Use of farnesoid X receptor agonists

Abstract

The present invention relates to FXR agonist compounds and methods of use thereof for treating, reversing, or promoting recovery from diseases and disorders such as acute diseases of the liver, e.g., severe alcohol-related hepatitis. In one aspect, the present invention provides a method of treating acute liver disease, comprising administering to a patient in need thereof an effective amount of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the acute liver disease is alcoholic hepatitis (AH).

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 333,287, filed April 21, 2022, and U.S. Provisional Patent Application No. 63 / 381,752, filed October 31, 2022, the contents of each of which are incorporated by reference in their entirety herein.

[0002] Technical Field The present invention relates to compounds and methods of use thereof for treating, ameliorating, or promoting recovery from diseases and disorders, such as acute diseases of the liver. [Background technology]

[0003] 2. Background of the Invention Alcoholic hepatitis (also known as alcohol-related hepatitis or acute alcohol-related hepatitis) is an acute form of alcohol-induced liver injury that appears with the consumption of large amounts of alcohol over a long period of time. Alcoholic hepatitis can range in severity from asymptomatic abnormalities in biochemistry to liver failure and death. Severe alcoholic hepatitis is a severe form of acute alcoholic liver disease caused by excessive alcohol consumption that can be characterized by the rapid onset of jaundice, fatigue, tender hepatomegaly, and features of a systemic inflammatory response (Shah NJ, Royer A, John S. Alcoholic Hepatitis. Stat Pearls. 2021 Jan; 1-8; hereby incorporated by reference). Severe alcoholic hepatitis (sAH) is a life-threatening medical condition with a mean 30-day mortality rate as high as 17% to 50% and a mean 1-year mortality rate of about 56% (Mathurin P., et al. Gastroenterology 1996 Jun;110(6):1847-53; Thursz, MR, et al. N Engl J Med. 2015 Apr 23;372(17):1619-28; hereby incorporated by reference). Treatment options for patients with sAH are limited to systemic corticosteroids (unless contraindicated by sepsis, infection, gastrointestinal bleeding, or acute kidney injury), along with supportive care, nutritional strategies, and alcohol abstinence. Corticosteroids do not confer long-term benefit in patients with sAH, and the risk of infection and GI bleeding limits their use. Additionally, liver transplantations for alcohol-related liver disease are currently at an all-time high (Noureddin, N., et al. Transplant Direct 2020 Oct 8;6(11):e612), and the number of patients awaiting and receiving liver transplants for acute alcohol-related hepatitis in the United States has increased substantially during the COVID-19 pandemic (Bitterman, T., et al. JAMA Netw. Open. 2021;4(7):e2118713).Unfortunately, patients with sAH and progressive liver failure who are non-responders to corticosteroid therapy and ineligible for liver transplantation are frequently relegated to palliative care (Singal, AK, et al. Am J Gastroenterol. 2018;113(2):175-94; hereby incorporated by reference). Another example of an acute liver disease with inadequate treatment options is acute decompensated liver disease, also known as acute exacerbation of chronic liver failure (ACLF). ACLF is a syndrome characterized by acute decompensation of chronic liver disease associated with organ failure and high short-term mortality. Alcoholic hepatitis and chronic viral hepatitis are the most common underlying liver diseases. Up to 40%-50% of cases of ACLF have no identifiable trigger, and in the remaining patients, sepsis, active alcoholism, and recurrent chronic viral hepatitis are the most common reported exacerbating factors. An excessive systemic inflammatory response appears to play a critical role in the development of ACLF. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Noureddin, N. et al., Transplant Direct (2020) 6(11): e612 [Non-Patent Document 2] Singal, AK et al., Am J Gastroenterol. (2018) 113(2):175~94 Summary of the Invention [Problem to be solved by the invention]

[0005] Thus, there remains a need for additional therapies to treat acute liver diseases such as sAH and ACLF. The present invention addresses this need and provides other related advantages. [Means for solving the problem]

[0006] Summary of the Invention In one aspect, the present invention provides a method for treating acute liver disease, comprising administering to a patient in need thereof an effective amount of Compound 1: [ka] or a pharma- ceutically acceptable salt or amino acid conjugate thereof.

[0007] In one aspect, the present invention provides a method of treating acute liver disease, comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the acute liver disease is alcoholic hepatitis (AH).

[0008] In another aspect, the present invention provides a method of treating acute liver disease, comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the acute liver disease is severe alcoholic hepatitis (sAH).

[0009] In yet another aspect, the present invention provides a method of treating acute liver disease, comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the acute liver disease is acute onset of chronic liver failure (ACLF).

[0010] In one aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the patient exhibits a Madley Discriminant Function (MDF) score of 32 or greater prior to treatment with Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof.

[0011] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF) comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the patient exhibits a Model for End-Stage Liver Disease (MELD or MELD-Na) score of 18 or greater, or 20 or greater, or 21 or greater, prior to treatment with Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof.

[0012] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the patient exhibits an MDF score of 32 to 60.

[0013] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF) comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the patient exhibits a MELD score of 18, or 20, or 21 to 25 or 30, or a MELD-Na score of 18, or 20, or 21 to 25 or 30.

[0014] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the patient exhibits a MELD score of 21 to 30 prior to treatment with Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof.

[0015] In one aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the patient exhibits a Madley Discriminant Function (MDF) score of 32 or greater and a MELD score of 21 to 30, inclusive, prior to treatment with Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof.

[0016] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the patient exhibits an AST of greater than or equal to 50 U / L (or IU / L) prior to treatment with Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof.

[0017] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the patient exhibits an AST / ALT ratio of 1.5 or greater prior to treatment with Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof.

[0018] In another aspect, the invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the patient exhibits one or more of an AST of 50 U / L or greater, an AST / ALT ratio of 1.5 or greater, a Madley Discriminant Function (MDF) score of 32 or greater, and / or a Model for End-Stage Liver Disease (MELD or MELD-Na) score of 18 or greater, or 20 or greater, or 21 or greater, e.g., 21-30, prior to treatment with Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof.

[0019] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method reduces the patient's MELD or MELD-Na score by at least 3 and / or reduces the patient's MDF score by at least 3 by day 28 of treatment.

[0020] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, is administered at a dose of about 1.0 mg to about 300 mg daily.

[0021] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, is administered at a dose of about 2.5 mg to about 300 mg daily.

[0022] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein Compound 1 is administered at a dose of from about 5 mg to about 120 mg daily.

[0023] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein Compound 1 is administered at a dose of from about 5 mg to about 100 mg daily.

[0024] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein Compound 1 is administered at a dose of from about 5 mg to about 50 mg daily.

[0025] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein Compound 1 is administered at a dose of from about 5 mg to about 25 mg daily.

[0026] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein Compound 1 is administered at a dose of from about 5 mg to about 10 mg daily.

[0027] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, is administered at a dose of about 5 mg to about 150 mg daily.

[0028] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, is administered at a dose of about 5 mg to about 120 mg daily.

[0029] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, is administered at a dose of about 10 mg to about 100 mg daily.

[0030] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, is administered at a dose of about 50 mg to about 250 mg daily.

[0031] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein Compound 1 is administered at a dose of about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 35 mg, about 45 mg, about 50 mg, about 60 mg, about 75 mg, about 85 mg, about 100 mg, about 115 mg, about 120 mg, about 125 mg, about 140 mg, about 150 mg, about 165 mg, about 175 mg, about 190 mg, or about 200 mg daily.

[0032] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH, or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, is administered in an amount of from about 1.0 mg to about 300 mg; 1.0 mg to about 300 mg; or from about 2.5 mg to about 300 mg; or from about 5 mg to about 100 mg; or from about 5 mg to about 50 mg; or from about 5 mg to about 25 mg; or from about 5 mg to about 10 mg. or about 5 mg to about 150 mg; or about 5 mg to about 120 mg; or about 10 mg to about 100 mg; or about 50 mg to about 200 mg; or about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 35 mg, about 45 mg, about 50 mg, about 60 mg, about 75 mg, about 85 mg, about 100 mg, about 115 mg, about 120 mg, 125 mg, about 140 mg, about 150 mg, about 165 mg, about 175 mg, about 190 mg, or about 200 mg.

[0033] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, and further comprising monitoring blood levels of a biomarker in the patient after administration of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the biomarker is selected from C4, FGF-19, and endogenous bile acids.

[0034] In another aspect, the present invention provides a method of treating an acute liver disease selected from sAH and ACLF, comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the patient has a chronic liver disease in addition to sAH or ACLF.

[0035] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF) comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the patient has alcohol-related (or alcohol-associated) liver disease (ALD), formerly known as alcoholic liver disease.

[0036] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the patient exhibits one or more of the following: (1) ongoing alcohol consumption for 6 months or longer of more than 40 g of alcohol per day if the patient is female and more than 60 g of alcohol per day if the patient is male, with abstinence less than 60 days prior to the onset of jaundice; (2) presence of elevated liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT] concentrations ≧50 IU / L but ≦400 IU / L and AST / ALT ratio ≧1:5); and (3) worsening jaundice accompanied by bilirubin concentrations greater than 3 mg / dL.

[0037] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF) comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the patient exhibits alcohol-related cirrhosis, hepatic fibrosis, steatosis, steatohepatitis, alcoholic hepatitis, or intestinal dysbiosis.

[0038] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH, or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the patient has previously been diagnosed with sAH and has suffered at least one recurrence of sAH.

[0039] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method improves 30-day survival of the patient compared to an otherwise similar patient who has not been administered Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof.

[0040] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method improves 60-day survival of the patient compared to an otherwise similar patient who has not been administered Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof.

[0041] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method improves 90-day survival of the patient compared to an otherwise similar patient who did not receive Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof.

[0042] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method improves 90-day transplant-free survival of the patient compared to an otherwise similar patient who did not receive Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof.

[0043] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method improves 28-day survival of the patient compared to an otherwise similar patient who did not receive Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof.

[0044] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method improves 6-month survival of the patient compared to an otherwise similar patient who did not receive Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof.

[0045] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method improves six-month transplant-free survival of the patient compared to an otherwise similar patient who did not receive Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof.

[0046] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method improves the patient's MELD and / or Lille score at 28 days and / or 90 days after administration of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, compared to an otherwise similar patient who did not receive Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof.

[0047] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF) comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method improves the incidence of hospital re-admission of the patient for alcohol-related hepatitis as compared to an otherwise similar patient who has not been administered Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof.

[0048] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method improves one or more of the patient's length of stay in the hospital, the number of days the patient spends in the ICU, the number of major medical procedures performed on the patient, and / or the number of emergency room visits by the patient, as compared to an otherwise similar patient who has not been administered Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof.

[0049] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof, wherein the method improves one or more pharmacokinetic and pharmacodynamic biomarkers including change from baseline in one or more serum liver biochemistries selected from ALP, AST, ALT, GGT and total and direct bilirubin; change from baseline in IL-6, hs-CRP, CK-18 and TNF-α at day 28; change from baseline in lipoproteins (LDL, HDL, VLDL), total cholesterol and / or triglycerides at day 28; and change from baseline in lipid metabolism (LBP), 16SrDNA, and / or alpha-1-antitrypsin and fecal samples for microbiome / metabolome analysis, compared to an otherwise similar patient who did not receive Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof.

[0050] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method improves survival (relative to standard of care (SOC)) by about 10% to about 40%.

[0051] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method improves survival by about 10% to about 30%.

[0052] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method improves survival by about 10% to about 20%.

[0053] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH, or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method provides for reduced health care utilization.

[0054] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH, or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method provides a reduction in liver-related events in patients with sAH.

[0055] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method provides a reduction in the patient's health care utilization by at least 10% over a 60 day period.

[0056] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method reduces one or more of readmission within 30 days of discharge, number of hospitalizations, length of stay, emergency room visits, intensive care unit (ICU) days, infectious complications selected from sepsis, pneumonia, urinary tract infections (UTI), cellulitis, spontaneous and bacterial peritonitis (SBP), and major medical procedures.

[0057] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF) comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, and further comprising co-administering to the patient an effective amount of an anti-inflammatory agent, an antibiotic, a probiotic, a fecal transplant, a Zn supplement, or any combination of these agents.

[0058] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, and further comprising co-administering to the patient an effective amount of pentoxifylline, augmentin, bovine colostrum, a corticosteroid (e.g., prednisolone or methylprednisolone), an ELAD agent, canakinumab, a TNF inhibitor, IL-22, N-acetylcysteine, metadoxine, IgG anti-LPS, probiotics, fecal transplants, Zn supplements, or any combination of these agents.

[0059] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH, or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the patient has AST or ALT>400 U / L, MDF>60 prior to treatment, MELD score>25 or>30 or MELD-Na>25 or>30 prior to treatment, chronic hepatitis B (hepatitis B surface antigen [HBsAg] positive), chronic hepatitis C (HCV and other causes of liver disease selected from hepatitis C virus (HIV) positive), acetaminophen hepatotoxicity, bile duct obstruction, and autoimmune liver disease; concomitant, a history of hepatocellular carcinoma (HCC), a history of liver transplantation, untreated sepsis, known to be positive for human immunodeficiency virus infection, uncontrolled gastrointestinal (GI) bleeding or controlled GI bleeding that was associated with shock or required transfusion of more than 3 units of blood within 7 days of initiating treatment, acute kidney injury defined as serum creatinine >133 μmol / L (>1.5 mg / dL) or requirement for renal replacement therapy, portal vein thrombosis, acute pancreatitis, or a severe associated illness selected from heart failure, acute myocardial infarction, severe arrhythmias, severe pulmonary disease, and neurological disease.

[0060] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method provides at least a 15% reduction in mortality compared to the standard of care (SOC) at 90 days.

[0061] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF) comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein the method provides a reduction in hospitalization (length of stay) by at least 15% and / or a reduction in progression to transplant by at least 15%.

[0062] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, is administered to the patient for about 30 to about 90 days.

[0063] In another aspect, the present invention provides a method of treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering to a patient in need thereof an effective amount of Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, wherein Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, is administered orally.

[0064] In another aspect, the invention provides a method of determining a patient's candidacy for therapeutic treatment for sAH, comprising determining the patient's MELD-Na score, where the patient's MELD-Na score is 18 or greater, e.g., between 21 and 30. In some embodiments, the method further comprises determining the patient's MDF score, e.g., where the patient's MDF score is between 32 and 60, inclusive.

[0065] In another aspect, the invention provides a method for treating sAH comprising the steps of selecting a patient with a MELD-Na score of 18 or greater, e.g., 21-30, and administering a therapeutic treatment for sAH, e.g., where the patient also has an MDF score of 32 or greater, e.g., 32 to 60, inclusive. In some embodiments, the therapeutic treatment comprises administering a pharmacologic agent to the patient and / or a liver transplant. [Brief description of the drawings]

[0066] [Figure 1-1]Clinical chemistry results and liver and ileum histology from a mouse alcoholic liver disease (ALD) study (Compound 1 is designated Comp1 and Compound 2 is designated Comp2). [Figure 1-2] Same as above. [Diagram 2] Same as above.

[0067] [Diagram 3] Study design for a Phase 2a, randomized, double-blind, placebo-controlled, multicenter, dose-escalation, proof-of-concept study to evaluate the safety, tolerability, efficacy, and pharmacokinetics of Compound 1 (Comp1) in subjects with severe alcohol-related hepatitis (sAH). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0068] Detailed Description of Certain Embodiments of the Invention 1. Overview of Exemplary Embodiments The present invention provides a method for treating an acute liver disease, comprising administering to a patient in need thereof an effective amount of an FXR agonist. In one aspect, the present invention provides a method for treating alcoholic hepatitis (AH), comprising administering to a patient in need thereof an effective amount of an FXR agonist. In one aspect, the present invention provides a method for treating an acute liver disease selected from severe alcoholic hepatitis (sAH) and acute exacerbation of chronic liver failure (ACLF), comprising administering to a patient in need thereof an effective amount of an FXR agonist.

[0069] In one aspect, the present invention provides a method of treating severe alcoholic hepatitis (sAH), comprising administering to a patient in need thereof an effective amount of an FXR agonist. The present invention provides a method of treating sAH that represents a significant advance over systemic corticosteroid therapy, which is the standard of care in the treatment of sAH.

[0070] The present invention further provides a method of treating ACLF, comprising administering to a patient in need thereof an effective amount of an FXR agonist.

[0071] In some embodiments, the FXR agonist is [ka] (3α,7α,11β-trihydroxy-6α-ethyl-5β-cholan-24-oic acid, also known as TC-100)

[0072] Or its pharmaceutically acceptable salt or amino acid conjugate. In some embodiments, the FXR agonist is a tauro- or glyco-conjugate of compound 1, or its pharmaceutically acceptable salt. Compound 1 can be prepared using methods known in the art, for example, as described in U.S. Pat. Nos. 11,066,437, 11,034,717 and 9,611,289, each of which is hereby incorporated by reference in its entirety. These patents also describe various FXR agonists that can be used according to the present invention.

[0073] In one aspect, the present invention provides an FXR agonist for use in treating acute liver disease.In one aspect, the present invention provides an FXR agonist for use in treating alcoholic hepatitis (AH).In one aspect, the present invention provides an FXR agonist for use in treating acute liver disease selected from severe alcoholic hepatitis (sAH) and acute exacerbation of chronic liver failure (ACLF).

[0074] In another aspect, the present invention provides compound 1 or its pharma- ceutically acceptable salt or amino acid conjugate for use in treating acute liver disease. In some embodiments, the acute liver disease is alcoholic hepatitis (AH). In some embodiments, the acute liver disease is severe alcoholic hepatitis (sAH). In some embodiments, the acute liver disease is moderate alcoholic hepatitis. In some embodiments, the acute liver disease is mild alcoholic hepatitis. In some embodiments, the acute liver disease is acute exacerbation of chronic liver failure (ACLF).

[0075] In one aspect, the present invention provides Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, for use in treating alcoholic hepatitis (AH).In one aspect, the present invention provides Compound 1, or a pharma- ceutically acceptable salt or amino acid conjugate thereof, for use in treating an acute liver disease selected from severe alcoholic hepatitis (sAH) and acute exacerbation of chronic liver failure (ACLF).

[0076] In some embodiments, the patient has chronic liver disease in addition to sAH or ACLF. In some embodiments, the chronic liver disease is cholestatic liver disease. In some embodiments, the chronic liver disease is non-cholestatic liver disease.

[0077] In some embodiments, the patient presents with a chronic liver condition in addition to an acute liver disease, such as AH or sAH or ACLF. In some embodiments, the patient presents with an acute liver disease or condition in addition to a chronic liver disease or condition, which may be selected from, but is not limited to, cirrhosis (alcohol-related cirrhosis), liver fibrosis, alcohol-related steatohepatitis (ASH), steatosis or cholestatic liver disease. In some embodiments, the patient presents with an acute liver disease or condition in addition to a chronic liver disease or condition, which may be selected from, but is not limited to, cirrhosis, liver fibrosis, alcohol-related steatohepatitis or steatosis. In some embodiments, the patient presents with cirrhosis. In some embodiments, the patient presents with liver fibrosis. In some embodiments, the patient presents with steatosis. In some embodiments, the patient presents with ASH. In some embodiments, the patient presents with alcoholic hepatitis.

[0078] In some embodiments, the patient has ALD selected from early ALD (stages 0-2) or advanced ALD (bridging fibrosis, stage 3; or cirrhosis, stage 4).

[0079] In some embodiments, the patient does not exhibit cirrhosis. In some embodiments, the patient exhibits a Madley Discriminant Function (MDF) score of 32 or greater prior to treatment with the FXR agonist.

[0080] In some embodiments, the patient presents with a model for end-stage liver disease (MELD or MELD-Na) score of 18 or greater prior to treatment with the FXR agonist.

[0081] In some embodiments, the patient presents with both an MDF score of 32 or greater and a MELD or MELD-Na score of 18 or greater prior to treatment with the FXR agonist.

[0082] In some embodiments, the patient presents with an MDF score of 32-60.

[0083] In some embodiments, the patient presents with a MELD score of 18 to 25 or 30, or a MELD-Na score of 18 to 25 or 30.

[0084] In some embodiments, the patient exhibits a MELD score of 21-30, or a MELD-Na score of 21-30.

[0085] In some embodiments, patients present with an MDF score of 20 to 31, optionally in combination with a MELD score of 18 to 25 or 30, or a MELD-Na score of 18 to 25 or 30.

[0086] In some embodiments, patients present with an MDF score of 32 or greater, optionally in combination with a MELD score of 10 to 20 (or MELD-Na<21), or a MELD score of 10 to 17 (or MELD-Na<18).

[0087] In some embodiments, patients present with an MDF score of 32 or greater in combination with a MELD score of 21-30 (or MELD-Na 21-30).

[0088] In some embodiments, the patient exhibits an MDF score of 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60.

[0089] In some embodiments, the patient presents with a MELD or MELD-Na score of 6, 7, 8, 9, or 10. In some embodiments, the patient presents with a MELD or MELD-Na score of 11, 12, 13, 14, 15, 16, or 17. In some embodiments, the patient presents with a MELD or MELD-Na score of 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

[0090] In some embodiments, the patient presents with an AST of 50 U / L or greater prior to treatment.

[0091] In some embodiments, the patient presents with an AST / ALT ratio of 1.5 or greater prior to treatment.

[0092] In some embodiments, the patient exhibits one or more of: AST of 50 U / L or greater; an AST / ALT ratio of 1.5 or greater; a Madrid Discriminant Function (MDF) score of 32 or greater; and / or a Model for End-Stage Liver Disease (MELD or MELD-Na) score of 18, 20 or 21 or greater, e.g., 21-30.

[0093] In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 1 mg to about 500 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 1 mg to about 300 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 1 mg to about 200 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 1 mg to about 150 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 1 mg to about 100 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 1 mg to about 50 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 1 mg to about 25 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 1 mg to about 10 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 2.5 mg to about 500 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 2.5 mg to about 300 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 2.5 mg to about 200 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 2.5 mg to about 150 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 2.5 mg to about 100 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 2.5 mg to about 50 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 2.5 to about 25 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 2.5 to about 10 mg.

[0094] In some embodiments, the method includes administering to a patient in need thereof an FXR agonist in an amount of about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 60 mg, about 75 mg, about 85 mg, about 100 mg, about 120 mg, or about 150 mg. In some embodiments, the method includes administering Compound 1 in an amount of about 2.5 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, or about 120 mg. In some embodiments, the method includes administering to a patient in need thereof an FXR agonist in an amount of about 5 mg to about 100 mg, or 5 mg to about 120 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 5 mg to about 50 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 5 to about 25 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 5 to about 10 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 5 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 10 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 25 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 50 mg. In some embodiments, the method comprises administering to a patient in need thereof an FXR agonist in an amount of about 100 mg.

[0095] In some embodiments, the methods provide improved 90-day transplant-free survival in patients compared to otherwise similar patients who were not administered Compound 1, or a pharma- ceutically acceptable salt, or amino acid conjugate thereof.

[0096] In some embodiments, the method provides a reduction in the Lille score at 7 days above the standard of care (SOC). In some embodiments, the method reduces the Lille score by 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 or more. In some embodiments, the method reduces the Lille score at 7 days by 0.1, 0.2, 0.3, or 0.4. In some embodiments, the method provides a Lille score of less than 0.4, 0.3, 0.2, 0.1, or 0.1.

[0097] In some embodiments, the methods provide a clinical outcome of a 7-day Lille score of less than 0.45. In some embodiments, the methods provide a clinical outcome of a 7-day Lille score of less than 0.45, and a reduction to less than 21, or to less than 20, or to less than 18, or a reduction of at least 10-25%, or at least 10-30%, or at least 10-35%, or at least 10-40% (or by at least 2 or 3) in MELD or MELD-Na score at 28 days, in combination with one, two, three, four, five, or more of the endpoints described below: [Table 7-1] [Table 7-2]

[0098] In some embodiments, the methods provide improvements in one or more of liver biochemistry and synthetic function, inflammation, lipoprotein metabolism, markers of farnesoid X receptor (FXR) activation, and bacterial translocation (e.g., lipopolysaccharide binding protein [LBP], 16S rDNA, alpha-1-antitrypsin).

[0099] In some embodiments, a patient's dose is increased up to 50 mg per day. In some embodiments, a patient's dose is increased up to 100 mg per day. In some embodiments, a patient's dose is increased up to 125, 150, 175, 200, 225, 250, 275, or 300 mg per day.

[0100] In some embodiments, the method reduces the patient's MELD or MELD-Na score by at least 2, at least 3, at least 4, at least 5, or at least 6 by day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by at least 2 by day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by at least 3 by day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by at least 4 by day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by at least 5 by day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by at least 6 by day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by 2 by day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by 3 by day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by 4 by day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by 5 by day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by 6 by day 28 or day 90 of treatment.

[0101] In some embodiments, the method reduces the MELD or MELD-Na score by 10-25%. In some embodiments, the method reduces the MELD or MELD-Na score by about 10%, about 15%, about 20% or about 25%. In some embodiments, the method reduces the MELD or MELD-Na score by about 30%, 35%, 40% or 50%. In some embodiments, the method reduces the MELD or MELD-Na score by at least 10-25%. In some embodiments, the method reduces the MELD or MELD-Na score by at least 10%, at least 15%, at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%.

[0102] In some embodiments, the method reduces the patient's MDF score by at least 2, at least 3, at least 4, at least 5, or at least 6 by day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MDF score by 5, 6, 7, 8, 9, or 10. In some embodiments, the method reduces the patient's MDF score by 5 or more. In some embodiments, the method reduces the MDF score by 10-25%. In some embodiments, the method reduces the MDF score by about 10%, about 15%, about 20%, or about 25%. In some embodiments, the method reduces the MDF score by about 30%, 35%, 40%, or 50%. In some embodiments, the method reduces the MDF score by at least 10-25%. In some embodiments, the method reduces the MDF score by at least 10%, at least 15%, at least 20%, or at least 25%.

[0103] In some embodiments, the method reduces the patient's MELD or MELD-Na score by at least 2-6 and / or reduces the patient's MDF score by at least 2-6 by day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by at least 2 and / or reduces the patient's MDF score by at least 2 by day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by at least 3 and / or reduces the patient's MDF score by at least 3 by day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by at least 4 and / or reduces the patient's MDF score by at least 4 by day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by at least 5 and / or reduces the patient's MDF score by at least 5 by day 28 or day 90 of treatment. In some embodiments, the methods reduce the patient's MELD or MELD-Na score by at least 6 and / or reduce the patient's MDF score by at least 6 by day 28 or day 90 of treatment.

[0104] In some embodiments, the method reduces the patient's MELD or MELD-Na score by at least 5 by day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MDF score by at least 5 by day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by at least 5 by day 28 or day 90 of treatment, and reduces the patient's MDF score by at least 5. In some embodiments, the method provides a reduction in MELD or MELD-Na score at 28 days or 90 days. In some embodiments, the method provides a reduction in MDF score at 28 days or 90 days.

[0105] In some embodiments, the method further comprises monitoring blood levels of a biomarker in the patient after administration of the FXR agonist of the present disclosure. In some embodiments, the biomarker is selected from C4, FGF-19, and endogenous bile acids.

[0106] In some embodiments, the patient has alcohol-related (or alcohol-associated) liver disease (ALD), also known as alcoholic liver disease, hi some embodiments, the patient presents with jaundice.

[0107] In some embodiments, the patient exhibits one or more of the following: (1) ongoing alcohol consumption of more than 40 g alcohol per day in women and more than 60 g alcohol per day in men for 6 months or longer, with abstinence less than 60 days prior to the onset of jaundice; (2) presence of elevated liver enzymes (aspartate aminotransferase [AST] and / or alanine aminotransferase [ALT] concentrations ≧50 IU / L but ≦400 IU / L and AST / ALT ratio ≧1:5); and (3) worsening jaundice with bilirubin concentrations greater than 3 mg / dL. In some embodiments, the patient is diagnosed with sAH following liver biopsy in addition to one, two, three, or all of the above symptoms.

[0108] In some embodiments, the patient presents with 6 months or more of ongoing alcohol consumption of more than 40 g alcohol per day in women and more than 60 g alcohol per day in men, with abstinence less than 60 days prior to the onset of jaundice. In some embodiments, the patient presents with the presence of elevated liver enzymes (aspartate aminotransferase [AST] and / or alanine aminotransferase [ALT] concentrations ≧50 IU / L but ≦400 IU / L and AST / ALT ratio ≧1:5). In some embodiments, the patient presents with worsening jaundice with bilirubin concentrations greater than 3 mg / dL. In some embodiments, the patient presents with the absence of any other causes of liver disease.

[0109] In some embodiments, the patient is deemed ineligible for a liver transplant by generally accepted criteria known in the art.

[0110] In some embodiments, the patient has an alcohol use disorder (AUD). AUD can be defined based on alcohol consumption, for example, consuming 3 or more alcoholic drinks per day (men) or 2 or more alcoholic drinks per day (women).

[0111] In some embodiments, the patient has previously been treated with a corticosteroid for sAH. In some embodiments, the patient has not responded to the corticosteroid. In some embodiments, the patient has a Lille score of greater than 0.45 after 7 days or more of treatment with a corticosteroid.

[0112] In some embodiments, the patient is currently hospitalized, i.e., is hospitalized before starting treatment with the FXR agonist. In some embodiments, the patient is currently hospitalized and exhibits an MDF score of at least 32 and a MELD score of 18, or 20, or 21 to 30; or a MELD-Na score of 18, or 20, or 21 to 25 or 30.

[0113] In some embodiments, the patient has suffered at least one recurrence of sAH, ie, has been previously diagnosed with and / or treated for sAH at least once.

[0114] In some embodiments, the patient exhibits, in addition to sAH, one or more of the following: obesity, metabolic syndrome, hepatitis C infection, or genetic polymorphisms such as in the patatin-like phospholipase domain protein 3, membrane-bound O-acyltransferase, and transmembrane 6 superfamily member 2 genes.

[0115] In some embodiments, the patient exhibits intestinal dysbiosis.

[0116] In some embodiments, the methods improve one or more measures of sAH, such as intestinal dysbiosis.

[0117] In some embodiments, the method improves the 30-day survival of a patient with sAH or ACLF compared to an otherwise similar patient with sAH or ACLF who was not administered an FXR agonist. In some embodiments, the method improves the 60-day survival of a patient compared to an otherwise similar patient who was not administered an FXR agonist. In some embodiments, the method improves the 90-day survival of a patient compared to an otherwise similar patient who was not administered an FXR agonist. In some embodiments, the method improves the 120-day, 180-day, or 1-year survival of a patient compared to an otherwise similar patient who was not administered an FXR agonist.

[0118] In some embodiments, the method improves the patient's 30-day mortality rate compared to otherwise similar patients not administered the FXR agonist. In some embodiments, the method improves the patient's 60-day mortality rate compared to otherwise similar patients not administered the FXR agonist. In some embodiments, the method improves the patient's 90-day mortality rate compared to otherwise similar patients not administered the FXR agonist. In some embodiments, the method improves the patient's 120-day mortality rate, 180-day mortality rate, or 1-year mortality rate compared to otherwise similar patients not administered the FXR agonist.

[0119] In some embodiments, the improvement in patient survival or mortality comprises an increase in survival or a decrease in mortality of about 10% to about 70%. Such an improvement may be measured, for example, over 30 days, 60 days, 90 days, 120 days, 180 days, a year, or more than a year. In some embodiments, the improvement in patient survival or mortality comprises an increase in survival or a decrease in mortality of about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, or about 10% to about 20%.

[0120] In some embodiments, the methods provide at least a 15% reduction in mortality compared to standard of care (SOC) at 90 days. In some embodiments, the methods provide a 15-20% reduction in mortality compared to SOC at 30 days. In some embodiments, the methods provide a 10% reduction in mortality at 6 months. In some embodiments, the methods provide a 5-10% absolute reduction in mortality at 1 year.

[0121] In some embodiments, the method provides a reduction in the risk of death for patients.In some embodiments, the method provides a reduction in the risk of death and the healthcare utilization for liver-related events in patients with sAH.In some embodiments, such reduction is compared with the current standard of care, for example, treatment with corticosteroids such as prednisolone.In some embodiments, FXR agonist, such as compound 1 or its pharmacologic acceptable salt or its amino acid conjugate, is applied as first-line therapy.

[0122] In some embodiments, the method provides a reduction in the patient's healthcare utilization by at least 10% over 30 days, 60 days, 90 days, 120 days, 180 days, or over a year, or longer than a year. As used herein, the term "healthcare utilization" includes one or more of the following: readmission within 30 days of discharge, number of hospitalizations, length of stay, emergency room visits, intensive care unit (ICU) days, and infectious complications (e.g., sepsis, pneumonia, urinary tract infection [UTI], cellulitis, spontaneous bacterial peritonitis [SBP]), and major medical procedures such as liver transplants. In some embodiments, the method provides a reduction in the patient's healthcare utilization by at least 20% over 30 days, 60 days, 90 days, 120 days, 180 days, or over a year, or longer than a year. In some embodiments, the method provides a reduction in patient health care utilization by at least 30% over 30 days, 60 days, 90 days, 120 days, 180 days, or over a year, or for longer than a year. In some embodiments, the method provides a reduction in patient health care utilization by about 10% to about 40% over 30 days, 60 days, 90 days, 120 days, 180 days, or over a year, or for longer than a year.

[0123] In some embodiments, the methods improve patient 90-day survival and reduce patient re-hospitalization by at least 10%, or at least 20%, or between 10% and 30%.

[0124] In some embodiments, the methods provide improvements in liver-related events (such as decompensation) or hospitalizations / re-hospitalizations.

[0125] In some embodiments, the methods provide a reduction in hospitalizations by at least 15%.

[0126] In some embodiments, the methods provide a reduction in progression to transplantation by at least 15%.

[0127] Compound 1, also known as TC-100, is a semi-synthetic bile acid derived from CDCA, a natural ligand for FXR. Compound 1 is the first reported example of an 11β-OH bile acid and the only known FXR-specific bile acid derivative with no activity against the bile acid G protein-coupled receptor TGR5. The 11β-OH not only confers FXR agonist specificity, but also makes compound 1 highly water-soluble (16-fold more so than obeticholic acid or OCA) and has a high critical micelle concentration like ursodeoxycholic acid, giving compound 1 a very low tendency for detergency and therefore low toxicity. The compound exhibited very low liver residence time and was immediately secreted almost intact into the bile and thus localized along the entire intestinal tract. Pellicciari, R., et al. J. Med. Chem. 2016, 59, 9201-9214.

[0128] As a targeted therapy with anti-inflammatory, anti-fibrotic and potentially anti-apoptotic effects, the FXR agonist Compound 1 could represent a significant advance over systemic corticosteroid therapy, which is the standard of care in treating patients with sAH. Compound 1 also has the potential to reduce intestinal permeability, which could provide a substantial advance over corticosteroids with respect to bacterial translocation and infectious complications seen in patients with sAH.

[0129] The targeted mechanism of action of FXR agonists such as Compound 1 represents a novel treatment option over the non-specific effects of corticosteroids, the current standard of care for sAH. As described in further detail herein, in one aspect, the present invention provides a method of treating alcoholic hepatitis or severe alcoholic hepatitis or ACLF, comprising administering to a patient in need thereof an effective amount of an FXR agonist described herein.

[0130] As targeted therapies with anti-inflammatory, anti-fibrotic and anti-apoptotic effects, the FXR agonists described herein fulfill a long-felt need in the art for effective therapies for acute liver diseases such as severe alcoholic hepatitis (sAH) and acute exacerbation of chronic liver failure (ACLF). Dysfunction of the gut-liver axis, including increased intestinal permeability, is a key promoter of alcohol-induced liver injury (Sehrawat, TS, et al. The knowns and unknowns of treatment for alcoholic hepatitis. Lancet Gastroenterol Hepatol. 2020;5(5)494-506). Recent mouse models suggest that extrahepatic FXR deficiency is essential for the development of alcohol-induced fatty liver and that intestinal FXR specifically may protect against steatohepatitis by maintaining intestinal integrity (Huang, M., et al. Enhanced alcoholic liver disease in mice with intestine-specific farnesoid X receptor deficiency. Lab Invest. 2020;100(9):1158-68).

[0131] Exemplary Diseases and Patient Populations—sAH Severe alcoholic hepatitis (sAH) is an acute liver disease that is distinct from other alcoholic liver diseases, many of which are chronic in nature. Moreover, sAH has distinctive histopathological and pathophysiological features and may exist in patients with underlying chronic liver disease, such as alcoholic liver disease (ALD) (Shah NJ, Royer A, John S. Alcoholic Hepatitis. Stat Pearls. 2021 Jan; 1-8; hereby incorporated by reference). During sAH, endotoxins or lipopolysaccharides (LPS), collectively referred to as pathogen-associated molecular patterns (PAMPs), cross the portal circulation and initiate an inflammatory cascade. Increased endotoxin levels in alcoholic hepatitis are caused by alcohol-induced qualitative and quantitative changes in the gut microbiota and increased intestinal permeability. LPS activates Kupffer cells and hepatic stellate cells via toll-like receptor 4 (TLR4) to generate reactive oxygen species (ROS), proinflammatory cytokines and chemokines, which together with alcohol contribute to hepatocellular injury. Other factors that contribute to hepatocellular injury include alcohol-induced activation of various immune cells (i.e., neutrophils, T cells, and other leukocytes), in addition, the direct effect of alcohol on adipose tissue results in the generation of damage-associated molecular patterns (DAMPs).

[0132] In the majority of AH cases, a liver biopsy is not required. However, a liver biopsy may be required to confirm the diagnosis of AH. Findings that confirm the diagnosis of AH on a liver biopsy include hepatocyte ballooning, neutrophil infiltration, and Mallory-Denk bodies in a background of varying degrees of steatosis and fibrosis (Singal, AK, et al. Journal of Hepatology 2019, vol.70, 305-313). The method of the present disclosure improves one or more histological measures of sAH, such as macrovesicular steatosis with at least one of the following: neutrophil infiltration, hepatocellular injury (ballooning), and Mallory-Denk bodies. The method of the present disclosure improves macrovesicular steatosis. The method of the present disclosure improves neutrophil infiltration. The method of the present disclosure improves hepatocellular injury (ballooning). The method of the present disclosure improves Mallory-Denk bodies.

[0133] Excessive alcohol consumption is one of the leading causes of liver disease and the seventh leading cause of premature death worldwide. Alcohol-induced liver injury can range from steatosis to alcohol-induced steatohepatitis with fibrosis, cirrhosis, and hepatocellular carcinoma. Unfortunately, many alcohol-related liver disease (ALD) patients are diagnosed at more advanced disease stages, and thus data on the prevalence of early disease is limited (Singal, AK, et al. "ACG clinical guideline: Alcoholic liver disease," Am J Gastroenterol. 2018;113(2):175-94; hereby incorporated by reference). The best estimate of the combined prevalence of non-cirrhotic and cirrhotic ALD is approximately 2% of the general population in the United States. Worldwide, deaths due to alcohol-induced cirrhosis account for approximately 10% of all alcohol-attributable deaths and nearly half of deaths due to chronic liver disease.

[0134] Alcoholic hepatitis (AH) (or alcohol-associated hepatitis), also referred to as symptomatic alcoholic steatohepatitis, is a clinical syndrome of acute hepatitis due to heavy alcohol consumption, with distinctive histopathological findings including steatohepatitis, neutrophil infiltration and fibrosis (Crabb, DW, et al., "Standard definitions and common data elements for clinical trials in patients with alcoholic hepatitis: Recommendation from the NIAAA Alcoholic Hepatitis Consortia," Gastroenterology 2016 Apr;150(4):785-90; hereby incorporated by reference). In most cases, the clinical diagnosis of AH is made in patients with rapid development of jaundice and liver-related complications, with documentation of persistent heavy alcohol use within 8 weeks of onset of symptoms and exclusion of other liver diseases (Singal, AK, et al. Am J Gastroenterol. 2018;113(2):175-94). In AH, abnormalities that may contribute to liver injury include the generation of oxidative stress as a by-product of ethanol metabolism and the "leakage" of endotoxin through the intestinal wall into the portal circulation. Endotoxin binds to receptors on Kupffer cells and activates an inflammatory response. The inflammatory response in the liver leads to hepatocellular dysfunction and death. Among the most important inflammatory cytokines is tumor necrosis factor (TNF)-alpha, and elevated levels correlate with the severity of liver disease. Morgan, TR Gastroenterol. Hepatol. (NY). 2007 Feb; 3(2): 97-99.

[0135] Direct hepatocellular injury is due to the cytotoxic effects of ethanol and its metabolites (e.g., acetaldehyde). Ethanol-induced injury induces an inflammatory response and is associated with high morbidity and mortality, especially in patients with severe disease. Ethanol metabolism also alters the redox state of hepatocytes, interfering with carbohydrate and lipid metabolism, thus contributing to hepatic steatosis. Alcohol increases the susceptibility of hepatocytes to free radical damage by activating the CYP2E1 enzyme, inducing mitochondrial dysfunction, depleting antioxidant stores, and recruiting inflammatory cells. Chronic alcohol abuse, especially when combined with malnutrition, further reduces cellular resilience to oxidative stress and often amplifies the effects of oxidative injury by depleting antioxidant stores. Proteasome dysfunction also plays a role in exacerbating oxidative stress and cellular injury. Secondary hepatocyte injury mediated by inflammatory cells also plays a central role in the pathophysiology of alcoholic hepatitis. Chronic alcohol exposure can lead to increased intestinal permeability and elevated levels of circulating pathogenic products (e.g., lipopolysaccharide), also known as pathogen-associated molecular patterns (PAMPs). Ethanol-injured hepatocytes release sterile inflammatory mediators known as damage-associated molecular patterns (DAMPs). DAMPs and PAMPs bind to pattern recognition receptors and potently stimulate the innate immune response. Activation of the innate immune response through cytokine- and chemokine-mediated attraction of circulating neutrophils and monocytes. This leads to dense neutrophil infiltration of the liver, a hallmark of alcoholic hepatitis. Adaptive immune responses mediated by B cells, T cells, and natural killer cells also contribute to the hepatic inflammatory storm. Thus, alcoholic hepatitis (or alcohol-related hepatitis) is a distinct disease (Sehrawat, TS, et al. "The knowns and unknowns of treatment for alcoholic hepatitis," Lancet Gastroenterol Hepatol. 2020;5(5)494-506; hereby incorporated by reference). Patients with sAH are defined by MDF≧32 and / or MELD>20.Short-term mortality rates for patients with sAH have been reported as high as 46% in previous interventional studies (Akriviadis, E., et al. "Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial," Gastroenterology 2000 Dec;119(6):1637-48; hereby incorporated by reference). More recent studies have reported longer-term 1-year mortality (or liver transplant) rates of 56% to 57% in patients with sAH (Thursz, MR, et al. "Prednisolone or pentoxifylline for alcoholic hepatitis," N Engl J Med. 2015 Apr 23;372(17):1619-28; hereby incorporated by reference). In support of this, a meta-analysis evaluating published mortality rates between 1971 and 2016 found that intermediate mortality from AH was as high as 44% at 180 days after hospitalization (Hughes, E., et al. "Survival from alcoholic hepatitis has not improved over time," PLoS One 2018;13(2):e0192393; hereby incorporated by reference).

[0136] Patients with acute alcoholic hepatitis will have elevations in total bilirubin and transaminases, typically at least 2-6 times the upper limit or normal. Severe alcoholic hepatitis may be characterized by bilirubin levels above 10-15 mg / dL, aspartate aminotransferase (AST) levels usually between 100 and 200 U / L (or IU / L) and almost always below 400 U / L (or IU / L), alanine aminotransferase (ALT) usually around 25-50% of AST values, somewhere in the range of 50-150 U / L (or IU / L), and other typical findings include fever, leukocytosis (white blood cells >10,000 / μL), ascites, and tender hepatomegaly (Morgan, TR Gastroenterol. Hepatol. (NY). 2007 Feb; 3(2): 97-99).

[0137] Current guidelines recommend alcohol withdrawal in all patients with AH and ALD. In addition, most patients with AH would benefit from nutritional support, including total calorie and protein supplementation. However, for patients with sAH (defined by MDF ≥ 32 and / or MELD score > 20), treatment options are limited to the addition of systemic corticosteroids along with supportive care and alcohol withdrawal.

[0138] The clinical utility of systemic corticosteroid therapy is largely limited by concerns over increased risk of infection and GI bleeding. Thus, all current guidelines recommend clinicians to use the Lille score after 7 days of corticosteroid therapy to identify non-responders to avoid the risk of unnecessary systemic steroid exposure (European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines: Management of alcohol-related liver disease. J Hepatol. 2018; 69:154-81; and Crabb, DW, et al. "Diagnosis and treatment of alcohol-associated liver diseases: 2019 Practice guidance from the American Association for the Study of Liver Diseases," Hepatology. 2020;70(1): 306-33; hereby incorporated by reference).

[0139] The Lille model is a medical modeling tool to predict mortality in patients with alcoholic hepatitis who are not responding to steroid therapy. The model risk stratifies patients receiving steroid treatment over 7 days to predict who will improve and who should be considered for alternative treatment options, including early referral for transplantation (Mathurin, P., et al., Early change in bilirubin levels is an important prognostic factor in severe alcoholic hepatitis treated with prednisolone. Hepatology, 2003, 38 (6): 1363-9). The model is based on age, albumin, bilirubin (initial), bilirubin (day 7), creatinine and prothrombin time (PT). Recent cohort studies demonstrate that people with a Lille score above 0.45 are more likely to be non-responders to steroid therapy (Louvet, A., et al., The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids, Hepatology 2007, 45 (6): 1348-54).

[0140] The Lille model can be used to predict mortality at 6 months. Lower scores indicated greater improvement (in response to corticosteroids). Typically, a score above 0.45 predicts 25% 6-month survival. A score below 0.45 predicts 85% 6-month survival. The Lille score at day 7 can range from below 0.1 to above 0.9. The Lille score at day 7 for responders is below 0.45 and for non-responders is above 0.45.

[0141] Several scores are used for 28-day mortality prognosis, such as the Madrid Discriminant Function (MDF), MELD or MELD-Na, ABIC, and GAHS. MDF is defined as 4.6×(patient-control PT)+serum bilirubin, with severe disease being a score of 32 or higher. An MDF score of less than 32 means mild to moderate alcoholic hepatitis. An MDF score equal to or greater than 32 means the person is likely to have severe alcoholic hepatitis and is a candidate for corticosteroid therapy or pentoxifylline treatment under the current standard of care. MDF less than 32 (mild to moderate AH) will not benefit from steroid therapy. Since there is some mortality associated with mild to moderate AH, it would be beneficial to have a therapy for this group (considering that steroids are not indicated as they do not confer a mortality benefit).

[0142] The Model for End-Stage Liver Disease (MELD) score is a prognostic scoring system based on laboratory parameters used to predict 3-month mortality from liver disease. MELD scores range from 6 to 40 and are based on results from several laboratory tests. MELD scores for mild AH range from 6 to 10. MELD scores for moderate AH range from 11 to 20. MELD scores for sAH range from 21 to 30. MELD is a 9.57 log e (S creatinine) + 3.78 log e (Serum bilirubin) +11.2log e (INR)+6.43. Severe disease is a MELD score of 21 or higher. Singal, AK, et al., "Diagnosis and Treatment of Alcohol-Associated Liver Disease," JAMA. 2021;326(2):165-176, hereby incorporated by reference.

[0143] A new version of MELD (MELD3.0) was recently developed that added female gender and albumin to the score and demonstrated slightly more accurate mortality prediction than MELD-Na in patients with cirrhosis. See Kim WR, et al. MELD 3.0: The Model for End-stage Liver Disease Updated for the Modern Era. Gastroenterology 2021 (available at https: / / doi.org / 10.1053 / j.gastro.2021.08.050), incorporated herein by reference. Each of the embodiments described herein that list MELD or MELD-Na ranges and / or values ​​is intended to also include the corresponding MELD3.0 ranges and / or values.

[0144] Severe AH is generally accepted to be defined by a Madrid Discriminant Function (MDF) score of 32 or greater or a MELD score of 21 or greater, with the range typically found to be 21-30. The MELD-Na score is a modification of the MELD score that adjusts for serum sodium. The MELD-Na score is the currently accepted standard for determining candidacy requirements for liver transplantation. The studies described herein include patients with MELD-Na scores of 18-25 (inclusive) and MDFs of 32 or greater.

[0145] Low serum sodium is an independent predictor of mortality in patients with cirrhosis. The MELD-Na score includes serum Na, which slightly improves the predictive accuracy of the MELD score in predicting mortality (Kim, WR, et al. N Engl J Med 2008; 359:1018-1026). MELD-Na is a validated scoring system used to assess the severity of chronic liver disease. The MELD-Na score is useful in assessing subjects with significant decompensation and is currently used by the Organ Procurement and Transplantation Network (OPTN) in the United States and the Eurotransplant (ET) region in Europe to manage the allocation of organs for liver transplantation. Increasing MELD-Na scores are associated with increasing severity of liver dysfunction and increased risk of 3-month mortality. The MELD-Na score, as appropriate, is derived from a subject's serum total bilirubin, serum creatinine and INR (International Normalized Ratio) to predict survival and is calculated according to the following formulas: MELD-Na score=10×[(0.957×ln(creatinine))+(0.378×ln(bilirubin))+(1.12×ln(INR))]+6.43; MELD-Na=MELD-Na-[0.025×MELD×(140-Na)]+140.

[0146] Patients with sAH and progressive liver failure who are non-responders to corticosteroid therapy and ineligible for liver transplantation are frequently referred to palliative care (Singal, AK, et al. Am J Gastroenterol. 2018;113(2):175-94). Given the limited treatment options, as well as the side effects and lack of long-term benefit of corticosteroid therapy, there remains a significant unmet medical need for patients with sAH.

[0147] In some embodiments, the patient is at least 18 years old. In some embodiments, the patient is at least 30 years old. In some embodiments, the patient is at least 35 years old. In some embodiments, the patient is at least 40 years old. In some embodiments, the patient is at least 60 years old. In some embodiments, the patient is between 18 and 65 years old. In some embodiments, the patient is at least 42, 45, 48, 50, 52, 55, 58, 62, 65, 68, 70, 72, 75, 78, or 80 years old. In some embodiments, the patient is between 40 and 60 years old. In some embodiments, the patient is between 60 and 85 years old. In some embodiments, the patient is between 40 and 50 years old. In some embodiments, the patient is between 70 and 80 years old.

[0148] In some embodiments, the patient is male. In some embodiments, the patient is female.

[0149] In some embodiments of the present disclosure, patients are stratified according to disease severity. Short-term mortality can be predicted using the Madrid Discriminant Function (MDF), Model for End-Stage Liver Disease (MELD or MELD-Na) score, Age-Bilirubin-International Normalized Ratio-Creatinine score, and Glasgow Alcoholic Hepatitis Score. Patients with severe AH (sAH) defined by a Madrid Discriminant Function of 32 or greater have 1-month mortality rates as high as 20%-50%, so 30-day survival was the endpoint of most trials in previous clinical studies. Maximum MDF scores are typically less than 60, as patients with MDF scores greater than 60 are more likely to require liver transplantation. In some embodiments, MELD or MELD-Na scores of 20 or greater or 21 or greater are used as criteria for selecting patients. In some embodiments, MELD or MELD-Na scores of 18 or greater are used as criteria for selecting patients. For example, a MELD score of 21 or greater predicts a 90-day mortality rate of 20%. Maximum MELD scores are typically less than 30, as patients with MELD scores above 30 are more likely to require liver transplantation. Failure to improve in serum bilirubin (Lille score) predicts patients with severe AH who are unlikely to benefit from continued corticosteroid therapy.

[0150] In some embodiments, the patient has mild alcoholic hepatitis. In some embodiments, the patient has moderate alcoholic hepatitis. In some embodiments, the patient has a Madrid Discriminant Function score of about 32, and / or a MELD or MELD-Na score of 18, 19, 20, 21, 22, 23, 24, or 25.

[0151] In some embodiments, the patient has a Madrid Discriminant Function score of 32 or greater, and / or a MELD or MELD-Na score of 21-30.

[0152] In some embodiments, the patient has underlying alcohol-related liver disease (ALD) associated with sAH.

[0153] In some embodiments, the patient presents with jaundice.

[0154] In some embodiments, the patient exhibits one or more of the following: (1) ongoing alcohol consumption for 6 months or longer, more than 40 g alcohol per day in women and more than 60 g alcohol per day in men, with abstinence less than 60 days prior to the onset of jaundice; (2) presence of elevated liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT] concentrations ≧50 IU / L but ≦400 IU / L and AST / ALT ratio ≧1:5); and (3) worsening jaundice with bilirubin concentrations greater than 3 mg / dL. In some embodiments, the patient is diagnosed with sAH following liver biopsy in addition to one, two, three, or all of the aforementioned symptoms of the disease.

[0155] In some embodiments, the patient is deemed ineligible for a liver transplant by generally accepted criteria known in the art.

[0156] In some embodiments, the patient has an alcohol use disorder (AUD), defined as consuming three or more alcoholic drinks per day (men) or two or more alcoholic drinks per day (women).

[0157] In some embodiments, the patient has previously been treated with a corticosteroid for sAH. In some embodiments, the patient has not responded to the corticosteroid. In some embodiments, the patient has a Lille score of greater than 0.45 after 7 days or more of treatment with a corticosteroid.

[0158] In some embodiments, the patient has an MDF score of 32 or higher, and / or a MELD or MELD-Na score of 18, or 20, or 21 or higher, for example, 21-30.

[0159] In some embodiments, the patient has asymptomatic sAH, or “walking AH.” In some embodiments, the patient has asymptomatic sAH, including cirrhosis.

[0160] In some embodiments, in addition to sAH, patients are diagnosed using the Child-Turcotte-Pugh criteria. In some embodiments, patients have a Child-Turcotte-Pugh score of 7 or greater, e.g., 7-15, 8-15, 9-15, 10-15, or 8-12.

[0161] In some embodiments, the patient presents with alcohol-related cirrhosis.

[0162] In some embodiments, the patient presents with alcohol-related liver fibrosis.

[0163] In some embodiments, the patient presents with alcohol-related steatosis.

[0164] In some embodiments, the patient presents with alcohol-associated steatohepatitis.

[0165] In some embodiments, the patient presents with alcoholic hepatitis.

[0166] In some embodiments, the patient has ALD in addition to sAH, where the ALD is selected from early ALD (stages 0-2) or advanced ALD (bridging fibrosis, stage 3; or cirrhosis, stage 4).

[0167] In some embodiments, the patient does not exhibit cirrhosis.

[0168] In some embodiments, the patient is currently hospitalized, i.e., hospitalized prior to beginning treatment with the FXR agonist. In some embodiments, the patient is currently hospitalized and exhibits an MDF score of at least 32 and a MELD score of 18, or 20, or 21 to 25 or 30, or a MELD-Na score of 18, 20, or 21 to 25 or 30.

[0169] In some embodiments, the patient has suffered at least one recurrence of sAH.

[0170] In some embodiments, the patient exhibits, in addition to sAH, one or more of the following: obesity, metabolic syndrome, hepatitis C infection, or genetic polymorphisms such as in the patatin-like phospholipase domain protein 3, membrane-bound O-acyltransferase, and transmembrane 6 superfamily member 2 genes.

[0171] In some embodiments, the patient exhibits intestinal dysbiosis.

[0172] In some embodiments, the methods improve one or more measures of sAH, such as intestinal dysbiosis.

[0173] In some embodiments, the present disclosure provides a method of determining patient candidacy for therapeutic treatment for sAH, comprising determining the patient's MELD-Na score, where the patient's MELD-Na score is greater than or equal to 18. In some embodiments, the method further comprises determining the patient's MDF score, for example, where the patient's MDF score is from 32 to 60, inclusive.

[0174] In some embodiments, the disclosure provides a method of determining patient candidacy for therapeutic treatment for sAH, comprising determining the patient's MELD score, where the patient's MELD score is 21 or greater, e.g., from 21 to 30. In some embodiments, the method further comprises determining the patient's MDF score, e.g., where the patient's MDF score is 32 or greater, e.g., from 32 to 60, inclusive.

[0175] In some embodiments, the disclosure provides a method for treating sAH comprising selecting a patient with a MELD-Na score of 18 or greater and administering a therapeutic treatment for sAH, e.g., where the patient also has an MDF score of 32 to 60, inclusive. In some embodiments, the therapeutic treatment comprises administering a pharmacological agent to the patient and / or a liver transplant.

[0176] In some embodiments, the disclosure provides a method for treating sAH comprising selecting a patient with a MELD score of 21 or greater, e.g., between 21 and 30, and administering a therapeutic treatment for sAH, e.g., where the patient also has an MDF score of 32 or greater, e.g., between 32 and 60, inclusive. In some embodiments, the therapeutic treatment comprises administering a pharmacological agent to the patient and / or a liver transplant.

[0177] In some embodiments, the method provides an improvement in one or more measures of a patient's health outcome. In the following embodiments of the invention, reference to "patient" or "the patient" may refer to an individual patient or a group of patients. For example, a reduction in a patient's health care utilization may refer to an individual patient or a group of patients.

[0178] In some embodiments, the method improves the patient's 30-day survival compared to an otherwise similar patient who was not administered an FXR agonist. In some embodiments, the method improves the patient's 60-day survival compared to an otherwise similar patient who was not administered an FXR agonist. In some embodiments, the method improves the patient's 90-day survival compared to an otherwise similar patient who was not administered an FXR agonist. In some embodiments, the method improves the patient's 120-day survival, 180-day survival, or 1-year survival compared to an otherwise similar patient who was not administered an FXR agonist.

[0179] In some embodiments, the method improves the patient's 30-day mortality rate compared to otherwise similar patients not administered the FXR agonist. In some embodiments, the method improves the patient's 60-day mortality rate compared to otherwise similar patients not administered the FXR agonist. In some embodiments, the method improves the patient's 90-day mortality rate compared to otherwise similar patients not administered the FXR agonist. In some embodiments, the method improves the patient's 120-day mortality rate, 180-day mortality rate, or 1-year mortality rate compared to otherwise similar patients not administered the FXR agonist.

[0180] In some embodiments, the improvement in patient survival or mortality comprises an increase in survival or a decrease in mortality of about 10% to about 70%. Such an improvement may be measured, for example, over 30 days, 60 days, 90 days, 120 days, 180 days, a year, or more than a year. In some embodiments, the improvement in patient survival or mortality comprises an increase in survival or a decrease in mortality of about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, or about 10% to about 20%. In some embodiments, an improvement in patient survival or mortality comprises an increase in survival or a decrease in mortality of about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 30% to about 70%, about 30% to about 60%, about 30% to about 50%, about 30% to about 40%, about 40% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 70%, about 50% to about 60%, or about 60% to about 70%. In some embodiments, an improvement in patient survival or mortality comprises an increase in survival or decrease in mortality of about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%.

[0181] In some embodiments, the method provides a reduction in the risk of death for patients.In some embodiments, the method provides a reduction in the risk of death and the healthcare utilization for liver-related events in patients with sAH.In some embodiments, such reduction is compared with the current standard of care, for example, treatment with corticosteroids such as prednisolone.In some embodiments, FXR agonist, such as compound 1 or its pharmacologic acceptable salt or its amino acid conjugate, is applied as first-line therapy.

[0182] In some embodiments, the method provides a reduction in the patient's healthcare utilization by at least 10% over 30 days, 60 days, 90 days, 120 days, 180 days, or over a year, or longer than a year. As used herein, the term "healthcare utilization" includes one or more of the following: readmission within 30 days of discharge, number of hospitalizations, length of stay, emergency room visits, intensive care unit (ICU) days, and infectious complications (e.g., sepsis, pneumonia, urinary tract infection [UTI], cellulitis, spontaneous bacterial peritonitis [SBP]), and major medical procedures such as liver transplants. In some embodiments, the method provides a reduction in the patient's healthcare utilization by at least 20% over 30 days, 60 days, 90 days, 120 days, 180 days, or over a year, or longer than a year. In some embodiments, the method provides a reduction in patient health care utilization by at least 30% over 30 days, 60 days, 90 days, 120 days, 180 days, or over a year, or for longer than a year. In some embodiments, the method provides a reduction in patient health care utilization by about 10% to about 40% over 30 days, 60 days, 90 days, 120 days, 180 days, or over a year, or for longer than a year.

[0183] In some embodiments, the method provides a reduction in patient health care utilization by about 10% to about 40% over 30 days, 60 days, 90 days, 120 days, 180 days, or over a year, or for longer than a year. In some embodiments, the method provides a reduction in patient health care utilization by about 20% to about 30% over 30 days, 60 days, 90 days, 120 days, 180 days, or over a year, or for longer than a year. In some embodiments, the method provides a reduction in patient health care utilization by about 10% to about 20% over 30 days, 60 days, 90 days, 120 days, 180 days, or over a year, or for longer than a year.

[0184] In some embodiments, the method reduces patient re-admissions by at least 10%, hi some embodiments, the method reduces patient re-admissions by 10-80%.

[0185] In some embodiments, the methods improve patient 90-day survival and reduce patient re-hospitalization by at least 10%.

[0186] In some embodiments, the method further comprises administering the FXR agonist in combination with another therapeutic agent. In some embodiments, the method further comprises co-administering to the patient an effective amount of an anti-inflammatory agent, an antibiotic, a probiotic, a fecal transplant, a zinc supplement, or any combination of these agents. In some embodiments, the other therapeutic agent can be an anti-inflammatory agent, an antibiotic (e.g., Augmentin), an antioxidant, a probiotic, a fecal transplant, a Zn supplement, or any combination of these agents. In some embodiments, the method comprises administering an FXR agonist and an anti-inflammatory agent. In some embodiments, the anti-inflammatory agent is a corticosteroid. For example, the corticosteroid may be selected from prednisolone (e.g., about 40 mg / d) or methylprednisolone (e.g., about 32 mg / d). In some embodiments, the additional therapeutic agent for co-administration is pentoxifylline. In some embodiments, the FXR agonist is administered in combination with a corticosteroid or pentoxifylline. In some embodiments, the method further comprises co-administering to the patient an effective amount of pentoxifylline, augmentin, bovine colostrum, corticosteroids (e.g., prednisolone or methylprednisolone), an ELAD agent, canakinumab, a TNF inhibitor, IL-22, N-acetylcysteine, metadoxine, IgG anti-LPS, probiotics, fecal transplants, Zn supplements, or any combination of these agents.

[0187] In some embodiments, further treatment includes alcohol cessation and / or counseling.

[0188] Exemplary Diseases and Patient Populations—ACLF Acute exacerbation of chronic liver failure (ACLF) is a syndrome characterized by acute decompensation of chronic liver disease associated with organ failure and high short-term mortality. Alcoholism and chronic viral hepatitis are the most common underlying liver diseases. Up to 40%-50% of cases of ACLF have no identifiable trigger, and in the remaining patients, sepsis, active alcoholism, and recurrent chronic viral hepatitis are the most common reported precipitating factors. An excessive systemic inflammatory response appears to play a critical role in the development of ACLF. Using a liver-adapted sequential organ assessment failure score, it is possible to triage patients with ACLF and prognosticate their outcome. The course of ACLF is dynamic and changes over the course of hospitalization. Most patients will have a clear prognosis between days 3 and 7 of hospitalization, and clinical decisions such as evaluation for liver transplantation or discussion of goals of care can be tailored using the clinical score. Bioartificial liver support systems, granulocyte-colony stimulating factor, or stem cell transplantation are under investigation for the medical care of this patient population, but the data are too early to implement them as standard of care.

[0189] In some embodiments, the patient is at least 18 years old. In some embodiments, the patient is at least 30 years old. In some embodiments, the patient is at least 35 years old. In some embodiments, the patient is at least 40 years old. In some embodiments, the patient is at least 60 years old. In some embodiments, the patient is between 18 and 65 years old. In some embodiments, the patient is at least 42, 45, 48, 50, 52, 55, 58, 62, 65, 68, 70, 72, 75, 78, or 80 years old. In some embodiments, the patient is between 40 and 65 years old. In some embodiments, the patient is between 65 and 85 years old. In some embodiments, the patient is between 40 and 50 years old. In some embodiments, the patient is between 70 and 80 years old.

[0190] In some embodiments, the patient is male. In some embodiments, the patient is female.

[0191] In some embodiments, the patient has an alcohol use disorder (AUD), defined as consuming three or more alcoholic drinks per day (men) or two or more alcoholic drinks per day (women).

[0192] In some embodiments, the patient has ACLF associated with ALD.

[0193] In some embodiments, the patient has ALD selected from early ALD (stages 0-2) or advanced ALD (bridging fibrosis, stage 3; or cirrhosis, stage 4).

[0194] In some embodiments, the patient has a Madrid Discriminant Function (MSF) score of 32 or higher, and / or a MELD or MELD-Na score of 18, 20, or 21 or higher, for example, 21-30.

[0195] In some embodiments, patients were diagnosed with ACLF using the Sequential [Sepsis-Related] Organ Failure Assessment, APACHE (Acute Physiology and Chronic Health Evaluation) or Acute Exacerbations of Chronic Liver Failure score.

[0196] In some embodiments, the patient presents with cirrhosis.

[0197] In some embodiments, the patient presents with liver fibrosis.

[0198] In some embodiments, the patient presents with steatosis.

[0199] In some embodiments, the patient presents with alcoholic hepatitis.

[0200] In some embodiments, the patient does not exhibit cirrhosis.

[0201] In some embodiments, the patient exhibits intestinal dysbiosis.

[0202] In some embodiments, the patient presents with ACLF as well as one or more of the following: obesity, metabolic syndrome, hepatitis C infection, or genetic polymorphisms such as in the patatin-like phospholipase domain protein 3, membrane-bound O-acyltransferase, and transmembrane 6 superfamily member 2 genes.

[0203] When ACLF is caused by sAH, the same therapeutic agents as sAH are used for treatment. There is an overlap in treatment options with other forms of ACLF, including antibiotics, supplements, antioxidants, and steroids. Antioxidants such as N-acetylcysteine ​​are used in ACLF.

[0204] In some embodiments, the method of the present disclosure includes a co-administered treatment. In some embodiments, the method includes administering an FXR agonist in combination with another therapeutic agent. In some embodiments, the other therapeutic agent can be an anti-inflammatory agent, an antibiotic (e.g., Augmentin), an antioxidant, a probiotic, a fecal transplant, a Zn supplement, or a combination of any of these agents. In some embodiments, the method includes administering an FXR agonist and an anti-inflammatory agent. In some embodiments, the anti-inflammatory agent is a corticosteroid. For example, the corticosteroid may be selected from prednisolone (e.g., about 40 mg / d) or methylprednisolone (e.g., about 32 mg / d). In some embodiments, the additional therapeutic agent for co-administration is pentoxifylline. In some embodiments, the FXR agonist is administered in combination with a corticosteroid or pentoxifylline. In some embodiments, the FXR agonist is administered in combination with N-acetylcysteine. In some embodiments, the additional treatment includes alcohol withdrawal and / or counseling.

[0205] 2. Use, Formulation and Administration Pharmaceutically acceptable compositions According to another embodiment, the present invention provides a composition comprising the disclosed compound and a pharma- ceutically acceptable carrier, adjuvant or vehicle.In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition.In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0206] The term "subject" or "patient" as used herein means a human.

[0207] The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.The pharmaceutically acceptable carrier, adjuvant or vehicle that may be used in the composition of the present invention includes, but is not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances (such as hydroxypropylmethylcellulose), polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0208] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the invention, or an active metabolite or amino acid conjugate thereof.

[0209] As used herein, the term "amino acid conjugate" refers to the conjugate of the compound of the present invention with any suitable amino acid.Taurine (-NH(CH2)2SO3H), glycine (-NHCH2CO2H) and sarcosine (-N(CH3)CH2CO2H) are examples of amino acid conjugates.Suitable amino acid conjugates of the compound have the added advantage of enhanced integrity in bile or intestinal fluid.Suitable amino acids are not limited to taurine, glycine and sarcosine.

[0210] As defined herein, the term "metabolites" refers to glucuronidated and sulfated derivatives of the compounds described herein, where one or more glucuronic acid or sulfate moieties are linked to the compounds of the invention. The glucuronic acid moiety may be linked to the compound via a glycosidic bond with a hydroxyl group (e.g., 3-hydroxyl, 7-hydroxyl, 11-hydroxyl) of the compound. The sulfated derivatives of the compound may be formed via sulfation of a hydroxyl group (e.g., 3-hydroxyl, 7-hydroxyl, 11-hydroxyl). Examples of metabolites include, but are not limited to, 3-O-glucuronide, 7-O-glucuronide, 11-O-glucuronide, 3-O-7-O-diglucuronide, 3-O-11-O-triglucuronide, 7-O-11-O-triglucuronide, and 3-O-7-O-11-O-triglucuronide of the compounds described herein, as well as 3-sulfate, 7-sulfate, 11-sulfate, 3,7-bisulfate, 3,11-bisulfate, 7,11-bisulfate, and 3,7,11-trisulfate of the compounds described herein.

[0211] As used herein, "pharmaceutical acceptable salts" refers to conventional non-toxic salts of the compounds of the present invention, in which the parent compound is modified by forming its acid or base salt. Suitable pharmaceutical acceptable salts according to the present disclosure can be easily determined and prepared by those skilled in the art, and include, for example, basic salts such as aluminum, calcium, lithium, magnesium, potassium, sodium and zinc salts of Compound 1, or organic salts such as quaternary ammonium salts of Compound 1.

[0212] The amount of the disclosed compound (i.e., active agent) to be present in a composition for use in the disclosed methods, or the disclosed pharmaceutical compositions, will generally be a therapeutically effective amount. A "therapeutically effective amount" or dose (or "effective amount") refers to the amount of active agent sufficient to produce the desired therapeutic result.

[0213] In certain embodiments, the effective amount refers to the titrated dosage administered during the titration period, hi other embodiments, the effective amount refers to the adjusted or re-adjusted dosage administered after the titration period.

[0214] "Starting dose" as used herein refers to the initial dose provided to a patient to provide a clinical effect while minimizing the onset or occurrence of adverse effects. The starting dose may, in certain instances, be less than the amount typically administered to a patient. The starting dose is provided in an amount that is titrated or gradually increased over the course of a titration period or during the course of treatment with an FXR agonist as described herein. The starting dose may, in certain instances, be greater than the amount typically administered to a patient. The starting dose is provided in an amount that is titrated or gradually increased or decreased over the course of a titration period or during the course of treatment with an FXR agonist as described herein to achieve the desired therapeutic result.

[0215] "Titration period" refers to the length of time during which a starting dose is administered to a patient. The titration period lasts for a specified length of time, during which the patient is often monitored for liver function and / or liver biochemistry, as described herein.

[0216] "Adjusted dose" as used herein refers to the dose of the disclosed FXR agonist or composition thereof administered after the end of the titration period. The adjusted dose may be increased or decreased compared to the starting dose, but as provided herein, the patient's tolerance and other factors described herein will determine the dosage of the adjusted dose. "Readjusted dose" as used herein refers to any altered dosage or dose frequency of the adjusted dose in a patient.

[0217] The amount of Compound 1, or a pharma- ceutically acceptable salt, or amino acid conjugate thereof, as provided above can refer to the starting dose administered during the titration period.

[0218] In certain embodiments, the starting daily dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 2.5 mg. In certain embodiments, the starting daily dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 5 mg. In certain embodiments, the starting daily dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 7.5 mg. In certain embodiments, the starting daily dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 10 mg. In certain embodiments, the starting daily dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 12.5 mg. In certain embodiments, the starting daily dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 15 mg. In certain embodiments, the starting daily dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 20 mg. In certain embodiments, the starting daily dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 25 mg. In certain embodiments, the starting daily dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 50 mg. In certain embodiments, the starting daily dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 100 mg. In certain embodiments, the starting daily dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 120 mg.

[0219] In some embodiments, a patient's adjusted dose may be increased to 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, or 120 mg. In some embodiments, a patient's adjusted daily dose may be increased to 5 mg. In some embodiments, a patient's adjusted daily dose may be increased to 10 mg. In some embodiments, a patient's adjusted daily dose may be increased to 25 mg. In some embodiments, a patient's adjusted daily dose may be increased to 50 mg. In some embodiments, a patient's adjusted daily dose may be increased to 100 mg. In some embodiments, a patient's adjusted daily dose may be increased to 120 mg. In some embodiments, a patient's adjusted dose may be increased to 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg.

[0220] In certain embodiments, the starting daily dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein can be 120 mg, 100 mg, 50 mg, 25 mg, 20 mg, 15 mg, 12.5 mg, 10 mg, 7.5 mg, or 5 mg.

[0221] In some embodiments, the patient's adjusted daily dose may be reduced by up to 100 mg. In some embodiments, the patient's adjusted daily dose may be reduced by up to 50 mg. In some embodiments, the patient's adjusted daily dose may be reduced by up to 25 mg. In some embodiments, the patient's adjusted dose may be reduced by up to 20 mg. In some embodiments, the patient's adjusted daily dose may be reduced by up to 10 mg. In some embodiments, the patient's adjusted daily dose may be reduced by up to 5 mg. In some embodiments, the patient's adjusted daily dose may be reduced by up to 2.5 mg. In some embodiments, the patient's adjusted dose may be reduced by up to 15 mg, 12.5 mg, 10 mg, 7.5 mg, 5 mg, or 2.5 mg.

[0222] The amount of compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof may refer to an adjusted dose administered after a titration period as described herein. In certain embodiments, the adjusted dose of compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 2.5 mg. In certain embodiments, the adjusted dose of compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 5 mg. In certain embodiments, the adjusted dose of compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 7.5 mg. In another embodiment, the adjusted dose of compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 10 mg. In certain embodiments, the adjusted dose of compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 12.5 mg. In certain embodiments, the adjusted dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 15 mg. In certain embodiments, the adjusted dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 20 mg. In yet another embodiment, the adjusted dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 25 mg. In yet another embodiment, the adjusted dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 50 mg. In yet another embodiment, the adjusted dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 100 mg.In yet another embodiment, the adjusted dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 120 mg. In yet another embodiment, the adjusted dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 150 mg. In yet another embodiment, the adjusted dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 200 mg. In yet another embodiment, the adjusted dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 250 mg. In yet another embodiment, the adjusted dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 300 mg.

[0223] The amount of compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof as provided above may refer to a re-adjusted dose administered after a titration period as described herein. In certain embodiments, the re-adjusted dose of compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate administered to a patient described herein may be 2.5 mg. In certain embodiments, the re-adjusted dose of compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate administered to a patient described herein may be 5 mg. In certain embodiments, the re-adjusted dose of compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate administered to a patient described herein may be 7.5 mg. In another embodiment, the re-adjusted dose of compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate administered to a patient described herein may be 10 mg. In yet another embodiment, the re-adjusted dose of compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate administered to a patient described herein may be 25 mg. In yet another embodiment, the re-adjusted dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 50 mg. In yet another embodiment, the re-adjusted dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 100 mg. In yet another embodiment, the re-adjusted dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 120 mg. In yet another embodiment, the re-adjusted dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 150 mg. In yet another embodiment, the re-adjusted dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 200 mg.In yet another embodiment, the reconstituted dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein can be 250 mg. In yet another embodiment, the reconstituted dose of Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein can be 300 mg.

[0224] The titration period may be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days in duration. In certain embodiments, the titration period comprises a time period of about 1 week, 2 weeks, 3 weeks, 4 weeks, or 5 weeks. In another embodiment, the titration period comprises a time period of about 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In another embodiment, the titration period may be longer than 6 months. In another embodiment, the titration period comprises a time period of about 3 days, 5 days, 7 days, 10 days, 14 days, 21 days, or 28 days. For example, the titration period can be about 1 week. In another example, the titration period can be about 2 weeks. In another example, the titration period can be about 3 days. In yet another example, the titration period can be about 5 days. In yet another example, the titration period can be about 5 days.

[0225] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intracisternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations may be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media.

[0226] For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween®, spans, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may be used for formulation purposes.

[0227] The pharmaceutically acceptable composition of the present invention may be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or liquids.For tablets for oral use, commonly used carriers include lactose and cornstarch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspensions are required for oral use, active ingredient is combined with emulsifying and suspending agents.If desired, certain sweeteners, flavorings or colorings may also be added.

[0228] Alternatively, the pharma- ceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These may be prepared by mixing the active substance with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols.

[0229] The pharma- ceutically acceptable compositions of this invention may be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. For each of these areas or organs, suitable topical formulations are readily prepared.

[0230] Topical application for the lower intestinal tract can be affected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical and transdermal patches may also be used.

[0231] For topical application, the provided pharma- ceutically acceptable composition may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.Alternatively, the provided pharma-ceutically acceptable composition may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharma-ceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0232] The pharma- ceutically acceptable compositions of the present invention may be administered by nasal aerosol or inhalation.Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0233] In some embodiments, the pharma- ceutically acceptable composition of the present disclosure is formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharma- ceutically acceptable composition of the present disclosure is administered without food. In other embodiments, the pharma- ceutically acceptable composition of the present disclosure is administered with food.

[0234] In other embodiments, the pharma- ceutically acceptable compositions of the present disclosure are formulated for intravenous (IV) administration.

[0235] The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, etc. The compositions should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of the compound can be administered to a patient receiving these compositions.

[0236] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, excretion rate, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the invention in a composition will also depend on the particular compound in the composition.

[0237] Treatment, duration and dosing As used herein, the term "treating" includes any effect that results in the improvement of a condition, disease, disorder, etc., e.g., lowering, reducing, modulating, or eliminating. "Treating" or "treatment" of a condition includes inhibiting an existing condition, i.e., halting the development of the condition or its clinical symptoms, or relieving the condition, i.e., causing temporary or permanent regression of the condition or its clinical symptoms.

[0238] "Preventing" a condition includes not causing clinical symptoms of a condition to develop in a subject who may be exposed to or predisposed to the condition, but who has not yet experienced or exhibited symptoms of the condition.

[0239] The term "inhibiting" or "inhibition" as used herein refers to any detectable positive effect on the progression of a disease or condition. Such positive effects can include delaying the progression of at least one symptom or sign of a disease or condition, alleviating or reversing a symptom or sign, and slowing further deterioration of a symptom or sign.

[0240] The disclosed methods of treatment include administration of the disclosed FXR agonists or compositions thereof as necessary to achieve the desired therapeutic effect. The compounds or compositions may be administered for as long as necessary to maintain the desired therapeutic effect.

[0241] In some embodiments, the FXR agonist of the present disclosure is administered for a period (duration of treatment) between about 1 week and about 12 months. In some embodiments, the FXR agonist is administered for a period between about 1 week and about 6 months. In some embodiments, the FXR agonist is administered for a period between about 1 week and about 3 months. In some embodiments, the FXR agonist is administered for a period between about 1 week and about 10 weeks. In some embodiments, the FXR agonist is administered for a period between about 1 week and about 6 weeks. In some embodiments, the FXR agonist is administered for a period between about 1 week and about 4 weeks. In some embodiments, the FXR agonist is administered for a period between about 1 week and about 3 weeks. In some embodiments, the FXR agonist is administered for a period between about 1 week and about 2 weeks. In some embodiments, the FXR agonist is administered for a period of about 1 week.

[0242] In some embodiments, the FXR agonist is administered to the patient for about 30 days. In some embodiments, the FXR agonist is administered to the patient for about 60 days. In some embodiments, the FXR agonist is administered to the patient for about 90 days. In some embodiments, the FXR agonist is administered to the patient for about 30 to about 90 days. In some embodiments, the FXR agonist is administered to the patient for about 30 to about 180 days. In some embodiments, the FXR agonist is administered to the patient for about 60 to about 120 days. In some embodiments, the FXR agonist is administered to the patient for about 90 to about 120 days. In some embodiments, the FXR agonist is administered to the patient for about 90 to about 180 days.

[0243] In some embodiments, the FXR agonist is administered to the patient for about 3 days to about 365 days. In some embodiments, the FXR agonist is administered to the patient for about 3 days, about 5 days, about 7 days, about 10 days, about 14 days, about 21 days, about 28 days, about 30 days, about 35 days, about 40 days, about 50 days, about 60 days, about 70 days, about 80 days, about 90 days, about 100 days, about 110 days, about 120 days, about 130 days, about 140 days, about 150 days, about 160 days, about 170 days, or about 180 days.

[0244] In some embodiments, the FXR agonist is administered for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, or as needed to produce the desired therapeutic effect.

[0245] In some embodiments, the FXR agonist, such as Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof, is administered daily at a dose of about 1 mg to about 300 mg. In some embodiments, the FXR agonist, such as Compound 1 or a pharma-ceutically acceptable salt or amino acid conjugate thereof, is administered daily at a dose of about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 85 mg, about 100 mg, about 120 mg, about 125 mg, about 140 mg, about 150 mg, about 165 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, or about 300 mg. In some embodiments, Compound 1 is administered daily at a dose of about 2.5 mg, about 5 mg, about 10 mg, about 25 mg, about 30 mg, about 35 mg, about 50 mg, about 75 mg, or about 100 mg.

[0246] In some embodiments, the FXR agonist, such as Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof, is administered in single or multiple doses sufficient to achieve a total daily dose of about 1 mg to about 150 mg.

[0247] In some embodiments, the FXR agonist, such as Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof, is administered three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, twice a week, once a week, or once every two weeks.

[0248] In some embodiments, the FXR agonist, such as Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof, is administered at a dose of about 1am to about 500mg. In some embodiments, the FXR agonist, such as Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof, is administered at a dose of about 2.5mg to about 300mg. In some embodiments, the FXR agonist, such as Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof, is administered at a dose of about 2.5mg to about 120mg, or about 2.5mg to about 100mg. In some embodiments, the FXR agonist of the present disclosure is administered at a dose of about 0.1mg to about 25mg. In some embodiments, the FXR agonist of the present disclosure is administered at a dose of about 2.5mg to about 50mg. In some embodiments, the FXR agonist of the present disclosure is administered at a dose of about 2.5mg to about 10mg. In some embodiments, the FXR agonist of the present disclosure is administered at a dose of about 2.5 mg to about 5 mg. In some embodiments, the FXR agonist of the present disclosure is administered at a dose of about 0.5 mg to about 5 mg. In some embodiments, the FXR agonist of the present disclosure is administered at a dose of about 0.5 mg to about 2.5 mg.

[0249] In some embodiments, the FXR agonist, such as Compound 1 or a pharma- ceutically acceptable salt thereof or an amino acid conjugate thereof, is administered at a dose of about 2.5 mg to about 120 mg, 2.5 mg to about 100 mg, about 5.0 mg to about 100 mg, about 10 mg to about 100 mg, or about 50 mg to about 100 mg. In some embodiments, the FXR agonist of the present disclosure is administered at a dose of about 2.5 mg to about 50 mg, about 10 mg to about 50 mg, or about 25 mg to about 50 mg. In some embodiments, the FXR agonist, such as Compound 1 or a pharma-ceutically acceptable salt thereof or an amino acid conjugate thereof, is administered at a dose of about 2.5 mg to about 120 mg, about 2.5 mg to about 100 mg, about 10 mg to about 100 mg, about 25 mg to about 100 mg, or about 50 mg to about 100 mg.

[0250] In some embodiments, the FXR agonist, such as Compound 1 or a pharma- ceutically acceptable salt or amino acid conjugate thereof, is administered in a single or multiple doses sufficient to achieve a total daily dose of about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, or about 150 mg. In some embodiments, the FXR agonist of the present disclosure is administered in a single or multiple doses sufficient to achieve a total daily dose of about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 100 mg, about 120 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg.

[0251] In some embodiments, the FXR agonist of the present disclosure is administered to a patient in a fasted state. In some embodiments, the FXR agonist is administered to a patient in a fed state.

[0252] The contents of each document cited in the specification are incorporated herein by reference in their entirety. EXAMPLES

[0253] Example Example 1 Treatment effects of three test articles on the development of alcoholic steatohepatitis in C57BL / 6J female mice the purpose The objective of this study was to evaluate the efficacy of the test articles obeticholic acid (OCA), Compound 1, and Compound 2 on liver and intestinal pathology in a mouse model of alcoholic steatohepatitis.

[0254] Compound 2 is a 3-deoxy, 11β-OH bile acid and FXR-specific bile acid derivative that has no activity against the bile acid G protein-coupled receptor TGR5 as described in US 10,815,267. [ka]

[0255] Test Article Formulation and Administration The dietary vehicles used in this study are described in the table below. [Table 1]

[0256] Preparation of formulations Dosage formulations were divided into aliquots when required so that they could be dispensed on each dosing occasion. [Table 2]

[0257] Preparation of vehicle Vehicle, 0.5% CMC (medium viscosity) in deionized water, was prepared prior to Day 1, stored in a refrigerator set to maintain 4° C., and used to dosing the appropriate groups. Vehicle was stirred at room temperature for at least 30 minutes prior to dosing.

[0258] Test Article Preparation Test articles for Groups 3-5 were prepared weekly, stored at 2-8°C until ready for use, and agitated at room temperature for 30 minutes prior to dosing. Dose formulations were sonicated as required and agitated during dosing.

[0259] Test articles for Groups 6-7 were prepared every 3 days, stored at controlled room temperature until ready for use, and stirred at room temperature for 30 minutes prior to dosing. Dose formulations were stirred during dosing. Dosing solutions were homogenous suspensions. Any observations regarding phase separation, color, and turbidity were noted.

[0260] Preparation of control diet To make 1 L of control diet, weigh 225.55 grams of dry mix (F1259SP control diet) into a container with a lid. Add 350 mL of RO grade water and shake vigorously for 30 seconds. Ensure that a homogenous suspension is obtained. Add 510 mL of RO water to 1 L. A blender can be used to obtain a homogenous suspension. The control diet is administered to all groups on day -28. Prepared diets may be stored at 4°C and dispensed within 3 days. Prepared diets should not be kept at room temperature for longer than 48 hours to prevent diet deterioration. Additionally, pre-weighed dry powder may be stored at 4°C for up to 1 week. Diets are stirred at room temperature for at least 30 minutes before dispensing.

[0261] Preparation of ethanol diet To prepare 1 L of alcohol diet (F1697SP ethanol diet), please refer to the table below. A blender can be used to obtain a homogenous suspension. The prepared diet may be stored at 4° C. and used within 48 hours. In addition, pre-weighed dry powder may be stored at 4° C. for up to 1 week. The diet was stirred at room temperature for at least 30 minutes before dispensing. [Table 3]

[0262] Testing Systems Species:Mouse System: C57BL / 6J (JAX number 000664) Status: Purpose-bred, naive Source: Jackson Laboratories Number of females: 138 (119 in study + 19 in reserve) Target age at 10 weeks Start of research:

[0263] Animal Identification Method: An electronic identification chip implanted under the skin or other approved identification method such as indelible ink if required.

[0264] Selection, allocation, replacement and disposition of animals Upon arrival, all animals were fed 5CR4 chow ad libitum. All animals were acclimated to the vivarium for at least 4 days after arrival at the testing facility. Animals were weighed on day -5 and then assigned to treatment groups based on body weight. Replacement: Any assigned animal deemed unsuitable for use in the study prior to the start of dosing was replaced by a replacement animal. After Study Day 1, the reserve animal was transferred to Study Group 1. General in-life assessment to include replacement animals until release from the study. Disposition: Disposition of all animals was documented in the study records.

[0265] Husbandry Animals were group-housed with a maximum of three animals per cage in polycarbonate cages containing appropriate bedding. Housing settings were as specified in the USDA Animal Welfare Act (9 CFR, parts 1, 2, and 3) and as described in the Guide for the Care and Use of Laboratory Animals.

[0266] Diet: 5CR4 chow until day -26; Lieber-DeCarli liquid diet from day -28 to day 15. Upon arrival at the testing facility, all animals received PMI Nutrition International Certified Rodent Chow #5CR4 ad libitum. If justified by clinical signs (e.g., broken / damaged incisors or other health changes), powdered form of the diet may be offered to individual animals during the chow diet phase (until day -26).

[0267] On days -28 and -27, all animals were offered both the Lieber-DeCarli liquid control diet (50 mL) and PMI Nutrition International Certified Rodent Chow #5CR4.

[0268] On day -26, all animals received a 50 mL ethanol diet (1% v / v ethanol). The percentage of alcohol in the diet was increased by 1% v / v each day until it reached 5% (v / v) on day -22 and was maintained at 5% v / v until the end of the study.

[0269] Starting on day 1 of cohort 2, animals housed in groups of 3 received an additional bottle of 50 mL (5% v / v ethanol). Caged groups containing 3 animals / cage received a total volume of 100 mL (split between two bottles). The alcohol diet was stirred continuously until dosing.

[0270] Fresh diet was prepared every other day from day -28 to day 14 and fed in the afternoon. Experimental design [Table 8]

[0271] Administration of Test and Control Articles Dose route and timing: Oral gavage (Groups 2-7) once daily (Days 1-14). The first day of dosing was designated as Day 1. Dose formulations were stirred continuously during dosing. Doses were given using a syringe attached to a gavage cannula.

[0272] Terminal plasma and tissue samples were collected and plasma was analyzed for TG, TC, ALT, AST, ALP, FGF15 (LCMS), TBIL and endotoxin.

[0273] Tissue collection and preservation Representative samples of tissues were collected and stored as described in the table below. Additional tissue samples were collected as necessary to clarify abnormal findings. [Table 4A] [Table 4B]

[0274] Liver lipid analysis Frozen liver samples from the main study were analyzed in duplicate for estimation of hepatic lipids, including triglycerides and cholesterol. Liver samples were kept on dry ice until transferred to sample management and stored in a freezer set to maintain -80°C until analysis.

[0275] histology Livers and small intestines collected from all animals in groups 1–7 (main study) were fixed in 10% neutral buffered formalin for 24–48 h, transferred to 70% EtOH, stored under ambient conditions, and transferred to the histopathology laboratory at the study facility.

[0276] Liver tissue Formalin-fixed liver tissue was trimmed to fit slides and stained with H&E and picrosirius red stains. Slides were scored by a Charles River board-certified veterinary pathologist.

[0277] small intestine tissue Formalin-fixed small intestinal tissue was trimmed to fit slides and stained with H&E and IHC antibodies (PV-1, ZO-1 and occludin). Slides were scored by a board-certified veterinary pathologist.

[0278] result As shown in the table below, Compound 1 improved survival better than OCA. Compound 2 (Comp2 in Figures 1 and 2) increased serum ALP but decreased bilirubin. The reduction in serum endotoxin is significant. For steatosis (graded 1-5 by a pathologist), the Compound 1 10mpk group was close to statistical significance. For fibrosis, as analyzed by Picrosirius Red, the animal model had no fibrosis at baseline or in the vehicle group. Minimal increases in fibrosis were seen at OCA 30mpk, Compound 1 30mpk, and Compound 2 30mpk. For the exploratory endpoint for the ileum, all H&E section IHC staining to tight junctions was normal and similar between groups. See Figures 1 and 2 for clinical chemistry results and liver and ileum histology from this study. Without wishing to be bound by theory, these results are believed to suggest improved intestinal function for all compounds, as well as a significant improvement in survival for the 10 mg / kg and 30 mg / kg Compound 1 (Comp1 in Figures 1 and 2) groups, which was superior to results with the other two compounds. [Table 5]

[0279] As shown in FIG. 2, serum bile acids were significantly increased in vehicle-treated ALD mice and were significantly reduced by both doses of Compound 1 (Comp1) and the high dose of Compound 2 (Comp2).

[0280] Example 2 A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Dose-Escalation, Proof-of-Concept Study to Evaluate the Safety, Tolerability, Efficacy, and Pharmacokinetics of Compound 1 in Subjects with Severe Alcohol-Associated Hepatitis Compound 1 is a modified bile acid with high potency and selectivity for the farnesoid X receptor (FXR). Due to its FXR-mediated effects, Compound 1 is a novel therapy for alcohol-related hepatitis. We describe below a Phase 2 proof-of-concept study evaluating the safety, tolerability, efficacy and pharmacokinetics of Compound 1 in patients with severe alcohol-related hepatitis (sAH).

[0281] This is a Phase 2a, randomized, double-blind, placebo-controlled, multicenter (approximately 25 sites worldwide), dose-escalation, proof-of-concept study evaluating the safety, tolerability, efficacy and PK of Compound 1 in initially hospitalized subjects with sAH.

[0282] Compound 1 is administered daily in capsule form in escalating doses starting at 5 mg.

[0283] In the absence of clinically significant safety or tolerability concerns, following review and approval by the sponsor's Global Safety Committee (GSC), a decision will be made to escalate the next dose cohort, following the same stepwise process (e.g., 10, 25, 50 and 100 mg (five dose cohorts)). Dose levels for additional cohorts of the remaining doses will be defined based on the safety and tolerability data of Compound 1 from the preceding cohorts. Dose escalation will not exceed a 3-fold increase from cohort to cohort and a maximum dose level of 120 mg.

[0284] Approximately 50 subjects with sAH (defined by a Model for End-Stage Liver Disease-Sodium [MELD-Na] score of 18 to 25 [inclusive]) aged 18 to 65 years, including approximately 50 subjects in the Compound 1 treatment group, will be enrolled in the study. Five dose cohorts are planned with doses of Compound 1 (or Comp1) ranging from 5 mg to 120 mg (Figure 3). Each dose cohort will consist of two groups containing a total of 10 subjects, with 8 subjects randomized to the study treatment (treatment group) and 2 subjects to placebo (control group). Assuming that the responder proportion based on the Lille model is 90% in the Compound 1 response cohort and 25% in the control cohort, a sample size of 8 subjects per arm will provide more than 80% power to detect treatment differences between the response and control cohorts at a two-sided alpha of 0.05.

[0285] The primary objective of the study is to evaluate the effect of Compound 1 treatment on sAH disease progression as assessed by Lille score at day 7. Secondary objectives include evaluation of the effect of Compound 1 treatment on MELD-Na score at day 28, mortality (short-term and mid-term mortality) and any infectious complications at 56 and 84 days or liver transplantation, as well as evaluation of the PK of Compound 1 and its metabolites glyco-Compound 1 and tauro-Compound 1 and evaluation of the safety and tolerability of Compound 1 in the proposed patient population. Safety and tolerability will be assessed by recording adverse events, laboratory evaluations, ECG, vital signs and physical examinations. Exploratory objectives / measures included: (1) occurrence of readmission (admission defined by stay of 24 hours or more) for alcohol-related hepatitis during the study period; (2) reason for admission, length of stay, ICU days, major medical procedures, and emergency room visits; (3) change from baseline in serum liver biochemistry (ALP, AST, ALT, GGT, and total and direct bilirubin); (4) measures of health-related quality of life (EQ-5D-5L), (5) change from baseline in IL-6, hs-CRP, CK-18, and TNF-α at day 28; (6) change from baseline in lipoproteins (LDL, HDL, VLDL), total cholesterol, and triglycerides at day 28; and (8) change from baseline in lipid metabolism (LBP), 16S rDNA, and alpha-1-antitrypsin and fecal samples for microbiome / metabolome analysis.

[0286] The control group (placebo-treated subjects) in the study will provide useful information regarding efficacy and safety outcomes in this patient population with severe alcohol-related hepatitis treated with standard of care. Placebo-treated subjects within a cohort will be blinded to study drug administration, while data across dose cohorts will be used for the overall analysis.

[0287] The dose levels for this Phase 2a clinical study were based on the overall safety and tolerability profile of Compound 1 established in the nonclinical program, and dose selection in this study was based on data from a Compound 1 Phase 1 dose escalation study. There were no adverse safety signals in nonclinical safety pharmacology studies with Compound 1. Compound 1 did not alter neurological function in male rats when tested at up to 180 mg / kg in the Irwin study. Respiratory function in dogs was not affected by single doses of Compound 1 up to 300 mg / kg. Results from an in vitro human ether-a-go-go related gene (hERG) study and an in vivo study in dogs dosed up to 300 mg / kg indicated that acute cardiovascular effects in humans are not expected. Testing of Compound 1 in an in vivo mouse bone marrow micronucleus assay and liver comet assay showed no evidence of DNA damage at the maximum dose of 2000 mg / kg / day over a 3-day period. Based on these results, Compound 1 is not considered genotoxic. In a Phase 1 study, no clinically significant AEs were observed at doses less than 50 mg in healthy subjects receiving single or repeated doses of Compound 1. The 5 mg dose taken once daily for 14 days was well tolerated.

[0288] The study is designed to evaluate increasing doses of Compound 1 in an escalating fashion (Figure 3). The decision to proceed to the next higher dose cohort will be made after clinical review of safety and tolerability. The study design includes five Compound 1 dose cohorts. Each dose cohort will consist of two groups containing a total of 10 subjects, with eight subjects randomized to the study treatment (treatment group) and two subjects to placebo (control group). Safety and tolerability will be assessed by examining the incidence of treatment-emergent unexpected serious adverse events (SAEs), investigational product discontinuations, and potential drug-induced liver injury (DILI) at each dose. Overall treatment-emergent adverse events (TEAEs), clinical laboratory tests, ECGs, and vital signs will be additionally considered. An increase in Lille score above 0.85 represents potential drug ineffectiveness (rather than liver injury) and will be taken into account as part of each dose escalation evaluation. Given the acute and progressive nature of sAH, it is important to monitor for potential drug-induced liver injury and / or hepatic decompensation. MELD-Na scores are reviewed at each visit where testing is performed.

[0289] Primary Efficacy Analysis: The primary efficacy analysis will be performed using the ITT population. The primary efficacy endpoint is the Lille score on day 7. The analysis of the Lille score will include all subjects with a Lille score on day 7. The Lille score will be analyzed as a categorical variable. In the primary efficacy analysis, subjects with a Lille score less than 0.45 will be counted as responders and subjects with a Lille score equal to or greater than 0.45 will be counted as non-responders. The percentages of responders and non-responders on day 7 will be summarized by treatment group and compared using Fisher's exact test. An additional descriptive analysis of the Lille score as a continuous variable will be performed. Efficacy assessment will start from the maximum tolerated dose and go down to lower dose levels using a sequential approach. If the higher dose level is statistically significant in the primary efficacy endpoint, the next lower dose level will be evaluated. Otherwise, efficacy assessment will be discontinued at the current dose level. The primary comparison of efficacy assessment will be at the maximum tolerated dose.

[0290] Secondary and exploratory efficacy analyses: Secondary and exploratory efficacy analyses will be performed using the ITT population. All continuous and categorical efficacy endpoints will be summarized using descriptive statistics at baseline and at each scheduled visit after baseline. For continuous endpoints, changes from baseline will also be summarized. Analysis of continuous endpoints will be performed using a repeated measures mixed effects model to evaluate the effect of treatment groups over time based on the ITT population. The dependent variable is the change from baseline. The model will include treatment group, visit, treatment by visit interactions as factors, and baseline values ​​as covariates. Analysis of categorical endpoints will be performed using Fisher's exact test. Any subjects with unknown mortality status at the specified time point will be excluded from the analysis of mortality. In addition, Lille score on day 7 will also be summarized as a continuous variable by treatment group and compared to Lille score as a dependent variable including treatment group as a fixed effect using an ANOVA model.

[0291] the purpose Main purpose: To evaluate the efficacy of Compound 1 as assessed by disease progression in severe alcohol-related hepatitis (sAH)

[0292]

[0293] Secondary Objectives: To evaluate the effect of Compound 1 on efficacy as assessed by the Model for End-Stage Liver Disease-Sodium (MELD-Na) score in sAH To evaluate the effect of Compound 1 on clinical outcomes in sAH as measured by short- and mid-term mortality and / or liver transplantation To evaluate the effect of Compound 1 on infectious complications in sAH To evaluate the pharmacokinetics (PK) of Compound 1 and its metabolites in subjects with sAH To evaluate the safety and tolerability of Compound 1 in subjects with sAH

[0294] Exploratory Objective - To evaluate the effect of Compound 1 on: Readmission due to alcohol-related hepatitis during the study period Measures of health care utilization Health-related quality of life The following scales: - Liver biochemistry and liver synthesis, renal function, hematology - inflammation - Lipid metabolism - Farnesoid X Receptor (FXR) Activation - Microbiome / Metabolome - Bacterial Translocation

[0295] Diagnosis and main inclusion criteria Target inclusion criteria 1. Male or female, aged 18 to 65 (inclusive) 2. Clinical diagnosis of sAH based on all of the following: A history of excessive alcohol use (>60 g / day for men or >40 g / day for women) for ≥6 months with abstinence <60 days prior to the onset of jaundice b. Serum total bilirubin > 3.0 mg / dL c. AST ≥ 50U / L (or IU / L) d. AST / ALT ratio ≧1.5 e. MDF≧32 and ≦60 f. MELD-Na score 18 or 20 or 21 to 25 (inclusive) 3. Onset of jaundice within 8 weeks of admission 4. Maximum 7 days from admission and no more (NMT) 5. Female subjects must be postmenopausal and surgically sterile, or if premenopausal (and not surgically sterile), must be prepared to use one or more highly effective methods of contraception during the study and for 90 days after the final dose of investigational product, as follows: surgical sterilization (such as tubal occlusion); placement of an intrauterine device (IUD) or intrauterine system (e.g., intrauterine hormone-releasing system [IUS]); combined (estrogen- and progesterone-containing) hormonal contraception associated with the inhibition of ovulation: oral; intravaginal; transdermal; progesterone-only hormonal contraception associated with the inhibition of ovulation: oral; injectable; implantable; sexual abstinence, where consistent with the subject's preferred and usual lifestyle (where abstinence is defined as refraining from heterosexual intercourse during the entire period of risk associated with study treatment). 6. Sexually active male subjects with a female partner of childbearing potential must agree to use condoms with spermicide and another approved highly effective method of contraception from the time of investigational product administration and for at least 90 days after the dose of investigational product as listed in Inclusion Criterion 5. 7. Male subjects must refrain from sperm donation from screening until at least 90 days after the last dose of investigational product. 8. Must provide written informed consent and agree to comply with the study protocol. In subjects with hepatic encephalopathy that may impair decision-making, consent will be obtained through hospital procedures (e.g., by a legally authorized representative). Subjects must agree to participate in alcohol use disorder (AUD) programming for the duration of the study, including post-hospitalization, as recommended by addiction medicine specialists at their local agency.

[0296] Exclusion criteria 1. Subjects taking systemic corticosteroids or obeticholic acid (OCA)-containing products within 30 days prior to screening, up to and including randomization. 2. Pregnant, planning pregnancy, of possible pregnancy (i.e., not willing to use effective birth control during the study), or currently breastfeeding or planning to breastfeed 3. Abstinence from alcohol consumption for at least 2 months prior to Day 1 4. AST or ALT > 400U / L 5. MDF<32 or >60 at screening 6. MELD-Na score <18 or >25 at screening (confirmed by repeat testing within 48 hours) 7. Other causes of liver disease, including chronic hepatitis B (hepatitis B surface antigen [HBsAg] positive), chronic hepatitis C (HCV) RNA positive, acetaminophen hepatotoxicity, bile duct obstruction, and autoimmune liver disease 8. Current or past history of hepatocellular carcinoma (HCC) 9. History of liver transplant or currently listed for liver transplant 10. Untreated sepsis (e.g., appropriate medical treatment for infection and / or septic shock has not been initiated) 11. Known positive for human immunodeficiency virus infection 12. Uncontrolled gastrointestinal (GI) bleeding or controlled GI bleeding that was associated with shock or required transfusion of more than 3 units of blood within 7 days of screening 13. Renal impairment defined as serum creatinine >133 μmol / L (>1.5 mg / dL) confirmed by repeat testing within 48 hours or requirement for renal replacement therapy 14. Portal vein thrombosis 15. Acute pancreatitis or acute gallbladder disease (e.g., cholecystitis) 16. Severe associated diseases (e.g., heart failure, acute myocardial infarction, severe arrhythmia, severe pulmonary disease, neurological disease) 17. Malignancy within 2 years prior to screening, with the exception of certain cancers cured by surgical resection (e.g., basal cell skin cancer). Subjects undergoing evaluation for possible malignancy are not eligible. 18. Positive urine drug screen (amphetamines, barbiturates, benzodiazepines, cocaine, and opiates) except in the setting of tetrahydrocannabinol (THC) or documented prescription medications (e.g., opiates, benzodiazepines, amphetamines, barbiturates, including medications prescribed as part of inpatient care. Subjects being treated for alcohol withdrawal may be exempt; verify with medical monitor). 19. Participating in a clinical research study and receiving any active investigational product being evaluated for the treatment of sAH in the 3 months prior to Day 1 20. Participation in another investigational drug or device study within 30 days prior to screening 21. Any other conditions or clinical laboratory results that, in the opinion of the investigator, might confound the results or would prevent compliance or completion of the study. 22. Have a positive SARS-CoV-2 test within 4 weeks of screening or received a SARS-CoV-2 vaccination within 2 weeks of screening

[0297] Investigational product, dosage and mode of administration Investigational product, Compound 1, capsules and matching placebo capsules for oral administration once daily. Investigational product, Compound 1, will be supplied in multiple capsule strengths ranging from 5 mg to 120 mg. Multiple Compound 1 capsules may be taken to achieve appropriate Compound 1 dose levels (e.g., 10 mg, 25 mg, 50 mg, and 100 mg). Matching placebo capsules will also be provided for blinding purposes. The study will be conducted in a double-blind (subjects and site staff) fashion with randomization in a 4:1 fashion for each dose cohort.

[0298] Reference therapy, dosage and mode of administration All eligible subjects will receive appropriate supportive measures, including nutritional support, as per local standard of care. Corticosteroid use will not be permitted for 30 days prior to screening and up to and including randomization, as it is intended that subjects complete the study without corticosteroid use if possible (ophthalmic steroids and low-dose topical or low-dose intranasal steroids are acceptable).

[0299] If systemic corticosteroids are initiated during the screening period, the subject will not be considered eligible for randomization. If systemic corticosteroids are initiated within the first 7 days after randomization, the subject will be discontinued and replaced in this study cohort. Use of systemic corticosteroids after randomization may be considered on an individual case basis if clinically warranted (e.g., Lille score >0.56 with elevated total bilirubin on day 7, or MELD-Na score increase >3 points not due to acute kidney injury).

[0300] Duration of the procedure Subjects will receive the investigational product over a 28-day period.

[0301] Evaluation criteria Endpoints supporting the primary, secondary and exploratory objectives of the study are as follows: [Table 6-1] [Table 6-2] C4=7α-hydroxy-4-cholesten-3-one; CK-18=cytokeratin 18; hs-CRP=high-sensitivity c-reactive protein; rDNA=ribosomal deoxyribonucleic acid; ECG=electrocardiogram; FGF-19=fibroblast growth factor 19; GGT=gamma glutamyl transferase; HDL=high-density lipoprotein; ICU=intensive care unit; IL-6=interleukin 6; IL-18=interleukin 18; KIM-1=kidney injury molecule-1; L-FABP=liver-type fatty acid binding protein; INR=international normalized ratio; LBP=lipopolysaccharide binding protein; LDL = low density lipoprotein; MELD-Na = model of end-stage liver disease-sodium; NGAL = neutrophil gelatinase-associated lipocalin; PK = pharmacokinetics; SAE = severe adverse events; SBP = spontaneous bacterial peritonitis; TEAE = treatment-emergent adverse events; TNF-α = tumor necrosis factor-alpha; VLDL = very low density lipoprotein

[0302] Example 3 A Phase 2b / 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Efficacy, and Pharmacokinetics of Compound 1 in Subjects with Severe Alcohol-Related Hepatitis We describe below a Phase 2b / 3 study evaluating the safety, tolerability, efficacy and pharmacokinetics of Compound 1 in patients with severe alcohol-related hepatitis (sAH).

[0303] This is a Phase 2b / 3, randomized, double-blind, placebo-controlled, multicenter (approximately 25 sites globally), dose-escalation, proof-of-concept study evaluating the safety, tolerability, efficacy and PK of Compound 1 in subjects with initially hospitalized sAH.

[0304] Approximately 50 subjects with sAH (defined by a Madrid discriminant function [MDF] ≥ 32 and a model for end-stage liver disease [MELD] score of 21-30 [inclusive]) aged 18-65 years, including approximately 50 subjects in the Compound 1 treatment group, will be enrolled in the study. Dose cohorts (2, 3, 4 or 5 cohorts) are planned with doses of Compound 1 (or Comp1) ranging from 5 mg to 120 mg. Each dose cohort will consist of two groups containing a total of 10 subjects, with 8 subjects randomized to the study treatment (treatment group) and 2 subjects to placebo (control group). Assuming that the responder proportion based on the Lille model is 90% in the Compound 1 responder cohort and 25% in the control cohort, a sample size of 8 subjects per arm will provide > 80% power to detect treatment differences between the responder and control cohorts at a two-sided alpha of 0.05.

[0305] This study will generally be conducted according to the objectives, procedures, inclusion and exclusion criteria, efficacy analyses, evaluation criteria, dosages and regimens described above in Example 2, modified as follows: The primary objective of the study is to evaluate the effect of Compound 1 treatment on 90-day transplant-free survival in patients with sAH. Secondary objectives include evaluation of the effect of Compound 1 treatment on mortality at 28 days (short-term mortality), MELD and Lille scores at 28 and 90 days, and evaluation of the safety and tolerability of Compound 1 in the proposed patient population at 28 and 90 days and at 6 months. Safety and tolerability will be assessed by recording adverse events, laboratory evaluations, ECGs, vital signs and physical examinations. Exploratory objectives / measures include: (1) mortality at 6 months; 2) incidence of readmission (hospitalization defined by stay ≥ 24 hours) for alcohol-related hepatitis during the study period; health care utilization, including reason for admission, length of stay, ICU days, major medical procedures, and emergency room visits; (3) change from baseline in serum liver biochemistry (ALP, AST, ALT, GGT, and total and direct bilirubin); change from baseline in IL-6, hs-CRP, CK-18, and TNF-α at day 28; change from baseline in lipoproteins (LDL, HDL, VLDL), total cholesterol, and triglycerides at day 28; and assessment of pharmacokinetic and pharmacodynamic biomarkers, including change from baseline in lipid metabolism (LBP), 16S rDNA, and alpha-1-antitrypsin and fecal samples for microbiome / metabolome analysis; and (4) measures of health-related quality of life (EQ-5D-5L).

Claims

1. A composition for use in a method for treating acute liver disease, wherein the method provides to a patient in need of compound 1: 【Chemistry 4】 A composition comprising the step of administering a pharmaceutically acceptable salt or amino acid conjugate thereof.

2. The composition according to claim 1, wherein the liver disease is alcoholic hepatitis (AH).

3. The composition according to claim 1, wherein the liver disease is severe alcoholic hepatitis (sAH).

4. The composition according to claim 1, wherein the liver disease is acute exacerbation of chronic liver failure (ACLF).

5. The composition according to any one of claims 1 to 4, wherein the patient exhibits a Madrid Discriminant Function (MDF) score of 32 or higher prior to treatment with compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate thereof.

6. The composition according to any one of claims 1 to 4, wherein the patient exhibits a model of end-stage liver disease (MELD or MELD-Na) score of 18 or greater, greater than 21, or 21 to 30 prior to treatment with compound 1 or a pharmaceutically acceptable salt thereof or amino acid conjugate.

7. The composition according to claim 6, wherein the patient exhibits an MDF score of 32 to 60.

8. The composition according to claim 5, wherein the patient exhibits a MELD score of 18 to 30 or 21 to 30, or a MELD-Na score of 18 to 25 or 21 to 30.

9. The composition according to claim 5, wherein the method reduces the patient's MELD or MELD-Na score by at least 3 and / or the patient's MDF score by at least 3 by the 28th or 90th day of treatment.

10. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate is administered daily in a dose of about 1.0 mg to about 300 mg.

11. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate is administered daily in a dose of about 2.5 mg to about 300 mg.

12. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate is administered daily in a dose of about 5 mg to about 100 mg, or about 5 mg to about 120 mg.

13. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate is administered daily in a dose of about 5 mg to about 50 mg.

14. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate is administered daily in a dose of about 5 mg to about 25 mg.

15. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate is administered daily in a dose of about 5 mg to about 10 mg.

16. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate is administered daily in a dose of about 5 mg to about 150 mg.

17. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate is administered daily in a dose of about 10 mg to about 100 mg, or about 5 mg to about 120 mg.

18. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate is administered daily in a dose of about 50 mg to about 200 mg.

19. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof or amino acid conjugate is administered daily in doses of about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 35 mg, about 45 mg, about 50 mg, about 60 mg, about 75 mg, about 85 mg, about 100 mg, about 115 mg, about 120 mg, about 125 mg, about 140 mg, about 150 mg, about 165 mg, about 175 mg, about 190 mg, or about 200 mg.

20. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate is administered in a single or multiple dose sufficient to achieve a total daily dose of about 1.0 mg to about 300 mg.

21. The composition according to claim 1, wherein the method further comprises the step of monitoring the blood level of a biomarker in the patient after administration of compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate, wherein the biomarker is selected from C4, FGF-19, and endogenous bile acids.

22. The composition according to claim 1, wherein the patient has chronic liver disease in addition to sAH or ACLF.

23. The composition according to claim 22, wherein the patient has alcoholic liver disease (ALD).

24. The composition according to claim 1, wherein the patient exhibits one or more of the following symptoms: (1) continuous alcohol consumption for six months or longer, of more than 40 g per day if the patient is female and more than 60 g per day if the patient is male, with a withdrawal of less than 60 days prior to the onset of jaundice; (2) the presence of elevated liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT] concentrations ≥ 50 IU / L (or U / L) but ≤ 400 IU / L (or U / L) and an AST / ALT ratio ≥ 1:5); and (3) worsening of jaundice accompanied by a bilirubin concentration greater than 3 mg / dL.

25. The composition according to claim 1, wherein the patient presents with alcohol-related cirrhosis, hepatic fibrosis, steatosis, fatty liver disease, alcoholic hepatitis, or intestinal dysbiosis.

26. The composition according to claim 1, wherein the patient has been previously diagnosed with sAH and has suffered at least one relapse of sAH.

27. The composition according to claim 1, wherein the method improves the 30-day survival of the patient compared to other similar patients who were not administered compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate.

28. The composition according to claim 1, wherein the method improves the 60-day survival of the patient compared to other similar patients who were not administered compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate.

29. The composition according to claim 1, wherein the method improves the 90-day survival of the patient compared to other patients who were not administered compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate, and who were otherwise similar.

30. The composition according to claim 1, wherein the method improves survival by about 10% to about 40%.

31. The composition according to claim 27, wherein the method improves survival by about 10% to about 30%.

32. The composition according to claim 27, wherein the method improves survival by about 10% to about 20%.

33. The composition according to claim 1, wherein the method provides a reduction in healthcare use.

34. The composition according to claim 33, wherein the method provides a reduction in liver-related events in a patient with sAH.

35. The composition according to claim 33, wherein the method provides at least a 10% reduction in the patient's healthcare use over a 60-day period.

36. The composition according to claim 33, wherein the method reduces readmission within 30, 60, or 90 days after discharge, the number of hospitalizations, the length of stay, visits to the emergency room, days in the intensive care unit (ICU), infectious complications selected from sepsis, pneumonia, urinary tract infection (UTI), cellulitis, spontaneous bacterial peritonitis (SBP), and one or more major medical procedures.

37. The composition according to claim 1, wherein the method further comprises the step of co-administering to the patient an effective amount of an anti-inflammatory agent, an antibiotic, an antioxidant, a probiotic, a fecal implant, a Zn supplement, or a combination thereof.

38. The composition according to claim 1, further comprising the step of co-administering to the patient an effective amount of pentoxifylline, Augmentin, bovine colostrum, corticosteroids (e.g., prednisolone or methylprednisolone), ELAD agents, canakinumab, TNF inhibitors, IL-22, N-acetylcysteine, metadoxine, IgG anti-LPS, probiotics, fecal implants, Zn supplements, or any combination thereof.

39. The aforementioned patient has AST or ALT > 400 U / L, MDF > 60 before treatment, MELD score > 25 or > 30 or MELD-Na > 25 or > 30 before treatment, chronic hepatitis B (hepatitis B surface antigen [HBsAg] positive), chronic hepatitis C (HCV The composition according to claim 1, which does not present with one or more severe related conditions selected from RNA-positive, acetaminophen hepatotoxicity, biliary obstruction, and other causes of liver disease selected from autoimmune liver disease; associated with, a history of hepatocellular carcinoma (HCC), a history of liver transplantation, untreated sepsis, known to be positive for human immunodeficiency virus infection, uncontrolled gastrointestinal (GI) bleeding or controlled GI bleeding associated with shock or requiring more than three units of blood transfusion within seven days of initiation of treatment, serum creatinine >133 μmol / L (>1.5 mg / dL) or acute kidney injury as defined as a requirement for renal replacement therapy, portal vein thrombosis, acute pancreatitis, or one or more severe related conditions selected from heart failure, acute myocardial infarction, severe arrhythmia, severe pulmonary disease, and neurological disorders.

40. The composition according to claim 1, wherein the method provides at least a 15% reduction in mortality compared to standard care (SOC) over 90 days.

41. The composition according to claim 1, wherein the method provides a reduction of at least 15% in hospitalizations and / or a reduction of at least 15% in progression to transplantation.

42. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate is administered to the patient over a period of about 30 to about 90 days.

43. The composition according to claim 1, characterized in that compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate is administered orally.

44. Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof, Approximately 1.0 mg to approximately 300 mg, Approximately 2.5 mg to approximately 300 mg, Approximately 5 mg to approximately 100 mg, Approximately 5 mg to approximately 50 mg, Approximately 5 mg to approximately 25 mg, Approximately 5 mg to approximately 10 mg, or Approximately 5 mg to approximately 150 mg, or Approximately 5 mg to approximately 120 mg Approximately 10 mg to approximately 100 mg, or Approximately 50 mg to approximately 200 mg, Approximately 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 35 mg, 45 mg, 50 mg, 60 mg, 75 mg, 85 mg, 100 mg, 115 mg, 120 mg, 125 mg, 140 mg, 150 mg, 165 mg, 175 mg, 190 mg, or 200 mg The composition according to claim 6, characterized in that it is administered in a single or multiple dose sufficient to achieve a total daily dose.

45. The composition according to claim 1, wherein the patient exhibits an AST of 50 U / L (or IU / L) or more prior to treatment with compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate thereof.

46. The composition according to claim 1, wherein the patient exhibits an AST / ALT ratio of 1.5 or greater prior to treatment with compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate thereof.

47. Prior to treatment with compound 1 or a pharmaceutically acceptable salt thereof or amino acid conjugate, AST of 50 U / L or more 1. AST / ALT ratio of 1.5 or higher, A Madrid Discriminant Function (MDF) score of 32 or higher, and Models for end-stage liver disease (MELD or MELD-Na) scores of 18 or higher, or 20 or higher, or 21 or higher, for example, 21-30. The composition according to claim 1, exhibiting one or more of the following:

48. A method for obtaining the MELD-Na score of a patient as an indicator for determining the candidate requirements for therapeutic treatment for sAH.

49. The method according to claim 48, further comprising the step of determining the MDF score of the patient.

50. The method according to claim 49, wherein the patient's MELD-Na score is 18 or higher.

51. The method according to claim 48, wherein the patient's MELD-Na score is 18 or higher.

52. The method according to claim 49, wherein the patient's MDF score is 32 or greater, for example, between 32 and 60, including both extreme values.

53. A method for obtaining the MELD-Na score or MELD score as an indicator for treating sAH, A method for indicating that a patient having a MELD-Na score of 18 or higher, or a MELD score of 21 to 30, will be subjected to therapeutic treatment for sAH.

54. The method according to claim 53, wherein the patient also has an MDF score ranging from 32 to 60, including values ​​at both ends.

55. The method according to claim 53 or 54, wherein the therapeutic procedure includes administering a pharmacological agent to the patient and / or performing a liver transplant.

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