Application of farnesoid X receptor agonist

Abstract

The present invention relates to FXR agonist compounds and methods for their use in treating, ameliorating, or promoting the recovery of diseases and disorders, such as acute liver diseases, such as severe alcohol-associated hepatitis.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 333,287, filed on April 21, 2022, and U.S. Provisional Application No. 63 / 381,752, filed on October 31, 2022, the contents of each of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to compounds and methods of use thereof for treating, alleviating or promoting recovery from diseases and disorders such as acute liver disease. Background of the Invention

[0005] Alcoholic hepatitis (also referred to as alcohol-related hepatitis or acute alcohol-related hepatitis) is an acute form of alcohol-induced liver damage that occurs with long-term heavy drinking. The severity of alcoholic hepatitis can range from asymptomatic biochemical disturbances to liver failure and death. Severe alcoholic hepatitis is a severe form of acute alcoholic liver disease caused by excessive drinking, characterized by the rapid onset of jaundice, discomfort, tender hepatomegaly, and systemic inflammatory responses (Shah NJ, Royer A, John S. Alcoholic Hepatitis. Stat Pearls. January 2021; 1-8; incorporated herein by reference). Severe alcoholic hepatitis (sAH) is a life-threatening medical condition with a high 30-day average mortality rate of 17% to 50% and a 1-year average 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; incorporated herein by reference). Treatment options for patients with sAH are limited to systemic corticosteroids (unless contraindicated such as sepsis, infection, gastrointestinal bleeding, or acute kidney injury) as well as supportive care, nutrition, and alcohol abstinence. Corticosteroids have no long-term benefit for patients with sAH, and their use is limited due to the risk of infection and GI bleeding. Furthermore, liver transplantation for alcohol-related liver disease is currently at an all-time high (Noureddin, N., et al. TransplantDirect 2020 Oct 8;6(11):e612), and the number of patients awaiting and undergoing liver transplantation for acute alcohol-related hepatitis in the United States has increased significantly 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 are not suitable for liver transplantation are often referred for palliative care (Singal, AK, et al. Am J Gastroenterol. 2018;113(2):175–94; incorporated herein by reference).

[0006] Another example of an acute liver disease with inadequate treatment options is acute decompensated liver disease, also known as acute-on-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 ACLF cases have no identifiable triggering factors; in the remaining patients, sepsis, active alcoholism, and relapses of chronic viral hepatitis are the most commonly reported precipitating factors. Excessive systemic inflammatory responses appear to play a crucial role in the development of ACLF.

[0007] Therefore, there remains a need for additional therapies for treating acute liver diseases such as sAH and ACLF. The present invention addresses this need and provides other related advantages. SUMMARY OF THE INVENTION

[0009] 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:

[0010]

[0011] or a pharmaceutically acceptable salt or amino acid conjugate thereof.

[0012] In one aspect, the present invention provides a method for treating an acute liver disease, comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the acute liver disease is alcoholic hepatitis (AH).

[0013] In another aspect, the present invention provides a method for treating acute liver disease, comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the acute liver disease is severe alcoholic hepatitis (sAH).

[0014] In yet another aspect, the present invention provides a method for treating acute liver disease, comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the acute liver disease is acute-on-chronic liver failure (ACLF).

[0015] In one aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein prior to treatment with Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof, the patient exhibits a Maddrey discriminant function (MDF) score of ≥32.

[0016] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein prior to treatment with Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof, the patient exhibits a Model for End-Stage Liver Disease (MELD or MELD-Na) score of ≥18, or ≥20, or ≥21.

[0017] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the patient exhibits an MDF score of 32 to 60.

[0018] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need 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.

[0019] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein prior to treatment with Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof, the patient exhibits a MELD score of 21 to 30.

[0020] In one aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein prior to treatment with Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof, the patient exhibits a Maddrey discriminant function (MDF) score of ≥32 and a MELD score of 21 to 30 (including endpoints).

[0021] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein prior to treatment with Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof, the patient exhibits an AST of ≥ (greater than or equal to) 50 U / L (or IU / L).

[0022] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein prior to treatment with Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof, the patient exhibits an AST / ALT ratio of ≥1.5.

[0023] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein prior to treatment with Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof, the patient exhibits one or more of the following: AST ≥ 50 U / L; AST / ALT ratio ≥ 1.5; Maddrey discriminant function (MDF) score ≥ 32; and / or Model for End-Stage Liver Disease (MELD or MELD-Na) score ≥ 18 or ≥ 20 or ≥ 21, e.g., 21-30.

[0024] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need 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 on day 28 of treatment.

[0025] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof is administered daily at a dose of about 1.0 mg to about 300 mg.

[0026] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof is administered daily at a dose of about 2.5 mg to about 300 mg.

[0027] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein Compound 1 is administered daily at a dose of about 5 mg to about 120 mg.

[0028] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein Compound 1 is administered daily at a dose of about 5 mg to about 100 mg.

[0029] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein Compound 1 is administered daily at a dose of about 5 mg to about 50 mg.

[0030] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein Compound 1 is administered daily at a dose of about 5 mg to about 25 mg.

[0031] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein Compound 1 is administered daily at a dose of about 5 mg to about 10 mg.

[0032] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof is administered daily at a dose of about 5 mg to about 150 mg.

[0033] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof is administered daily at a dose of about 5 mg to about 120 mg.

[0034] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof is administered daily at a dose of about 10 mg to about 100 mg.

[0035] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof is administered daily at a dose of about 50 mg to about 250 mg.

[0036] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein Compound 1 is administered daily 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.

[0037] In another aspect, the present invention provides a method for 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 Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof is administered in an amount sufficient to achieve about 1.0 mg to about 300 mg; 1.0 mg to about 300 mg; or about 2.5 mg to about 300 mg; or about 5 mg to about 100 mg; or about 5 mg to about 50 mg; or about 5 mg to about 25 mg; or about 5 mg to about 10 mg; or about 5 mg or 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 of a total daily dose.

[0038] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, and further comprising monitoring the blood levels of biomarkers in the patient after administration of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof, wherein the biomarker is selected from C4, FGF-19 and endogenous bile acid.

[0039] In another aspect, the present invention provides a method for treating an acute liver disease selected from sAH and ACLF, comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the patient suffers from a chronic liver disease in addition to sAH or ACLF.

[0040] In another aspect, the present invention provides a method for treating an acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the patient suffers from alcohol-related (or alcohol-associated) liver disease (ALD), formerly known as alcoholic liver disease.

[0041] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the patient exhibits one or more of the following: (1) if the patient is a female, continuous drinking of more than 40 g of alcohol per day, and if the patient is a male, continuous drinking of more than 60 g of alcohol per day, for 6 months or longer, and abstinence for less than 60 days before the onset of jaundice; (2) the 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 and a bilirubin concentration greater than 3 mg / dL.

[0042] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the patient exhibits alcohol-related cirrhosis, liver fibrosis, steatosis, steatohepatitis, alcoholic hepatitis or intestinal dysbiosis.

[0043] In another aspect, the present invention provides a method of treating an acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the patient has previously been diagnosed with sAH and has suffered at least one relapse of sAH.

[0044] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the method improves the patient's 30-day survival rate compared to other similar patients who are not administered Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof.

[0045] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the method improves the patient's 60-day survival rate compared to other similar patients who are not administered Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof.

[0046] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the method improves the patient's 90-day survival rate compared to other similar patients who are not administered Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof.

[0047] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the method improves the patient's 90-day transplant-free survival rate compared to other similar patients who are not administered Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof.

[0048] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the method improves the patient's 28-day survival rate compared to other similar patients who are not administered Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof.

[0049] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the method improves the patient's 6-month survival rate compared to other similar patients who are not administered Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof.

[0050] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the method improves the patient's 6-month transplant-free survival rate compared to other similar patients who are not administered Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof.

[0051] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the method improves the patient's MELD and / or Lille score on day 28 and / or day 90 after administration of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof, compared to other similar patients who have not been administered Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof.

[0052] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the method improves the incidence of hospital readmission for alcohol-related hepatitis in the patient compared to other similar patients who are not administered Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof.

[0053] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the method improves one or more of the following: 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 for the patient, compared to other similar patients not administered Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof.

[0054] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the method improves one or more pharmacokinetic and pharmacodynamic biomarkers compared to other similar patients not administered Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof, including: changes from baseline in one or more serum liver biochemistries selected from ALP, AST, ALT, GGT, and total bilirubin and direct bilirubin; changes from baseline in IL-6, hs-CRP, CK-18, and TNF-α at day 28; changes from baseline in lipoproteins (LDL, HDL, VLDL), total cholesterol, and / or triglycerides at day 28; and changes from baseline in lipid metabolism (LBP), 16S rDNA, and / or stool samples for alpha-1-antitrypsin and microbiome / metabolome analysis.

[0055] 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 pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the method improves survival by about 10% to about 40% (relative to standard of care (SOC)).

[0056] 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 pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the method improves survival by about 10% to about 30%.

[0057] 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 pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the method improves survival by about 10% to about 20%.

[0058] 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 pharmaceutically acceptable salt or amino acid conjugate thereof, to a patient in need thereof, wherein the method provides a reduction in healthcare utilization.

[0059] In another aspect, the present invention provides a method of treating an acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the method provides a reduction in liver-related events in patients with sAH.

[0060] In another aspect, the present invention provides a method of treating an acute liver disease (e.g., AH, sAH, or ACLF) comprising administering an effective amount of Compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof, to a patient in need thereof, wherein the method provides at least a 10% reduction in the patient's healthcare utilization within 60 days.

[0061] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the method reduces one or more of the following: readmission within 30 days after discharge, number of hospitalizations, length of hospital stay, emergency room visits, intensive care unit (ICU) days, infectious complications selected from sepsis, pneumonia, urinary tract infection (UTI), cellulitis, spontaneous bacterial peritonitis (SBP), and major medical procedures.

[0062] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, and also comprising co-administering an effective amount of an anti-inflammatory agent, an antibiotic, a probiotic, a fecal transplant, a Zn supplement, or a combination of any of those agents to the patient.

[0063] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, and further comprising 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 transplants, Zn supplements, or a combination of any of those agents.

[0064] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the patient does not exhibit one or more of the following: AST or ALT>400U / L, MDF>60 before treatment, MELD score>25 or>30 or MELD-Na>25 or>30 before treatment, selected from chronic hepatitis B (hepatitis B surface antigen [HBsAg] positive), chronic hepatitis C (HCV RNA positive), acetaminophen hepatotoxicity, biliary obstruction, and other causes of liver disease with autoimmune liver disease; with a previous history of hepatocellular carcinoma (HCC), a history of liver transplantation, untreated sepsis, known positive human immunodeficiency virus infection, uncontrolled gastrointestinal (GI) bleeding associated with shock or requiring transfusion of more than 3 units of blood or controlled GI bleeding within 7 days of starting treatment, defined as serum creatinine >133 μmol / L (>1.5 mg / dL) or acute kidney injury requiring renal replacement therapy, portal vein thrombosis, acute pancreatitis, or a serious associated disease selected from heart failure, acute myocardial infarction, severe arrhythmia, severe lung disease, and neurologic disease.

[0065] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the method provides at least a 15% reduction in mortality at 90 days compared to standard of care (SOC).

[0066] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein the method provides a reduction in hospitalization (length of stay) by at least 15% and / or a reduction in progression to transplantation by at least 15%.

[0067] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof is administered to the patient for about 30 days to about 90 days.

[0068] In another aspect, the present invention provides a method for treating acute liver disease (e.g., AH, sAH or ACLF), comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof to a patient in need thereof, wherein Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof is administered orally.

[0069] In another aspect, the invention provides a method for determining a patient's candidacy for therapeutic treatment of sAH, comprising determining the patient's MELD-Na score, wherein the patient's MELD-Na score is ≥ 18, e.g., 21 to 30. In some embodiments, the method further comprises determining the patient's MDF score, e.g., wherein the patient's MDF score is from 32 to 60, inclusive.

[0070] In another aspect, the invention provides a method for treating sAH, comprising selecting a patient with a MELD-Na score ≥ 18, e.g., 21-30; and administering a therapeutic treatment for sAH, e.g., wherein the patient also has an MDF score of > 32, e.g., from 32 to 60 (including endpoints). In some embodiments, the therapeutic treatment comprises administering a pharmaceutical agent and / or a liver transplant to the patient. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] Figure 1 and Figure 2 : Clinical chemistry results and liver and ileum histology from a mouse alcoholic liver disease (ALD) study (Compound 1 is denoted as Comp 1 and Compound 2 is denoted as Comp 2).

[0073] Figure 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 (Comp 1) in subjects with severe alcohol-related hepatitis (sAH).

[0074] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

[0075] 1. General Description of Exemplary Embodiments

[0076] The present invention provides a method for treating acute liver disease, comprising administering an effective amount of a FXR agonist to a patient in need thereof. In one aspect, the present invention provides a method for treating alcoholic hepatitis (AH), comprising administering an effective amount of a FXR agonist to a patient in need thereof. In one aspect, the present invention provides a method for treating an acute liver disease selected from severe alcoholic hepatitis (sAH) and acute-on-chronic liver failure (ACLF), comprising administering an effective amount of a FXR agonist to a patient in need thereof.

[0077] 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 a 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 for treating sAH.

[0078] The present invention also provides a method for treating ACLF, comprising administering an effective amount of a FXR agonist to a patient in need thereof.

[0079] In some embodiments, the FXR agonist is

[0080]

[0081] (3α,7α,11β-trihydroxy-6α-ethyl-5β-cholane-24-oic acid, also known as TC-100)

[0082] Or a pharmaceutically acceptable salt or amino acid conjugate thereof. In some embodiments, the FXR agonist is a taurine conjugate or a glycine conjugate of compound 1, or a pharmaceutically acceptable salt thereof. Compound 1 can be prepared using methods known in the art, such as described in U.S. Patents Nos. 11,066,437, 11,034,717, and 9,611,289, each of which is incorporated herein by reference in its entirety. These patents also describe various FXR agonists that can be used according to the present invention.

[0083] In one aspect, the present invention provides FXR agonists for use in treating acute liver disease. In one aspect, the present invention provides FXR agonists for use in treating alcoholic hepatitis (AH). In one aspect, the present invention provides FXR agonists for use in treating acute liver disease selected from severe alcoholic hepatitis (sAH) and acute-on-chronic liver failure (ACLF).

[0084] In another aspect, the present invention provides compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof 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-on-chronic liver failure (ACLF).

[0085] In one aspect, the present invention provides Compound 1 or a pharmaceutically 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 pharmaceutically acceptable salt or amino acid conjugate thereof for use in treating an acute liver disease selected from severe alcoholic hepatitis (sAH) and acute-on-chronic liver failure (ACLF).

[0086] In some embodiments, the patient has a chronic liver disease in addition to sAH or ACLF. In some embodiments, the chronic liver disease is a cholestatic liver disease. In some embodiments, the chronic liver disease is a non-cholestatic liver disease.

[0087] In some embodiments, in addition to an acute liver disease, such as AH or sAH or ACLF, the patient also exhibits a chronic liver condition. In some embodiments, in addition to a chronic liver disease or condition, there is an acute liver disease or condition, which may be selected from, but not limited to, cirrhosis (alcohol-related cirrhosis), liver fibrosis, alcohol-related fatty hepatitis (ASH), steatosis, or cholestatic liver disease. In some embodiments, in addition to a chronic liver disease or condition, there is an acute liver disease or condition, which may be selected from, but not limited to, cirrhosis, liver fibrosis, alcohol-related fatty hepatitis, or steatosis. In some embodiments, the patient exhibits cirrhosis. In some embodiments, the patient exhibits liver fibrosis. In some embodiments, the patient exhibits fatty degeneration. In some embodiments, the patient exhibits ASH. In some embodiments, the patient exhibits alcoholic hepatitis.

[0088] 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).

[0089] In some embodiments, the patient does not exhibit cirrhosis.In some embodiments, the patient exhibits a Maddrey Discriminant Function (MDF) score of ≥32 prior to treatment with the FXR agonist.

[0090] In some embodiments, the patient exhibits a Model for End-Stage Liver Disease (MELD or MELD-Na) score of ≥18 prior to treatment with the FXR agonist.

[0091] In some embodiments, prior to treatment with the FXR agonist, the patient exhibits both an MDF score of ≥32 and a MELD or MELD-Na score of ≥18.

[0092] In some embodiments, the patient exhibits an MDF score of 32-60.

[0093] In some embodiments, the patient exhibits a MELD score of 18 to 25 or 30 or a MELD-Na score of 18 to 25 or 30.

[0094] In some embodiments, the patient exhibits a MELD score of 21 to 30, or a MELD-Na score of 21 to 30.

[0095] In some embodiments, the patient exhibits 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.

[0096] In some embodiments, the patient exhibits an MDF score of ≥32, optionally combined with a MELD score of 10 to 20 (or MELD-Na<21); or a MELD score of 10 to 17 (or MELD-Na<18).

[0097] In some embodiments, the patient exhibits an MDF score of ≥32 in combination with a MELD score of 21-30 (or MELD-Na21-30).

[0098] 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.

[0099] In some embodiments, the patient exhibits a MELD or MELD-Na score of 6, 7, 8, 9, or 10. In some embodiments, the patient exhibits a MELD or MELD-Na score of 11, 12, 13, 14, 15, 16, or 17. In some embodiments, the patient exhibits a MELD or MELD-Na score of 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

[0100] In some embodiments, the patient exhibits an AST > 50 U / L prior to treatment.

[0101] In some embodiments, the patient exhibits an AST / ALT ratio ≥ 1.5 prior to treatment.

[0102] In some embodiments, the patient exhibits one or more of the following: AST ≥ 50 U / L; AST / ALT ratio ≥ 1.5; Maddrey discriminant function (MDF) score ≥ 32; and / or Model for End-Stage Liver Disease (MELD or MELD-Na) score ≥ 18, 20, or 21, e.g., 21-30.

[0103] In some embodiments, the method comprises administering to a patient in need thereof an amount of about 1 mg to about 500 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 1 mg to about 300 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 1 mg to about 200 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 1 mg to about 150 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 1 mg to about 100 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 1 mg to about 50 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 1 mg to about 25 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 1 mg to about 10 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 2.5 mg to about 500 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 2.5 mg to about 300 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 2.5 mg to about 200 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 2.5 mg to about 150 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 2.5 mg to about 100 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 2.5 mg to about 50 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 2.5 mg to about 25 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 2.5 mg to about 10 mg of a FXR agonist.

[0104] In some embodiments, the method comprises administering to a patient in need thereof 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 of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof 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 of compound 1. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 5 mg to about 100 mg or 5 mg to about 120 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 5 mg to about 50 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 5 mg to about 25 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 5 mg to about 10 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 5 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 10 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 25 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 50 mg of a FXR agonist. In some embodiments, the method comprises administering to a patient in need thereof an amount of about 100 mg of a FXR agonist.

[0105] In some embodiments, the method provides improved 90-day transplant-free survival in patients compared to otherwise similar patients not administered Compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof.

[0106] In some embodiments, the method provides a 7-day Lille score relative to a standard of care (SOC) reduction. 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 by 0.1, 0.2, 0.3, or 0.4 for 7 days. In some embodiments, the method provides a Lille score of 0.4, 0.3, 0.2, 0.1, or less than 0.1.

[0107] In some embodiments, the method provides a clinical outcome of a 7-day Lille score <0.45. In some embodiments, the method provides a 7-day Lille score <0.45 and a 28-day MELD or MELD-Na score reduced to <21, or <20, or <18, or reduced by at least 10%-25%, or at least 10%-30%, or at least 10%-35%, or at least 10%-40% (or at least 2 or 3), combined with one, two, three, four, five or more endpoints described below:

[0108]

[0109]

[0110] In some embodiments, the method provides improvements in one or more of: liver biochemistry and liver 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).

[0111] In some embodiments, the patient's dose is increased to a maximum of 50 mg / day. In some embodiments, the patient's dose is increased to a maximum of 100 mg / day. In some embodiments, the patient's dose is increased to a maximum of 125 mg / day, 150 mg / day, 175 mg / day, 200 mg / day, 225 mg / day, 250 mg / day, 275 mg / day, or 300 mg / day.

[0112] 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 on 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 on 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 on 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 on 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 on 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 on day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by 2 on day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by 3 on day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by 4 on day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by 5 on day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MELD or MELD-Na score by 6 on day 28 or day 90 of treatment.

[0113] 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%.

[0114] 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 on 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%.

[0115] 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 on 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 on 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 on 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 on 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 on 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 and / or reduces the patient's MDF score by at least 6 on day 28 or day 90 of treatment.

[0116] In some embodiments, the method reduces the patient's MELD or MELD-Na score by at least 5 on day 28 or day 90 of treatment. In some embodiments, the method reduces the patient's MDF score by at least 5 on 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 reduces the patient's MDF score by at least 5 on day 28 or day 90 of treatment. In some embodiments, the method provides a reduction in MELD or MELD-Na score at 28 or day 90. In some embodiments, the method provides a reduction in MDF score at 28 or day 90.

[0117] In some embodiments, the method further comprises monitoring the blood level of a biomarker in the patient after administration of the FXR agonist of the disclosure. In some embodiments, the biomarker is selected from C4, FGF-19, and endogenous bile acids.

[0118] In some embodiments, the patient suffers from alcohol-related (or alcohol-associated) liver disease (ALD), also known as alcoholic liver disease. In some embodiments, the patient exhibits jaundice.

[0119] In some embodiments, the patient exhibits one or more of the following: (1) persistent drinking of more than 40 g of alcohol per day for women and more than 60 g of alcohol per day for men for 6 months or longer, and abstinence for less than 60 days before 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 a bilirubin concentration greater than 3 mg / dL. In some embodiments, in addition to one, two, three, or all of the foregoing signs, the patient is diagnosed with sAH after liver biopsy.

[0120] In some embodiments, the patient shows that women continue to drink more than 40g of alcohol per day and men continue to drink more than 60g of alcohol per day for 6 months or more, and abstinence is less than 60 days before the onset of jaundice. In some embodiments, the patient shows that there is an increase in liver enzymes (aspartate aminotransferase [AST] and / or alanine aminotransferase [ALT] concentration ≥50IU / L but ≤400IU / L and AST / ALT ratio ≥1:5). In some embodiments, the patient shows worsening jaundice and the bilirubin concentration is greater than 3mg / dL. In some embodiments, the patient shows that there is no other cause of liver disease.

[0121] In some embodiments, the patient is deemed unsuitable for liver transplantation according to generally accepted criteria known in the art.

[0122] In some embodiments, the patient suffers from alcohol use disorder (AUD). AUD can be defined based on alcohol consumption, for example, consuming 3 or more alcoholic beverages per day (males) or 2 or more alcoholic beverages per day (females).

[0123] In some embodiments, the patient has previously been treated with corticosteroids for sAH. In some embodiments, the patient is unresponsive to corticosteroids. In some embodiments, the patient exhibits a Lille score greater than 0.45 after treatment with corticosteroids for 7 days or more.

[0124] In some embodiments, the patient is currently hospitalized, i.e., was hospitalized prior to initiation of treatment with a 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.

[0125] In some embodiments, the patient has suffered at least one relapse of sAH, ie, has been previously diagnosed and / or treated for sAH at least once.

[0126] In some embodiments, in addition to sAH, the patient exhibits one or more of the following: obesity, metabolic syndrome, hepatitis C infection, or genetic polymorphisms such as patatin-like phospholipase domain protein 3, membrane-bound O-acyltransferase, and transmembrane 6 superfamily member 2 genes.

[0127] In some embodiments, the patient exhibits intestinal dysbiosis.

[0128] In some embodiments, the methods improve one or more measures of sAH, such as intestinal dysbiosis.

[0129] In some embodiments, the method improves the 30-day survival rate of a patient with sAH or ACLF compared to an otherwise similar patient with sAH or ACLF who is not administered a FXR agonist. In some embodiments, the method improves the 60-day survival rate of a patient compared to an otherwise similar patient who is not administered a FXR agonist. In some embodiments, the method improves the 90-day survival rate of a patient compared to an otherwise similar patient who is not administered a FXR agonist. In some embodiments, the method improves the 120-day, 180-day, or 1-year survival rate of a patient compared to an otherwise similar patient who is not administered a FXR agonist.

[0130] In some embodiments, the method improves the patient's 30-day mortality rate compared to other similar patients not administered with the FXR agonist. In some embodiments, the method improves the patient's 60-day mortality rate compared to other similar patients not administered with the FXR agonist. In some embodiments, the method improves the patient's 90-day mortality rate compared to other similar patients not administered with the FXR agonist. In some embodiments, the method improves the patient's 120-day, 180-day, or 1-year mortality rate compared to other similar patients not administered with the FXR agonist.

[0131] In some embodiments, the improvement of the survival rate or mortality rate of the patient includes an increase in the survival rate or a decrease in the mortality rate of about 10% to about 70%. Such improvements can be measured in, for example, 30 days, 60 days, 90 days, 120 days, 180 days, 1 year or more than 1 year. In some embodiments, the improvement of the survival rate or mortality rate of the patient includes an increase in the survival rate or a decrease in the mortality rate 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%.

[0132] In some embodiments, the method provides at least a 15% reduction in mortality at 90 days compared to standard of care (SOC). In some embodiments, the method provides a 15%-20% reduction in mortality at 30 days compared to SOC. In some embodiments, the method provides a 10% reduction in mortality at 6 months. In some embodiments, the method provides an absolute reduction in mortality of 5%-10% at 1 year.

[0133] In some embodiments, the method provides a reduction in the risk of death in a patient. In some embodiments, the method provides a reduction in the risk of death from liver-related events and health care utilization in patients with sAH. In some embodiments, such reduction is compared to the current standard of care (e.g., treatment with a corticosteroid such as prednisolone). In some embodiments, a FXR agonist, such as Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof, is prescribed for first-line therapy.

[0134] In some embodiments, the method provides a reduction of at least 10% in the patient's health care utilization rate within 30 days, 60 days, 90 days, 120 days, 180 days, or 1 year or more than 1 year. As used herein, the term "health care utilization rate" includes one or more of the following: readmission within 30 days after 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 transplantation. In some embodiments, the method provides a reduction of at least 20% in the patient's health care utilization rate within 30 days, 60 days, 90 days, 120 days, 180 days, or 1 year or more than 1 year. In some embodiments, the method provides a reduction of at least 30% in the patient's health care utilization rate within 30 days, 60 days, 90 days, 120 days, 180 days, or 1 year or more than 1 year. In some embodiments, the method provides a reduction in the patient's healthcare utilization of about 10% to about 40% over 30 days, 60 days, 90 days, 120 days, 180 days, or 1 year or more.

[0135] In some embodiments, the method improves the patient's 90-day survival rate and reduces the patient's hospital readmission rate by at least 10%, or at least 20%, or between 10% and 30%.

[0136] In some embodiments, the method provides improvement in liver-related events (such as decompensation) or hospitalization / rehospitalization.

[0137] In some embodiments, the method provides at least a 15% reduction in hospitalizations.

[0138] In some embodiments, the method provides at least a 15% reduction in progression to transplantation.

[0139] Compound 1, also known as TC-100, is a semisynthetic bile acid derived from CDCA (a natural ligand of FXR). Compound 1 is the first reported example of 11β-OH bile acid and is the only known FXR-specific bile acid derivative that is inactive for the bile acid G-protein coupled receptor TGR5. 11β-OH not only confers FXR agonist specificity, but also gives Compound 1 a high degree of water solubility (16 times that of obeticholic acid or OCA), with a high critical micelle concentration, such as ursodeoxycholic acid, giving Compound 1 a very low tendency to decontamination, and therefore low toxicity. The compound shows a very low liver residence time, which is mainly secreted into the bile as is, and is therefore located throughout the intestine. Pellicciari, R., et al. J. Med. Chem. 2016, 59, 9201-9214.

[0140] As a targeted therapy with anti-inflammatory, anti-fibrotic, and potentially anti-apoptotic effects, the FXR agonist Compound 1 may represent a significant advance over systemic corticosteroid therapy, the standard of care in the treatment of patients with sAH. Compound 1 may also reduce intestinal permeability and may provide a considerable improvement over corticosteroids in terms of bacterial translocation and infectious complications observed in patients with sAH.

[0141] The targeted mechanism of action of FXR agonists such as Compound 1 represents a new treatment option relative to 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 a FXR agonist described herein.

[0142] As targeted therapies with anti-inflammatory, anti-fibrotic and anti-apoptotic effects, the FXR agonists described herein meet the long-standing need in the art for effective therapies for acute liver diseases such as severe alcoholic hepatitis (sAH) and acute-on-chronic liver failure (ACLF). Gut-liver axis dysfunction, including increased intestinal permeability, is an important driver 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 have shown that extrahepatic FXR deficiency is critical for the development of alcohol-induced fatty liver, and in particular, intestinal FXR can 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).

[0143] Exemplary Disease and Patient Population—sAH

[0144] Severe alcoholic hepatitis (sAH) is an acute liver disease different from other alcoholic liver diseases, many of which are chronic in nature. In addition, sAH has unique histopathological and pathophysiological characteristics, and may be present in patients with potential chronic liver diseases such as alcoholic liver disease (ALD) (Shah NJ, Royer A, John S. Alcoholic Hepatitis. Stat Pearls. January 2021; 1-8; incorporated herein by reference). During sAH, endotoxin or lipopolysaccharide (LPS), collectively referred to as pathogen-associated molecular patterns (PAMPs), enter the portal circulation and initiate an inflammatory cascade. Elevated endotoxin levels in alcoholic hepatitis are caused by qualitative and quantitative changes induced by alcohol in the intestinal microbiota and increased intestinal permeability. LPS activates Kupffer cells and hepatic stellate cells via toll-like receptor 4 (TLR4), and produces reactive oxygen species (ROS), proinflammatory cytokines and chemokines, which together with alcohol cause hepatocyte damage. 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, direct effects of alcohol on adipose tissue lead to the generation of damage-associated molecular patterns (DAMPs).

[0145] In most cases of AH, a liver biopsy is not required. However, a liver biopsy may be required to confirm the diagnosis of AH. In the context of varying degrees of steatosis and fibrosis, findings based on liver biopsy confirming the diagnosis of AH include ballooning of hepatocytes, neutrophil infiltration, and Mallory-Denk bodies (Singal, AK et al. Journal of Hepatology 2019, Vol. 70, 305–313). The method of the present disclosure improves one or more histological measurements of sAH such as macrovesicular steatosis with at least one of the following: neutrophil infiltration, hepatocyte damage (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 hepatocyte damage (ballooning). The method of the present disclosure improves Mallory-Denk bodies.

[0146] Excessive drinking is one of the main causes of liver disease and the seventh leading cause of premature death worldwide. Alcohol-induced liver damage can range from fatty degeneration to alcohol-induced steatohepatitis with fibrosis to cirrhosis and hepatocellular carcinoma. Unfortunately, many patients with alcohol-related liver disease (ALD) are diagnosed at a later stage of the disease, and therefore data on the prevalence of early disease are limited (Singal, AK, et al. "ACG clinical guideline: Alcoholic liver disease," Am J Gastroenterol. 2018; 113 (2): 175–94; incorporated herein by reference). The best estimated combined prevalence of non-cirrhotic ALD and cirrhotic ALD is about 2% of the total U.S. population. Globally, deaths due to alcohol-induced cirrhosis account for about 10% of all deaths caused by alcohol and nearly half of deaths due to chronic liver disease.

[0147] Alcoholic hepatitis (AH) (or alcohol-related hepatitis), also known 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 dataelements for clinical trials in patients with alcoholic hepatitis: Recommendation from the NIAAA Alcoholic Hepatitis Consortia," Gastroenterology 2016 Apr; 150(4):785-90; incorporated herein by reference). Most commonly, the clinical diagnosis of AH is made in patients with rapid development of jaundice and liver-related complications, combined with a documented history of continued heavy alcohol consumption within 8 weeks of symptom onset and the exclusion of other liver diseases (Singal, AK et al. Am J Gastroenterol. 2018; 113(2):175–94). In AH, abnormalities that may lead to liver damage include the generation of oxidative stress as a byproduct of ethanol metabolism and "leakage" of endotoxins through the intestinal wall and into the portal circulation. Endotoxins bind to receptors on Kupffer cells and activate an inflammatory response. The inflammatory response in the liver leads to hepatocyte dysfunction and death. Among the most important inflammatory cytokines is tumor necrosis factor (TNF)-α, whose elevated levels correlate with the severity of liver disease. Morgan, TR Gastroenterol. Hepatol. (NY). 2007 Feb;3(2):97–99.

[0148] Direct hepatocellular injury is due to the cytotoxic effects of ethanol and its metabolites, such as acetaldehyde. Ethanol-induced injury triggers 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 and interferes with carbohydrate and lipid metabolism, leading to hepatic steatosis. Alcohol increases the susceptibility of hepatocytes to free radical damage by activating the CYP2E1 enzyme, which induces mitochondrial dysfunction, depletes antioxidant reserves, and recruits inflammatory cells. Chronic alcohol abuse, especially when combined with malnutrition, often aggravates the effects of oxidative damage by further reducing cellular resilience to oxidative stress and depleting antioxidant reserves. Proteasome dysfunction also plays a role in exacerbating oxidative stress and cellular damage. 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 circulating pathogenic products, such as lipopolysaccharide, also known as pathogen-associated molecular patterns (PAMPs). Hepatocytes damaged by ethanol release sterile inflammatory mediators called damage-associated molecular patterns (DAMPs). DAMPs and PAMPs bind to pattern recognition receptors and effectively stimulate innate immune responses. The innate immune response is activated by cytokine-mediated and chemokine-mediated attraction of circulating neutrophils and monocytes. This leads to dense neutrophil infiltration of the liver, which is a hallmark of alcoholic hepatitis. Adaptive immune responses mediated by B cells, T cells, and natural killer cells also contribute to the liver inflammatory storm. Therefore, alcoholic hepatitis (or alcohol-related hepatitis) is a unique disease (Sehrawat, TS et al. "The knowns and unknowns of treatment for alcoholic hepatitis," Lancet Gastroenterol Hepatol. 2020; 5 (5) 494–506; incorporated herein by reference). Patients with sAH are defined as MDF ≥ 32 and / or MELD> 20. In previous interventional studies, short-term mortality rates in patients with sAH were reported to be as high as 46% (Akriviadis, E., et al. "Pentoxifylline improves short-term survival insevere acute alcoholic hepatitis: a double-blind, placebo-controlled trial," Gastroenterology 2000 Dec;119(6):1637-48; incorporated herein by reference).A recent study reported a longer term 1-year mortality rate (or liver transplantation) 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; incorporated herein by reference). In support of this, in a meta-analysis evaluating published mortality rates between 1971 and 2016, the median mortality rate due to AH within 180 days of hospitalization was found to be as high as 44% (Hughes, E. et al. "Survival from alcoholic hepatitis has not improved over time" PLoS One 2018;13(2):e0192393; incorporated herein by reference).

[0149] Patients with acute alcoholic hepatitis will have elevated total bilirubin and transaminases, usually at least 2-6 times the upper or normal value. Severe alcoholic hepatitis can be identified by the following signs: bilirubin levels exceeding 10 mg / dL-15 mg / dL; aspartate aminotransferase (AST) levels usually between 100 U / L and 200 U / L (or IU / L), and almost always less than 400 U / L (or IU / L); alanine aminotransferase (ALT) is usually about 25%-50% of the AST value, somewhere in the range of 50 U / L-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).

[0150] Current guidelines recommend alcohol abstinence for all patients with AH and ALD. In addition, most patients with AH will benefit from nutritional support, including total caloric and protein supplementation. However, for patients with sAH (as 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 abstinence.

[0151] The clinical utility of systemic corticosteroid therapy is largely limited due to increased infection risk and concerns about GI bleeding. Therefore, all current guidelines recommend that clinicians use the Lille score to identify non-responders after 7 days of corticosteroid therapy 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; incorporated herein by reference).

[0152] The Lille model is a medical modeling tool used to predict mortality in patients with alcoholic hepatitis who do not respond to steroid therapy. The model risk stratifies patients who have received steroid therapy for 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 have shown that patients with a Lille score higher than 0.45 may 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).

[0153] The Lille model can be used to predict mortality at 6 months. Lower scores indicate more improvement (corticosteroid response). Typically, a score>0.45 predicts a 6-month survival rate of 25%. A score<0.45 predicts a 6-month survival rate of 85%. The Lille score on the 7th day can be in the range of less than 0.1 and greater than 0.9. The responder has a Lille score<0.45 on the 7th day, and the non-responder has a Lille score>0.45 on the 7th day.

[0154] Several scores, such as the Maddrey discriminant function (MDF), MELD or MELD-Na, ABIC, and GAHS are used for 28-day mortality prediction. MDF is defined as 4.6×(patient-control PT)+serum bilirubin, with a score of 32 or higher for severe disease. An MDF score below 32 means mild to moderate alcoholic hepatitis. An MDF score equal to or greater than 32 means that a person may have severe alcoholic hepatitis and is a candidate for corticosteroid therapy or pentoxifylline treatment under the current standard of care. An MDF less than 32 (mild to moderate AH) does not benefit from steroid therapy. There is some mortality associated with mild to moderate AH, so therapy for this group is beneficial (assuming that steroids are not applicable as they do not provide a mortality benefit).

[0155] The Model for End-Stage Liver Disease (MELD) score is a prognostic scoring system based on laboratory parameters that is used to predict 3-month mortality due to 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 for sAH ranges from 21 to 30. MELD is defined as 9.57 log e (S-creatinine) + 3.78log 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, incorporated herein by reference.

[0156] A new version of MELD (MELD 3.0) has recently been developed, which adds women and albumin to the score, showing slightly more accurate mortality predictions in patients with cirrhosis than MELD-Na. See Kim WR et al. MELD3.0: The Model for End-stage Liver Disease Updated for the ModernEra. Gastroenterology 2021 (available online at https: / / doi.org / 10.1053 / j.gastro.2021.08.050), incorporated herein by reference. Each embodiment of listing MELD or MELD-Na ranges and / or values ​​described herein is intended to also include corresponding MELD 3.0 ranges and / or values.

[0157] It is generally recognized that severe AH is defined by a Maddrey discriminant function (MDF) score of ≥32 or a MELD score of ≥=21, with a range of 21-30 generally observed. The MELD-Na score is a modification of the MELD score that adjusts serum sodium. The MELD-Na score is currently a recognized standard for determining candidacy for liver transplantation. The study described herein includes patients with a MELD-Na score of 18-25 (including endpoints) and MDF ≥32.

[0158] Low serum sodium is an independent predictor of mortality in patients with cirrhosis. The MELD-Na score includes serum Na; the score 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 for assessing the severity of chronic liver disease. The MELD-Na score can be used to assess subjects with severe decompensation and is currently used by the Organ Procurement and Transplantation Network (OPTN) in the European Organ Storage and Transportation Organization (Eurotransplant) (ET) region of the United States and the European Union for the management of organ allocation for liver transplantation. An increase in the MELD-Na score is associated with an increase in the severity of liver dysfunction and an increased risk of death within 3 months. The MELD-Na score is derived from the subject's serum total bilirubin, serum creatinine and INR (International Normalized Ratio), as appropriate, to predict survival, and is calculated according to the following formula: MELD-Na score = 10x[(0.957x ln(creatinine))+(0.378x ln(bilirubin))+(1.12x ln(INR))]+6.43; MELD-Na = MELD-Na-[0.025×MELD×(140-Na)]+140.

[0159] Patients with sAH and progressive liver failure who are non-responders to corticosteroid therapy and are not suitable for liver transplantation are often referred for palliative care (Singal, AK et al. Am J Gastroenterol. 2018; 113(2):175–94). Given the limited treatment options, side effects, and lack of long-term benefit of corticosteroid therapy, patients with sAH still have significant unmet medical needs.

[0160] 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 18 to 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 40-60 years old. In some embodiments, the patient is 60-85 years old. In some embodiments, the patient is 40-50 years old. In some embodiments, the patient is 70-80 years old.

[0161] In some embodiments, the patient is male. In some embodiments, the patient is female.

[0162] In some embodiments of the present disclosure, patients are stratified according to the severity of the disease. Maddrey discriminant function (MDF), end-stage liver disease model (MELD or MELD-Na) score, age-bilirubin-international normalized ratio-creatinine score and Glasgow alcoholic hepatitis score can be used to predict short-term mortality. The 1-month mortality rate of patients with severe AH (sAH) defined by Maddrey discriminant function of 32 or greater is as high as 20%-50%, so in previous clinical studies, 30-day survival rate is the endpoint of most trials. The maximum MDF score is usually less than 60, because patients with MDF scores exceeding 60 may need liver transplantation. In some embodiments, MELD or MELD-Na scores ≥20 or ≥21 are used as the criteria for selecting patients. In some embodiments, MELD or MELD-Na scores ≥18 are used as the criteria for selecting patients. For example, a MELD score of 21 or higher predicts a 90-day mortality rate of 20%. The maximum MELD score is usually less than 30, because patients with MELD scores exceeding 30 may need liver transplantation. Failure of improvement in serum bilirubin (Lille score) predicts that patients with severe AH are unlikely to benefit from continued corticosteroid therapy.

[0163] 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 Maddrey discriminant function score of about 32, and / or a MELD or MELD-Na score of 18, 19, 20, 21, 22, 23, 24, or 25.

[0164] In some embodiments, the patient has a Maddrey discriminant function score of ≥32, and / or a MELD or MELD-Na score of 21-30.

[0165] In some embodiments, the patient has underlying alcohol-related liver disease (ALD) associated with sAH.

[0166] In some embodiments, the patient exhibits jaundice.

[0167] In some embodiments, the patient exhibits one or more of the following: (1) persistent drinking of more than 40 g of alcohol per day for women and more than 60 g of alcohol per day for men for 6 months or longer, and abstinence for less than 60 days before the onset of jaundice; (2) the 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 a bilirubin concentration greater than 3 mg / dL. In some embodiments, in addition to one, two, three, or all of the foregoing signs of disease, the patient is diagnosed with sAH following a liver biopsy.

[0168] In some embodiments, the patient is deemed unsuitable for liver transplantation according to generally accepted criteria known in the art.

[0169] In some embodiments, the patient has alcohol use disorder (AUD), defined as consuming 3 or more alcoholic beverages per day (for men) or 2 or more alcoholic beverages per day (for women).

[0170] In some embodiments, the patient has previously been treated with corticosteroids for sAH. In some embodiments, the patient is unresponsive to corticosteroids. In some embodiments, the patient exhibits a Lille score greater than 0.45 after treatment with corticosteroids for 7 days or more.

[0171] 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, such as 21-30.

[0172] In some embodiments, the patient has asymptomatic sAH or "walking AH." In some embodiments, the patient has asymptomatic sAH including cirrhosis.

[0173] In some embodiments, in addition to sAH, the Child-Turcotte-Pugh criteria are used to diagnose the patient. In some embodiments, the patient has a Child-Turcotte-Pugh score of 7 or greater, such as 7-15, 8-15, 9-15, 10-15, or 8-12.

[0174] In some embodiments, the patient exhibits alcohol-related cirrhosis.

[0175] In some embodiments, the patient exhibits alcohol-related liver fibrosis.

[0176] In some embodiments, the patient exhibits alcohol-related steatosis.

[0177] In some embodiments, the patient exhibits alcohol-related steatohepatitis.

[0178] In some embodiments, the patient exhibits alcoholic hepatitis.

[0179] In some embodiments, the patient has ALD in addition to sAH, wherein the ALD is selected from early ALD (stages 0-2) or late ALD (bridging fibrosis, stage 3; or cirrhosis, stage 4).

[0180] In some embodiments, the patient does not exhibit cirrhosis.

[0181] In some embodiments, the patient is currently hospitalized, i.e., was hospitalized prior to initiation of treatment with a 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 21-30; or a MELD-Na score of 18, 20 or 21 to 25 or 30.

[0182] In some embodiments, the patient has suffered at least one relapse of sAH.

[0183] In some embodiments, in addition to sAH, the patient exhibits one or more of the following: obesity, metabolic syndrome, hepatitis C infection, or genetic polymorphisms such as patatin-like phospholipase domain protein 3, membrane-bound O-acyltransferase, and transmembrane 6 superfamily member 2 genes.

[0184] In some embodiments, the patient exhibits intestinal dysbiosis.

[0185] In some embodiments, the methods improve one or more measures of sAH, such as intestinal dysbiosis.

[0186] In some embodiments, the present disclosure provides a method of determining a patient's candidacy for therapeutic treatment of sAH, comprising determining the patient's MELD-Na score, wherein the patient's MELD-Na score is ≥ 18. In some embodiments, the method further comprises determining the patient's MDF score, e.g., wherein the patient's MDF score is from 32 to 60, inclusive.

[0187] In some embodiments, the present disclosure provides a method of determining the candidacy of a patient for therapeutic treatment of sAH, comprising determining the patient's MELD score, wherein the patient's MELD score is ≥ 21, e.g., from 21 to 30. In some embodiments, the method further comprises determining the patient's MDF score, e.g., wherein the patient's MDF score is ≥ 32, e.g., from 32 to 60 (inclusive).

[0188] In some embodiments, the present disclosure provides a method of treating sAH, comprising selecting a patient with a MELD-Na score ≥ 18; and administering a therapeutic treatment for sAH, e.g., wherein the patient also has an MDF score from 32 to 60 (inclusive). In some embodiments, the therapeutic treatment comprises administering a pharmaceutical agent and / or a liver transplant to the patient.

[0189] In some embodiments, the present disclosure provides a method for treating sAH, comprising selecting a patient with a MELD score ≥ 21, e.g., from 21 to 30; and administering a therapeutic treatment for sAH, e.g., wherein the patient also has an MDF score of ≥ 32, e.g., from 32 to 60 (inclusive). In some embodiments, the therapeutic treatment comprises administering a pharmaceutical agent and / or a liver transplant to the patient.

[0190] In some embodiments, the method provides an improvement in one or more measurements of a patient's health outcome. In the following embodiments of the invention, reference to "a 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.

[0191] In some embodiments, the method improves the patient's 30-day survival rate compared to other similar patients who are not administered FXR agonists. In some embodiments, the method improves the patient's 60-day survival rate compared to other similar patients who are not administered FXR agonists. In some embodiments, the method improves the patient's 90-day survival rate compared to other similar patients who are not administered FXR agonists. In some embodiments, the method improves the patient's 120-day, 180-day, or 1-year survival rate compared to other similar patients who are not administered FXR agonists.

[0192] In some embodiments, the method improves the patient's 30-day mortality rate compared to other similar patients not administered with the FXR agonist. In some embodiments, the method improves the patient's 60-day mortality rate compared to other similar patients not administered with the FXR agonist. In some embodiments, the method improves the patient's 90-day mortality rate compared to other similar patients not administered with the FXR agonist. In some embodiments, the method improves the patient's 120-day, 180-day, or 1-year mortality rate compared to other similar patients not administered with the FXR agonist.

[0193] In some embodiments, the improvement of the survival rate or mortality rate of the patient includes an increase in the survival rate or a decrease in the mortality rate of about 10% to about 70%. Such improvements can be measured in, for example, 30 days, 60 days, 90 days, 120 days, 180 days, 1 year or more than 1 year. In some embodiments, the improvement of the survival rate or mortality rate of the patient includes an increase in the survival rate or a decrease in the mortality rate 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, the improvement of the survival rate or mortality rate of the patient comprises an increase in survival rate or a decrease in mortality rate 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, the improvement of the survival rate or mortality rate of the patient comprises an increase in survival rate or a decrease in mortality rate of about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%.

[0194] In some embodiments, the method provides a reduction in the risk of death in a patient. In some embodiments, the method provides a reduction in the risk of death from liver-related events and health care utilization in patients with sAH. In some embodiments, such reduction is compared to the current standard of care (e.g., treatment with a corticosteroid such as prednisolone). In some embodiments, a FXR agonist, such as Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof, is prescribed for first-line therapy.

[0195] In some embodiments, the method provides a reduction of at least 10% in the patient's health care utilization rate within 30 days, 60 days, 90 days, 120 days, 180 days, or 1 year or more than 1 year. As used herein, the term "health care utilization rate" includes one or more of the following: readmission within 30 days after 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 transplantation. In some embodiments, the method provides a reduction of at least 20% in the patient's health care utilization rate within 30 days, 60 days, 90 days, 120 days, 180 days, or 1 year or more than 1 year. In some embodiments, the method provides a reduction of at least 30% in the patient's health care utilization rate within 30 days, 60 days, 90 days, 120 days, 180 days, or 1 year or more than 1 year. In some embodiments, the method provides a reduction in the patient's healthcare utilization of about 10% to about 40% over 30 days, 60 days, 90 days, 120 days, 180 days, or 1 year or more.

[0196] In some embodiments, the method provides a reduction of about 10% to about 40% in the patient's health care utilization rate within 30 days, 60 days, 90 days, 120 days, 180 days, or 1 year or more. In some embodiments, the method provides a reduction of about 20% to about 30% in the patient's health care utilization rate within 30 days, 60 days, 90 days, 120 days, 180 days, or 1 year or more. In some embodiments, the method provides a reduction of about 10% to about 20% in the patient's health care utilization rate within 30 days, 60 days, 90 days, 120 days, 180 days, or 1 year or more.

[0197] In some embodiments, the method reduces the patient's hospital readmission by at least 10%. In some embodiments, the method reduces the patient's hospital readmission by 10%-80%.

[0198] In some embodiments, the method improves the patient's 90-day survival rate and reduces the patient's hospital readmission by at least 10%.

[0199] In some embodiments, the method also includes administering an FXR agonist combined with another therapeutic agent. In some embodiments, the method also includes administering an effective amount of an anti-inflammatory agent, an antibiotic, a probiotic, a fecal transplant, a zinc supplement, or a combination of any of those agents to the patient. In some embodiments, another 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 those 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, a corticosteroid can be selected from prednisolone (e.g., about 40mg / d) or methylprednisolone (e.g., about 32mg / d). In some embodiments, the other therapeutic agent for co-administration is pentoxifylline. In some embodiments, FXR agonists are administered in combination with corticosteroids or pentoxifylline. In some embodiments, the method further comprises 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, a probiotic, a fecal transplant, a Zn supplement, or a combination of any of those agents.

[0200] In some embodiments, the additional treatment includes alcohol abstinence and / or alcohol counseling.

[0201] Exemplary Disease and Patient Population—ACLF

[0202] Acute-on-chronic liver failure (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 ACLF cases have no identifiable trigger; in the remaining patients, sepsis, active alcoholism, and relapses of chronic viral hepatitis are the most commonly reported precipitating factors. Excessive systemic inflammatory responses appear to play a crucial role in the development of ACLF. Using the liver-adapted Sequential Organ Assessment Failure Score, the outcome of patients with ACLF can be classified and predicted. The course of ACLF is dynamic and changes over the course of the hospital admission. Most patients will have a clear prognosis between hospital days 3 and 7, and clinical scores can be used to tailor clinical decisions, such as liver transplant evaluation or goals of care discussions. Bioartificial liver support systems, granulocyte colony-stimulating factor, or stem cell transplantation are being studied for medical care in this patient population; however, data are too early to implement them as standard of care.

[0203] 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 18-65 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 40-65 years old. In some embodiments, the patient is 65-85 years old. In some embodiments, the patient is 40-50 years old. In some embodiments, the patient is 70-80 years old.

[0204] In some embodiments, the patient is male. In some embodiments, the patient is female.

[0205] In some embodiments, the patient has alcohol use disorder (AUD), defined as consuming 3 or more alcoholic beverages per day (for men) or 2 or more alcoholic beverages per day (for women).

[0206] In some embodiments, the patient has ALD-related ACLF.

[0207] 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).

[0208] In some embodiments, the patient has a Maddrey discriminant function (MSF) score of 32 or higher, and / or a MELD or MELD-Na score of 18, 20, or 21 or higher, such as from 21-30.

[0209] In some embodiments, the patient has been diagnosed with ACLF using the Sequential [Sepsis-Related] Organ Failure Evaluation, APACHE (Acute Physiology and Chronic Health Evaluation), or Acute-on-Chronic Liver Failure score.

[0210] In some embodiments, the patient exhibits cirrhosis of the liver.

[0211] In some embodiments, the patient exhibits liver fibrosis.

[0212] In some embodiments, the patient exhibits steatosis.

[0213] In some embodiments, the patient exhibits alcoholic hepatitis.

[0214] In some embodiments, the patient does not exhibit cirrhosis.

[0215] In some embodiments, the patient exhibits intestinal dysbiosis.

[0216] In some embodiments, in addition to ACLF, the patient exhibits one or more of the following: obesity, metabolic syndrome, hepatitis C infection, or genetic polymorphisms, such as patatin-like phospholipase domain protein 3, membrane-bound O-acyltransferase, and transmembrane 6 superfamily member 2 genes.

[0217] When ACLF is induced by sAH, it is treated with the same therapeutic agents used for sAH. In the case of other forms of ACLF, there is overlap in treatment options, including antibiotics, supplements, antioxidants, and steroids. Antioxidants such as N-acetylcysteine ​​are used in ACLF.

[0218] In some embodiments, the method of the present disclosure includes the treatment of co-administration. In some embodiments, the method includes the administration of an FXR agonist combined with another therapeutic agent. In some embodiments, another 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 those agents. In some embodiments, the method includes the administration of an FXR agonist and an anti-inflammatory agent. In some embodiments, the anti-inflammatory agent is a corticosteroid. For example, a corticosteroid can be selected from prednisolone (e.g., about 40 mg / d) or methylprednisolone (e.g., about 32 mg / d). In some embodiments, the other therapeutic agent for co-administration is pentoxifylline. In some embodiments, an FXR agonist is administered in combination with a corticosteroid or pentoxifylline. In some embodiments, an FXR agonist is administered in combination with N-acetylcysteine. In some embodiments, additional treatment includes alcohol withdrawal and / or alcohol counseling.

[0219] 2. Use, preparation and administration

[0220] Pharmaceutically acceptable compositions

[0221] According to another embodiment, the present invention provides a composition comprising a disclosed compound and a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, the composition of the present invention is formulated for use in patients who need such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0222] As used herein, the term "subject" or "patient" means a human.

[0223] The term "pharmaceutically acceptable carrier, excipient or vehicle" refers to a non-toxic carrier, excipient or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, excipients or vehicles that can be used in the compositions of the present invention include, but are 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, saturated partial glyceride mixtures of vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (e.g., hydroxypropyl methylcellulose), polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0224] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, ester salt or other derivative of a compound of the invention which, when administered to a recipient, is capable of providing, directly or indirectly, a compound of the invention or an active metabolite or amino acid conjugate thereof.

[0225] As used herein, the term "amino acid conjugate" refers to a conjugate of a compound of the 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 additional advantage of enhancing the integrity of bile or intestinal fluid. Suitable amino acids are not limited to taurine, glycine and sarcosine.

[0226] As defined herein, the term "metabolite" refers to glucuronidated derivatives and sulfated derivatives of compounds described herein, wherein one or more glucuronic acid or sulfuric acid moieties are connected to compounds of the present invention. The glucuronic acid moiety can be connected to the compound by a glycosidic bond with the hydroxyl group (e.g., 3-hydroxyl, 7-hydroxyl, 11-hydroxyl) of the compound. The sulfated derivative of the compound can be formed by the sulfation of the 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.

[0227] As used herein, "pharmaceutically acceptable salts" refers to conventional non-toxic salts of the compounds of the invention wherein the parent compound is modified by forming acid or base salts thereof. Suitable pharmaceutically acceptable salts according to the present disclosure can be readily determined and prepared by one skilled in the art, and will include, for example, basic salts of Compound 1 such as aluminum, calcium, lithium, magnesium, potassium, sodium and zinc salts or organic salts such as quaternary ammonium salts of Compound 1.

[0228] The amount of the disclosed compound (i.e., active agent) that should be present in the composition for use in the disclosed methods or disclosed pharmaceutical compositions will generally be a therapeutically effective amount. A "therapeutically effective amount" or dosage (or "effective amount") refers to the amount of the active agent sufficient to produce the desired therapeutic result.

[0229] In certain embodiments, the effective amount refers to the titrated dosage administered during the titration period. In other embodiments, the effective amount refers to the adjusted or re-adjusted dosage administered after the titration period.

[0230] As used herein, a "starting dose" refers to the initial dose provided to a patient that provides a clinical effect while minimizing the onset or occurrence of side effects. In some cases, the starting dose may be less than the amount typically administered to a patient. The starting dose is provided in an amount that is adjusted or gradually increased during the course of the adjustment period or during the course of treatment with the FXR agonists described herein. In some cases, the starting dose may be greater than the amount typically administered to a patient. The starting dose is provided in an amount that is adjusted or gradually increased or decreased during the course of the adjustment period or during the course of treatment with the FXR agonists described herein to achieve a desired therapeutic outcome.

[0231] The "adjustment period" refers to the length of time that a patient is administered the starting dose. The adjustment period lasts for a specific length of time, during which the patient's liver function and / or liver biochemistry as described herein is typically monitored.

[0232] As used herein, "adjusted dose" refers to the dose of the FXR agonist of the present disclosure or composition thereof administered after the adjustment period. The adjusted dose may be increased or decreased compared to the starting dose, but, as provided herein, patient tolerance and other factors described herein determine the dose amount of the adjusted dose. As used herein, "re-adjusted dose" refers to any changed dose amount or dose frequency of the adjusted dose in a patient.

[0233] The amount of Compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof, as provided above may refer to the starting dose administered during the adjustment period.

[0234] In certain embodiments, the starting daily dose of compound 1 or a pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 120 mg.

[0235] In some embodiments, the adjusted dose for a patient may be increased to 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, or 120 mg. In some embodiments, the adjusted daily dose for a patient may be increased to 5 mg. In some embodiments, the adjusted daily dose for a patient may be increased to 10 mg. In some embodiments, the adjusted daily dose for a patient may be increased to 25 mg. In some embodiments, the adjusted daily dose for a patient may be increased to 50 mg. In some embodiments, the adjusted daily dose for a patient may be increased to 100 mg. In some embodiments, the adjusted daily dose for a patient may be increased to 120 mg. In some embodiments, the adjusted daily dose for a patient 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.

[0236] In certain embodiments, the starting daily dose of Compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof, administered to a patient described herein may be 120 mg, 100 mg, 50 mg, 25 mg, 20 mg, 15 mg, 12.5 mg, 10 mg, 7.5 mg, or 5 mg.

[0237] In some embodiments, the adjusted daily dose for a patient may be reduced to 100 mg. In some embodiments, the adjusted daily dose for a patient may be reduced to 50 mg. In some embodiments, the adjusted daily dose for a patient may be reduced to 25 mg. In some embodiments, the adjusted daily dose for a patient may be reduced to 20 mg. In some embodiments, the adjusted daily dose for a patient may be reduced to 10 mg. In some embodiments, the adjusted daily dose for a patient may be reduced to 5 mg. In some embodiments, the adjusted daily dose for a patient may be reduced to 2.5 mg. In some embodiments, the adjusted daily dose for a patient may be reduced to 15 mg, 12.5 mg, 10 mg, 7.5 mg, 5 mg, or 2.5 mg.

[0238] The amount of compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof may refer to an adjusted dose administered after an adjustment period as described herein. In certain embodiments, the adjusted dose of compound 1 or a pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically acceptable salt or amino acid conjugate thereof administered to a patient described herein may be 20 mg. In still another embodiment, the adjusted dose of compound 1 or a pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically acceptable salt or amino acid conjugate thereof, administered to a patient described herein may be 300 mg.

[0239] The amount of compound 1 or its pharmaceutically acceptable salt or amino acid conjugate as provided above may refer to the readjusted dose administered after the adjustment period as described herein. In certain embodiments, the readjusted dose of compound 1 or its pharmaceutically acceptable salt or amino acid conjugate administered to a patient described herein may be 2.5 mg. In certain embodiments, the readjusted dose of compound 1 or its pharmaceutically acceptable salt or amino acid conjugate administered to a patient described herein may be 5 mg. In certain embodiments, the readjusted dose of compound 1 or its pharmaceutically acceptable salt or amino acid conjugate administered to a patient described herein may be 7.5 mg. In another embodiment, the readjusted dose of compound 1 or its pharmaceutically acceptable salt or amino acid conjugate administered to a patient described herein may be 10 mg. In still another embodiment, the readjusted dose of compound 1 or its pharmaceutically acceptable salt or amino acid conjugate administered to a patient described herein may be 25 mg. In yet another embodiment, the readjusted dose of compound 1 or its pharmaceutically acceptable salt or amino acid conjugate administered to a patient described herein may be 50 mg. In yet another embodiment, the re-adjusted dose of compound 1, or a pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically acceptable salt or amino acid conjugate thereof, administered to a patient described herein may be 200 mg. In yet another embodiment, the re-adjusted dose of compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof, administered to a patient described herein may be 250 mg. In yet another embodiment, the re-adjusted dose of compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof, administered to a patient described herein may be 300 mg.

[0240] The adjustment period can be a period of about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days. In certain embodiments, the adjustment period includes a period of about 1 week, 2 weeks, 3 weeks, 4 weeks, or 5 weeks. In another embodiment, the adjustment period includes a period of about 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In another embodiment, the adjustment period can be longer than 6 months. In another embodiment, the adjustment period includes a period of about 3 days, 5 days, 7 days, 10 days, 14 days, 21 days, or 28 days. For example, the adjustment period can be about 1 week. In another example, the adjustment period can be about 2 weeks. In another example, the adjustment period can be about 3 days. In still another example, the adjustment period can be about 5 days. In yet another example, the adjustment period can be about 5 days.

[0241] The composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intracisternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the composition is administered orally, intraperitoneally or intravenously. The sterile injectable form of the composition of the present invention can be an aqueous or oily suspension. These suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable products can also be sterile injectable solutions or suspensions in nontoxic parenteral acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. In acceptable vehicles and solvents that can be adopted are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are routinely used as solvents or suspension media.

[0242] For this purpose, any gentle fixed oil can be adopted, including synthetic monoglyceride or diglyceride. Fatty acid, such as oleic acid and its glyceride derivatives, can be used to prepare injectable, as natural pharmaceutically acceptable oil such as olive oil or castor oil, especially with its polyoxyethylated form. These oil solutions or suspensions can also contain long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersant that is generally used for preparing pharmaceutically acceptable dosage form (including emulsion and suspension). Other conventional surfactants such as Tween, Span and other emulsifiers or the bioavailability enhancer that is generally used for making pharmaceutically acceptable solid, liquid or other dosage form can also be used for the purpose of preparation.

[0243] The pharmaceutically acceptable compositions of the present invention can be orally administered in any oral acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, conventional carriers include lactose and corn starch. Lubricants such as magnesium stearate are also usually added. For oral administration in the form of capsules, useful diluents include lactose and dry corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavoring agents or coloring agents may also be added.

[0244] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycol.

[0245] The pharmaceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0246] Topical application to the lower intestinal tract can be achieved in a rectal suppository formulation (see above) or in a suitable enema formulation.Topical and transdermal patches may also be used.

[0247] For topical application, the pharmaceutically acceptable composition provided can be formulated into a suitable ointment containing an active component suspended or dissolved in one or more carriers. The carrier for topical application of the compound of the present invention includes but is not limited to mineral oil, liquid vaseline, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutically acceptable composition provided can be formulated into a suitable lotion or emulsifiable paste containing an active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include but are not limited to mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0248] The pharmaceutically acceptable compositions of the present invention may also 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 solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters for enhancing bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents.

[0249] In some embodiments, the pharmaceutically acceptable compositions of the present disclosure are formulated for oral administration. Such preparations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present disclosure are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0250] In other embodiments, the pharmaceutically acceptable compositions of the present disclosure are formulated for intravenous (IV) administration.

[0251] The amount of the compound of the invention that can be combined with carrier materials to produce a single dosage form of the composition will vary depending on the host being treated, the particular mode of administration. The composition should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day can be administered to a patient receiving these compositions.

[0252] 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, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the specific disease being treated. The amount of the compound of the present invention in the composition will also depend on the specific compound in the composition.

[0253] Treatment, duration, and dosage

[0254] As used herein, the term "treat" includes any action resulting in an improvement in a condition, disease, disorder, etc., such as alleviation, reduction, regulation, or elimination. "Treating" or "treatment" of a disease state includes inhibiting an existing disease state, i.e., arresting the development of a disease state or its clinical symptoms, or relieving a disease state, i.e., causing temporary or permanent regression of a disease state or its clinical symptoms.

[0255] "Preventing" a disease state includes causing clinical symptoms of the disease state to not develop in a subject who may be exposed to or susceptible to the disease state but who does not yet experience or display symptoms of the disease state.

[0256] As used herein, the term "inhibiting" or "inhibition" refers to any detectable positive effect on the progression of a disease or condition. Such a positive effect can include a delay in the progression of at least one symptom or sign of a disease or condition, a reduction or reversal of a symptom or sign, and a slowing of further worsening of a symptom or sign.

[0257] The disclosed treatment methods include administering the FXR agonist of the present disclosure or a composition thereof as needed to obtain the desired therapeutic effect. The compound or composition may be administered for a desired period of time to maintain the desired therapeutic effect.

[0258] In some embodiments, the FXR agonist of the present disclosure is administered for a period of time between about 1 week and about 12 months (treatment duration). In some embodiments, the FXR agonist is administered for a period of time between about one week and about six months. In some embodiments, the FXR agonist is administered for a period of time between about one week and about three months. In some embodiments, the FXR agonist is administered for a period of time between about one week and about ten weeks. In some embodiments, the FXR agonist is administered for a period of time between about one week and about six weeks. In some embodiments, the FXR agonist is administered for a period of time between about one week and about four weeks. In some embodiments, the FXR agonist is administered for a period of time between about one week and about three weeks. In some embodiments, the FXR agonist is administered for a period of time between about one week and about two weeks. In some embodiments, the FXR agonist is administered for a period of time between about one week and about two weeks.

[0259] 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 days to about 90 days. In some embodiments, the FXR agonist is administered to the patient for about 30 days to about 180 days. In some embodiments, the FXR agonist is administered to the patient for about 60 days to about 120 days. In some embodiments, the FXR agonist is administered to the patient for about 90 days to about 120 days. In some embodiments, the FXR agonist is administered to the patient for about 90 days to about 180 days.

[0260] In some embodiments, the FXR agonist is administered to the patient from 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.

[0261] In some embodiments, the FXR agonist is administered for about one month, about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about eleven months, about twelve months, or as needed to bring about the desired therapeutic effect.

[0262] In some embodiments, the FXR agonist, such as Compound 1, or a pharmaceutically 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 pharmaceutically 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.

[0263] In some embodiments, a FXR agonist such as Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof is administered in a single dose or multiple doses sufficient to achieve a total daily dose of about 1 mg to about 150 mg.

[0264] In some embodiments, a FXR agonist such as Compound 1 or a pharmaceutically acceptable salt thereof, or an 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.

[0265] In some embodiments, FXR agonists such as Compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate thereof are administered at a dose of about 1 mg to about 500 mg. In some embodiments, FXR agonists such as Compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate thereof are administered at a dose of about 2.5 mg to about 300 mg. In some embodiments, FXR agonists such as Compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate thereof are administered at a dose of about 2.5 mg to about 120 mg or about 2.5 mg to about 100 mg. In some embodiments, the FXR agonists of the present disclosure are administered at a dose of about 0.1 mg to about 25 mg. In some embodiments, the FXR agonists of the present disclosure are administered at a dose of about 2.5 mg to about 50 mg. In some embodiments, the FXR agonists of the present disclosure are administered at a dose of about 2.5 mg to about 10 mg. In some embodiments, the FXR agonists of the present disclosure are administered at a dose of about 2.5 mg to about 5 mg. In some embodiments, the FXR agonists of the present disclosure are administered at a dose of about 0.5 mg to about 5 mg. In some embodiments, the FXR agonists of the present disclosure are administered at a dose of about 0.5 mg to about 2.5 mg.

[0266] In some embodiments, FXR agonists such as Compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate thereof are 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 agonists of the present disclosure are 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, FXR agonists such as Compound 1 or a pharmaceutically acceptable salt thereof or an amino acid conjugate thereof are 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.

[0267] In some embodiments, the FXR agonist, such as Compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof, is administered in a single dose 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 dose 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.

[0268] In some embodiments, the FXR agonists of the disclosure are administered to a patient in a fasted state. In some embodiments, the FXR agonists are administered to a patient in a fed state.

[0269] The contents of each document cited in the specification are incorporated herein by reference in their entirety.

[0270] Example

[0271] Example 1: Therapeutic effects of three test articles on the development of alcoholic steatohepatitis in C57BL / 6J female mice

[0272] Target

[0273] The goal of this study was to evaluate the efficacy of the test articles obeticholic acid (OCA), compound 1, and compound 2 against liver and intestinal pathology in a mouse model of alcoholic steatohepatitis.

[0274] Compound 2 is a 3-deoxy, 11β-OH bile acid and FXR-specific bile acid derivative that is inactive towards the bile acid G-protein coupled receptor TGR5, as described in US Pat. No. 10,815,267.

[0275]

[0276] Preparation and administration of test articles

[0277] The dietary vehicles used in this study are described in the table below.

[0278] Table 1: Formulations used in the study

[0279]

[0280] Preparation of formulations

[0281] Dosing formulations were divided into aliquots when necessary to allow them to be dispensed for each dosing occasion.

[0282] Table 2: Preparation details

[0283]

[0284] Preparation of vehicle

[0285] Vehicle was prepared prior to day 1 at 0.5% CMC (medium viscosity) in deionized water and stored in a refrigerator set to maintain 4° C. and used for dosing of appropriate groups. Vehicle was stirred at room temperature for at least 30 minutes prior to dosing.

[0286] Test article preparation

[0287] Test articles for Groups 3-5 were prepared weekly, stored at 2-8°C until ready for use, and stirred at room temperature for 30 minutes prior to dosing. Dosing preparations were sonicated as needed and stirred during dosing.

[0288] The 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 before dosing. The dosing formulations were stirred during dosing. The dosing solution was a uniform suspension. Any observations regarding phase separation, color, turbidity were recorded.

[0289] Preparation of control diet

[0290] To prepare 1L control diet, weigh 225.55 grams of dry mixture (F1259SP-control diet) into a covered container. Add 350mL of RO grade water and shake vigorously for 30 seconds. Make sure to obtain a uniform suspension. Add 510mL of RO water to make it 1L. A blender can be used to obtain a uniform suspension. Control diets were administered to all groups on day -28. The prepared diets can be stored at 4°C and distributed within 3 days. The prepared diets should not be stored for more than 48 hours at room temperature to prevent the diet from spoiling. In addition, pre-weighed dry powders can be stored at 4°C for up to a week. Before distribution, the diet was stirred at room temperature for at least 30 minutes.

[0291] Preparation of ethanol diet

[0292] Please refer to the table below to prepare 1L of alcohol diet (F1697SP-ethanol diet). A blender can be used to obtain a uniform suspension. The prepared diet can be stored at 4°C and used within 48 hours. In addition, the pre-weighed dry powder can be stored at 4°C for up to one week. Before dispensing, the diet was stirred at room temperature for at least 30 minutes.

[0293] Table 3: Preparation of ethanol diet

[0294]

[0295] Test system

[0296] Species: Mouse

[0297] Strain: C57BL / 6J (JAX#000664)

[0298] Condition: Specially bred, original

[0299] Source: The Jackson Laboratory

[0300] Number of females: 138 (119 in research + 19 in reserve)

[0301] Target age at 10 weeks

[0302] Study started:

[0303] Animal identification

[0304] Method: Subcutaneously implanted electronic identification chip or other approved identification method such as indelible ink where required.

[0305] Animal selection, allocation, replacement and disposal

[0306] Upon arrival, all animals were fed a 5CR4 diet ad libitum. All animals were acclimated to the animal housing room 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: Before dosing began, any designated animal that was considered unsuitable for the study was replaced with a replacement animal. After study day 1, spare animals were transferred to study group 1. General in vivo assessments, including replacement animals, until release from the study. Disposal: The disposal of all animals was recorded in the study record.

[0307] Livestock

[0308] Animals were housed in groups of up to 3 per cage in polycarbonate cages, including appropriate bedding. Housing arrangements 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.

[0309] Diet: 5CR4 chow until day -26; Lieber-DeCarli liquid diet, day -28 to day 15. Upon arrival at the testing facility, all animals were placed ad libitum on PMI Nutrition International certified 5CR4 rodent chow. During the chow diet phase (until day -26), individual animals could be provided with a diet in the form of meals as needed for clinical signs (e.g., broken / damaged incisors or other health changes).

[0310] On days -28 and -27, all animals were provided with both a Lieber DeCarli liquid control diet (50 mL) and PMI Nutrition International certified rodent chow No. 5CR4.

[0311] On day -26, all animals received a 50 mL ethanol diet (1% v / v ethanol). The alcohol percentage in the liquid diet increased by 1% v / v each day until reaching 5% (v / v) on day -22 and remained at 5% v / v until the end of the study.

[0312] Beginning on Day 1 of Cohort 2, triple-housed animals received an additional bottle of 50 mL (5% v / v ethanol). Group-housed cages containing 3 animals per cage received a total volume of 100 mL (divided between the two bottles). The alcohol diet was stirred continuously until administration.

[0313] From day -28 to day 14, prepare fresh diet every other day and serve it in the afternoon.

[0314] Experimental design

[0315]

[0316] N / A = Not Applicable, No. = Quantity, Conc. = Concentration, QD = Once Daily

[0317] a Based on most recent weight.

[0318] b Baseline / treatment start controls (main study Cohort 2 necropsy on Day -3 and Cohort 1 - Day 2 and Cohort 2 - Day 1; PK / BioA Cohort 1 necropsy 24 hours post-dose on Day 14).

[0319] Administration of test and control articles

[0320] Administration route and timing: oral gavage (Groups 2-7), once daily (Days 1-14). The first day of administration is designated as Day 1. The administration formulation is continuously stirred during administration. Administration is performed using a syringe with an attached gavage cannula.

[0321] The terminal plasma and tissue samples were collected and analyzed for TG, TC, ALT, AST, ALP, FGF15 (LCMS), TBIL and endotoxin.

[0322] Tissue collection and preservation

[0323] Representative tissue samples were collected and preserved as described in the following table. Additional tissue samples were collected as needed to clarify abnormal findings.

[0324] Table 4A: Description of tissue collection and storage (main study)

[0325]

[0326]

[0327] X = procedure to be performed; - = not applicable. a All liver lobes were collected before flushing the ileum.

[0328] Table 4B: Tissue Collection and Storage (PK / BioA)

[0329]

[0330]

[0331] X = procedure to be performed; - = not applicable.

[0332] Liver lipid analysis

[0333] Frozen liver samples from the main study were analyzed in duplicate to assess liver 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.

[0334] Histology

[0335] Livers and small intestines collected from all animals in Groups 1-7 (main study) were fixed in 10% neutral buffered formalin for 24-48 hours and transferred to 70% EtOH, stored under ambient conditions, and transferred to the histopathology laboratory of the testing institution.

[0336] Liver tissue

[0337] Formalin-fixed liver tissue was trimmed into slides and stained with H&E and picrosirius red stains. The slides were scored by a Charles River board-certified veterinary pathologist.

[0338] Small Intestinal Tissue

[0339] Formalin-fixed small intestinal tissue was trimmed onto slides and stained with H&E and IHC antibodies (PV-1, ZO-1, and occludin). The slides were scored by a board-certified veterinary pathologist.

[0340] result

[0341] As shown in the table below, compound 1 improved survival better than OCA. Figure 1 and Figure 2 Comp2 in ) increased serum ALP but decreased bilirubin. Serum endotoxin was significantly reduced. For steatosis (graded 1-5 by pathologists), the compound 110 mpk group approached statistical significance. For fibrosis as analyzed by Pico Sirius Red, the animal models had no fibrosis in the baseline or vehicle groups. Minimal increases in fibrosis were observed in OCA 30 mpk, compound 1 30 mpk, and compound 2 30 mpk. For exploratory endpoints in the ileum, all H&E sections IHC staining of tight junctions were normal and identical between groups. See Figure 1 and Figure 2 , clinical chemistry results and liver and ileum histology from this study. Without wishing to be bound by theory, it is believed that these results indicate improved intestinal function in the case of all compounds, and that 10 mg / kg and 30 mg / kg of compound 1 ( Figure 1 and Figure 2 The survival rate of the Comp 1) group was greatly improved.

[0342] Table 5: Research results

[0343]

[0344] *Including animals used for PK

[0345] like Figure 2 As shown in , serum bile acids were significantly increased in vehicle-treated ALD mice and were significantly reduced by both the low dose of Compound 1 (Comp 1) and the high dose of Compound 2 (Comp 2).

[0346] 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-Related Hepatitis

[0347] Compound 1 is a modified bile acid with high potency and selectivity for the farnesoid X receptor (FXR). Due to its FXR-mediated action, compound 1 is a new treatment 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).

[0348] 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 subjects with sAH who are initially hospitalized.

[0349] Compound 1 was administered daily in capsule form at increasing doses starting from 5 mg and increasing stepwise.

[0350] If there are no clinically significant safety or tolerability issues, and after review and approval by the Sponsor's Global Safety Committee (GSC), a decision will be made to upgrade to the next dose cohort, following the same stepwise process (e.g., 10 mg, 25 mg, 50 mg, and 100 mg (5 dose cohorts)). The dose levels for the remaining dose additional cohorts will be defined based on the safety and tolerability data of compound 1 from the previous cohorts. The dose escalation that varies with cohort will not increase by more than 3 times, and the maximum dose level will be 120 mg.

[0351] Approximately 50 subjects aged 18 to 65 years (inclusive) with sAH (defined by Maddrey Discriminant Function [MDF] ≥32 and ≤60 and Model for End-Stage Liver Disease-Sodium [MELD-Na] score of 18 to 25 (inclusive)) are enrolled in the study, including approximately 50 subjects in the Compound 1 treatment group. Five dose cohorts are planned, with doses ranging from 5 mg to 120 mg of Compound 1 (or Comp 1) ( Figure 3 ). Each dose cohort consisted of 2 groups with a total of 10 subjects, of which 8 subjects were randomized to study treatment (treatment group) and 2 subjects were randomized to placebo (control group). Assuming that the responder rate based on the Lille model was 90% in the compound 1 response cohort and 25% in the control cohort, a sample size of 8 subjects per group provided >80% power to detect a treatment difference between the response cohort and the control cohort, with a 2-sided alpha of 0.05.

[0352] The primary objective of the study was to evaluate the effect of Compound 1 treatment on sAH disease progression as assessed by the Lille score at day 7. Secondary objectives included evaluating the effect of Compound 1 treatment on the MELD-Na score at day 28, mortality (short-term mortality and mid-term mortality) or liver transplantation and any infectious complications at days 56 and 84, and evaluating the PK of Compound 1 and its metabolites glycine-Compound 1 and taurine-Compound 1, as well as evaluating the safety and tolerability of Compound 1 in the proposed patient population. Safety and tolerability were assessed by recording adverse events, laboratory evaluations, ECGs, vital signs, and physical examinations. Exploratory objectives / measures included (1) the incidence of alcohol-related hepatitis readmission during the study period (hospitalization defined as a length of stay ≥24 hours); (2) reasons for hospitalization, length of stay, ICU days, major medical procedures, and emergency department visits; (3) changes 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) changes from baseline in IL-6, hs-CRP, CK-18, and TNF-α at day 28; (6) changes from baseline in lipoproteins (LDL, HDL, VLDL), total cholesterol, and triglycerides at day 28; and (8) changes from baseline in lipid metabolism (LBP), 16S rDNA, and stool samples for α-1-antitrypsin and microbiome / metabolome analyses.

[0353] The control group (placebo-treated subjects) in the study provides useful information about efficacy and safety results in a patient population with severe alcohol-related hepatitis treated with standard of care. Placebo-treated subjects within the cohort are intended to be blinded to study drug administration, and data across dose cohorts will be used for the overall analysis.

[0354] The dose levels for this Phase 2a clinical study are based on the overall safety and tolerability profile of compound 1 established in nonclinical programs, and the dose selection in this study is based on data from a Phase 1 dose escalation study of compound 1. There were no adverse safety signals in the nonclinical safety pharmacology study of compound 1. In the Irwin study, compound 1 did not alter neurological function in male rats when tested up to 180 mg / kg. Single doses of compound 1 up to 300 mg / kg did not affect respiratory function in dogs. Results from in vitro human ether-à-go-go related gene (hERG) studies and results from in vivo studies in dogs at doses up to 300 mg / kg indicate that acute cardiovascular effects in humans are not expected. Testing of compound 1 in the in vivo mouse bone marrow micronucleus assay and liver comet assay showed no evidence of DNA damage at doses up to 2000 mg / kg / day for 3 days. Based on these results, compound 1 is not considered genotoxic. In the Phase 1 study, no AEs of clinical concern were observed in healthy subjects administered single or repeated doses of compound 1 at doses less than 50 mg. A 5 mg dose taken once daily for 14 days was well tolerated.

[0355] The study was designed to evaluate the efficacy of increasing doses of compound 1 in a stepwise manner ( Figure 3 ). After clinical review of safety and tolerability, the decision to proceed to the next higher dose cohort was made. The study design included five compound 1 dose cohorts. Each dose cohort consisted of 2 groups, containing a total of 10 subjects, of which 8 subjects were randomly assigned to study treatment (treatment group) and 2 subjects were randomly assigned to placebo (control group). Safety and tolerability were assessed by examining the incidence of unexpected treatment-emergent serious adverse events (SAEs) at each dose, study product discontinuation, and potential drug-induced liver injury (DILI). Additional considerations included overall treatment-emergent adverse events (TEAEs), clinical laboratory tests, ECGs, and vital signs. An increase in the Lille score to >0.85 represents potential drug ineffectiveness (rather than liver injury) and is considered as part of each dose escalation assessment. 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 were reviewed at each visit when the laboratory was drawn.

[0356] Primary efficacy analysis: The primary efficacy analysis was performed using the ITT population. The primary efficacy endpoint was the Lille score on day 7. For the analysis of the Lille score, all subjects with Lille scores on day 7 will be included. The Lille score was analyzed as a categorical variable. In the primary efficacy analysis, subjects with a Lille score <0.45 were counted as responders, and subjects with a Lille score>=0.45 were counted as non-responders. The percentages of responders and non-responders on day 7 were summarized for the treatment group and compared using Fisher's exact test. Additional descriptive analysis was performed on the Lille score as a continuous variable. The efficacy evaluation will start with the highest tolerated dose and be reduced to a lower dose level using a sequential approach. If the higher dose level is statistically significant for the primary efficacy endpoint, the next lower dose level is evaluated. Otherwise, the efficacy evaluation is stopped at the current dose level. The main comparison of the efficacy evaluation is based on the highest tolerated dose.

[0357] Secondary and exploratory efficacy analyses: Secondary and exploratory efficacy analyses were performed using the ITT population. Descriptive statistics were used to summarize all continuous and categorical efficacy endpoints at baseline and at each scheduled post-baseline visit. For continuous endpoints, changes from baseline will also be summarized. Analyses of continuous endpoints were performed using a mixed-effects repeated measures model to assess the effect of treatment group over time based on the ITT population. The dependent variable was the change from baseline. The model will include treatment group, visit, interaction of treatment by visit, and baseline value as covariates as factors. Analyses of categorical endpoints were performed using Fisher's exact test. Any subject whose death status was unknown at a specified time point will be excluded from the mortality analysis. In addition, the Lille score at day 7 will be summarized by treatment group as a continuous variable and compared using an ANOVA model with the Lille score as the dependent variable and treatment group as a fixed effect.

[0358] Target

[0359] Main objectives:

[0360] To evaluate the efficacy of Compound 1 as assessed by disease progression in severe alcohol-associated hepatitis (sAH)

[0361] Secondary Objectives:

[0362] To evaluate the effect of Compound 1 on the efficacy of sAH as assessed by the Model for End-Stage Liver Disease-Sodium (MELD-Na) score

[0363] To evaluate the effect of Compound 1 on clinical outcomes in sAH as assessed by short-term and mid-term mortality and / or liver transplantation

[0364] To evaluate the effect of compound 1 on infectious complications in sAH

[0365] To evaluate the pharmacokinetics (PK) of compound 1 and its metabolites in subjects with sAH

[0366] To evaluate the safety and tolerability of Compound 1 in subjects with sAH

[0367] Exploratory objectives - Evaluate the effect of compound 1 on:

[0368] Readmissions due to alcohol-related hepatitis during the study period

[0369] ·Measurement of health care utilization

[0370] Health-related quality of life

[0371] The following measurement results:

[0372] - Liver biochemistry and liver synthetic function, renal function, hematology

[0373] -Inflammation

[0374] -Lipid metabolism

[0375] - Farnesoid X receptor (FXR) activation

[0376] - Microbiome / Metabolome

[0377] - Bacterial translocation

[0378] Diagnosis and main inclusion criteria

[0379] Subject inclusion criteria

[0380] 1. Male or female aged 18 to 65 years (inclusive)

[0381] 2. Clinical diagnosis of sAH based on all of the following:

[0382] a. History of excessive alcohol consumption (>60 g / day [male] or >40 g / day [female]) for ≥6 months with abstinence for <60 days before onset of jaundice

[0383] b. Serum total bilirubin>3.0mg / dL

[0384] c.AST ≥ 50 U / L (or IU / L)

[0385] d.AST / ALT ratio ≥1.5

[0386] e.MDF≥32 and ≤60

[0387] f. MELD-Na score is 18, 20, or 21 to 25 (inclusive)

[0388] 3. Onset of jaundice within 8 weeks of admission

[0389] 4. Up to but not exceeding (NMT) 7 days after admission

[0390] 5. Female subjects must be postmenopausal and surgically sterile, or, if premenopausal (and non-surgical sterile), be prepared to use ≥ 1 highly effective contraceptive method during the study and within 90 days after the last dose of study drug, as follows: surgical sterilization (bilateral fallopian tube occlusion, etc.); placement of an intrauterine device (IUD) or intrauterine system (e.g., intrauterine hormone-releasing system [IUS]); combined (estrogen and progesterone-containing) hormonal contraceptives associated with ovulation inhibition: oral, intravaginal, transdermal; progesterone-only hormonal contraceptives associated with ovulation inhibition: oral, injectable, implantable; abstinence, if consistent with the subject's preferences and usual lifestyle (where abstinence is defined as avoiding heterosexual intercourse during the entire risk period associated with study treatment).

[0391] 6. Male subjects who have sexual intercourse with female partners of reproductive potential must agree to use condoms containing spermicide and agree to use another approved highly effective contraceptive method from the time of study product administration until at least 90 days after study product administration, as listed in Inclusion Criteria 5.

[0392] 7. Male subjects are not allowed to donate sperm within at least 90 days from screening to the last dose of the study product.

[0393] 8. Written informed consent must be provided and agreement to abide by the study protocol. For subjects with hepatic encephalopathy that may impair decision-making, consent was obtained according to hospital procedures (e.g., by a legally authorized representative).

[0394] Subjects must agree to participate in an alcohol use disorder (AUD) program during the study period (including after hospitalization) as recommended by local institutional addiction medicine specialists.

[0395] Subject exclusion criteria

[0396] 1. Subjects taking systemic corticosteroids or obeticholic acid (OCA)-containing products within 30 days prior to screening (up to and including randomization).

[0397] 2. Pregnant, planning to become pregnant, possibly pregnant (i.e., unwilling to use effective birth control during the study period), or currently or planning to breastfeed

[0398] 3. Stopped drinking for ≥ 2 months before Day 1

[0399] 4. AST or ALT>400 U / L

[0400] 5. MDF <32 or >60 during screening

[0401] 6. MELD-Na score <(less than) 18 or >25 at screening (confirmed by repeated laboratory tests within 48 hours)

[0402] 7. Other causes of liver disease, including chronic hepatitis B (HBsAg positive), chronic hepatitis C (HCV) RNA positive, acetaminophen hepatotoxicity, biliary obstruction, and autoimmune liver disease

[0403] 8. Current or past history of hepatocellular carcinoma (HCC)

[0404] 9. History of liver transplantation or currently on the liver transplant list

[0405] 10. Untreated sepsis (eg, appropriate medical therapy for infection and / or septic shock has not been initiated)

[0406] 11. Known human immunodeficiency virus infection positive

[0407] 12. Uncontrolled gastrointestinal (GI) bleeding or controlled GI bleeding associated with shock or requiring transfusion of more than 3 units of blood within 7 days of screening

[0408] 13. Renal impairment is defined as serum creatinine >133 μmol / L (>1.5 mg / dL) confirmed by repeated testing within 48 hours or the need for renal replacement therapy

[0409] 14. Portal vein thrombosis

[0410] 15. Acute pancreatitis or acute gallbladder disease (e.g. cholecystitis)

[0411] 16. Serious related diseases (such as heart failure, acute myocardial infarction, severe arrhythmia, severe lung disease, nervous system disease)

[0412] 17. Malignant tumor within 2 years prior to screening, except for specific cancers that have been cured by surgical resection (e.g. basal cell skin cancer). Subjects who are being evaluated for possible malignant tumors are not eligible

[0413] 18. Positive urine drug screen (amphetamines, barbiturates, benzodiazepines, cocaine, and opioids), except for tetrahydrocannabinol (THC), or in the case of documented prescription medications (e.g., opioids, benzodiazepines, amphetamines, barbiturates, including those prescribed as part of inpatient management. Subjects who are being treated for alcohol withdrawal may be exempted, check with the medical monitor)

[0414] 19. Participated in a clinical study and received any active investigational product being evaluated for the treatment of sAH within 3 months prior to Day 1

[0415] 20. Participation in another investigational drug or device study within 30 days prior to screening

[0416] 21. Any other conditions or clinical laboratory results that the investigator believes may confound the results, or hinder compliance or completion of the study

[0417] 22. Positive SARS coronavirus 2 (SARS-CoV-2) test within 4 weeks of screening or SARS-CoV-2 vaccination within 2 weeks of screening

[0418] Study products, dosages and routes of administration

[0419] Research product compound 1 capsules and matching placebo capsules are used for oral administration once daily. Research product compound 1 is provided with a variety of capsule specifications within the range of 5mg to 120mg. Multiple compound 1 capsules can be taken to reach appropriate compound 1 dosage levels (e.g., 10mg, 25mg, 50mg and 100mg). Matching placebo capsules will also be provided for blinding. This study is carried out in a double-blind (subject and research center staff) mode, and each dose queue is randomized in a 4:1 mode.

[0420] Reference therapy, dosage and administration

[0421] All eligible subjects will receive appropriate supportive measures, including nutritional support, according to local standards of care. No corticosteroids will be allowed within 30 days prior to screening and up to (and including) randomization, as the aim is to enable subjects to complete the study without corticosteroids, if possible (ophthalmic steroids and low-dose topical or low-dose intranasal steroids are permitted).

[0422] If systemic corticosteroids are started during the screening period, the subject will not be considered eligible for randomization. If systemic corticosteroids are started within the first 7 days after randomization, the subject will be discontinued and replaced in that study cohort. Systemic corticosteroids may be considered on a case-by-case basis after randomization if there is clinical justification (e.g., Lille score >0.56 on Day 7 and elevated total bilirubin or elevated MELD-Na score >3 points that is not due to acute kidney injury).

[0423] Duration of treatment

[0424] Subjects will receive the study product for 28 days.

[0425] Evaluation Criteria

[0426] The endpoints supporting the primary, secondary, and exploratory objectives of this study are as follows:

[0427]

[0428]

[0429] 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 for end-stage liver disease-sodium; NGAL = neutrophil gelatinase-associated lipocalin; PK = pharmacokinetics; SAE = serious adverse event; SBP = spontaneous bacterial peritonitis; TEAE = treatment-emergent adverse event; TNF-α = tumor necrosis factor-α; VLDL = very low-density lipoprotein.

[0430] Example 3: 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

[0431] 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).

[0432] This is a Phase 2b / 3, 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 subjects with sAH who are initially hospitalized.

[0433] Approximately 50 subjects with sAH (defined by Maddrey discriminant function [MDF] ≥ 32 and Model for End-Stage Liver Disease [MELD] score of 21-30 [inclusive]) aged 18 to 65 years (inclusive) were enrolled in the study, including approximately 50 subjects in the Compound 1 treatment group. Dose cohorts (2, 3, 4, or 5 cohorts) were planned with doses ranging from 5 mg to 120 mg Compound 1 (or Comp 1). Each dose cohort consisted of 2 groups with a total of 10 subjects, of which 8 subjects were randomized to study treatment (treatment group) and 2 subjects were randomized to placebo (control group). Assuming that the responder rate based on the Lille model was 90% in the Compound 1 response cohort and 25% in the control cohort, a sample size of 8 subjects per group provided > 80% power to detect a treatment difference between the response cohort and the control cohort, with a 2-sided alpha of 0.05.

[0434] The study was generally conducted according to the objectives, procedures, inclusion and exclusion criteria, efficacy analysis, evaluation criteria, dosing and dosing regimen described in Example 2 above, with the following modifications: The primary objective of the study was to evaluate the effect of Compound 1 treatment on 90-day transplant-free survival in patients with sAH. Secondary objectives included evaluating the effect of Compound 1 treatment on 28-day mortality (short-term mortality), MELD and Lille scores at days 28 and 90, and evaluating the safety and tolerability of Compound 1 in the proposed patient population at days 28 and 90 and at 6 months. Safety and tolerability were assessed by recording adverse events, laboratory evaluations, ECGs, vital signs, and physical examinations. Exploratory objectives / measures included (1) mortality at 6 months; (2) health care utilization, including: incidence of readmission for alcohol-related hepatitis during the study period (hospitalization defined as hospital stay ≥24 hours); reasons for hospitalization, length of stay, ICU days, major medical procedures, and emergency department visits; (3) assessment of pharmacokinetic and pharmacodynamic biomarkers, including: changes from baseline in serum liver biochemistry (ALP, AST, ALT, GGT, and total and direct bilirubin); changes from baseline in IL-6, hs-CRP, CK-18, and TNF-α at day 28; changes from baseline in lipoproteins (LDL, HDL, VLDL), total cholesterol, and triglycerides at day 28; and changes from baseline in lipid metabolism (LBP), 16S rDNA, and stool samples for alpha-1-antitrypsin and microbiome / metabolome analyses; and (4) measures of health-related quality of life (EQ-5D-5L).

Claims

1. A method for treating acute liver disease, comprising administering an effective amount of compound 1 to a patient in need thereof: or a pharmaceutically acceptable salt or amino acid conjugate thereof.

2. The method of claim 1, wherein the liver disease is alcoholic hepatitis (AH).

3. The method of claim 1, wherein the liver disease is severe alcoholic hepatitis (sAH).

4. The method of claim 1, wherein the liver disease is acute-on-chronic liver failure (ACLF).

5. The method according to any one of claims 1-4, wherein the patient exhibits a Maddrey discriminant function (MDF) score of ≥32 prior to treatment with Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof.

6. The method according to any one of claims 1-4, wherein the patient exhibits a Model for End-Stage Liver Disease (MELD or MELD-Na) score of ≥18, or greater than 21, or 21-30 prior to treatment with Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof.

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

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

9. The method according to any one of claims 5-8, 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 on day 28 or day 90 of treatment.

10. The method of any one of claims 1-9, wherein Compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof, is administered daily at a dose of about 1.0 mg to about 300 mg.

11. The method of any one of claims 1-10, wherein Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof is administered daily at a dose of about 2.5 mg to about 300 mg.

12. The method of any one of claims 1-11, wherein Compound 1 is administered daily at a dose of about 5 mg to about 100 mg or about 5 mg to about 120 mg.

13. The method of any one of claims 1-12, wherein Compound 1 is administered daily at a dose of about 5 mg to about 50 mg.

14. The method of any one of claims 1-13, wherein Compound 1 is administered daily at a dose of about 5 mg to about 25 mg.

15. The method of any one of claims 1-14, wherein Compound 1 is administered daily at a dose of about 5 mg to about 10 mg.

16. The method of any one of claims 1-10, wherein Compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof, is administered daily at a dose of about 5 mg to about 150 mg.

17. The method of any one of claims 1-10, wherein Compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof, is administered daily at a dose of about 10 mg to about 100 mg or about 5 mg to about 120 mg.

18. The method of any one of claims 1-10, wherein Compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof, is administered daily at a dose of about 50 mg to about 200 mg.

19. The method of any one of claims 1-10, wherein Compound 1 is administered daily 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.

20. The method of any one of claims 1-9, wherein Compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof, is administered in a single dose or multiple doses sufficient to achieve a total daily dose of about 1.0 mg to about 300 mg.

21. The method according to any one of claims 1-20, further comprising monitoring the blood level of a biomarker in the patient after administration of Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof, wherein the biomarker is selected from C4, FGF-19, and endogenous bile acid.

22. The method of any one of claims 1-21, wherein the patient has a chronic liver disease in addition to sAH or ACLF.

23. The method of claim 22, wherein the patient has alcoholic liver disease (ALD).

24. The method of any one of claims 1-23, wherein the patient exhibits one or more of the following symptoms: (1) if the patient is female, continuous drinking of more than 40 g of alcohol per day, and if the patient is male, continuous drinking of more than 60 g of alcohol per day, for 6 months or longer, and abstinence for less than 60 days before the onset of jaundice; (2) 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 AST / ALT ratio ≥1:5); and (3) worsening jaundice with a bilirubin concentration greater than 3 mg / dL.

25. The method of any one of claims 1-24, wherein the patient exhibits alcohol-related cirrhosis, liver fibrosis, steatosis, steatohepatitis, alcoholic hepatitis, or intestinal dysbiosis.

26. The method of any one of claims 1-25, wherein the patient has been previously diagnosed with sAH and has suffered at least one relapse of sAH.

27. The method of any one of claims 1-26, wherein the method improves the patient's 30-day survival rate compared to otherwise similar patients not administered Compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof.

28. The method of any one of claims 1-27, wherein the method improves the patient's 60-day survival rate compared to otherwise similar patients not administered Compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof.

29. The method of any one of claims 1-28, wherein the method improves the patient's 90-day survival rate compared to an otherwise similar patient not administered Compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof.

30. The method of any one of claims 27-29, wherein the method improves survival by about 10% to about 40%.

31. The method of any one of claims 27-29, wherein the method improves survival by about 10% to about 30%.

32. The method of any one of claims 27-29, wherein the method improves survival by about 10% to about 20%.

33. The method of any one of claims 1-32, wherein the method provides a reduction in healthcare utilization.

34. The method of claim 33, wherein the method provides a reduction in liver-related events in patients suffering from sAH.

35. The method of claim 33 or 34, wherein the method provides at least a 10% reduction in the patient's healthcare utilization over 60 days.

36. The method of any one of claims 33-35, wherein the method reduces one or more of: hospital readmissions, number of hospitalizations, length of stay, emergency room visits, intensive care unit (ICU) days, infectious complications selected from sepsis, pneumonia, urinary tract infection (UTI), cellulitis, spontaneous bacterial peritonitis (SBP), and major medical procedures within 30, 60, or 90 days after discharge.

37. The method of any one of claims 1-36, further comprising co-administering to the patient an effective amount of an anti-inflammatory agent, an antibiotic, an antioxidant, a probiotic, a fecal transplant, a Zn supplement, or a combination of any of those agents.

38. The method of any one of claims 1-36, 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, a probiotic, a fecal transplant, a Zn supplement, or a combination of any of those agents.

39. The method according to any one of claims 1-38, wherein the patient does not exhibit one or more of the following: AST or ALT>400 U / L, MDF>60 before treatment, MELD score>25 or>30 or MELD-Na>25 or>30 before treatment, selected from chronic hepatitis B (hepatitis B surface antigen [HBsAg] positive), chronic hepatitis C (HCV RNA positive), acetaminophen hepatotoxicity, biliary obstruction, and other causes of liver disease with autoimmune liver disease; with a previous history of hepatocellular carcinoma (HCC), a history of liver transplantation, untreated sepsis, known positive human immunodeficiency virus infection, uncontrolled gastrointestinal (GI) bleeding associated with shock or requiring transfusion of more than 3 units of blood or controlled GI bleeding within 7 days of starting treatment, defined as serum creatinine >133 μmol / L (>1.5 mg / dL) or acute kidney injury requiring renal replacement therapy, portal vein thrombosis, acute pancreatitis, or a serious associated disease selected from heart failure, acute myocardial infarction, severe arrhythmia, severe lung disease, and neurologic disease.

40. The method of any one of claims 1-39, wherein the method provides at least a 15% reduction in mortality at 90 days compared to standard of care (SOC).

41. The method of any one of claims 1-40, wherein the method provides at least a 15% reduction in hospitalization and / or at least a 15% reduction in progression to transplantation.

42. The method of any one of claims 1-41, wherein Compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof, is administered to the patient for about 30 days to about 90 days.

43. The method of any one of claims 1-42, wherein Compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof, is administered orally.

44. The method of claim 6, wherein Compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof, is administered in a single dose or multiple doses sufficient to achieve a total daily dose of: from about 1.0 mg to about 300 mg; or about 2.5 mg to about 300 mg; or about 5 mg to about 100 mg; or from about 5 mg to about 50 mg; or about 5 mg to about 25 mg; or about 5 mg to about 10 mg; or from about 5 mg to about 150 mg; or from about 5 mg to about 120 mg; or from 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.

45. The method of any one of claims 1-9, wherein the patient exhibits AST ≥ 50 U / L (or IU / L) prior to treatment with Compound 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof.

46. ​​The method of any one of claims 1-9, wherein the patient exhibits an AST / ALT ratio ≥ 1.5 prior to treatment with Compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof.

47. The method of any one of claims 1-9, wherein the patient exhibits one or more of the following prior to treatment with Compound 1, or a pharmaceutically acceptable salt or amino acid conjugate thereof: AST ≥ 50 U / L; AST / ALT ratio ≥1.5; Maddrey discriminant function (MDF) score ≥32; and Model for End-Stage Liver Disease (MELD or MELD-Na) score ≥18, or ≥20, or ≥21, such as 21-30.

48. A method of determining a patient's candidacy for therapeutic treatment of sAH, comprising determining the patient's MELD-Na score.

49. The method of claim 48, further comprising determining the patient's MDF score.

50. The method of claim 49, wherein the patient has a MELD-Na score ≥ 18.

51. The method of claim 48, wherein the patient has a MELD-Na score ≥ 18.

52. The method of claim 49, wherein the patient has an MDF score > 32, such as from 32 to 60, inclusive.

53. A method for treating sAH, comprising: Select patients with a MELD-Na score ≥18 or a MELD score of 21-30, and Administer therapeutic treatment for sAH.

54. The method of claim 53, wherein the patient further has an MDF score from 32 to 60, inclusive.

55. The method of claim 53 or 54, wherein the therapeutic treatment comprises administering a pharmaceutical agent and / or a liver transplant to the patient.

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