, a patient is diagnosed as having a cholestatic condition if serum levels of all three of the diagnostic markers: alkaline phosphatase, GGT, and 5’ nucleotidase, are considered abnormally elevated. The normal serum level of these markers may vary to some degree from laboratory to laboratory and from procedure to procedure, depending on the testing protocol. Thus, a physician is able to determine, based on the specific laboratory and test procedure, what an abnormally elevatedblood level is for each of the markers. For example, a patient suffering from a cholestatic condition generally has greater than about 125 IU / L alkaline phosphatase, greater than about 65 IU / L GGT, and greater than about 17 NIL 5' nucleotidase in the blood. Because of the variability in the level of serum markers, a cholestatic condition may be diagnosed on the basis of abnormal levels of these three markers in addition to at least one of the symptoms mentioned above, such as itching (pruritus).

[0153] Pruritus is an adverse event (AE) and must be graded for severity (i.e., intensity). Because pruritus is a subjective symptom and its occurrence and magnitude are not readily measured by objective tools, clinical judgment is applied to determine its severity and management in each subject. In order to assess the potential improvement in pruritus with treatment, baseline pruritus presence (yes / no) and severity is determined. Severity of Pruritus: 1 = Mild (Mild or localized; topical intervention indicated); 2 = Moderate (Intense or widespread; intermittent; skin changes from scratching (e.g., edema, papulation, excoriations, lichenification, oozing / crusts); oral intervention indicated; limiting instrumental activities of daily living); 3 = Severe (Intense or widespread; constant; limiting self-care activities of daily living or sleep; oral corticosteroid or immunosuppressive therapy indicated). The present disclosure also relates to a method of treating of a FXR mediated disease or a liver disease or condition, e.g., PBC, with a decreased incidence of adverse events, such as pruritus, comprising administering to a subject in need thereof, a composition according to any of Composition 1 or 1.1 et seq. In one aspect, the method results in the subject having decreased incidence, or decreased severity, of side effects (e.g., pruritus) compared to a subject treated with OCA monotherapy.

[0154] The term “primary biliary cholangitis”, previously called “primary biliary cirrhosis”, often abbreviated PBC, is an autoimmune disease of the liver marked by the slow progressive destruction of the small bile ducts of the liver, with the intralobular ducts (Canals of Hering) affected early in the disease. When these ducts are damaged, bile builds up in the liver (cholestasis) and over time damages the tissue. This can lead to scarring, fibrosis and cirrhosis. PBC is characterized by interlobular bile duct destruction. Histopathologic findings of primary biliary cirrhosis include: inflammation of the bile ducts, characterized by intraepithelial lymphocytes, and periductal epithelioid granulomata. There are 4 stages of PBC.Stage 1 — Portal Stage: Normal sized triads; portal inflammation, subtle bile duct damage. Granulomas are often detected in this stage.Stage 2 — Periportal Stage: Enlarged triads; periportal fibrosis and / or inflammation. Typically, this stage is characterized by the finding of a proliferation of small bile ducts.Stage 3 — Septal Stage: Active and / or passive fibrous septa.Stage 4 — Biliary Cirrhosis: Nodules present; garland

[0155] The term “primary sclerosing cholangitis” (PSC) is a disease of the bile ducts that causes inflammation and subsequent obstruction of bile ducts both at an intrahepatic (inside the liver) and extrahepatic (outside the liver) level. The inflammation impedes the flow of bile to the gut, which can ultimately lead to cirrhosis of the liver, liver failure and liver cancer.

[0156] The term “organ” refers to a differentiated structure (as in a heart, lung, kidney, liver, etc.) consisting of cells and tissues and performing some specific function in an organism. This term also encompasses bodily parts performing a function or cooperating in an activity (e. , an eye and related structures that make up the visual organs). The term “organ” further encompasses any partial structure of differentiated cells and tissues that is potentially capable of developing into a complete structure (e.g., a lobe or a section of a liver).

[0157] The term "about," as used herein, in conjunction with a numeral, refers to a value that is ± 10% (inclusive) of that numeral. It should further be appreciated that when a numerical range is disclosed herein, any numerical value falling within the range is also specifically disclosed.

[0158] All publications and patent documents cited herein are hereby incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the description and examples provided herein are for purposes of illustration and not limitation of the claims that follow.

[0159] In the specification, the singular forms also include the plural, unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the case of conflict, the present specification controls. All percentages and ratios used herein, unless otherwise indicated, are by weight.

[0160] EXAMPLES

[0161] Example 1 - A Controlled Phase 3 Study Evaluating the Efficacy, Safety, and Tolerability of the Fixed Dose Combination of Obeti cholic Acid and Bezafibrate in Subjects with Primary Biliary Cholangitis

[0162] A Phase 3, randomized, double-blind (DB), parallel -group study will evaluate the efficacy, safety, tolerability, and PK of the a OCA / BZF Fixed Dose Combination (FDC) bilayer tablet containing 5 mg of OCA in an immediate release layer and 400 mg of BZF in a sustained release (SR) layer compared to placebo, OCA alone (OCA 5 mg), or BZF alone (BZF 400 mg SR) in subjects with PBC over a treatment period of 12 months.

[0163] Subjects will be randomized in a 1 :2:2:3 ratio to 1 of the 4 treatment arms: (A) Placebo; (B) OCA 5 mg once daily (QD); (C) BZF 400 mg SR (QD); (D) OCA / BZF FDC (OCA 5 mg + BZF 400 mg SR) (QD).

[0164] The primary objective is to assess the effects of OCA / BZF FDC on ALP and total bilirubin in comparison with placebo, OCA alone, or BZF alone in subjects with Primary Biliary Cholangitis (PBC).

[0165] The secondary objectives are to assess the effects of OCA / BZF FDC versus placebo, OCA alone, or BZF alone on the following: Biochemical disease markers, including ALP, total bilirubin (TB), ALT, GGT, AST; Safety and tolerability; and Disease-specific symptoms as assessed by health-related quality of life questionnaires (Fatigue impact score [FIS]).

[0166] The additional (exploratory) objectives are to assess the effects of the OCA / BZF FDC versus placebo, OCA alone, or BZF alone on the following: Pharmacokinetics (PK); PK / pharmacodynamic (PD) relationships with biomarkers and safety / efficacy markers;Noninvasive assessments of liver fibrosis; Hepatocellular injury by histology (inflammatory,structural [portal, parenchymal] and fibrotic assessments); Disease-specific symptoms as assessed by health-related quality of life questionnaires (PBC-40 and EuroQol five dimensions questionnaire [EQ-5D-5L]); Disease severity scores (GLOBE and, UK-PBC); and Exploratory immune markers.

[0167] Inclusion and Exclusion Criteria

[0168] Diagnosis And Main Criteria For Inclusion:

[0169] Subjects are required to meet all the following criteria in order to be included in the study:1. A definite or probable diagnosis of PBC (consistent with the European Association for the Study of the Liver [EASL] and the American Association for the Study of Liver Diseases [AASLD] guidelines [Lindor 2019; EASL 2017]), as demonstrated by the presence of at least 2 of the following 3 diagnostic factors:• History of elevated ALP levels for at least 6 months;• Positive antimitochondrial antibody (AMA) titer, or if AMA negative or low titer (<1 : 80), PBC-specific antibodies (anti-GP210 and / or anti-SPlOO) and / or antibodies against the major M2 components (pyruvate dehydrogenase-E2, 2-oxo-glutaric acid dehydrogenase complex);• Liver biopsy results consistent with PBC (collected at any time before Screening)2. At least one of the following qualifying biochemistry values (the mean of both Screening visits):• ALP >1.5x ULN;• Total bilirubin >ULN but <2x ULN3. Age >18 years4. Taking UDCA for at least 12 months (stable dose for >3 months) before Day 1 or no UDCA for at least 3 months before Day 1 ; or no treatment with UDCA due to intolerance5. Contraception: Female subjects must be postmenopausal, surgically sterile, or, if premenopausal (and not surgically sterile), be prepared to use >1 highly effective method of contraception during the study and for 30 days after the end of treatment. Highlyeffective methods of contraception per the Clinical Trials Facilitation and Coordination Group (CTFG) guidelines are those that alone or in combination results in a failure rate of less than 1% per year when used consistently and correctly. These highly effective contraception methods avoid the potential embryofetal risks from exposure to investigational medicinal products. Highly effective methods of contraception are as follows:• Intrauterine device o intrauterine device (IUD) o intrauterine hormone-releasing system (IUS)• Bilateral tubal occlusion• Vasectomy (partner)• Combined (estrogen and progestogen containing) hormonal contraception (e.g., oral, intravaginal or transdermal) associated with inhibition of ovulation. If oral contraceptives are used, they must be used in combination with a male or female condom. Female subjects should have been on the hormone contraception for at least 8 days prior to Day 1• Progestogen-only hormonal contraception (e.g., oral, injectable or implantable) associated with inhibition of ovulation. If oral contraceptives are used, they must be used in combination with a male or female condom. Female subjects should have been on the hormone contraception for at least 8 days prior to Day 1• Sexual abstinence, as a form of highly effective contraception if in line with the preferred and usual lifestyle of the subject, is defined as avoiding all types of sexual activity that could result in pregnancy during the entire period of the study treatment until at least 14 days or 5 half-lives, whichever is longer, after the last dose of investigational product. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study. Must provide written informed consent and agree to comply with the study protocolKey Exclusion Criteria:1. History or presence of other concomitant liver diseases including any of the following:• Hepatitis C virus (HCV) infection and ribonucleic acid positive• Active Hepatitis B virus (HBV) infection; however, subjects who have seroconverted [hepatitis B surface antigen negative (sAg-); hepatitis B surface antibody positive (sAB+); hepatitis B e-antigen negative (eAg-), hepatitis B e- antibody positive (eAB+; HBV DNA negative) may be included in this study after consultation with the Medical Monitor o Subj ects should be excluded if positive HBV DNA or HCV RNA• Primary sclerosing cholangitis• Alcoholic liver disease• Definite autoimmune liver disease or PBC-autoimmune hepatitis (AIH) overlap• Non-Alcoholic Steatohepatitis (NASH)• Gilbert’s Syndrome• Rare liver conditions such as Wilson’s disease, hemochromatosis, alpha-one antitrypsin deficiency, or other conditions identified by the investigator.2. Clinical complications of PBC including:• History of liver transplant, current placement on a liver transplant list, or current Model for End-Stage Liver Disease (MELD) score >12. Subjects who are placed on a transplant list despite a relatively early disease stage (for example per regional guidelines) may be eligible as long as they do not meet any of the other exclusion criteria.3. History or presence of any of the following decompensating events:• C h i l d P u g h ( CP)- Score >7• Clinical evidence of decompensated liver disease or obvious portal hypertension o Varices (including a history of esophageal ligation) o Ascites / hepatic hydrothorax o Spontaneous bacterial peritonitis (SBP) o Hepatic encephalopathy o Jaundice (with total bilirubin >3 mg / dL [>51.3 pmol / L])• Biochemical evidence of hepatic impairment, decompensation, or injury including at least one of the following: o Total bilirubin >2X ULN o International normalized ratio (INR) >1.7 o Albumin <3.5 g / dL o MELD >12 o ALT >5X ULN• Known or suspected hepatocellular carcinoma (HCC)• Prior trans-jugular intrahepatic portosystemic or peritoneovenous shunt procedure• Hepatorenal syndrome (type I or II) or an estimated glomerular filtration rate (eGFR) <60 mL / minute• Portopulmonary hypertension• Hepatopulmonary syndrome Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget’s disease) or which may diminish life expectancy to <2 years, including known cancers (except carcinomas in situ or other stable, relatively benign conditions) Presence of any other disease or condition that interferes with the absorption, distribution, metabolism, or excretion of drugs including bile salt metabolism in the intestine (e.g., inflammatory bowel disease or gastric bypass procedure [gastric lap band is acceptable]) Current or history of gallbladder disease with or without cholelithiasis History of acute or current pancreatitis History of drug-induced myopathy Chronic Kidney Disease (serum creatinine >1.5 mg / dL (>135 pmol / L); eGFR<60 mL / min) or undergoing dialysis Platelet count <150,000 / pl at Screening Visits 1 and 2 (at both Screening visits) Known history of human immunodeficiency virus (HIV) infection History or presence of clinically concerning cardiac arrhythmias likely to affect survival during the study, or Screening (pretreatment) QT or QTc interval of >450 milliseconds for males or >470 milliseconds for femalesSevere pruritus, as defined in the full protocol, or required systemic treatment for pruritus (e.g., with bile acid sequestrants [BAS] or rifampicin) within 2 months of Day 1. Subjects who plan to use or will use BAS during the study will not be eligible. History of known or suspected clinically significant (CS) hypersensitivity to OCA, BZF, or other fibrates or any of their components If female, known pregnancy, or has a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating Other CS medical conditions that are not well controlled or for which medication needs are anticipated to change during the study (e.g., type 2 diabetes mellitus, hypothyroidism, nephritic syndrome, dysproteinemia, obstructive liver disease), dyslipidemia, and / or up to the discretion of the Investigator Treatment with the following medications 30 days before Day 1 or plans to use these medications during the study: azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate mofetil, pentoxifylline, statins or lipid-lowering agents, budesonide and other systemic corticosteroids, monoamine oxidase inhibitors (MAOIs), and potentially hepatotoxic drugs (including a-methyl-dopa, sodium valproic acid, isoniazide, and nitrofurantoin) Treatment with the following medications 12 months before Day 1 or plans to use these medications during the study: antibodies or immunotherapy directed against interleukins or other cytokines or chemokines Participation in another investigational product biologic, or medical device study within 30 days before Screening Treatment with commercially available OCA or participation in a previous study involving OCA within 3 months before Screening Unable to tolerate BZF, other fibrates, known photoallergic or phototoxic reactions to BZF or other fibrates, treatment with commercially available fibrates, or participation in a previous study involving fibrates or PPAR-agonists within 2 weeks months before Screening History of or ongoing alcohol or drug abuse within 1 year before Day 1. Subjects with moderate alcohol use within the past 3 months will be excluded from this study.Moderate alcohol consumption is defined as 1 standard drink per day for women and 2 drinks per day for men; whereby 1 standard drink is equivalent to: 12 oz beer (5% alcohol), 5 ounces of wine (12% alcohol), and 1.5 ounces of 80 proof (40% alcohol)23. History of noncompliance with medical regimens, or is considered by the Investigator not able to meet the requirements as specified in the protocol at the Screening visits and throughout the duration of the study24. Blood or plasma donation within 30 days before Day 125. Mental illness or other condition which may impair decision making, such that the validity of informed consent or ability to be compliant with the study is uncertain26. A creatine kinase (CK) value at Screening >5x ULN or any abnormal laboratory value that is considered CS in the opinion of the Investigator and Sponsor (at either Screening visit)27. Known or suspected nephrotic range proteinuria defined as an excretion of protein in the urine of 3.6 grams or greater in a 24-hour period (using either a 24 hour urine or a spot urine protein / creatinine ratio).Outcomes / Endpoints

[0170] The primary efficacy endpoint is ALP normalization or ALP decrease of >60% from baseline at Month 12; and Total Bilirubin Normalization (<0.6x ULN) and Total Bilirubin Reduction >20% from baseline at Month 12.

[0171] The secondary endpoints are:• Normalization rates (all <1 ,0x ULN) at Month 12 of individual biochemical disease markers: ALP, TB, ALT, GGT, AST• Change from baseline to Month 12 in ALP, TB, GGT, ALT, AST• Incidence of treatment emergent adverse events (TEAEs)• Change from baseline to Month 12 in cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol• Incidence and time to adjudicated events of hepatic injury• Change from baseline in pruritus numerical rating scale (NRS) at Month 6. Weekly averaged pruritus NRS in subjects with baseline NRS >4. The NRS is a scale of 0 (no itching) to 10 (worst imaginable itching).Change from baseline in FIS at Month 12Change from baseline in FIS >1 to Month 6The additional (exploratory) endpoints are:• Plasma concentrations of OCA and BZF and their metabolites• Change from baseline in AST to platelet ratio index (APRI), enhanced liver fibrosis (ELF), Fibroscan (TE), and Fibrosis-4 (FIB-4)• Optional liver biopsies to be offered to all subjects to assess hepatocellular injury by histology• Change from baseline in PBC-40 and EQ-5D-5L• Change from baseline in GLOBE and UK-PBC• Change from baseline in immunoglobulins, cytokines, and markers of inflammation

[0172] Methodology’.

[0173] This Phase 3, randomized, double-blind (DB), parallel-group study will evaluate the efficacy, safety, tolerability, and PK of the OCA / BZF FDC (OCA 5 mg + BZF 400 mg sustained release [SR]) compared to placebo, OCA alone (OCA 5 mg), or BZF alone (BZF 400 mg SR) in subjects with PBC over a treatment period of 12 months. The total duration of subject participation in this Phase 3 study will be a maximum of approximately 60 weeks, including a treatment period of 52 weeks.

[0174] Screening Phase (2 weeks and up to 8 weeks): Subjects will be screened for a period of 2 to 8 weeks before being randomized into the study to allow for the collection of repeat serum chemistry samples (there will be 2 Screening visits at least 2 weeks apart) for verification of inclusion / exclusion criteria and to establish baseline values (including Day 1).

[0175] Double-Blind Treatment Phase (12 months): All subjects will receive ursodeoxycholic acid (UDCA) based on tolerability. Subjects who meet the entry requirements will be randomized in a 1 :2:2:3 ratio on Day 1 to receive one of the following 4 treatments:

[0176] (A) Placebo

[0177] (B) OCA 5 mg (OCA 5 mg immediate release [IR] tablet, once daily (QD))

[0178] (C) BZF 400 mg SR (BZF 400 mg SR tablet, QD)

[0179] (D) OCA / BZF FDC (OCA 5 mg IR / BZF 400 mg SR tablet, QD)

[0180] To preserve the study blind, all tablets will have the same appearance and will be administered to subjects in each treatment group from Day 1 to the end of the DB Treatment Phase. Subjects will be instructed to begin dosing on Day 1 and to take assigned investigational product at approximately the same time each day (morning dosing for the entire study is preferred to align with all study visits). Subjects must be instructed to swallow all tablets; investigational product must not be chewed, divided, or crushed and must be taken with food and water (ad libitum) throughout the study. At study visits, all doses of investigational product will be administered at the clinic. Predose trough PK blood samples will be performed at Week 2 and Months 1, 2, 3, 6, 9, and 12.

[0181] All subjects will receive UDCA based on tolerability. Subjects currently on UDCA should continue administration of their pre-study dose of UDCA throughout study participation.

[0182] Randomization will be stratified by one of the following:• Total bilirubin level (<0.7x or >0.7x ULN but <2x ULN)• ALP >1.5x ULN

[0183] After the Day 1 Visit, subsequent clinic visits during the DB Phase will occur at approximately Week 2, Month 1, Month 2, Month 3, and then every 3 months until Month 12 end of DB (EODB) for the assessment of efficacy, safety, tolerability, and PK.

[0184] At the completion of the present Phase 3 trial, subjects will transition to an openlabel, externally controlled Phase 4 study and receive OCA / BZF FDC (OCA 5 mg + BZF 400 mg SR). The Phase 4 study will include a real-world external comparator.

[0185] An elective paired biopsy will be offered to all subjects at baseline (present Phase 3 study) and Month 18 (planned Phase 4 study). Subjects who consent to the paired biopsy will be placed into a liver biopsy subpopulation. Subjects who do not transition to the Phase 4 study will be offered an elective biopsy at Month 12.

[0186] Statistical Methods:

[0187] Analysis Populations:

[0188] Intent-to-Treat (ITT) Population: The ITT Population will include all randomized subjects. Treatment assignment will be based on randomized treatment.

[0189] Safety Population: The Safety Population will include all subjects who received at least one dose of placebo, BZF, OCA, or OCA / BZF FDC. Treatment assignment will be based on the actual treatment that is received.

[0190] PK Population: The PK Population will include all subjects who receive OCA, BZF, or OCA / BZF FDC and have at least one quantifiable PK sample without any major protocol deviations that may potentially affect plasma exposure.

[0191] Efficacy Analyses:

[0192] The ITT Population will be the population used for efficacy and exploratory analyses. Baseline is defined as Day 1.

[0193] The primary endpoints, (A: the rate of normalization of ALP or ALP decrease of >40% from baseline at Month 12, and rate of normalization of total bilirubin <0.6x ULN from baseline at Month 12; or B: ALP normalization or ALP decrease of >60% from baseline at Month 12; and Total Bilirubin Normalization (<0.6x ULN) and Total Bilirubin Reduction >20% from baseline at Month 12), will be compared using a Cochran Mantel Haenszel (CMH) test stratified by the randomization stratification factors. For the secondary endpoints, the normalization rates of ALP, TB, ALT, GGT, and AST. will be analyzed using the same method.

[0194] For continuous endpoints, change from baseline in PBC-40, NRS, FIS, EQ-5D- 5L, as well as the biochemical disease markers, will be analyzed using a mixed effect model repeated measures (MMRM) to evaluate the effect of treatment groups over time. The model will include the terms of treatment group, visit, treatment by visit interaction, randomization stratification variables as factors, and the baseline value as a covariate.

[0195] All efficacy endpoints will also be summarized using descriptive statistics.

[0196] Safety Analyses:

[0197] The Safety Population will be the population used for safety analyses. Baseline is defined as Day 1.

[0198] Safety data, including SAEs, TEAEs, physical examinations, electrocardiograms (ECGs), vital signs, clinical laboratory assessments (including a lipid panel), and treatment discontinuations, will be compared across all treatment groups.

[0199] The incidence of TEAEs and SAEs will be tabulated by system organ class and preferred term for each treatment group and similarly by severity and relationship to treatment.

[0200] A TEAE is any event not present before the initiation of the investigational product or any event already present, which worsens in either severity or frequency following exposure to the investigational product.

[0201] Laboratory parameters and vital signs will be summarized (including Hy’s law) by treatment group using descriptive statistics at baseline and at each scheduled postbaseline visit. The change from baseline will also be summarized. ECGs will be summarized by treatment group using frequency at each visit. The shift from baseline will also be summarized.

[0202] Safety data will be summarized using descriptive statistics.

[0203] PK / PD Analyses:

[0204] The PK Population will be the primary population used for the PK / PD analyses and includes those who receive OCA, BZF, or OCA / BZF FDC and have enough quantifiable PK / PD samples without any major protocol deviations that could potentially affect plasma exposure.

[0205] To characterize the PK / PD of OCA / BZF FDC, OCA, and BZF on the following in all subjects using a sparse sample approach:

[0206] PK of OCA, BZF, and their metabolites (steady state)

[0207] PK / PD relationships of OCA and its conjugates or BZF or both with safety / efficacy markers.

[0208] The PK Population will be the primary population to be used for PK and PK / PD analyses. PK parameter estimates will be determined for OCA and BZF and their metabolites using a population approach. Non-compartmental analyses may be considered if deemed appropriate.

[0209]

[0210] Example 2:

[0211] The Controlled Phase 3 Study Evaluating the Efficacy, Safety, and Tolerability of the Fixed Dose Combination of Obeticholic Acid and Bezafibrate in Subjects with Primary Biliary Cholangitis as described in Example 1 is performed wherein the OCA / BZF FDC tablet of arm D has the following composition:

[0212] While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not to be limited to the disclosed embodiments, but to the contrary, it is intended to cover various modifications or equivalent arrangements included within the spirit and scope of the appended claims. The scope is to be accorded the broadest interpretation so as to encompass all such modifications and equivalent structures as is permitted under the law.

[0213] Each of the patents, books, articles and other printed publications referenced herein are incorporated by reference in their entireties for all purposes.

Claims

What is claimed is:

1. A pharmaceutical composition comprising: a first layer comprising obeticholic acid (OCA) , i.e., a compound of formula (1):(1)or a pharmaceutically acceptable salt, solvate, or amino acid, sulfate or glucuronide conjugate, or prodrug thereof; and a second layer comprising bezafibrate or a pharmaceutically acceptable salt or ester thereof; wherein the composition is a bilayer tablet.

2. The bilayer tablet pharmaceutical composition of claim 1, wherein the first layer comprises OCA in an amount of about 1 mg to about 10 mg; e.g., in an amount of about 1 mg, or about 1.5 mg, or about 2 mg, or about 2.5 mg, or about 3 mg, or about 3.5 mg, or about 4 mg, or about 4.5 mg, or about 5 mg.

3. The bilayer tablet pharmaceutical composition of claim 1, wherein the first layer comprises OCA in an amount of about 2 mg, or about 2.5 mg, or about 3 mg, or about 3.5 mg, or about 4 mg, or about 4.5 mg, or about 5 mg.

4. The bilayer tablet pharmaceutical composition of claim 1, wherein the first layer comprises OCA in an amount of about 2.5 mg or about 3 mg, or about 4 mg, or about 5 mg.

5. The bilayer tablet pharmaceutical composition of claim 1, wherein the first layer comprises OCA in an amount of about 5 mg.

6. The bilayer tablet pharmaceutical composition of any of claims 1-5, wherein the second layer comprises bezafibrate in an amount of about 200 mg to about 400 mg.

7. The bilayer tablet pharmaceutical composition of any of claims 1-5, wherein the second layer comprises bezafibrate in an amount of about 300 mg.

8. The bilayer tablet pharmaceutical composition of any of claims 1-45 wherein the second layer comprises bezafibrate in an amount of about 400 mg.

9. The bilayer tablet pharmaceutical composition of any of claims 1-5, wherein the first layer comprises OCA in an amount of about 2.5 mg or about 3 mg, or about 4 mg, or about 5 mg; and the second layer comprises bezafibrate in an amount of about 400 mg.

10. The bilayer tablet pharmaceutical composition of any of claims 1-5, wherein the first layer comprises OCA in an amount of about 2.5; and the second layer comprises bezafibrate in an amount of about 400 mg.

11. The bilayer tablet pharmaceutical composition of any of claims 1 -5, wherein the first layer comprises OCA in an amount of about 3 mg; and the second layer comprises bezafibrate in an amount of about 400 mg.

12. The bilayer tablet pharmaceutical composition of any of claims 1-5, wherein the first layer comprises OCA in an amount of about 5 mg; and the second layer comprises bezafibrate in an amount of about 400 mg.

13. The bilayer tablet pharmaceutical composition of any of claims 1-12, wherein the second layer is a sustained release layer.

14. The bilayer tablet pharmaceutical composition of any of claims 1-12, wherein the first layer is an immediate release layer.

15. The bilayer tablet pharmaceutical composition of any of claims 1-12, wherein the first layer is an immediate release layer and the second layer is a sustained release layer.

16. The bilayer tablet pharmaceutical composition of any of claims 1-15, wherein the second layer comprises a release-controlling agent.

17. The bilayer tablet pharmaceutical composition of claim 16, wherein the releasecontrolling agent comprises hypromellose, or hydroxypropylcellulose, or a combination thereof.

18. The bilayer tablet pharmaceutical composition of claim 16 or claim 17, wherein the release-controlling agent is present in the form of particles having a particle size distribution wherein: NLT 99.0% of the particles pass through a 40 U.S. Standard Sieve; NLT 90.0% of the particles pass through a 100 U.S. Standard Sieve; and between 50.0% and 80.0% of the particles pass through a 230 U.S. Standard Sieve.

19. The bilayer tablet pharmaceutical composition of any of claims 1-18, wherein: the first layer further comprises one or more of a filler / binder, a disintegrant, a lubricant and a glidant; and the second layer further comprises one or more of a filler / binder, a release controlling agent, a second binder, a glidant and a lubricant.

20. The bilayer tablet pharmaceutical composition of claim 19, wherein: in the first layer:the filler / binder, when present, is present in an amount of from about 85% to about 92% by weight of the first layer, or from about 88% to about 91% by weight of the first layer; or from about 89% to about 90% by weight of the first layer; or about 89.5% by weight of the first layer; the di sint egrant, when present, is present in an amount of from about 4.0% to about 8.0% by weight of the first layer, or from about 5.0% to about 7.0% by weight of the first layer; or about 6.0% by weight of the first layer; the lubricant, when present, is present in an amount of from about 0.1% to about 2.0% by weight of the first layer, or from about 0.5% to about 1.5% by weight of the first layer; or about 1.0% by weight of the first layer; the glidant, when present, is present in an amount of from about 0.1% to about 2.0% by weight of the first layer, or from about 0.5% to about 1.5% by weight of the first layer; or about 1% by weight of the first layer; and in the second layer: the release-controlling agent, when present, is present in an amount of from about 12% to about 25% by weight of the second layer, or from about 15% to about 21% by weight of the second layer; or from about 16% to about 20% by weight of the second layer; or from about or from about 17% to about 19% by weight of the second layer; or about 18% by weight of the second layer; the filler / binder, when present, is present in an amount of from about 10% to about 25% by weight of the second layer, or from about 12% to about 20% by weight of the second layer; or from about 14% to about 18% by weight of the second layer; or from about 16% to about 17% by weight of the second layer; or about 16.4% by weight of the second layer; the second binder, when present, is present in an amount of from about 0.5% to about 5% by weight of the second layer, or from about 1% to about 3% by weight of the second layer; or from about 1% to about 2.5% by weight of the second layer; or from about 1% to about 2% by weight of the second layer; or about 1.5% to 2% by weight of the second layer; or about 1.75% by weight of the second layer;the lubricant, when present, is present in an amount of from about 0.5% to about 5% by weight of the second layer, or from about 1% to about 3% by weight of the second layer; or from about 1.0% to about 2.5% by weight of the second layer; or from about 1.5% to about 2.0% by weight of the second layer; or about 1.75% by weight of the second layer; and the glidant, when present, is present in an amount of from about 0.1% to about 3.0% by weight of the second layer, or from about 0.1% to about 2.5% by weight of the second layer; or from about 1% to about 2.5% by weight of the second layer; or from about 1.0% to about 2.0% by weight of the second layer; or about 1.47% or about 1.5% by weight of the second layer.

21. The bilayer tablet pharmaceutical composition of any of claims 1-20, wherein the composition further comprises a coating.

22. The bilayer tablet pharmaceutical composition of claim 21, wherein the coating is present in an amount of from about 0.5% to about 5.0% by weight of the total weight of the composition; or from about 1.0% to about 5.0 % by weight of the total weight of the composition; or from about 2.0% to about 4.0 % by weight of the total weight of the composition; or about 3.0 % by weight of the total weight of the composition.

23. The Composition, of claim 20, having the following composition:

24. The Composition, of claim 20, having the following composition:

25. The bilayer tablet pharmaceutical composition of any of claims 19-24, wherein: in the first layer: the filler / binder comprises microcrystalline cellulose; the disintegrant comprises sodium starch glycolate; the lubricant comprises magnesium stearate; the glidant comprises colloidal silicon dioxide; andin the second layer: the release-controlling agent comprises hydroxypropyl methylcellulose (HPMC or hypromellose); e.g., Methocel™; e.g. Methocel™ KI OOLV; the filler / binder comprises microcrystalline cellulose; the second binder comprises hydroxypropyl cellulose; the lubricant comprises magnesium stearate; the glidant comprises colloidal silicon dioxide; and the coating comprises Opadry® AMB II White.

26. The bilayer tablet pharmaceutical composition of any of claims 19-25, wherein the Composition has the following composition:

27. The bilayer tablet pharmaceutical composition of any of claims 19-25, wherein the Composition has the following composition:

28. The bilayer tablet pharmaceutical composition of any of claims 1-27, wherein the composition comprises OCA dimer in an amount of <1.0% w / w; e.g. <0.5% w / w; e.g.,<0.2% w / w; e.g., <0.1% w / w; e.g., < 0.09% w / w, < 0.075% w / w, < 0.05% w / w, <0.025% vi / , < 0.01% vi / , or < 0.001% w / w.

29. The bilayer tablet pharmaceutical composition of any of claims 1-28 wherein the composition comprises A-(4-chlorobenzoyl)tyramine in an amount of <1.0% ilw, e.g. <0.5% w / w; e.g., <0.2% w / w; e.g., <0.1% w / w; e.g., < 0.09% w / w, < 0.07% w / w, < 0.06% w / w, < 0.05% w / w, < 0.025% w / w, < 0.01% w / w, or < 0.001% w / w.

30. The bilayer tablet pharmaceutical composition of any of claims 1-29, wherein the composition comprises BZF ethyl ester in an amount of <1.0% w / w; e.g. <0.75% w / w; e.g. <0.5% w / w; e.g., <0.2% w / w; e.g., <0.1% w / w; e.g., < 0.08% w / w, < 0.07% w / w, < 0.06% w / w, < 0.05% w / w, < 0.04% w / w, < 0.025% w / w, < 0.01% w / w, or < 0.001% w / w.

31. The bilayer tablet pharmaceutical composition of any of claims 1 -29, wherein the composition comprises OCA / BZF conjugate in an amount of <1.0% w / w; e.g. <0.5% w / w; e.g., <0.2% w / w; e.g., <0.1% w / w; e.g., < 0.09% w / w, < 0.075% w / w, < 0.05% w / w, < 0.025% w / w, < 0.01% w / w, or < 0.001% w / w.

32. The bilayer tablet pharmaceutical composition of any of claims 1-31, wherein the combined amount of total impurities present in the composition is <5% w / w; e.g., <4% w / w; e.g. <3% w / w; e.g. <2% w / w; e.g., <1% w / w; e.g. <0.5% w / w; e.g., <0.4% w / w; e.g., <0.3% w / w; e.g., < 0.25% w / w, e.g., < 0.2% w / w, e.g., < 0.1% w / w, e.g., < 0.025% w / w, e.g., < 0.01% w / w33. The bilayer tablet pharmaceutical composition according to any of claims 1-32, wherein the composition is for use in the treatment of an FXR mediated disease or condition selected from primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), portal hypertension, bile acid diarrhea, a chronic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis C infection, an alcoholic liver disease, liver damage due to progressive fibrosis, liver fibrosis, drug- induced cholestasis, hereditary cholestasis, biliary atresia, and intrahepatic cholestasis of pregnancy.

34. The bilayer tablet pharmaceutical composition according to claim 33, wherein the composition is for use in the treatment of primary biliary cholangitis (PBC).

35. The bilayer tablet pharmaceutical composition according to any of claims 1-32, wherein the composition is for administration once daily (QD).

36. A method of increasing the efficacy of OCA comprising administering to a patient in need thereof a composition comprising OCA and bezafibrate according to any of claims 1-35.

37. A method of treating or preventing an FXR mediated disease or condition, reducing the level of one or more liver enzymes, or inhibiting or reversing fibrosis in a subject in need thereof, comprising administering to the subject a composition according to any of claims 1-35.

38. The method of claim 37, wherein the FXR mediated disease or condition is selected from primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), portal hypertension, bile acid diarrhea, a chronic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis C infection, an alcoholic liver disease, liver damage due to progressive fibrosis, liver fibrosis, drug-induced cholestasis, hereditary cholestasis, biliary atresia, and intrahepatic cholestasis of pregnancy.

39. The method of claim 38, wherein the FXR mediated disease or condition is chronic liver disease.

40. The method of claim 38, wherein the FXR mediated disease or condition is a cholestatic liver disease.

41. The method of claim 38, wherein the FXR mediated disease or condition is PBC.

42. The method of claim 38 wherein the FXR mediated disease or condition is NASH.

43. The method of claim 38, wherein the FXR mediated disease or condition is liver fibrosis.

44. The method of claim 38, wherein the FXR mediated disease or condition is liver fibrosis associated with NASH.

45. The method of any of claims 37-44, wherein the composition is administered as a first- line treatment of the FXR mediated disease or condition.

46. The method of claim 45, wherein the composition is administered as a monotherapy for treatment of the FXR mediated disease or condition.

47. The method of claim 45, wherein the composition is administered as combination therapy with a second agent; e.g., with UDCA, for treatment of the FXR mediated disease or condition.

48. The method of any of claims 37-44, wherein the composition is administered to a subject who has an inadequate therapeutic response to UDCA, or who is unable to tolerate UDCA, for the treatment of the FXR mediated disease or condition.

49. The method of any of claims 37-44, wherein the composition is administered for the treatment or prevention of primary biliary cholangitis (PBC) either in combination with ursodeoxycholic acid (UDCA) with an inadequate response to UDCA or as monotherapy in patients unable to tolerate UDCA.

50. The method of any of claims 37-49, wherein the method results in ALP normalization or ALP reduction of >60% from baseline at month 12 of treatment; and / or normalization of Total Bilirubin (<0.6 x ULN) and / or Total Bilirubin Reduction of >20% from baseline at month 12 of treatment.

51. The method of any of claims 37-49, wherein the method results in ALP normalization or ALP reduction of >60% from baseline at month 12 of treatment; and normalization of Total Bilirubin (<0.6 x ULN), and Total Bilirubin Reduction of >20% from baseline at month 12 of treatment.

52. The method of any of claims 37-49, wherein the method results in one or more of an ALP of <1.67 x ULN, a >15% reduction in ALP, and total bilirubin <ULN.

53. The method of any of claims 37-49, wherein the method results in an ALP of <1.67 x ULN, a >15% reduction in ALP, and total bilirubin <ULN.

54. The method of any of claims 37-49, wherein the method results in a normalization rate achieved for one or more of the biochemical disease markers of < about 0.8 x ULN, < about 0.9 x ULN, < about 1.0 x ULN, < about 1.1 x ULN, or < about 1.2 x ULN at month 12 after commencement of treatment; for example where the biochemical disease markers include one or more of ALP, total bilirubin (TB), ALT, GGT, and AST.

55. The method of any of claims 37-49, wherein the method results in one or more of:• Normalization of ALP or a reduction >50% of ALP; and a total bilirubin of <0.6 X ULN at month 12;• >50% reduction in ALP at month 12;• total bilirubin of <0.6 X ULN at month 12;• 40% reduction of ALT and normalization of ALT at month 12;• 18% reduction of AST at month 12 with 90% of patients normalizing AST at month 12;• 76% reduction of GGT at month 12 with 75% of patients normalizing GGT at month 12;• 30% reduction in pruritus from baseline NRS score;• 18% reduction in mean baseline total cholesterol.

56. The method of any of claims 37-49, wherein the method results in one or more of:• Normalization rates (all <1 ,0x ULN) at Month 12 of individual biochemical disease markers; e.g., one or more of ALP, TB, ALT, GGT, AST;• Change from baseline to Month 12 in one or more of ALP, TB, GGT, ALT, AST• Incidence of treatment emergent adverse events (TEAEs);• Change from baseline to Month 12 in cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol;• Incidence and time to adjudicated events of hepatic injury;• Change from baseline in pruritus numerical rating scale (NRS) at Month 6;• Weekly averaged pruritus NRS in subjects with baseline NRS >4, where NRS is a scale of 0 (no itching) to 10 (worst imaginable itching);• Change from baseline in FIS at Month 12;• Change from baseline in FIS >1 to Month 6.

57. A method of mitigating adverse events elicited or caused by OCA monotherapy (e.g., pruritus), comprising administering to a subject in need thereof, a composition according to any of claims 1-35.

58. A method for decreasing one or more liver enzymes, comprising administering to a subject in need thereof, a composition according to any of any of claims 1-35.

59. The method of claim 58, wherein the one or more liver enzymes are selected from alkaline phosphatase (ALP, AP, or Aik Phos), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), and 5’ nucleotidase; and the amount or activity of the one or more liver enzymes are reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, as compared to a control subject.

60. A method for normalizing biochemical disease markers, including ALP, total bilirubin (TB), ALT, GGT, and AST in a subject suffering from a FXR mediated disease or condition, for example PBC, comprising administering to a subject in need thereof, a composition according to any of any of claims 1-35.

61. The method of claim 60, wherein the method results in ALP normalization or ALP decrease of >60% from baseline at month 12 of treatment; and / or normalization of Total Bilirubin ( <0.6x ULN) and / or Total Bilirubin Reduction of >20% from baseline at month62. The method of claim 60, wherein the method results in a normalization rate for one or more of the biochemical disease markers of < about 0.8 x ULN, < about 0.9 x ULN, < about 1.0 x ULN, < about 1.1 x ULN, or < about 1.2 x ULN at month 12 after commencement of treatment.

63. The method of claim 60, wherein the method results in ALP normalization or ALP reduction of >60% from baseline at month 12 of treatment; and / or normalization of Total Bilirubin (<0.6 x ULN) and / or Total Bilirubin Reduction of >20% from baseline at month 12 of treatment.

64. The method of claim 60, wherein the method results in ALP normalization or ALP reduction of >60% from baseline at month 12 of treatment; and normalization of Total Bilirubin (<0.6 x ULN), and Total Bilirubin Reduction of >20% from baseline at month 12 of treatment.

65. The method of claim 60, wherein the method results in one or more of an ALP of <1.67 x ULN, a >15% reduction in ALP, and total bilirubin <ULN.

66. The method of claim 60, wherein the method results in an ALP of <1.67 x ULN, a >15% reduction in ALP, and total bilirubin < ULN.

67. The method of claim 60, wherein the method results in a normalization rate for one or more of the biochemical disease markers of < about 0.8 x ULN, < about 0.9 x ULN, < about 1.0 x ULN, < about 1.1 x ULN, or < about 1.2 x ULN at month 12 after commencement of treatment; for example where the biochemical disease markers include one or more of ALP, total bilirubin (TB), ALT, GGT, and AST.

68. A method for extending the transplant-free survival of a patient having a FXR mediated disease or condition, or a cholestatic disease or condition, comprising administering atherapeutically effective amount of a pharmaceutical composition according to any one of claims 1-35 to a subject in need thereof.

69. The method of claim 68, wherein the FXR mediated disease or condition is selected from primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), portal hypertension, bile acid diarrhea, a chronic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis C infection, an alcoholic liver disease, liver damage due to progressive fibrosis, liver fibrosis, drug-induced cholestasis, hereditary cholestasis, biliary atresia, and intrahepatic cholestasis of pregnancy.

70. The method of any of claims 37-69, wherein the method further comprising stratifying the subject for the risk of hepatocellular carcinoma (HCC).

71. A method for preparing a bilayer tablet pharmaceutical composition according to any of claims 1-35, comprising:(a) preparing an OCA blend layer, said layer comprising OCA, one or more fillers / binders, a glidant and a lubricant;(b) preparing a fibrate blend layer, said layer comprising a fibrate, a release-control agent, one or more fillers / binders, a glidant and a lubricant;(c) compressing the layers to form a compressed tablet; and(d) coating the tablet with a coating agent.

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