Farnesoid X receptor agonists for the treatment of diseases

Abstract

Described herein is the use of farnesoid X receptor (FXR) agonists, alone or in combination with additional treatments, in the treatment or prevention of diseases, conditions, or disorders that would benefit from treatment with an FXR agonist.

Description

[Technical Field]

[0001] Cross-referencing of related technologies This application claims the interests of U.S. Provisional Patent Application No. 62 / 991,292 filed on 18 March 2020, U.S. Provisional Patent Application No. 63 / 069,667 filed on 24 August 2020, and U.S. Provisional Patent Application No. 63 / 140,735 filed on 22 January 2021, each of which is incorporated herein by reference in whole.

[0002] This specification describes therapeutic strategies for the treatment of conditions, diseases, or disorders that would benefit from treatment using farnesoid X receptor agonists alone or in combination with other therapeutic agents. [Background technology]

[0003] The farnesoid X receptor (FXR) is a nuclear receptor expressed in the liver, intestines, kidneys, and adipose tissue. FXR modulates various target genes involved in the synthesis and transport of bile acids, lipid metabolism, and the regulation of glucose homeostasis. Activation of FXR is a therapeutic approach for many metabolic and liver diseases. [Overview of the Initiative]

[0004] In one embodiment, a method for treating or preventing a liver disease or condition, a lipid disorder or disorder, a metabolic inflammation-mediated disease or disorder, or a combination thereof, comprising administering a compound (Compound 1) which is 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate or a pharmaceutically acceptable salt thereof to a subject in need thereof is described herein.

[0005] In some embodiments, the liver disease or condition is steatohepatitis, cholangitis, fatty liver disease, cholestasis, cirrhosis, fibrous liver disease, hepatitis, primary biliary cholangitis, biliary atresia, Alagille syndrome, IFALD (intestinal insufficiency-associated liver disease), parenteral nutrition-associated liver disease (PNALD), hepatitis, hepatocellular carcinoma, cholangiocarcinoma, or a combination thereof.

[0006] In some embodiments, steatohepatitis is non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), or HIV-associated steatohepatitis.

[0007] In some embodiments, the liver disease or condition is non-alcoholic steatohepatitis (NASH).

[0008] In some embodiments, the liver disease or condition is NASH with hepatic fibrosis.

[0009] In some embodiments, the liver disease or condition is NASH without hepatic fibrosis.

[0010] In some embodiments, the cholangitis is primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC).

[0011] In some embodiments, fatty liver disease is non-alcoholic fatty liver disease (NAFLD) or alcohol-related fatty liver disease.

[0012] In some embodiments, cholestasis is either intrahepatic or extrahepatic.

[0013] In some embodiments, cholestasis is either pregnancy-related intrahepatic cholestasis or progressive familial intrahepatic cholestasis (PFIC).

[0014] In some embodiments, the cirrhosis is HIV-related cirrhosis.

[0015] In some embodiments, the metabolic inflammatory-mediated disease or disorder is diabetes.

[0016] In some embodiments, the diabetes is type 2 diabetes.

[0017] In some embodiments, the lipid disease or disorder is dyslipidemia. Dyslipidemia is a condition where the lipids in the blood are in abnormal amounts. In some embodiments, the lipids are selected from triglycerides, cholesterol, and phospholipids. In some embodiments, a long-term increase in insulin concentration leads to dyslipidemia. In some embodiments, an increase in the concentration of O-GlcNAc transferase (OGT) causes dyslipidemia.

[0018] In some embodiments, the fibrotic liver disease is a fibrotic liver disease resulting from non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), hepatitis C virus (HCV), cirrhosis, Wilson's disease, HIV-related steatohepatitis, HIV-related cirrhosis, or congenital hepatic fibrosis.

[0019] In some embodiments, the hepatitis is acute hepatitis, chronic hepatitis, fulminant hepatitis, viral hepatitis, bacterial hepatitis, parasitic hepatitis, toxic and drug-induced hepatitis, alcoholic hepatitis, autoimmune hepatitis, non-alcoholic steatohepatitis (NASH), neonatal hepatitis, or ischemic hepatitis.

[0020] In some embodiments, the hepatitis is autoimmune hepatitis.

[0021] In some embodiments, the liver disease or condition is Alagille syndrome.

[0022] In some embodiments, the liver disease or condition is biliary atresia.

[0023] In some embodiments, the liver disease or condition is hepatocellular carcinoma.

[0024] In some embodiments, the liver disease or condition is bile duct cancer.

[0025] In some embodiments, treating liver disease or condition, lipid disorder or impairment, metabolic inflammation-mediated disease or impairment, or a combination thereof, includes increasing serum FGF-19 concentration, decreasing serum 7α-hydroxy-4-cholesten-3-one (C4) concentration, decreasing serum bile acid concentration, or a combination thereof.

[0026] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered systemically to the subject. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered orally, by injection, or intravenously to the subject.

[0027] In some embodiments, in addition to compound 1 or a pharmaceutically acceptable salt thereof, at least one additional therapeutic agent is administered to the subject.

[0028] In another embodiment, a method for treating or preventing fatty liver disease in a subject is described herein, comprising administering to a subject having fatty liver disease a compound (Compound 1) which is 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate. In some embodiments, the fatty liver disease is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or alcoholic steatohepatitis (ASH). In some embodiments, treating fatty liver disease includes reducing liver fat, improving liver tissue appearance, improving liver blood tests, improving cholestatic pruritus, or a combination thereof. In some embodiments, the subject has diabetes mellitus. In some embodiments, diabetes mellitus is type 2 diabetes mellitus. In some embodiments, treating or preventing fatty liver disease involves increasing serum FGF-19 concentration, decreasing serum 7α-hydroxy-4-cholesten-3-one (C4) concentration, decreasing serum bile acid concentration, or a combination thereof.

[0029] In another embodiment, the following method is described herein for treating or preventing a gastrointestinal disorder or condition, comprising administering a compound (Compound 1) which is 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate or a pharmaceutically acceptable salt thereof to a subject in need.

[0030] In some embodiments, the gastrointestinal disease or condition is necrotizing enterocolitis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), gastroenteritis, radiation enteritis, pseudomembranous colitis, enteritis, celiac disease, postoperative inflammation of the intestines, graft-versus-host disease, bile acid reflux, or colorectal cancer.

[0031] In some embodiments, the gastrointestinal disorder or condition is inflammatory bowel disease (IBD).

[0032] In some embodiments, inflammatory bowel disease (IBD) is Crohn's disease or ulcerative colitis.

[0033] In some embodiments, irritable bowel syndrome (IBS) is defined as diarrhea-predominant irritable bowel syndrome (IBS-D), constipation-predominant irritable bowel syndrome (IBS-C), mixed-type IBS (IBS-M), unclassifiable IBS (IBS-U), or biliary acid diarrhea (BAD).

[0034] In some embodiments, IBS-D is caused by malabsorption of bile acids.

[0035] In some embodiments, the gastrointestinal disease or condition is colitis. In some embodiments, the colitis is ulcerative colitis, microscopic colitis, or pseudomembranous colitis.

[0036] In some embodiments, the enteritis is radiation enteritis or chemotherapy-induced enteritis.

[0037] In some embodiments, the gastroenteritis is idiopathic gastroenteritis.

[0038] In some embodiments, the gastrointestinal disorder or condition is bile acid reflux with gastroesophageal reflux disease (GERD). In some embodiments, the gastrointestinal disorder or condition is bile acid reflux without GERD.

[0039] In some embodiments, the gastrointestinal disorder or condition includes elevated serum FGF-19 concentration, decreased serum 7α-hydroxy-4-cholesten-3-one (C4) concentration, decreased serum bile acid concentration, or a combination thereof.

[0040] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered systemically to the subject. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered non-systemically to the subject. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered orally, by injection, or intravenously to the subject.

[0041] In another embodiment, a method for treating or preventing a kidney disease or condition is described herein, comprising administering a compound (Compound 1) which is 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate or a pharmaceutically acceptable salt thereof to a subject in need.

[0042] In some embodiments, the kidney disease or condition is renal fibrosis, acute kidney injury, chronic kidney injury, ischemic nephropathy, diabetic nephropathy, tubulointerstitial nephritis / nephropathy, glomerulonephritis / nephropathy, or a combination thereof.

[0043] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered systemically to a subject.

[0044] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject orally, by injection, or intravenously.

[0045] In another embodiment, a method for treating or preventing cancer is described herein, comprising administering a compound (Compound 1) which is 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0046] In some embodiments, the cancer is prostate cancer, colorectal cancer, or hepatocellular carcinoma.

[0047] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered systemically to the subject. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered orally, by injection, or intravenously to the subject.

[0048] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to a mammal in doses of about 1 mg to about 300 mg of compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to a mammal in doses of about 1 mg to about 30 mg of compound 1. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to a mammal in doses of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 12 mg, about 15 mg, about 20 mg, or about 25 mg. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to a mammal in doses of about 3 mg or about 6 mg.

[0049] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered systemically to a subject. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered orally, by injection, or intravenously to a subject. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to mammals in the form of an oral solution, oral suspension, powder, pill, tablet, or capsule.

[0050] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered non-systemically to the subject.

[0051] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to mammals daily. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered to mammals once daily.

[0052] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered orally to mammals, comprising a dose-adjusted administration schedule or regimen. In some embodiments, the dose-adjusted schedule comprises administering an initial dose of compound 1 or a pharmaceutically acceptable salt thereof daily over a period of time, followed by administering compound 1 or a pharmaceutically acceptable salt thereof daily at a higher dose than the initial dose. In some embodiments, the period of time includes 1 day, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks.

[0053] In some embodiments, the dose adjustment schedule includes dose escalation or dose decrement of compound 1 or a pharmaceutically acceptable salt thereof, followed by optional re-escalation. In some embodiments, the dose adjustment schedule includes administering compound 1 or a pharmaceutically acceptable salt thereof at an initial dose for about one week, and if the patient tolerates the initial dose, increasing the dose by an amount equal to a first increment, or if the patient does not tolerate the initial dose, decreasing the dose by an amount equal to a first increment. In some embodiments, the dose adjustment schedule further includes administering compound 1 or a pharmaceutically acceptable salt thereof at an increased dose for about one week, and if the patient tolerates the increased dose, further increasing the dose by an amount equal to a second increment, or administering compound 1 or a pharmaceutically acceptable salt thereof at a reduced dose for about one week, and if the patient tolerates the reduced dose, optionally increasing the dose by an amount equal to a second increment. In some embodiments, the dose adjustment schedule is repeated until an optimized dose is obtained.

[0054] In some embodiments, any therapeutic method described herein further comprises administering at least one additional therapeutic agent to the target in addition to compound 1 or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, at least one additional therapeutic agent is an angiotensin 2 receptor agonist, a ketohexokinase (KHK) inhibitor, a mitochondrial uncoupler or protonophore, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a sodium-glucose cotransporter 1 / 2 (SGLT1 / 2) coinhibitor, a dihydroceramide desaturase 1 (DES-1) inhibitor, an integrin aVb1 inhibitor, an integrin aVb6 inhibitor, a NOD-like receptor protein 3 (NLRP3) inhibitor, a cyclophyllin inhibitor, a glucagon-like peptide-1 (GLP-1) agonist, a 17-β hydroxysteroid dehydrogenase 13 (17b-HSD13) inhibitor, a thyroid hormone receptor β (THR-β) agonist, or a combination thereof.

[0056] In some embodiments, at least one additional therapeutic agent is a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a sodium-glucose cotransporter 1 / 2 (SGLT1 / 2) cotransporter, a glucagon-like peptide-1 (GLP-1) agonist, or a combination thereof.

[0057] In another embodiment, a method for evaluating the clinical response to treatment with 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate (compound 1) or a pharmaceutically acceptable salt thereof in subjects with fatty liver disease, wherein (a) before initiating treatment with compound 1, the subjects with fatty liver disease The Specified Method comprises (b) evaluating the liver fat content (LFC) of a subject with fatty liver disease, (c) administering compound 1 to a subject with fatty liver disease at an initial daily dose for an initial period, and (d) continuing daily administration of compound 1 if the LFC from step (a) is higher than the LFC from step (b), or discontinuing daily administration of the FXR agonist if the LFC from step (b) is substantially similar to the LFC from step (a).

[0058] In some embodiments, the initial period is approximately 2 weeks, 3 weeks, or 4 weeks. In some embodiments, the initial period is approximately 4 weeks. In some embodiments, compound 1 is administered to the subject according to a dose adjustment schedule. In some embodiments, the dose adjustment schedule includes one or more cycles of administering compound 1 at an initial daily dose for approximately one week, followed by administering compound 1 at an increased daily dose or a decreased daily dose, followed by optionally increasing the daily dose of compound 1 administered. In some embodiments, the initial daily dose is less than the initial daily dose in step (b). In some embodiments, the administration cycle is repeated.

[0059] In some embodiments, the method further includes (i) evaluating the liver fat content (LFC) of a subject with fatty liver disease about 12 weeks after treatment with compound 1, and (ii) adjusting the daily dose of compound 1 if the relative change in LFC between step (c) and step (i) is less than about 10%.

[0060] In some embodiments, adjusting the daily dose of compound 1 includes increasing the daily dose of compound 1. In some embodiments, adjusting the daily dose of compound 1 includes decreasing the daily dose of compound 1. In some embodiments, if the relative change in LFC between step (c) and step (i) is less than 10%, adjusting the daily dose of compound 1 includes increasing the daily dose of compound 1 agonist. In some embodiments, if the relative change in LFC between step (c) and step (i) is less than 20%, adjusting the daily dose of compound 1 includes increasing the daily dose of compound 1.

[0061] In some embodiments, adjusting the daily dose of compound 1 includes increasing the daily dose in a dose adjustment schedule.

[0062] In some embodiments, the initial daily dose of compound 1 in step (b) is about 1 mg to about 3 mg. In some embodiments, if the relative change in LFC between step (c) and step (i) is less than 10%, adjusting the daily dose of the FXR agonist involves increasing the daily dose of compound 1 from about 1 mg to about 3 mg to about 3 mg to about 12 mg.

[0063] In some embodiments, the initial daily dose of compound 1 in step (b) is about 1 mg to about 6 mg. In some embodiments, if the relative change in LFC between step (c) and step (i) is less than 10%, adjusting the daily dose of the FXR agonist involves increasing the daily dose of compound 1 from about 1 mg to about 6 mg to about 3 mg to about 12 mg.

[0064] In some embodiments, LFCs are evaluated by magnetic resonance imaging-proton density lipid fraction (MRI-PDFF).

[0065] A manufactured product is provided, comprising packaging material, compound 1 or a pharmaceutically acceptable salt thereof contained within the packaging material, and a label indicating that compound 1 or a pharmaceutically acceptable salt thereof is used to modulate the activity of FXR, or for the treatment, prevention, or improvement of one or more symptoms of a disease or condition that would benefit from the modulation of FXR activity.

[0066] Other purposes, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, various changes and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art from this detailed description, so it should be understood that the detailed description and specific examples, while illustrating specific embodiments, are given only as examples. [Brief explanation of the drawing]

[0067] [Figure 1]Figure 1 shows the change from baseline in the NAFLD activity score (NAS) after administration of compound 1 in a NASH mouse model. [Figure 2] Figure 2 shows the improvement rate of fibrosis in a NASH mouse model after administration of compound 1, as measured by liver tissue images. [Figure 3A] Figure 3A shows the concentration of liver triglycerides per gram of liver after administration of compound 1. [Figure 3B] Figure 3B shows the concentration of liver cholesterol per gram of liver after administration of compound 1. [Figure 4] Figure 4 shows the percentage change in body weight from baseline in a mouse model of T cell adoptive transfer colitis after administration of compound 1. [Figure 5] Figure 5 shows the change in the weight-to-length ratio of the entire colon in a mouse model of T-cell adoptive transfer colitis after administration of compound 1. [Figure 6] Figure 6 shows the histopathological score of the entire colon in a mouse model of T-cell adoptive transfer colitis after administration of compound 1. [Figure 7] Figure 7 shows the drug concentrations of compound 1 in plasma after 7 days of oral administration in non-human primates. [Figure 8] Figure 8 shows the changes in C4 concentration after 7 days of oral administration of compound 1 in non-human primates. [Figure 9] Figure 9 shows the drug concentration of compound 1 in plasma on day 14 after 14 days of oral administration in humans. [Figure 10] Figure 10 shows the change in C4 concentration on day 14, 14 days after administration of compound 1 in humans. [Figure 11] Figure 11 shows the daily changes in C4 concentration during a 14-day administration of compound 1 in humans. [Modes for carrying out the invention]

[0068] FXR plays a crucial role in suppressing hepatitis and regulating lipid metabolism. The nuclear hormone receptor farnesoid X receptor (also known as FXR or nuclear receptor subfamily 1, group H, member 4 (NR1H4)) (OMIM:603826) functions as a regulator of bile acid metabolism. FXR is a ligand-activated transcription receptor expressed in diverse tissues, including the adrenal glands, kidneys, stomach, duodenum, jejunum, ileum, colon, gallbladder, liver, macrophages, and white and brown adipose tissue. Bile acids function as endogenous ligands for FXR, thereby inducing FXR-dependent changes in the gene expression network for intestinal and systemic release of bile acids. Bile acids are the major oxidation products of cholesterol and, in some cases, when secreted into the intestines, become regulators of cholesterol absorption. The rate-limiting step in the conversion of cholesterol to bile acids is catalyzed by the cytochrome p450 enzyme cholesterol 7-α-hydroxylase (CYP7A1) and occurs in the liver. Activation of FXR represses CYP7A1 transcription by increasing the expression level of the small heterodimer partner (SHP) in the liver (also known as nuclear receptor subfamily 0, group B, member 2, or NR0B2) and the gut expression of fibroblast growth factor 15 (FGF15) in mice and fibroblast growth factor 19 (FGF-19) in humans. SHP represses the liver receptor homolog (LRH-1), a nuclear receptor necessary for CYP7A1 gene expression, through interaction with LRH-1, forming a non-functional heterodimer. In some cases, FGF15 / 19 released from the gut then activates fibroblast growth factor receptor 4 in the liver, leading to the activation of the mitogen-activated protein kinase (MAPK) signaling pathway that represses CYP7A1.

[0069] In some embodiments, FXR activation leads to a reduction in hepatitis. For example, FXR activation has been shown to antagonize the NF-κB pathway involved in hepatitis (Wang et al., Hepatology 48(5):1632-1643, 2008). In some embodiments, FXR activation reduces inflammation in the gastrointestinal tract. For example, FXR activation reduces the production of inflammatory cytokines such as interleukin (IL) 1-β, IL-2, IL-6, tumor necrosis factor α (TNF-α), and interferon γ (Stojancevic et al, Can J Gastroenterol, 26(9):631-637, 2012).

[0070] There is an unmet need for therapeutic agents that specifically target molecular targets and / or pathways involved in liver diseases such as fibrous liver disease, metabolic liver disease, and inflammatory liver disease.

[0071] In certain embodiments, a method for treating liver disease in a subject in need is disclosed herein, comprising administering an FXR agonist, for example, compound 1 or a pharmaceutically acceptable salt thereof, to the subject.

[0072] In certain embodiments, methods for treating metabolic liver disease in subjects in need are further disclosed herein, comprising administering an FXR agonist, for example, compound 1 or a pharmaceutically acceptable salt thereof, to the subject.

[0073] In certain embodiments, methods for treating fibrous liver disease in subjects in need are further disclosed herein, comprising administering an FXR agonist, for example, compound 1 or a pharmaceutically acceptable salt thereof, to the subject.

[0074] In certain embodiments, methods for treating gastrointestinal disorders in subjects in need are further disclosed herein, comprising administering a farnesoid X receptor (FXR) agonist, for example, compound 1 or a pharmaceutically acceptable salt thereof, to the subject.

[0075] In certain embodiments, methods for treating inflammation in a subject in need are further disclosed herein, comprising administering an FXR agonist, for example, compound 1 or a pharmaceutically acceptable salt thereof, to the subject.

[0076] Furthermore, in certain embodiments, pharmaceutical compositions comprising an FXR agonist, such as compound 1 or a pharmaceutically acceptable salt thereof, are disclosed herein.

[0077] (Liver disease) In certain embodiments, methods for treating or preventing liver disease in subjects in need are disclosed herein, comprising administering an FXR agonist to the subject. In some embodiments, in addition to the FXR agonist, at least one additional therapeutic agent is administered to the subject. In some embodiments, the FXR agonist is compound 1 or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the liver disease is alcoholic liver disease or non-alcoholic liver disease. In some embodiments, the liver disease is alcoholic liver disease. Exemplary alcoholic liver diseases or conditions include, but are not limited to, fatty liver (steatosis), cirrhosis, alcoholic steatohepatitis (ASH), or alcoholic hepatitis. In some embodiments, an FXR agonist is administered to a subject in need as a method of treating or preventing fatty liver (steatosis), cirrhosis, alcoholic steatohepatitis (ASH), or alcoholic hepatitis.

[0079] (Steatosis) Lipidosis, also known as dyslipidemia, dyslipidemia, or dyslipidemia, is a process that explains the abnormal retention of lipids within cells.

[0080] Steadysia most commonly affects the liver, the main organ of lipid metabolism, and this condition is commonly known as fatty liver disease. Steadysia can also occur in other organs, such as the kidneys, heart, and muscles. A variety of risk factors are associated with steadysia and include, but are not limited to, diabetes, protein malnutrition, hypertension, cytotoxicity, obesity, anoxia, and sleep apnea.

[0081] Lipid dyslipidemia reflects a disruption in the normal processes of triglyceride synthesis and removal. Excess lipids accumulate in vesicles that replace the cytoplasm. In mild cases, it is not particularly harmful to cells, but large accumulations can destroy cellular components, and in severe cases, cells may even rupture.

[0082] In some embodiments, administration of FXR agonists to mammals with steatosis reduces steatosis in mammals.

[0083] In some cases, steatosis is reduced by approximately 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%. In some cases, this level of steatosis is compared to the level of steatosis in mammals not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammals. In some embodiments, the additional therapeutic agents are anti-inflammatory agents, metabolites, or antifibrotic agents.

[0084] In several cases, administration of FXR agonists to mammals with steatosis reduces mammalian liver fat by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more.

[0085] Hepatic steatohepatitis, also known as fatty liver disease, is a condition in which excessive amounts of triglyceride lipids accumulate in liver cells and may be accompanied by progressive inflammation of the liver, also known as steatohepatitis. In some embodiments, the FXR agonists disclosed herein reduce fatty liver disease (hepatic steatohepatitis) or steatohepatitis in mammals. In some examples, FXR agonists reduce hepatic steatohepatitis or steatohepatitis in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, hepatic steatohepatitis or steatohepatitis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some cases, this level of hepatic steatohepatitis or steatohepatitis is compared to the level of hepatic steatohepatitis or steatohepatitis in mammals not treated with the FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammals. In some embodiments, additional therapeutic agents are anti-inflammatory agents, metabolites, or antifibrotic agents.

[0086] (Cirrhosis of the liver) Cirrhosis is a condition in which the liver suffers long-term damage that affects its function. Symptoms of cirrhosis include, but are not limited to, fatigue, edema of the lower legs, jaundice, easy bruising, fluid accumulation in the abdomen, and spider veins. Cirrhosis is most commonly caused by alcohol, hepatitis B, hepatitis C, and non-alcoholic liver disease. In some embodiments, the FXR agonists disclosed herein reduce mammalian cirrhosis. In some examples, FXR agonists reduce mammalian cirrhosis by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, the level of cirrhosis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some cases, the level of cirrhosis is compared to the level of cirrhosis in mammals not treated with an FXR agonist. In some embodiments, an additional therapeutic agent is administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolite, or an antifibrotic agent.

[0087] (Alcoholic Steatohepatitis (ASH)) Alcoholic steatohepatitis is a condition in which excessive amounts of triglyceride lipids accumulate in liver cells due to long-term alcohol consumption, and may be accompanied by progressive hepatitis. In some embodiments, the FXR agonists disclosed herein reduce alcoholic steatohepatitis in mammals. In some examples, FXR agonists reduce alcoholic steatohepatitis in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, the level of alcoholic steatohepatitis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some cases, this level of alcoholic steatohepatitis is compared to the level of alcoholic steatohepatitis in mammals not treated with the FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammals. In some embodiments, additional therapeutic agents are anti-inflammatory agents, metabolites, or antifibrotic agents.

[0088] (Alcoholic hepatitis) Alcoholic hepatitis is hepatitis caused by excessive alcohol intake. It is typically associated with fatty liver and contributes to the progression of fibrosis, which leads to cirrhosis. In some embodiments, the FXR agonists disclosed herein reduce alcoholic hepatitis in mammals. In some embodiments, FXR agonists reduce alcoholic hepatitis in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, the level of alcoholic hepatitis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some cases, this level of alcoholic hepatitis is compared to the level of alcoholic hepatitis in mammals not treated with the FXR agonist. In some embodiments, an additional therapeutic agent is administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolite, or an antifibrotic agent.

[0089] (metabolic liver disease) In some embodiments, farnesoid X receptor (FXR) agonists are administered to subjects in need as a method for treating or preventing non-alcoholic liver disease. In some embodiments, non-alcoholic liver disease is a metabolic liver disease. In some embodiments, the metabolic disease is accompanied by hepatic fibrosis. In some embodiments, the metabolic liver disease is caused by obesity, hypertension, dyslipidemia, type 2 diabetes, impaired glucose tolerance, impaired fasting blood glucose, or insulin resistance.

[0090] In certain embodiments, methods for treating or preventing metabolic liver disease in subjects in need are disclosed herein, comprising administering a farnesoid X receptor (FXR) agonist to the subject. In some embodiments, the metabolic liver disease is non-alcoholic fatty liver disease (NAFLD), intrahepatic cholestasis, or extrahepatic cholestasis. In some embodiments, a farnesoid X receptor (FXR) agonist is administered to a subject in need as a method for treating or preventing non-alcoholic fatty liver disease (NAFLD), intrahepatic cholestasis, or extrahepatic cholestasis.

[0091] In some embodiments, the regulation of metabolic processes such as bile acid synthesis, bile acid circulation, glucose metabolism, lipid metabolism, or insulin sensitivity is regulated by FXR activation. Furthermore, in some embodiments, dysregulation of metabolic processes such as bile acid synthesis, bile acid circulation, glucose metabolism, lipid metabolism, or insulin sensitivity results in metabolic disorders such as diabetes or diabetes-related conditions or disorders, alcoholic or non-alcoholic liver disease or conditions, intestinal inflammation, or cell proliferation disorders.

[0092] In some embodiments, elevated bile acid concentrations are associated with insulin resistance. For example, insulin resistance can lead to decreased glucose uptake from the blood and increased de novo glucose production in the liver. In some cases, intestinal sequestration of bile acids has been shown to improve insulin resistance by promoting the secretion of glucagon-like peptide-1 (GLP1) from intestinal L cells. GLP-1 is an incretin derived from the transcript of the proglucagon gene. GLP-1 is released in response to food intake and regulates appetite and gastrointestinal function and promotes insulin secretion from the pancreas. Biologically active forms of GLP-1 include GLP-1-(7-37) and GLP-1-(7-36)NH2, which result from the selective cleavage of the proglucagon molecule.

[0093] In some embodiments, FXR activation also correlates with the folding and secretion of pancreatic polypeptides such as peptide YY (PYY or PYY3-36). In some cases, peptide YY is a gastrointestinal hormone peptide that modulates neuronal activity in the hypothalamus and brainstem, brain regions involved in reward processing. In some cases, decreased PYY levels correlate with increased appetite and weight gain.

[0094] In some cases, FXR activation indirectly leads to a decrease in plasma triglycerides. Triglyceride clearance from the bloodstream is mediated by lipoprotein lipase (LPL). LPL activity is enhanced by the induction of its activator, apolipoprotein CII, and suppression of its inhibitor, apolipoprotein CIII, in the liver occurs upon FXR activation.

[0095] In some cases, FXR activation further modulates energy expenditure, such as the differentiation and function of adipocytes. Adipose tissue contains adipocytes or fat cells. In some cases, adipocytes further differentiate into brown adipose tissue (BAT) or white adipose tissue (WAT). The function of BAT is to generate body heat, while WAT functions as a fat-storing tissue. In some embodiments, FXR activation enhances thermogenesis and browning of WAT. In some embodiments, FXR activation increases the amount of BAT.

[0096] In some cases, FXR is widely expressed in the gut. In some cases, FXR activation has been shown to induce the expression and secretion of FGF-19 (or FGF15 in mice) in the gut. FGF-19 is a hormone that regulates bile acid synthesis and affects glucose metabolism, lipid metabolism, and energy expenditure. In some cases, FGF-19 has also been observed to regulate adipocyte function and differentiation. In fact, one study showed that administering FGF-19 to mice fed a high-fat diet increased energy expenditure, regulated adipocyte differentiation and function, reversed weight gain, and improved insulin resistance (see Fu et al., “Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes.” Endocrinology 145:2594-2603 (2004)).

[0097] In some cases, gut FXR activity has been shown to be involved in reducing abnormal growth of the microbiome, such as during feeding (Li et al., Nat Commun 4:2384, 2013). For example, one study showed that FXR activation correlated with increased expression of several genes in the ileum, including Ang2, iNos, and Il18, which have established antibacterial activity (Inagaki et al., Proc Natl Acad Sci USA 103:3920-3925, 2006).

[0098] G protein-coupled bile acid receptor 1 (also known as GPBAR2, GPCR19, bile acid membrane receptor, M-BAR, or TGR5) is a cell surface receptor for bile acids. When TGR5 is activated by bile acids, intracellular cAMP production is induced, which in turn leads to an increase in triiodothyronine through the activation of deiodinase (DIO2) in the bile acid thromboembolic acid (BAT), resulting in increased energy expenditure.

[0099] (Non-alcoholic fatty liver disease (NAFLD)) Non-alcoholic fatty liver disease (NAFLD) is associated with excessive fat (steatosis) in the liver due to causes other than excessive alcohol consumption. NAFLD can manifest as simple steatosis or as steatosis with inflammation and liver damage, classified as non-alcoholic steatohepatitis (NASH). In some embodiments, NAFLD is associated with obesity, type 2 diabetes, and metabolic syndrome. Metabolic syndrome is the overlap of at least three medical conditions, including but not limited to obesity, elevated blood pressure, elevated fasting blood glucose, elevated serum triglycerides, and high and low density lipoprotein (LDL) concentrations.

[0100] According to the National Institutes of Health, approximately 30-40% of adults in the United States have NAFLD, and about 20% of those have NASH. NASH is characterized by inflammation and enlargement of the liver. Over time, individuals with NASH may develop liver scarring or fibrosis, which can progress to cirrhosis. Approximately 40% of patients diagnosed with NASH progress to more advanced fibrosis or cirrhosis (fibrosis stage 2 or higher), increasing their risk of hepatocellular carcinoma or liver cancer, as well as cardiovascular disease. NASH is commonly associated with obesity and type 2 diabetes.

[0101] In some embodiments, the FXR agonists disclosed herein are used to treat NAFLD. In some examples, FXR agonists reduce NAFLD in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, NAFLD is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some cases, this level of NAFLD is compared to the level of NAFLD in mammals not treated with the FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammals. In some embodiments, the additional therapeutic agents are anti-inflammatory agents, metabolites, or antifibrotic agents.

[0102] (Cholestasis) Cholestasis is an obstruction or cessation of bile flow, which in some cases leads to hepatotoxicity due to the accumulation of bile acids and other toxins in the liver. In some embodiments, cholestasis is intrahepatic or extrahepatic. In some embodiments, intrahepatic cholestasis is caused by amyloidosis, intrahepatic bacterial abscess supplied exclusively intravenously, lymphoma, pregnancy, primary biliary cholangitis, primary or metastatic liver cancer, cholangiocarcinoma, primary sclerosing cholangitis, sarcoidosis, a severe infection spread through the bloodstream (sepsis), tuberculosis, or viral hepatitis. In some embodiments, extrahepatic cholestasis is caused by bile duct tumors, cysts compressing the bile ducts (stenosis), gallstones in the common bile duct, pancreatitis, pancreatic tumors or pseudocysts, pressure on the bile ducts by nearby masses or tumors, or primary sclerosing cholangitis. In some embodiments, cholestasis is caused by drugs. In some embodiments, cholestasis is caused by antibiotics such as ampicillin and other penicillins, anabolic steroids, oral contraceptives, chlorpromazine, cimetidine, estradiol, imipramine, prochlorperazine, terbinafine, or tolbutamide.

[0103] In some cases, cholestasis is a component of many liver diseases, including but not limited to cholelithiasis, pregnancy-related cholestasis, primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). In some cases, obstruction is due to gallstones, biliary trauma, drugs, one or more additional liver diseases, or cancer. In some cases, enterohepatic circulation of bile acids allows for the absorption of fats and fat-soluble vitamins from the intestines and the removal of metabolic byproducts such as cholesterol, toxins, and bilirubin from the liver. In some cases, FXR activation induces the expression of the tubular bile transporter BSEP (ABCB11) and multidrug resistance-associated protein 2 (MRP2; ABCC2, cMOAT), and suppresses genes involved in bile acid biosynthesis, such as sterol 12α-hydroxylase (CYP8B1) and CYP7A1.

[0104] In some embodiments, the FXR agonists disclosed herein are used to treat cholestasis in mammals. In some examples, FXR agonists reduce cholestasis in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, cholestasis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some cases, this level of cholestasis is compared to the level of cholestasis in mammals not treated with the FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammals. In some embodiments, the additional therapeutic agents are anti-inflammatory agents, metabolites, or antifibrotic agents.

[0105] (Fibrous liver disease) In certain embodiments, methods for treating or preventing fibrous liver disease in subjects requiring such treatment are disclosed herein, including administering a farnesoid X receptor (FXR) agonist to the subject. In some embodiments, fibrous liver disease includes hepatic fibrosis. In some embodiments, fibrous liver disease is caused by drugs or chemicals or mechanical obstruction, by impairment affecting hepatic blood flow, by α-1 antitrypsin deficiency, copper storage disorder, fructosemia, galactosemia, glycogen storage disorder, iron overload syndrome, dyslipidemia, peroxisomal disease, tyrosinemia, bacterial infection, parasitic infection, viral infection, etc. In some embodiments, fibrous liver disease disorders affecting hepatic blood flow are Budd-Chiari syndrome, heart failure, hepatic veno-occlusive disease, or portal vein thrombosis. In some embodiments, drugs or chemicals causing fibrous liver disease are amiodarone, chlorpromazine, isoniazid, methotrexate, methyldopa, oxyphenisatin, alcohol, or tolbutamide. In some embodiments, the mechanical obstruction causing fibrous liver disease is bile duct stenosis due to liver scarring from liver surgery or impacted gallstones.

[0106] In some embodiments, fibrous liver disease is non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, congenital hepatic fibrosis, or autoimmune hepatitis.

[0107] (Hepatic fibrosis) Hepatic fibrosis is not an independent disease, but rather a histological change in the liver involving abnormal amounts of collagen fiber deposition in the extracellular space of hepatocytes. Hepatic fibrosis is caused by inflammation and liver damage. Liver damage leads to activated hepatic stellate cells increasing the production and accumulation of extracellular matrix (ECM) proteins, resulting in hepatocyte hardening and increased loss of blood infusion into the liver.

[0108] In some embodiments, the FXR agonists disclosed herein are used to treat hepatic fibrosis in mammals. In some examples, FXR agonists reduce hepatic fibrosis in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, hepatic fibrosis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some cases, this level of hepatic fibrosis is compared to the level of hepatic fibrosis in mammals not treated with the FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammals. In some embodiments, the additional therapeutic agents are anti-inflammatory agents, metabolites, or antifibrotic agents.

[0109] (Non-alcoholic steatohepatitis (NASH)) Non-alcoholic fatty liver disease (NAFLD) is associated with excess fat in the liver (stiposis) and may progress to non-alcoholic steatohepatitis (NASH), which is defined by histological features of inflammation, cell death, and fibrosis. In some cases, primary NASH is correlated with insulin resistance, while secondary NASH is caused by medical or surgical conditions, or, but not limited to, medications such as tamoxifen. In some cases, NASH progresses to advanced fibrosis, hepatocellular carcinoma, or end-stage liver disease requiring a liver transplant.

[0110] In some cases, NASH develops as a result of triglyceride (TG) imbalance. For example, dysfunctional adipocytes secrete pro-inflammatory molecules such as cytokines and chemokines, leading to insulin resistance and failure to suppress lipolysis in adipocytes. In some cases, this failure to suppress lipolysis leads to the release of free fatty acids (FFAs) into the circulation and uptake into the liver. In some cases, excessive accumulation of FFAs in the form of triglycerides (TGs) in lipid droplets leads to oxidative stress, mitochondrial dysfunction, and increased expression of inflammatory molecules.

[0111] In some cases, FXR activation inhibits triglyceride (TG) / fatty acid (FA) synthesis, which is facilitated by repressing sterol regulatory element-binding protein 1c (SREBP1c) via SHP activation. In some cases, FXR further increases TG clearance by stimulating lipoprotein lipase (LPL) activity and increases hepatic uptake of remnants and low-density lipoproteins by inducing syndecan 1 (SDC1) and the very low-density lipoprotein receptor (VLDLR).

[0112] Traditionally, NASH was diagnosed using liver biopsy, and the NAFLD Activity Score (NAS) was used to assess severity. The NAS is a point-based scale system from low to high that assesses and scores three categories: (a) steatosis or fatty liver (0-3), (b) hypertrophy (0-2), which is one form of damage to hepatocytes, and (c) inflammation of the liver (0-3). The three categories are summed up on a score range from 0 to 8, with higher scores indicating greater severity of NASH. In addition to the NAS, the histological features of the liver are also assessed for fibrosis using a scale from 0 to 4. Stage 0 is no fibrosis, stage 4 is cirrhosis, and the intervening stages indicate the concentration of fibrosis between stage 0 and stage 4.

[0113] In some embodiments, NAS scores of 0–2 are considered not to diagnose NASH, scores of 3–4 are considered borderline, not to diagnose NASH, or positive, and scores of 5–8 are considered to diagnose NASH.

[0114] Non-invasive methods are increasingly being used to diagnose NASH and fibrosis. Both ultrasound and magnetic resonance imaging (MRI) have shown that they can accurately assess hepatic steatohepatia and fibrosis. In addition, a variety of blood tests, including the measurement of common liver function markers such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as more specialized markers for fibrosis, are also being used to assess hepatic steatohepatia.

[0115] In some embodiments, the FIB-4 scoring system is used to assess hepatic fibrosis. The FIB-4 index is a simple, accurate, non-invasive, and readily available clinical laboratory index that has been reported to be helpful in assessing the presence or absence of signs of hepatic fibrosis in patients with NAFLD, including liver biopsies and other liver-related complications. The FIB-4 scoring system uses a combination of the patient's age, platelet count, AST, and ALT. FIB-4 scores of 0–1.29 typically indicate a low risk of advanced hepatic fibrosis. FIB-4 scores of 1.30–2.67 typically indicate a moderate risk of advanced hepatic fibrosis. FIB-4 scores greater than 2.67 typically indicate a high risk of progressive fibrosis and a high risk of other liver-related events.

[0116] In some embodiments, administration of compound 1 or a pharmaceutically acceptable salt thereof to mammals with hepatic fibrosis induces regression of hepatic fibrosis. In some embodiments, regression of hepatic fibrosis is observed after daily administration of compound 1 or a pharmaceutically acceptable salt thereof for about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 24 weeks, about 26 weeks, about 52 weeks, or more than about 52 weeks.

[0117] In some embodiments, fibrosis regression is defined as a decrease in the fibrosis score across a pair of consecutive measurements, regardless of the scoring system used. Differences in fibrosis scores are useful as histological outcomes in clinical trials evaluating the effects of various drugs.

[0118] In some embodiments, regression of fibrosis is defined as a decrease in the FIB-4 score. In some embodiments, the FIB-4 score decreases by at least 0.5, 1, 1.5, 2, or more than 2.

[0119] In some embodiments, treating NASH with an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) involves reducing the NAS score by 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, the reduction in the NAS score is observed after daily administration of compound 1 or a pharmaceutically acceptable salt thereof for about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 24 weeks, about 26 weeks, about 52 weeks, or beyond about 52 weeks.

[0120] In some embodiments, treating NASH with compound 1 or a pharmaceutically acceptable salt thereof includes reducing hepatic fat, alleviating hepatic fibrosis, improving liver tissue findings, improving liver blood tests, improving cholestatic pruritus, or a combination thereof.

[0121] In some embodiments, the measured results are compared to a control. In some embodiments, the control is an individual that has not been administered the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof). In some embodiments, the control is an individual that has not been administered the full dose of the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof). In some embodiments, the control is the baseline of the individual before administration of the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof).

[0122] In some embodiments, the resulting measurements are obtained after administering compound 1 or a pharmaceutically acceptable salt thereof daily for about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 24 weeks, about 26 weeks, about 52 weeks, or more than about 52 weeks.

[0123] In some embodiments, a reduction of approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in liver fat from baseline is obtained after administration of compound 1 or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, a reduction in liver fibrosis includes a decrease of at least 1, at least 2, at least 3, or more liver fibrosis scores from baseline.

[0125] In some embodiments, the liver blood test includes measuring alanine aminotransferase (ALT) concentration, aspartate aminotransferase (AST) concentration, gamma glutamyltransferase (GGT), triglyceride (TG) concentration, total cholesterol concentration, high-density lipoprotein (HDL) concentration, low-density lipoprotein (LDL) concentration, or a combination thereof.

[0126] The biochemical pattern typically observed in hepatic steatohepatopathy due to NAFLD is elevated transaminase concentrations, in which case alanine aminotransferase (ALT) concentration exceeds aspartate aminotransferase (AST) concentration. However, as hepatic steatohepatopathy progresses to NASH and associated hepatic fibrosis, AST concentration increases, resulting in an elevated AST:ALT ratio. In some embodiments, GGT concentration increases along with the NAFLD transaminase pattern. In some embodiments, both ALT and GGT have been shown to some extent to correlate with the presence of fatty liver on ultrasound and liver fat content measured by magnetic resonance imaging spectroscopy, but AST has not been correlated.

[0127] In some embodiments, ALT concentration decreases by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more from baseline. In some embodiments, AST concentration decreases by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more from baseline. In some embodiments, GGT concentration decreases by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more from baseline. In some embodiments, TG concentration decreases by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more from baseline. In some embodiments, HDL concentration increases by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more from baseline. In some embodiments, LDL concentration decreases by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more from baseline.

[0128] In some embodiments, additional therapeutic agents are administered to mammals. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolite, or an anti-fibrotic agent.

[0129] (Primary biliary cholangitis (PBC)) PBC is a liver disease primarily caused by autoimmune destruction of the bile ducts that transport bile acids (BA) from the liver, leading to cholestasis. As PBC progresses, the persistent accumulation of toxic BA causes progressive liver damage. Chronic inflammation and fibrosis progress to cirrhosis. PBC is a chronic, progressive disease that typically manifests in middle age. Current treatments for PBC include ursodeoxycholic acid (UDCA). Other FXR agonists are also being investigated as potential treatments. Increased FXR activity correlates with decreased bile acid synthesis and can reduce the accumulation of bile acids in the liver associated with PBC. In some embodiments, the FXR agonists disclosed herein are used to treat primary biliary cholangitis (PBC) in mammals. In some examples, FXR agonists reduce PBC in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, PBC is reduced by approximately 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%. In some cases, this PBC level is compared to the PBC level in mammals not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammals. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolite, or an antifibrotic agent.

[0130] (Primary sclerosing cholangitis (PSC)) Primary sclerosing cholangitis (PSC) is a chronic and progressive cholestatic liver disease. PSC is characterized by progressive inflammation, fibrosis, and stenosis of the hepatic ducts. Common symptoms include itching and jaundice. This disease is strongly correlated with inflammatory bowel disease (IBD). Approximately 5% of patients with ulcerative colitis develop PSC. Up to 70% of PSC patients have IBD, the most common being ulcerative colitis. In some embodiments, the FXR agonists disclosed herein are used to treat primary sclerosing cholangitis (PSC). In some examples, FXR agonists reduce mammalian PSC by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, PSC is reduced by approximately 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%. In some cases, this PSC level is compared to the PSC level in mammals not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammals. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolite, or an antifibrotic agent.

[0131] (Congenital or neonatal liver disease) Congenital or neonatal liver diseases include, but are not limited to, congenital hepatic fibrosis, biliary atresia, Alagille syndrome, progressive familial intrahepatic cholestasis-1 (PFIC-1), PFIC-2, PFIC-3, α-1 antitrypsin deficiency, common bile duct cyst, and Wilson's disease. In some embodiments, congenital or neonatal liver diseases are rare liver diseases.

[0132] Congenital hepatic fibrosis is a rare genetic disorder associated with abnormal development of the portal vein and bile ducts, and periportal fibrosis leading to portal hypertension. In some embodiments, the FXR agonists disclosed herein are used to treat congenital hepatic fibrosis in mammals. In some cases, FXR agonists reduce congenital hepatic fibrosis in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, congenital hepatic fibrosis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some cases, this level of congenital hepatic fibrosis is compared to the level of congenital hepatic fibrosis in mammals not treated with the FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammals. In some embodiments, additional therapeutic agents are anti-inflammatory agents, metabolites, or anti-fibrotic agents.

[0133] Biliary atresia, also known as extrahepatic bile duct hypovolemia or progressive obstructive cholangiopathies, is a rare disease that develops in infants in which the bile ducts develop abnormally before birth, resulting in inflammation and / or obstruction after birth. This obstruction leads to the accumulation of bile acids and other compounds that can damage the liver. This condition affects approximately 1 in 15,000 infants. Symptoms of biliary atresia include jaundice, dark urine, alcoholic stools, weight loss, and hypersensitivity. Children with biliary atresia may not be able to properly digest fats and may be affected by vitamin and protein deficiencies. If left untreated, this condition can be fatal. Currently, there is no cure for biliary atresia, and treatment requires surgery. People with biliary atresia show elevated levels of bile acids in their blood and plasma. In addition, patients with biliary atresia also show decreased expression of FXR. Increased FXR activity correlates with decreased bile acid synthesis and can reduce the accumulation of bile acids in the liver associated with biliary atresia. In some embodiments, the FXR agonists disclosed herein are used to treat biliary atresia in mammals. In some examples, FXR agonists reduce biliary atresia in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, biliary atresia is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some cases, this level of biliary atresia is compared to the level of biliary atresia in mammals not treated with the FXR agonist. In some embodiments, an additional therapeutic agent is administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolite, or an antifibrotic agent.

[0134] Alagille syndrome is an autosomal dominant genetic disorder that causes biliary dysplasia, bile duct hypoplasia, or bile duct atresia. In Alagille syndrome, abnormalities in the bile ducts reduce the liver's ability to transport bile acids. This can lead to the accumulation of bile acids in the liver, potentially causing scarring that prevents the liver from functioning properly. Treatment of the symptoms of Alagille syndrome involves the administration of ursodeoxycholic acid, an FXR agonist, which has been shown to help the flow of bile from the liver. In some embodiments, the FXR agonists disclosed herein are used to treat Alagille syndrome in mammals. In some cases, FXR agonists reduce Alagille syndrome in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, Alagille syndrome is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some cases, the level of Alagille syndrome is compared to the level of Alagille syndrome in mammals not treated with an FXR agonist. In some embodiments, an additional therapeutic agent is administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolite, or an antifibrotic agent.

[0135] Progressive familial intrahepatic cholestasis (PFIC) is a group of genetic disorders that cause progressive cholestasis in infants and young adults, leading to cirrhosis and ultimately requiring a liver transplant. There are three variations of PFIC: PFIC-1, PFIC-2, and PFIC-3. PFIC-1 is caused by mutations in the ATP8B1 gene, which encodes FIC-1. FIC-1 is involved in the transmembrane movement of phospholipids. PFIC-2 is caused by mutations in the ABCB11 gene, which encodes the bile salt efferent pump (BSEP). PFIC-3 is caused by mutations in the ABCB4 gene, which encodes multidrug resistance protein 3 (MDR3), resulting in phosphatidylcholine translocation. Because PFIC is correlated with the accumulation of bile acids in the liver, FXR agonists have been investigated as a potential treatment for PFIC. While some success has been seen in animal models, patients receiving treatment have an increased frequency of dyslipidemia in response to treatment. In some embodiments, the FXR agonists disclosed herein are used to treat any of the PFIC or its variations in mammals. In some examples, the FXR agonists reduce any of the PFIC or its variations in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, any of the PFIC or its variations is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some cases, this level of any of the PFIC or its variations is compared to the level of PFIC in a mammal not treated with the FXR agonist. In some embodiments, an additional therapeutic agent is administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolite, or an antifibrotic agent.

[0136] Alpha-1 antitrypsin deficiency is a genetic disorder that causes insufficient production of alpha-1 antitrypsin (A1AT), leading to the accumulation of A1AT in the liver. A1AT deficiency causes many diseases, including but not limited to cirrhosis, autoimmune hepatitis, chronic obstructive pulmonary disease (COPD), asthma, or emphysema. In some embodiments, the FXR agonists disclosed herein are used to treat A1AT deficiency in mammals. In some examples, FXR agonists reduce A1AT deficiency in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, A1AT deficiency is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some cases, the level of A1AT deficiency was compared to the level of A1AT deficiency in mammals not treated with an FXR agonist. In some embodiments, an additional therapeutic agent is administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolite, or an antifibrotic agent.

[0137] Common bile duct cysts are congenital disorders involving cystic dilation of the bile ducts, which can further develop into cholangitis. Common bile duct cysts are classified into types I, II, III, IVa, IVb, V, and VI. In some embodiments, the FXR agonists disclosed herein are used to treat common bile duct cysts in mammals. In some cases, FXR agonists reduce common bile duct cysts in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, common bile duct cysts are reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, additional therapeutic agents are anti-inflammatory agents, metabolites, or antifibrotic agents.

[0138] Wilson's disease is an autosomal recessive disorder in which copper is not properly excreted from the body. The symptoms of Wilson's disease typically affect the brain and liver. Complications of Wilson's disease include, but are not limited to, hepatic encephalopathy, portal hypertension, chronic active hepatitis, acute liver failure, hemolytic anemia, and splenomegaly. In some embodiments, the FXR agonists disclosed herein are used in the treatment of Wilson's disease or its complications in mammals. In some cases, the FXR agonist and additional therapeutic agents reduce Wilson's disease or its complications in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, Wilson's disease or its complications are reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, additional therapeutic agents are administered to mammals. In some embodiments, the additional therapeutic agents are anti-inflammatory agents, metabolites, or antifibrotic agents.

[0139] (autoimmune hepatitis) Autoimmune hepatitis is a chronic autoimmune disease characterized by chronic inflammation and necrosis of the liver, leading to cirrhosis. In some embodiments, the FXR agonists disclosed herein are used to treat autoimmune hepatitis in mammals. In some examples, FXR agonists reduce autoimmune hepatitis in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, autoimmune hepatitis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some cases, this level of autoimmune hepatitis is compared to the level of autoimmune hepatitis in mammals not treated with the FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammals. In some embodiments, the additional therapeutic agents are anti-inflammatory agents, metabolites, or antifibrotic agents.

[0140] (Other liver diseases or conditions) In some embodiments, the FXR agonists disclosed herein are used to treat, prevent, or slow the progression of end-stage hepatitis in mammals. In some examples, FXR agonists reduce end-stage hepatitis symptoms in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, end-stage hepatitis symptoms are reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some cases, this progression of end-stage hepatitis is compared to the progression of end-stage hepatitis in mammals not treated with an FXR agonist. In some embodiments, additional therapeutic agents are administered to the mammals. In some embodiments, the additional therapeutic agents are anti-inflammatory agents, metabolites, or antifibrotic agents.

[0141] Hepatocellular carcinoma (HMCC) is the most common type of liver cancer and frequently occurs in people with chronic liver diseases such as hepatitis B and C. In many cases, FXR expression and signaling are downregulated in HMCC patients. Given the role that FXR plays in regulating bile acid metabolism, suppressing inflammatory signaling, and promoting tissue repair, it is hypothesized that FXR plays a crucial role in preventing hepatocellular carcinogenesis. Furthermore, several studies have shown that treatment of cancer cells with FXR agonists results in inhibition of cell proliferation. In some embodiments, the FXR agonists disclosed herein are used to treat mammalian HMCC. In some examples, FXR agonists reduce the symptoms of mammalian HMCC by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, the symptoms of hepatocellular carcinoma are reduced by approximately 5% to 50%, 5% to 25%, 10% to 20%, or 10% to 30%. In some cases, this progression of hepatocellular carcinoma is compared to the progression of hepatocellular carcinoma in mammals not treated with FXR agonists. In some embodiments, additional therapeutic agents are administered to mammals. In some embodiments, the additional therapeutic agents are anti-inflammatory agents, metabolites, or antifibrotic agents.

[0142] In some embodiments, the FXR agonists disclosed herein reduce mammalian liver enzymes. In some examples, FXR agonists reduce mammalian liver enzymes (e.g., serum ALT and / or AST concentrations) by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, the liver enzyme concentration decreases by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some cases, this liver enzyme concentration is compared to the liver enzyme concentration in mammals not treated with the FXR agonist. In some embodiments, an additional therapeutic agent is administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolite, or an antifibrotic agent.

[0143] In some embodiments, the FXR agonists disclosed herein reduce mammalian liver triglycerides. In some examples, FXR agonists reduce mammalian liver triglycerides by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, the liver triglyceride concentration decreases by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some cases, this liver triglyceride concentration is compared to the liver triglyceride concentration in mammals not treated with the FXR agonist. In some embodiments, an additional therapeutic agent is administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolite, or an antifibrotic agent.

[0144] (cholangiocarcinoma) Bile duct cancer is a type of cancer that develops in an individual's bile ducts. The cause of the genetic mutations that lead to this cancer is not clear, but risk factors include primary sclerosing cholangitis, chronic liver disease, and other bile duct problems. Inflammation and cholestasis are important factors in the formation of cholangiocarcinoma. Cholangiocarcinoma is classified according to its location within the liver. Intrahepatic cholangiocarcinoma is the least common type and begins in the small bile ducts within the liver. Hilar cholangiocarcinoma (also called Klatskin tumor) occurs in the hilum, the region where the two major bile ducts merge and exit the liver. Hilar cholangiocarcinoma is the most common form of cholangiocarcinoma. Another form of cholangiocarcinoma is called distal cholangiocarcinoma and occurs in the bile ducts outside the liver.

[0145] Bile acids can activate the epidermal growth factor receptor (EGFR) and increase the expression of cyclooxygenase 2 (COX-2). COX-2 dysregulates the growth of cholangiocarcinoma, enhances apoptosis resistance, and positively modulates tumorigenic signaling pathways such as hepatocyte growth factor, IL-6, and EGFR. Therefore, a potential correlation between bile acid concentration and the incidence and progression of cholangiocarcinoma is suggested.

[0146] FXR expression is downregulated in cholangiocarcinoma cells compared to healthy cholangiocarcinoma cells. Multiple studies have shown that treatment of human intrahepatic cholangiocarcinoma cell cultures with the FXR agonist obeticholic acid can promote FXR expression in vitro. Cholangiocarcinoma cells treated with the FXR agonist showed decreased proliferation and increased apoptosis.

[0147] In some embodiments, the FXR agonists disclosed herein are used to treat cholangiocarcinoma in mammals. In some embodiments, cholangiocarcinoma is intrahepatic cholangiocarcinoma. In some embodiments, cholangiocarcinoma is hilar cholangiocarcinoma. In some embodiments, cholangiocarcinoma is distal cholangiocarcinoma. In some embodiments, treatment with an FXR agonist reduces the proliferation of cholangiocarcinoma cells by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In some embodiments, treatment with an FXR agonist increases apoptosis of cholangiocarcinoma cells by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In some embodiments, treatment with an FXR agonist increases FXR expression in cholangiocarcinoma cells by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%.

[0148] In one embodiment, described herein are methods for treating or preventing liver disease or conditions in mammals, comprising administering an FXR agonist disclosed herein alone or in combination with other therapeutic agents to a mammal. In some embodiments, the liver disease or condition is fibrous liver disease, metabolic liver disease, rare liver disease, or any combination thereof.

[0149] (Gastrointestinal disease) In certain embodiments, methods for treating or preventing gastrointestinal disorders in subjects requiring such treatment are disclosed herein, comprising administering a farnesoid X receptor (FXR) agonist to the subject. In some embodiments, the gastrointestinal disorder is related to liver disease. In some embodiments, the gastrointestinal disorder is related to fibrous liver disease. In some embodiments, the gastrointestinal disorder is related to metabolic liver disease. In some embodiments, the gastrointestinal disorder is irritable bowel syndrome (IBS), diarrhea-predominant irritable bowel syndrome (IBS-D), constipation-predominant irritable bowel syndrome (IBS-C), mixed-type IBS (IBS-M), unclassifiable IBS (IBS-U), or biliary acid diarrhea (BAD). In some embodiments, gastrointestinal disorders include bile acid malabsorption, graft-versus-host disease, Crohn's disease, inflammatory bowel disease, necrotizing colitis, gastritis, ulcerative colitis, gastroenteritis, radiation enteritis, pseudomembranous colitis, chemotherapy-induced enteritis, gastroesophageal reflux disease (GERD), peptic ulcer, non-ulcerative dyspepsia (NUD), celiac disease, intestinal celiac disease, postoperative inflammation, gastrointestinal carcinogenesis, or any combination thereof.

[0150] (irritable bowel syndrome) Irritable bowel syndrome (IBS) is a combination of symptoms, such as abdominal pain and changes in bowel patterns, that persist for a long period (often several years). The cause of IBS remains unknown, but problems with bowel motility, food sensitivities, genetic factors, bacterial overgrowth in the small intestine, and issues with the gut-brain axis are thought to play a potential role. In some cases, IBS is accompanied by diarrhea and is classified as diarrheal IBS (IBS-D). In some cases, IBS is accompanied by constipation and is classified as constipated IBS (IBS-C). In some cases, IBS is accompanied by alternating patterns of diarrhea and constipation and is classified as mixed IBS (IBS-M). In some cases, IBS is not accompanied by diarrhea or constipation and is classified as unclassifiable IBS (IBS-U). In some cases, IBS has four distinct variations: IBS-D, IBS-C, IBS-M, and IBS-U.

[0151] In some embodiments, the symptoms of IBS resemble those of different conditions. In some embodiments, symptoms of sugar dyspepsia, celiac disease, gluten intolerance without celiac disease, exocrine pancreatic insufficiency, bacterial overgrowth in the small intestine, microscopic colitis, or bile acid malabsorption (BAM) resemble those of IBS-D. In some embodiments, symptoms of anismus, pelvic floor dyscoping or puborectalis spasm, or perineal prolapse syndrome resemble those of IBS-C. In some embodiments, certain conditions influence the symptoms of patients with IBS. In some embodiments, certain conditions are the primary cause of symptoms in patients with IBS. In some embodiments, non-limiting examples of these conditions include sugar dyspepsia, celiac disease, gluten intolerance without celiac disease, exocrine pancreatic insufficiency, bacterial overgrowth in the small intestine, microscopic colitis, bile acid malabsorption (BAM), anismus, pelvic floor dyscolation, puborectalis muscle spasm, or perineal prolapse syndrome, which resemble the symptoms of IBS-C.

[0152] In some embodiments, the FXR agonists disclosed herein are used in combination with other therapeutic agents disclosed herein in the treatment of any of the IBS or its variations in mammals. In some examples, the FXR agonists reduce the symptoms caused by any of the IBS or its variations in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, any of the IBS or its variations are reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, an additional therapeutic agent is administered to the mammal. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolite, or an antifibrotic agent.

[0153] (Bile acid malabsorption) Bile acid malabsorption (BAM), also known as bile acid diarrhea (BAD), bile acid-induced diarrhea, bile acid or bile-secreting bowel disease, or bile salt malabsorption, is a condition in which the presence of bile acids in the colon causes diarrhea. BAM can be caused by a variety of conditions, including Crohn's disease, cholecystectomy, celiac disease, radiation therapy, and pancreatic diseases. In some cases, BAM is idiopathic. In some cases, BAM is caused by medications such as metformin.

[0154] In some embodiments, BAM is caused by the overproduction of bile acids. Bile acid synthesis is negatively regulated by ileal fibroblast growth factor 19 (FGF-19). Low levels of FGF-19 lead to an increase in bile acids. Activation of FXR promotes FGF-19 synthesis, resulting in a decrease in bile acid concentrations. Bile acid synthesis is also regulated by serum 7α-hydroxy-4-cholesten-3-one (C4) concentration, a marker of bile acid synthesis in the liver. C4 decreases when FXR is activated. Patients with BAM have higher C4 concentrations, and therefore higher concentrations of bile acids.

[0155] In some embodiments, treating BAM with compound 1 or a pharmaceutically acceptable salt thereof includes increasing serum FGF-19 concentration, decreasing serum C4 concentration, improving one or more clinical symptoms of BAM, or a combination thereof.

[0156] In some embodiments, serum FGF-19 concentrations increase by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more from baseline.

[0157] In some embodiments, serum C4 concentration decreases by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more from baseline.

[0158] Clinical symptoms of BAM include, but are not limited to, increased bowel movement frequency, worsening of stool consistency (e.g., diarrhea), abdominal pain, and bloating.

[0159] Improvement in one or more clinical symptoms is compared to a control. In some embodiments, the control is an individual who has not been administered the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof). In some embodiments, the control is an individual who has not been administered the full dose of the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof). In some embodiments, the control is the baseline of the individual before administration of the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof).

[0160] In some embodiments, improvement of one or more clinical symptoms is obtained after daily administration of compound 1 or a pharmaceutically acceptable salt thereof for about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 24 weeks, about 26 weeks, about 52 weeks, or more than about 52 weeks.

[0161] Improvement in one or more clinical symptoms of BAM includes a decrease in bowel movement frequency, improvement in stool consistency, relief of abdominal pain, reduction in bloating, or a combination thereof.

[0162] In some embodiments, a reduction in the frequency of bowel movements includes having one, two, three, four, five, six, or seven or more fewer bowel movements per day.

[0163] In some embodiments, improvement in clinical symptoms is measured as a change from baseline in stool type according to the Bristol Stool Scale. The Bristol Stool Scale is a medical aid designed to classify stools on a scale from 1 to 7 according to the increase in water content.

[0164] In some embodiments, abdominal pain improves by at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, or 5 points or more from baseline on the WAP pain scale.

[0165] In some embodiments, the FXR agonists disclosed herein are used in combination with other therapeutic agents disclosed herein in the treatment of BAM in mammals. In some embodiments, the FXR agonists disclosed herein are used in combination with other therapeutic agents disclosed herein to reduce bile acid synthesis. In some embodiments, the FXR agonists disclosed herein lower bile acid concentrations. In some embodiments, the FXR agonists disclosed herein are used in combination with other therapeutic agents disclosed herein to prevent BAM. In some examples, the FXR agonists disclosed herein are used in combination with other therapeutic agents disclosed herein to reduce BAM symptoms in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, BAM is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, additional therapeutic agents are administered to mammals. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolite, or an anti-fibrotic agent.

[0166] (Graft-versus-host disease (GvHD)) Graft-versus-host disease (GvHD) is a medical complication that develops after the transplantation of tissue or cells from a tissue-incompatible donor (i.e., a genetically or immunologically different donor). Immune cells within the donated tissue or cells (graft) recognize the recipient (host) as a foreign body and initiate an immune attack. Non-limited examples of transplanted tissues or cells that can cause GvHD include blood products, stem cells such as bone marrow cells, and organs. There are various types of GvHD depending on where the symptoms appear or develop. For example, cutaneous GvHD, hepatic GvHD, ocular GvHD, neuromuscular GvHD, urogenital GvHD, and gastrointestinal (GI) tract GvHD. Symptoms of gastrointestinal GvHD include dysphagia, painful swallowing, weight loss, nausea, vomiting, diarrhea, and / or abdominal cramps. Gastrointestinal GvHD causes mucosal shedding and severe intestinal inflammation. Inflammation of the biliary epithelium is easily controlled by nuclear receptors such as glucocorticoid receptors (GR), FXR, or peroxisome proliferator-activated receptors (PPARs).

[0167] In some embodiments, the FXR agonists disclosed herein are used in combination with other therapeutic agents disclosed herein in the treatment of GvHD or complications of GvHD in mammals. In some embodiments, the FXR agonists disclosed herein are used in combination with other therapeutic agents disclosed herein in the treatment of ductal gland (GI) GvHD or complications of ductal gland GvHD in mammals. In some examples, the FXR agonists disclosed herein are used in combination with other therapeutic agents disclosed herein to reduce ductal gland GvHD or complications of ductal gland GvHD in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, ductal gland GvHD or complications of ductal gland GvHD are reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, the FXR agonists disclosed herein are used in combination with other therapeutic agents disclosed herein to reduce intestinal inflammation caused by GI duct GvHD. In some embodiments, the FXR agonists disclosed herein reduce intestinal inflammation caused by GI duct GvHD by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolite, or an antifibrotic agent.

[0168] (inflammatory bowel disease (IBD)) Inflammatory bowel disease (IBD) is an autoimmune disease characterized by a range of inflammatory conditions affecting the colon and small intestine. Ulcerative colitis (UC) and Crohn's disease are the main types of inflammatory bowel disease. FXR activity is reduced in IBD patients. Increasing FXR activity by administering the FXR agonists disclosed herein, either alone or in combination with additional therapeutic agents disclosed herein, prevents and / or reduces the symptoms of IBD. Increasing FXR activity by administering the FXR agonists disclosed herein, either alone or in combination with additional therapeutic agents disclosed herein, reduces intestinal inflammation in IBD patients. In some embodiments, FXR activation suppresses inflammation and maintains the intestinal barrier in inflammatory bowel disease.

[0169] FXR, expressed in the gastrointestinal tract, has been shown to regulate tight junctions between epithelial cells. This is important for maintaining the gut microbiota and the barrier from the mucosa. In some embodiments, FXR also helps regulate the gut microbiome population by influencing antimicrobial molecules released by gastrointestinal epithelial cells. Activation of FXR also reduces the production and amount of bile acids in the gastrointestinal tract. Bile acids are known to be pro-inflammatory and may exacerbate diarrheal symptoms and affect the gut microbiota. Several published studies have shown that FXR knockout mice exhibited exacerbated colitis when exposed to chemical irritants such as TNBS (trinitrobenzenesulfonic acid).

[0170] Several published studies have shown that FXR activation prevents chemically induced intestinal inflammation, improves symptoms of colitis, inhibits epithelial permeability, and reduces goblet cell loss. Furthermore, FXR activation inhibits the production of inflammatory cytokines in mouse colon mucosa in vivo and in various immune cell populations ex vivo (RM Gadaleta et al., Gut. 2011 Apr;60(4):463-72).

[0171] Compound 1 was evaluated in a mouse model of immune-mediated colitis. This correlates with human IBD because the primary mechanism of injury in this preclinical model involves T cell-mediated inflammation. Mice were administered compound 1 (oral, 0.1 mg / kg, 0.3 mg / kg, or 1 mg / kg daily), a medium (negative control), or 0.5 mg of anti-IL-12 / 23 antibody (positive control) weekly by IP injection. After 4 weeks of treatment, treatment with compound 1 and anti-IL12 / 23 antibody showed statistically significant improvement in the histological features of the colon.

[0172] In some embodiments, the FXR agonists disclosed herein are used in combination with other therapeutic agents disclosed herein in the treatment of IBD in mammals. In some embodiments, the FXR agonists disclosed herein are used in combination with other therapeutic agents disclosed herein to reduce intestinal inflammation. In some embodiments, the FXR agonists disclosed herein are used in combination with other therapeutic agents disclosed herein to prevent IBD. In some cases, the FXR agonists disclosed herein are used in combination with other therapeutic agents disclosed herein to reduce IBD symptoms in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, IBD is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolite, or an antifibrotic agent.

[0173] In some embodiments, treating UC with compound 1 or a pharmaceutically acceptable salt thereof includes increasing serum FGF-19 concentration, decreasing serum C4 concentration, improving one or more clinical symptoms of UC, or a combination thereof.

[0174] In some embodiments, serum FGF-19 concentrations increase from baseline by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more than 90%. In some embodiments, serum FGF-19 concentrations increase by about 100% or more from baseline.

[0175] In some embodiments, serum C4 concentration decreases by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more from baseline.

[0176] UC involves the rectum, spreading proximal in a continuous pattern and potentially affecting part or all of the colon. Clinical conditions of disease activity include bloody diarrhea (with or without mucus), urinary urgency, tenesmus, abdominal pain, weight loss, fever, and malaise. In patients with widespread or severe inflammation, acute complications such as toxic megacolon, which can lead to severe bleeding or perforation, may occur. Patients with UC have a higher risk of colorectal cancer compared to the general population.

[0177] The short-term treatment goal for disease activity relapse is to bring the patient into remission by reducing the severity of the signs and symptoms of disease activity and achieving their resolution. The long-term treatment goal after this is achieved is to reduce the frequency of subsequent relapses. In both treatment phases (treatment of disease activity relapse and long-term treatment), the relevant treatment goal is to influence the disease process itself (by reducing inflammation of the colonic mucosa).

[0178] Improvement in one or more clinical symptoms is compared to a control. In some embodiments, the control is an individual who has not been administered the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof). In some embodiments, the control is an individual who has not been administered the full dose of the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof). In some embodiments, the control is the baseline of the individual before administration of the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof).

[0179] In some embodiments, improvement of one or more clinical symptoms is obtained after daily administration of compound 1 or a pharmaceutically acceptable salt thereof for about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 24 weeks, about 26 weeks, about 52 weeks, or more than about 52 weeks.

[0180] Improvement in one or more clinical symptoms of UC includes reduced rectal bleeding, reduced bowel movement frequency, improved stool consistency, improved endoscopic assessment of the colonic mucosa, reduced abdominal pain, reduced bloating, or a combination thereof. In some embodiments, improvement in one or more clinical symptoms of UC is assessed using a score index. Score indexes include, but are not limited to, the UC-100 score, the Endoscopic Severity Index of Ulcerative Colitis (UCEIS), the Roberts Histological Index (RHI), the Mayo score (MS), and the Inflammatory Bowel Disease Questionnaire (IBDQ).

[0181] In some embodiments, the composite UC-100 score is used to assess the severity of ulcerative colitis. The composite UC-100 score is obtained by the following formula: 1 + 16 × Mayo bowel movement frequency subscore [0-3] + 6 × Mayo endoscopy subscore [0-3] + 1 × Roberts histopathology index score [0-33]). The composite UC-100 score ranges from 1 (no disease activity) to 100 (severe disease activity).

[0182] In some embodiments, treating UC with compound 1 or a pharmaceutically acceptable salt thereof results in a score of 1 point or more from baseline, 2 points or more, 3 points or more, 4 points or more, 5 points or more, 6 points or more, 7 points or more, 8 points or more, 9 points or more, 10 points or more, 11 points or more, 12 points or more, 13 points or more, 14 points or more, 15 points or more, 16 points or more, 17 points or more, 18 points or more, 19 points or more, 20 points or more, 21 points or more, 22 points or more, 23 points or more, 24 points or more, 25 points or more Includes the average change in UC-100 score of 50 points or more, including 26 points or more, 27 points or more, 28 points or more, 29 points or more, 30 points or more, 31 points or more, 32 points or more, 33 points or more, 34 points or more, 35 points or more, 36 points or more, 37 points or more, 38 points or more, 39 points or more, 40 points or more, 41 points or more, 42 points or more, 43 points or more, 44 points or more, 45 points or more, 46 points or more, 47 points or more, 48 points or more, 49 points or more, 50 points or more, or more than 50 points.

[0183] In some embodiments, treatment of UC with compound 1 or a pharmaceutically acceptable salt thereof includes a mean change in total Mayo score of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points or more from baseline.

[0184] In some embodiments, treatment of UC with compound 1 or a pharmaceutically acceptable salt thereof includes a mean change in partial Mayo score of 1, 2, 3, 4, 5, 6, 7, or 8 points from baseline.

[0185] In some embodiments, treating UC with compound 1 or a pharmaceutically acceptable salt thereof involves increasing the proportion of subjects who achieve a clinical response. In some embodiments, the proportion of subjects who achieve a clinical response is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or 40% or more.

[0186] In some embodiments, treating UC with compound 1 or a pharmaceutically acceptable salt thereof involves increasing the proportion of subjects who achieve clinical remission. In some embodiments, the proportion of subjects who achieve clinical response remission is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or 40% or more.

[0187] In some embodiments, treating UC with compound 1 or a pharmaceutically acceptable salt thereof involves increasing the proportion of subjects who achieve corticosteroid-free remission. Corticosteroid-free remission is often defined as clinical remission without concomitant corticosteroid use at a particular point in time in patients who were using corticosteroids at baseline.

[0188] In some embodiments, a reduction in the frequency of bowel movements includes having one, two, three, four, five, six, or seven or more bowel movements per day.

[0189] In some embodiments, improvement in clinical symptoms is measured as a change from baseline in stool type according to the Bristol Stool Scale. The Bristol Stool Scale is a medical aid designed to classify stools on a scale from 1 to 7 according to the increase in water content.

[0190] In one embodiment, a method for treating or preventing a mammalian gastrointestinal disease or condition is described herein, comprising administering an FXR agonist disclosed herein to a mammal. In some embodiments, the gastrointestinal disease or condition is necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, gastroenteritis, radiation enteritis, pseudomembranous colitis, chemotherapy-induced enteritis, gastroesophageal reflux disease (GERD), peptic ulcer, non-ulcerative dyspepsia (NUD), celiac disease, intestinal celiac disease, postoperative inflammation, gastric carcinogenesis, graft-versus-host disease, or any combination thereof. In some embodiments, the gastrointestinal disease or condition is inflammatory bowel disease.

[0191] (Gastrointestinal cancer) FXR is primarily expressed in tissues exposed to high concentrations of bile acids, including the entire gastrointestinal tract, liver, bile ducts, and gallbladder. Recent observations have indicated a positive correlation between a high-fat diet and the incidence of colon cancer. High-fat diet intake correlates with elevated bile acid concentrations in the colonic lumen, resulting from increased bile acids in fecal excretion. Individuals consuming a Western diet, as well as patients diagnosed with colon cancer, show elevated secondary bile acid concentrations in their feces. Elevated secondary bile acid concentrations adversely affect the structure and function of the colonic epithelium through multiple mechanisms, including oxidative damage to DNA, inflammation, NFκB activation, and increased cell proliferation. Consequently, bile acids can be considered tumorigenic factors in the development of colorectal cancer.

[0192] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is used in the treatment of gastrointestinal cancer. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is used in combination with an additional therapeutic agent in the treatment of gastrointestinal cancer. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) slows or prevents the progression of gastrointestinal cancer through the activation of FXR.

[0193] In some embodiments, gastrointestinal cancer is anal cancer, colon cancer, esophageal cancer, gallbladder cancer, biliary tract cancer, liver cancer, bile duct cancer, pancreatic cancer, peritoneal cancer, rectal cancer, colorectal cancer, small intestine cancer, stomach cancer, gastrointestinal stromal tumor (GIST), neuroendocrine tumor (NET), or small intestine cancer. In some embodiments, gastrointestinal cancer is colorectal cancer.

[0194] (kidney disease) Disclosed herein are methods for treating renal disease in subjects in need, comprising administering a farnesoid X receptor (FXR) agonist and additional therapeutic agents to the subject in certain embodiments. In some embodiments, the renal disease is related to liver disease. In some embodiments, the renal disease is related to fibrotic liver disease. In some embodiments, the renal disease is related to [unspecified condition]. In some embodiments, the renal disease is related to metabolic conditions such as, but not limited to, diabetes mellitus, metabolic syndrome, NAFLD, insulin resistance, fatty acid metabolism disorders, and cholestasis. In some embodiments, the renal disease is diabetic nephropathy, fibrosis-related renal disease, fibrosis-unrelated renal disease, renal fibrosis, or any combination thereof. In some embodiments, the renal disease is related to tubulointerstitial nephritis / nephropathy. In some embodiments, the renal disease is related to glomerulonephritis / nephropathy.

[0195] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is used to treat tubulointerstitial nephritis / nephropathy and / or glomerulonephritis / nephropathy. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is used to treat tubulointerstitial nephritis / nephropathy. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is used to treat glomerulonephritis / nephropathy.

[0196] In some embodiments, tubulointerstitial nephritis / nephropathy is drug-induced tubulointerstitial nephritis / nephropathy, toxic tubulointerstitial nephritis, radiation-induced tubulointerstitial nephritis, ischemic tubulointerstitial nephritis, or idiopathic tubulointerstitial nephritis.

[0197] In some embodiments, glomerulonephritis / nephropathy is IgA nephropathy, focal segmental glomerulosclerosis, minimal change glomerulonephritis, drug-induced glomerulonephritis, infection-induced (post-streptococcal) glomerulonephritis, vasculitis-induced glomerulonephritis, or glomerulonephritis secondary to a systemic disease, including but not limited to amyloidosis or systemic lupus erythematosus.

[0198] (diabetic nephropathy) In some embodiments, factors contributing to kidney disease include hyperlipidemia, hypertension, hyperglycemia, and proteinuria, all of which lead to further kidney damage and further stimulate extracellular matrix deposition. Furthermore, glucose dysregulation leads to stimulation of cytokine release and increased expression of extracellular matrix deposition. Regardless of the primary cause, kidney damage can lead to renal fibrosis and the associated loss of renal function.

[0199] Diabetic nephropathy is a kidney disease characterized by damage to the glomeruli of the kidneys. Diabetes contributes to the overproduction of reactive oxygen species, leading to nephrotic syndrome and glomerular scarring. As diabetic nephropathy progresses, the glomerular filtration barrier (GFB) becomes increasingly damaged, resulting in proteins from the blood leaking through the barrier and accumulating in Bowman's space.

[0200] In some embodiments, the FXR agonists disclosed herein are used in combination with other therapeutic agents disclosed herein in the treatment of diabetic nephropathy in mammals. In some examples, the FXR agonist and the additional therapeutic agent reduce the symptoms of diabetic nephropathy in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, diabetic nephropathy is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolite, or an antifibrotic agent.

[0201] (renal fibrosis) Renal fibrosis is characterized by fibroblast activation and excessive deposition of extracellular matrix or connective tissue in the kidney. This is a characteristic of chronic kidney disease. FXR plays a crucial role in protecting against renal fibrosis. Activation of FXR suppresses renal fibrosis and reduces the accumulation of extracellular matrix proteins in the kidney.

[0202] In some embodiments, FXR agonists (e.g., Compound 1 or a pharmaceutically acceptable salt thereof) are used to treat diseases or conditions associated with renal fibrosis. Renal fibrosis can develop due to a variety of diseases and impairments of the kidneys. Examples of such diseases and injuries include chronic kidney disease, metabolic syndrome, vesicoureteral reflux, tubulointerstitial renal fibrosis, IgA nephropathy, diabetes mellitus (including diabetic nephropathy), Alport syndrome, HIV-associated nephropathy, resulting glomerulonephritis (GN), including but not limited to focal segmental glomerulosclerosis and membranous glomerulonephrosis, mesangial capillary GN, and resulting interstitial fibrosis and tubular atrophy (IFTA), including but not limited to recovery after acute kidney injury (AKI), acute obstructive nephropathy, and drug-induced renal fibrosis.

[0203] In some embodiments, the FXR agonists disclosed herein are used in combination with other therapeutic agents disclosed herein in the treatment of renal fibrosis in mammals. In some examples, the FXR agonist and the additional therapeutic agent reduce the symptoms of renal fibrosis in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, renal fibrosis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolite, or an antifibrotic agent.

[0204] In one embodiment, a method for treating or preventing a renal disease or condition in a mammal is described herein, comprising administering an FXR agonist disclosed herein to the mammal. In some embodiments, the renal disease or condition is diabetic nephropathy, fibrosis-related renal disease, fibrosis-unrelated renal disease, renal fibrosis, metabolic disease-related renal disease, chronic kidney disease, polycystic kidney disease, acute nephritis, or any combination thereof.

[0205] (inflammation) In certain embodiments, methods for treating or preventing inflammation in a subject in need are disclosed herein, comprising administering a farnesoid X receptor (FXR) agonist and additional therapeutic agents to the subject. In some embodiments, the additional therapeutic agent is any of the following: an antifibrotic agent, an anti-inflammatory agent, a metabolic agent, an anti-inflammatory agent, or any other therapeutic agent described herein.

[0206] In some embodiments, hepatitis is hepatitis. In some embodiments, hepatitis is acute hepatitis, chronic hepatitis, or fulminant hepatitis. In some embodiments, hepatitis is viral hepatitis, bacterial hepatitis, parasitic hepatitis, toxic and drug-induced hepatitis, alcoholic hepatitis, autoimmune hepatitis, non-alcoholic steatohepatitis (NASH), neonatal hepatitis, or ischemic hepatitis. In some embodiments, viral hepatitis is viral hepatitis, hepatitis A, hepatitis B, hepatitis C, hepatitis D, or hepatitis E. In some embodiments, hepatitis is associated with fibrous liver disease or metabolic liver disease.

[0207] In some embodiments, the FXR agonists disclosed herein are used in combination with other therapeutic agents disclosed herein in the treatment of inflammation or inflammatory conditions in mammals. In some examples, the FXR agonists disclosed herein are used in combination with other therapeutic agents disclosed herein to reduce the symptoms or conditions of inflammation in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, the inflammation or inflammatory condition is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, a metabolite, or an anti-fibrotic agent.

[0208] In one embodiment, a method for treating or preventing an inflammatory condition in a mammal is described herein, comprising administering an FXR agonist disclosed herein (e.g., Compound 1 or a pharmaceutically acceptable salt thereof) to the mammal. In some embodiments, the inflammatory condition includes inflammation of the liver, inflammation of the kidneys, inflammation of the gastrointestinal tract, or any combination thereof.

[0209] (FXR Agonist) In one embodiment, the FXR agonist for use in any of the methods described herein has a non-bile acid chemical structure. In some embodiments, the FXR agonist for use in any of the methods described herein provides sustained exposure when administered to mammals. In some embodiments, the FXR agonist for use in any of the methods described herein has continuous target engagement with FXR. In some embodiments, the FXR agonist for use in any of the methods described herein is suitable for once-daily oral administration. In some embodiments, the FXR agonist for use in any of the methods described herein has a non-bile acid chemical structure, provides sustained exposure with continuous target engagement, and is suitable for once-daily oral administration.

[0210] In some embodiments, the FXR agonist for use in any of the embodiments described herein is a compound having the following structure of compound 1,

[0211] [ka] or a pharmaceutically acceptable salt thereof.

[0212] Compound 1 is also known as "4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate". Other names may also be known.

[0213] Oveticolic acid (OCA) is an FXR agonist containing the chemical structure of a bile acid. Published clinical studies have demonstrated the clinical efficacy of OCA as an FXR agonist, but it has been associated with adverse side effects at high doses, including pruritus, increased LDL cholesterol, and hepatotoxicity. In several embodiments, in appropriate in vitro assays evaluating the binding of FXR agonists to FXR, compound 1 showed at least 30 times greater potency than OCA. In several embodiments, the increased potency of compound 1 suggests a potential broader therapeutic concentration range compared to OCA.

[0214] In some embodiments, compound 1 demonstrated sustained FXR involvement in preclinical animal models, based on pharmacokinetic and pharmacodynamic markers. In some embodiments, compound 1 demonstrates sustained FXR involvement that enables once-daily administration of compound 1.

[0215] In several embodiments, in appropriate assays evaluating such activity, compound 1 demonstrated that it could negligibly or not inhibit cytochrome P450 3A4 (CYP3A4), a drug-metabolizing enzyme in the liver.

[0216] The synthesis of compound 1 is described in U.S. Patent Application No. 16 / 573,993, filed September 17, 2019, and International Patent Application No. PCT / US2019 / 051603, also filed September 17, 2019.

[0217] In some embodiments, the FXR agonist for use in any of the methods described herein has a non-bile acid chemical structure.

[0218] In some embodiments, the FXR agonist for use in any of the methods described herein is Compound 1 or a pharmaceutically acceptable salt thereof, obeticholic acid or a pharmaceutically acceptable salt thereof (Intercept), silofexor or a pharmaceutically acceptable salt thereof (Gilead), EDP-305 or a pharmaceutically acceptable salt thereof (Enanta), tropifexor or a pharmaceutically acceptable salt thereof (Novartis), EYP001 or a pharmaceutically acceptable salt thereof (Enyo), LMB673 or a pharmaceutically acceptable salt thereof (Novartis), TERN-101 or a pharmaceutically acceptable salt thereof (Terns), or AGN242266 or a pharmaceutically acceptable salt thereof (Allergan). In some embodiments, the FXR agonist for use in any of the methods described herein is silofexor or a pharmaceutically acceptable salt thereof, EDP-305 or a pharmaceutically acceptable salt thereof, tropifexor or a pharmaceutically acceptable salt thereof, EYP001 or a pharmaceutically acceptable salt thereof, LMB673 or a pharmaceutically acceptable salt thereof, TERN-101 or a pharmaceutically acceptable salt thereof, or AGN-242266 or a pharmaceutically acceptable salt thereof. In some embodiments, the FXR agonist is fexalamine or a pharmaceutically acceptable salt thereof.

[0219] (Specific terminology) The section headings used in this specification are for organizational purposes only and should not be interpreted as limiting the subject matter described.

[0220] Unless otherwise specified, the following terms used in this application have the definitions set forth below. The use of the term "including," and other forms such as "include," "includes," and "included," is not limited to these terms.

[0221] As used herein with respect to formulations, compositions, or components, the term “acceptable” means that they do not cause any lasting adverse effects on the general health of the mammal being treated.

[0222] As used herein, the term “modulate” means to interact with a target directly or indirectly in such a way as to alter its activity, and includes, but are not limited to, enhancing, inhibiting, limiting, or amplifying the activity of the target.

[0223] As used herein, the term “modulator” refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0224] As used herein, terms such as “administer,” “give delivery,” and “dosage” refer to methods used to enable the delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or intravenous infusion), topical, and rectal administration. Those skilled in the art will be familiar with the administration techniques used in the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0225] As used herein, terms such as "concurrent administration" encompass the administration of selected therapeutic agents to a single patient and are intended to include therapeutic regimens in which drugs are administered via the same or different routes of administration, or simultaneously or at different times.

[0226] As used herein, the terms “effective dose” or “therapeutic effective dose” refer to a sufficient amount of an administered drug or compound that alleviates, to some extent, one or more symptoms of the disease or condition being treated. Results include reduction and / or mitigation of the signs, symptoms, or causes of the disease, or other desirable changes in the biological system. For example, an “effective dose” for therapeutic use is the amount of a composition containing the compounds disclosed herein that is required to clinically significantly alleviate the symptoms of the disease. The appropriate “effective” dose in any individual case is determined at arbitrary discretion using techniques such as dose-escalation studies.

[0227] As used herein, the terms “enhance” or “enhancing” mean increasing or extending the potency or duration of a desired effect. Therefore, with respect to the enhancement of the effect of a therapeutic agent, “enhancing” refers to the ability to increase or extend either the potency or duration of the effect of another therapeutic agent on a system. As used herein, “enhancing effective dose” refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0228] As used herein, the term “pharmaceutical combination” means a product resulting from a mixture or combination of multiple active ingredients, and includes both immobilized and unimmobilized combinations of active ingredients. The term “immobilized combination” means that both the active ingredient, e.g., the compound described herein or a pharmaceutically acceptable salt thereof, and the adjuvant are administered to the patient simultaneously in the form of a single entity or dosage. The term “unimmobilized combination” means that the active ingredient, e.g., the compound described herein or a pharmaceutically acceptable salt thereof, and the adjuvant are administered to the patient as separate entities, simultaneously, in parallel, or sequentially without time constraints. Such administrations provide effective concentrations of the two compounds in the patient’s body. The latter also applies to cocktail therapies, e.g., administration of three or more active ingredients.

[0229] The terms “subject” or “patient” encompass mammals. Examples of mammals include, but are not limited to, any species of the mammalian class, such as humans, non-human primates like chimpanzees, and other ape and monkey species. In one embodiment, the mammal is human.

[0230] As used herein, the terms “to treat,” “to treat,” or “to cure” include alleviating, reducing or improving at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, for example, alleviating a disease or condition, causing regression of a disease or condition, halting the progression of a disease or condition, alleviating a condition caused by a disease or condition, or preventing and / or curatively stopping the symptoms of a disease or condition.

[0231] The terms “about” or “approximately” mean that a particular value is within a tolerance range determined by those skilled in the art, which in part depends on how the value is measured or determined, for example, the limitations of the measuring system. Where a particular value is stated in the application and claims, unless otherwise specified, the term “about” should be assumed to mean an acceptable tolerance range for that particular value.

[0232] (Pharmaceutical composition) The pharmaceutical compositions are formulated by conventional means using one or more pharmaceutically acceptable inactive components that facilitate the processing of the active compound into a pharmaceutically useful formulation. The appropriate formulation depends on the chosen route of administration. Summaries of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E., Remington: Pharmaceutical Sciences (Mack Publishing Co., Easton, Pennsylvania, 1975), Liberman, H.A. and Lachman, L.: Pharmaceutical Dosage Forms (Marcel Decker, New York, NY, 1980), and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins, 1999), and are incorporated herein by reference to such disclosures.

[0233] In some embodiments, the pharmaceutical compositions described herein are administered parenterally or enterally. The administration of the compositions described herein is influenced by any method that enables delivery of the compound to the site of action. These methods include, but are not limited to, delivery by enteral routes (including oral, gastric or duodenal feeding tubes, rectal suppositories and rectal enemas) and parenteral routes (including injection or infusion, including intra-arterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, subarachnoid, intravascular, intravenous, intravitreous, epidural and subcutaneous), and the most appropriate route depends, for example, on the condition and impairments of the recipient. In some embodiments, the pharmaceutical compositions described herein are administered orally.

[0234] In some embodiments, the pharmaceutical compositions described herein are in the form of powders, tablets, capsules, suspensions, liquids, dispersions, solutions, or emulsions.

[0235] In some embodiments, pharmaceutical compositions suitable for oral administration are provided as separate units such as capsules, pills, or tablets, each containing a predetermined amount of active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil liquid emulsions.

[0236] Pharmaceutical compositions for oral use include tablets, gelatin-based press-fit capsules, and soft-seal capsules made of gelatin and plasticizers such as glycerol or sorbitol. Tablets are made by compression or molding with the optional use of one or more auxiliary components. Compressed tablets are prepared by compressing a free-flowing active ingredient, such as a powder or granules, optionally mixed with a binder, an inert diluent, or a smoothing agent, surfactant, or dispersant, using appropriate machinery. Molded tablets are made by molding a mixture of powder compounds moistened with an inert liquid diluent using appropriate machinery. In some embodiments, tablets are formulated by coating or notching to provide sustained or controlled release of the active ingredient therein. All formulations for oral administration must be in a dosage appropriate for such administration. Press-fit capsules contain an active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a smoothing agent such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound is dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added. The sugar-coated tablet core is coated with a suitable coating. For this purpose, a concentrated sugar solution is used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbopole gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. In some embodiments, dyes or pigments are added to the tablet or sugar-coated tablet coating to identify or characterize different combinations of active compound dosages.

[0237] In some embodiments, the pharmaceutical composition is formulated for parenteral administration by infusion, such as bolus injection or continuous infusion. In some embodiments, the formulation for infusion is provided in unit dosage form, for example, in ampoules or multi-dose containers, with the addition of preservatives. In some embodiments, the composition takes the form of a suspension, solution or emulsion in an oily or aqueous medium and includes compounding agents such as suspending agents, stabilizers and / or dispersants. In some embodiments, the composition is provided in unit or multi-dose containers, such as sealed ampoules and vials, and is stored in powder form or lyophilized (lyophilized) state requiring only the addition of a sterile liquid carrier, such as physiological saline or sterile water free of pyrogens, immediately before use. In some embodiments, instant injectable solutions and suspensions are prepared from the aforementioned types of sterile powders, granules and tablets.

[0238] In some embodiments, pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oil-based) sterile injection solutions of the active compound, comprising antioxidants, buffers, bacteriostatic agents, and solutes to make the formulation isotonic with the blood of the person to be administered to, and aqueous and non-aqueous sterile suspensions comprising suspending agents and thickeners. Suitable lipophilic solvents or media include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In some embodiments, the aqueous injection suspension comprises a substance that increases the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. In some embodiments, optionally, the suspension comprises a suitable stabilizer or agent that increases the solubility of the compound and allows for the preparation of high-concentration solutions.

[0239] In some embodiments, the pharmaceutical composition is also formulated as a depot formulation. In some embodiments, such sustained-release formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Therefore, for example, the compound may be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a sparingly soluble derivative, for example, as a sparingly soluble salt.

[0240] In particular, it should be understood that, in addition to the components described herein, the compounds and compositions described herein, in some embodiments, include other agents commonly used in the art, taking into account the type of formulation in question. For example, in some embodiments, the compounds and compositions described herein, suitable for oral administration, include flavoring agents.

[0241] (Administration method and treatment regimen) In one embodiment, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is used to prepare a drug for treating or preventing any one of the diseases or conditions described herein in a mammal. A method for treating any of the diseases or conditions described herein in a mammal in need of such treatment comprises administering a pharmaceutical composition comprising an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof), an active metabolite, and a prodrug to the mammal in a therapeutically effective amount.

[0242] In certain embodiments, compositions containing the compounds described herein are administered for preventive and / or therapeutic purposes. In certain therapeutic uses, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent at least one symptom of the disease or condition. The effective dose for this use will vary depending on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, as well as the judgment of the attending physician. The therapeutically effective dose may be determined at will by means of a method including, but not limited to, dose escalation and / or dose determination clinical trials.

[0243] In prophylactic use, a composition containing an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered to patients who are susceptible to, or otherwise at risk of, a particular disease, disorder, or condition. Such an amount is defined as a “prophylactically effective amount or dose.” In this use, the exact amount also depends on the patient’s health condition, body weight, etc. When used in a patient, the amount effective for this use will vary depending on the severity and course of the disease, disorder, or condition, previous treatments, the patient’s health condition and response to the drug, and the judgment of the attending physician. In one embodiment, prophylactic treatment involves administering a pharmaceutical composition containing an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) to a mammal that has previously experienced at least one symptom of the disease being treated and is currently in remission, in order to prevent recurrence of symptoms of the disease or condition.

[0244] In certain embodiments where the patient's condition does not improve, the physician may, at their discretion, administer an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) chronically, i.e., over a long period including the patient's lifetime, to improve, or otherwise control or limit, the symptoms of the patient's disease or condition.

[0245] In certain embodiments where the patient's condition improves, the dose of the administered drug is temporarily reduced or temporarily interrupted for a period of time (i.e., a “drug-free period”). In certain embodiments, the length of the drug-free period is between approximately 2 days and approximately 1 year, and includes, but are not limited to, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, approximately 7 days, approximately 10 days, approximately 12 days, approximately 15 days, approximately 20 days, approximately 28 days, or approximately 28 days or more. The dose reduction during the drug-free period is, but are not limited to, approximately 10% to 100%, and includes, but are not limited to, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 95%, and approximately 100%.

[0246] Once the patient's condition improves, a maintenance dose is administered as needed. Subsequently, in certain embodiments, the dose, or frequency of administration, or both, is reduced as a function of symptoms to a level at which the improved disease, disorder, or condition is maintained. However, in certain embodiments, the patient requires long-term, intermittent treatment if symptoms recur.

[0247] In one embodiment, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered daily to a person requiring treatment with an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof). In some embodiments, the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered once daily. In some embodiments, the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered twice daily. In some embodiments, the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered every other day. In some embodiments, the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered twice weekly.

[0248] In some cases, the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered once daily, twice daily, or more frequently. In some cases, the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered twice daily. In some embodiments, the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered daily, every day, every other day, five days a week, once a week, every other week, two weeks a month, three weeks a month, once a month, twice a month, three times a month, or more frequently. In some embodiments, the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered twice daily, for example, in the morning and evening. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, 4 years, 5 years, 10 years, or longer. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered twice daily for at least about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or longer. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered once daily, twice daily, three times daily, four times daily, or more than four times daily for at least about one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, or longer.

[0249] In general, the dose of an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) used in the treatment of the diseases or conditions described herein in humans is typically in the range of about 0.01 mg to about 10 mg per kg of body weight per single dose. In one embodiment, the desired dose is preferably provided as a single dose or as divided doses administered simultaneously (or over a short period) or at appropriate intervals, for example, two, three, four or more divided doses per day. In some embodiments, the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is preferably provided as a divided dose administered once daily simultaneously (or over a short period). In some embodiments, the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is preferably provided as a divided dose administered twice daily in equal amounts.

[0250] In some embodiments, the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered orally to humans in doses ranging from approximately 0.01 mg / kg body weight to approximately 10 mg / kg body weight per single dose. In some embodiments, the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered to humans in a continuous dosing schedule. In some embodiments, the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered to humans in a continuous daily dosing schedule.

[0251] The term “sequential dosing schedule” refers to administering a particular therapeutic agent at regular intervals. In some embodiments, a sequential dosing schedule refers to administering a particular therapeutic agent at regular intervals without any drug-free periods. In some other embodiments, a sequential dosing schedule refers to administering a particular therapeutic agent in a cycle. In some other embodiments, a sequential dosing schedule refers to administering a particular therapeutic agent in a cycle of drug administration, followed by a drug-free period from the particular therapeutic agent (e.g., a washout period or other such period during which the drug is not administered). For example, in some embodiments, the therapeutic agent is administered once daily, twice daily, three times daily, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, seven times a week, every other day, every three days, or every four days; or the therapeutic agent is administered daily for one week followed by one week without administration; the therapeutic agent is administered daily for two weeks followed by one or two weeks without administration; the therapeutic agent is administered daily for three weeks followed by one, two, or three weeks without administration; the therapeutic agent is administered daily for four weeks followed by one, two, three, or four weeks without administration; the therapeutic agent is administered weekly followed by one week without administration; or the therapeutic agent is administered every other week followed by two weeks without administration. In some embodiments, daily administration is once daily. In some embodiments, daily administration is twice daily. In some embodiments, daily administration is three times daily. In some embodiments, daily administration is more than three times daily.

[0252] The term "continuous daily dosing schedule" refers to administering a specific therapeutic agent at approximately the same time each day. In some embodiments, the daily dosing is once a day. In some embodiments, the daily dosing is twice a day. In some embodiments, the daily dosing is three times a day. In some embodiments, the daily dosing is more than three times a day.

[0253] In some embodiments, a certain amount of FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered once daily.

[0254] In certain embodiments where no improvement in the symptoms of the disease or condition is observed in humans, the daily dose of the FXR agonist (e.g., compound 1, or a pharmaceutically acceptable salt thereof) is increased. In some embodiments, the once-daily dosing schedule is changed to a twice-daily dosing schedule. In some embodiments, a three-daily dosing schedule is used to increase the amount of FXR agonist (e.g., compound 1, or a pharmaceutically acceptable salt thereof) administered. In some embodiments, the frequency of inhalation administration is increased to more regular and repeated doses. max The dose is increased to provide a concentration. In some embodiments, the dose frequency is increased to provide sustained or more regular exposure to an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof). In some embodiments, the dose frequency is increased to repeatedly provide a higher Cmax concentration more regularly and to provide maintained or more regular exposure to an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof).

[0255] In any of the embodiments described above, there are further embodiments comprising a single dose of an effective amount of an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof), and further embodiments include the FXR agonist being administered (i) once daily or (ii) multiple times during the day.

[0256] In any of the embodiments described above, there are further embodiments comprising multiple doses of an effective amount of FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof), including further embodiments in which (i) the FXR agonist is administered as a single dose, either sequentially or intermittently; (ii) the interval between doses is every 6 hours; (iii) the FXR agonist is administered to a mammal every 8 hours; (iv) the FXR agonist is administered to a mammal every 12 hours; or (v) the FXR agonist is administered to a mammal every 24 hours. In further or alternative embodiments, the method comprises a drug-free period in which the administration of the FXR agonist is temporarily interrupted or the dose of the FXR agonist administered is temporarily reduced, and at the end of the drug-free period, the administration of the FXR agonist is resumed. In one embodiment, the length of the drug-free period varies from 2 days to 1 year.

[0257] Generally, appropriate doses of FXR agonists for human administration range from approximately 0.01 mg / kg / day to approximately 25 mg / kg / day (e.g., approximately 0.2 mg / kg / day, 0.3 mg / kg / day, 0.4 mg / kg / day, 0.5 mg / kg / day, 0.6 mg / kg / day, 0.7 mg / kg / day, 0.8 mg / kg / day, 0.9 mg / kg / day, 1 mg / kg / day, 2 mg / kg / day, 3 mg / kg / day, 4 mg / kg / day, 5 mg / kg / day, 6 mg / kg / day, 7 mg / kg / day, 8 mg / kg / day, 9 mg / kg / day, 10 mg / kg / day, 15 mg / kg / day, 20 mg / kg / day, or 25 mg / kg / day). Alternatively, appropriate doses of FXR agonist for human administration range from approximately 0.01 mg / day to approximately 1000 mg / day, approximately 1 mg / day to approximately 400 mg / day, or approximately 1 mg / day to approximately 300 mg / day. In other embodiments, appropriate doses of FXR agonist for human administration range from approximately 1 mg / day, approximately 2 mg / day, approximately 3 mg / day, approximately 4 mg / day, approximately 5 mg / day, approximately 6 mg / day, approximately 7 mg / day, approximately 8 mg / day, approximately 9 mg / day, approximately 10 mg / day, approximately 15 mg / day, approximately 20 mg / day, approximately 25 mg / day, approximately 30 mg / day, approximately 35 mg / day, approximately 40 mg / day, approximately 45 mg / day, approximately 50 mg / day, approximately 55 mg / day, approximately 60 mg / day, approximately 65 mg / day, and approximately 70 mg The dosage is approximately 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 175 mg / day, 200 mg / day, 225 mg / day, 250 mg / day, 275 mg / day, 300 mg / day, 325 mg / day, 350 mg / day, 375 mg / day, 400 mg / day, 425 mg / day, 450 mg / day, 475 mg / day, or 500 mg / day. In some embodiments, the dosage is administered more than once a day (e.g., two, three, four times a day, or more).

[0258] In some embodiments, a suitable dose of compound 1 or a pharmaceutically acceptable salt thereof for administration to humans is about 1 mg / day to about 300 mg / day. In some embodiments, a suitable dose of compound 1 or a pharmaceutically acceptable salt thereof for administration to humans is about 5 mg / day to about 150 mg / day. In some embodiments, a suitable dose of compound 1 or a pharmaceutically acceptable salt thereof for administration to humans is about 5 mg / day to about 100 mg / day. In some embodiments, a suitable dose of compound 1 or a pharmaceutically acceptable salt thereof for administration to humans is about 5 mg / day to about 80 mg / day. In some embodiments, a suitable dose of compound 1 or a pharmaceutically acceptable salt thereof for administration to humans is about 5 mg / day to about 50 mg / day. In some embodiments, appropriate doses of compound 1 or a pharmaceutically acceptable salt thereof for administration to humans are about 150 mg / day to about 300 mg / day, about 150 mg / day to about 250 mg / day, or about 150 mg / day to about 200 mg / day. In some embodiments, the dose is administered once daily. In some embodiments, the dose is administered more than once daily (e.g., two, three, four times, or more times per day). In some embodiments, the above amounts refer to the amount of compound 1.

[0259] In some embodiments, suitable doses of compound 1 or a pharmaceutically acceptable salt thereof for administration to humans are about 1 mg / day, about 2 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, about 6 mg / day, about 7 mg / day, about 8 mg / day, about 9 mg / day, about 10 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day, about 50 mg / day, about 55 mg / day, about 60 mg / day, about 65 mg / day, about 70 mg / day, about 75 mg / day, about 80 mg / day, about 85 mg / day, about 90 mg / day, about 95 mg / day, about 100 mg / day, about 125 mg / day, or about 150 mg / day. In some embodiments, appropriate doses of compound 1 or a pharmaceutically acceptable salt thereof for administration to humans are about 1 mg / day, about 2 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, about 6 mg / day, about 7 mg / day, about 8 mg / day, about 9 mg / day, about 10 mg / day, about 12 mg / day, about 15 mg / day, about 20 mg / day, or about 25 mg / day. In some embodiments, appropriate doses of compound 1 or a pharmaceutically acceptable salt thereof for administration to humans are about 1 mg / day, about 2 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, or about 6 mg / day. In some embodiments, appropriate doses of compound 1 or a pharmaceutically acceptable salt thereof for administration to humans are about 3 mg / day. In some embodiments, appropriate doses of compound 1 or a pharmaceutically acceptable salt thereof for administration to humans are about 6 mg / day. In some embodiments, a suitable dose of compound 1 or a pharmaceutically acceptable salt thereof for administration to humans is about 9 mg / day. In some embodiments, a suitable dose of compound 1 or a pharmaceutically acceptable salt thereof for administration to humans is about 12 mg / day. In some embodiments, the dose is administered once daily. In some embodiments, the dose is administered more than once daily (e.g., two, three, four times, or more times per day). In some embodiments, the above amounts refer to the amount of compound 1.

[0260] In some embodiments, appropriate doses of compound 1 or a pharmaceutically acceptable salt thereof for administration to humans are about 5 mg / day, about 10 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day, about 50 mg / day, about 55 mg / day, about 60 mg / day, about 65 mg / day, about 70 mg / day, about 75 mg / day, about 80 mg / day, about 85 mg / day, about 90 mg / day, about 95 mg / day, about 100 mg / day, about 125 mg / day, or about 150 mg / day. In some embodiments, the dose is administered once daily. In some embodiments, the dose is administered more than once daily (e.g., two, three, four times, or more times per day). In some embodiments, the above amounts refer to the amount of compound 1.

[0261] In some embodiments, appropriate doses of compound 1 or a pharmaceutically acceptable salt thereof for administration to humans are approximately 150 mg / day, approximately 155 mg / day, approximately 160 mg / day, approximately 165 mg / day, approximately 170 mg / day, approximately 175 mg / day, approximately 180 mg / day, approximately 185 mg / day, approximately 190 mg / day, approximately 195 mg / day, approximately 200 mg / day, approximately 205 mg / day, approximately 210 mg / day, The dosage is approximately 215 mg / day, approximately 220 mg / day, approximately 225 mg / day, approximately 230 mg / day, approximately 235 mg / day, approximately 240 mg / day, approximately 245 mg / day, approximately 250 mg / day, approximately 255 mg / day, approximately 260 mg / day, approximately 265 mg / day, approximately 270 mg / day, approximately 275 mg / day, approximately 280 mg / day, approximately 285 mg / day, approximately 290 mg / day, approximately 295 mg / day, or approximately 300 mg / day. In some embodiments, the dosage is administered once daily. In some embodiments, the dosage is administered more than once daily (e.g., two, three, four times, or more times per day). In some embodiments, the above amounts refer to the amount of compound 1.

[0262] In some embodiments, the daily dose or amount of active ingredient in the dosage form may be lower or higher than the ranges shown herein, based on many variables relating to the individual treatment regimen. In various embodiments, the daily dose and unit dose may vary depending on many variables, including but not limited to the disease or condition being treated, the mode of administration, the individual subject's requirements, the severity of the disease or condition being treated, the individual person's condition (e.g., body weight), any specific additional therapeutic agents administered (if applicable), and the judgment of a general practitioner.

[0263] The toxicity and therapeutic effect of such treatment regimens are LD 50 and ED 50 This is determined by standard pharmaceutical procedures in cell culture or experimental animals, including but not limited to the determination of LD50. The dose-to-toxicity ratio is the therapeutic index, and LD50 is the dose-to-toxicity ratio. 50 Against ED 50 It is expressed as a ratio. In certain embodiments, data obtained from cell culture assays and animal studies are used when formulating a range of therapeutically effective daily doses and / or therapeutically effective unit doses for use in mammals, including humans. In some embodiments, the daily dose of the FXR agonist is the ED with the least toxicity. 50 It is within the range of circulating concentrations, including [the specified amount]. In certain embodiments, the range of daily doses and / or unit doses varies within this range depending on the dosage form used and the route of administration used.

[0264] Several published clinical trials have shown that OCA has demonstrated a proven clinical benefit, measured by liver biopsy, for improvement in both NAS and fibrosis. However, pruritus associated with OCA has limited the use of high doses in clinical trials. Furthermore, OCA is characterized by side effects of increased LDL cholesterol and hepatotoxicity, which also limits the use of high doses.

[0265] In some embodiments, administration of an FXR agonist to a subject causes pruritus. In some embodiments, the pruritus associated with administration of the FXR agonist is reduced in severity or resolved by continuous administration of the FXR agonist. In some embodiments, the pruritus associated with FXR agonist administration is correlated with the dose. In some embodiments, minimizing and / or resolving the pruritus associated with FXR agonist administration includes adjusting the dose of the FXR agonist administered.

[0266] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered according to a dosing schedule. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered via a dosing schedule to minimize adverse events associated with administration of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, adjustment of the dose of Compound 1 or a pharmaceutically acceptable salt thereof enables the subject to tolerate Compound 1 or a pharmaceutically acceptable salt thereof, minimizes adverse events associated with administration of Compound 1 or a pharmaceutically acceptable salt thereof, maximizes the likelihood that an optimized dose of Compound 1 or a pharmaceutically acceptable salt thereof will be administered to and tolerated by the subject, or enables combinations thereof. In some embodiments, dose adjustment includes dose escalation.

[0267] As used herein, a subject is said to "tolerate" a dose of a compound if administration of that dose to the subject does not result in unacceptable adverse events and unacceptable combinations of adverse events. One of ordinary skill in the art will understand that the tolerance level is a subjective measure and that what may be tolerable for one patient may not be tolerable for another patient. For example, one subject may not tolerate pruritus, a second subject may tolerate mild pruritus but not moderate pruritus, and a third subject may tolerate moderate pruritus but not severe pruritus.

[0268] As used herein, "adverse event" refers to an undesirable medical event associated with treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the adverse event is pruritus.

[0269] As used herein, "optimized dose" refers to a therapeutically optimized dose tailored to the needs of a particular subject, which elicits the desired biological or medical response in the subject and is the highest dose of Compound 1 or the dose of a pharmaceutically acceptable salt of Compound 1 equivalent to the highest dose of Compound 1 that can be tolerated by the subject, which is determined by the subject, optionally in consultation with the subject's healthcare provider.

[0270] As used herein, "dose adjustment" of a compound refers to increasing the amount of the compound until the subject is no longer able to tolerate an increased amount. Dose escalation can be achieved by one or more dose increases, which may be the same or different. In some embodiments, the method comprises administering Compound 1 or a pharmaceutically acceptable salt thereof once daily at an initial dose over an initial period, followed by subsequent dose escalation of Compound 1 or a pharmaceutically acceptable salt thereof to a higher dose once daily. In some embodiments, the initial period includes 1 day, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, 10 weeks, about 11 weeks, or about 12 weeks. In some embodiments, this cycle is repeated until an optimized dose is achieved.

[0271] In some embodiments, the method of dose adjustment comprises administering Compound 1 or a pharmaceutically acceptable salt thereof once daily at an initial dose for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks, followed by subsequent daily dose escalation of Compound 1 or a pharmaceutically acceptable salt thereof to a higher dose. In some embodiments, this cycle is repeated until an optimized dose is achieved.

[0272] In some embodiments, the dose adjustment method involves administering compound 1 or a pharmaceutically acceptable salt thereof once daily at an initial dose for about 1, 2, 3, 4, 5, 6, 7, or 8 weeks, followed by dose escalation to higher doses of compound 1 or a pharmaceutically acceptable salt thereof once daily. In some embodiments, this cycle is repeated until an optimized dose is achieved. In some embodiments, the method involves administering compound 1 or a pharmaceutically acceptable salt thereof once daily at an amount equivalent to about 3 mg of compound 1 for about 1, 2, 3, 4, 5, 6, 7, or 8 weeks, followed by dose escalation to about 6 mg of compound 1 or a pharmaceutically acceptable salt thereof once daily.

[0273] In some embodiments, the method of dose adjustment includes dose escalation or dose decrement of compound 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, followed by any subsequent dose escalation.

[0274] In some embodiments, the dose adjustment schedule includes administering compound 1 or a pharmaceutically acceptable salt or solvate thereof at an initial dose for about one week, and if the patient tolerates the initial dose, increasing the dose by an amount equal to a first increment, or if the patient does not tolerate the initial dose, decreasing the dose by an amount equal to a first increment.

[0275] In some embodiments, the initial dose corresponds to approximately 1 mg to approximately 30 mg of compound 1. In some embodiments, the initial dose corresponds to approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 6 mg, approximately 7 mg, approximately 8 mg, approximately 9 mg, approximately 10 mg, approximately 11 mg, approximately 12 mg, approximately 13 mg, approximately 14 mg, approximately 15 mg, approximately 16 mg, approximately 17 mg, approximately 18 mg, approximately 19 mg, approximately 20 mg, approximately 21 mg, approximately 22 mg, approximately 23 mg, approximately 23 mg, approximately 25 mg, approximately 26 mg, approximately 27 mg, approximately 28 mg, approximately 29 mg, or approximately 30 mg of compound 1. In some embodiments, the initial dose corresponds to approximately 1 mg, approximately 3 mg, approximately 5 mg, approximately 6 mg, approximately 12 mg, or approximately 25 mg of compound 1. In some embodiments, the initial dose corresponds to approximately 3 mg of compound 1. In some embodiments, the initial dose corresponds to approximately 6 mg of compound 1.

[0276] In some embodiments, the dose adjustment schedule further includes administering compound 1 or a pharmaceutically acceptable salt thereof at an increased dose for about one week, and if the patient tolerates the increased dose, further increasing the dose by an amount equal to a second increment; or administering compound 1 or a pharmaceutically acceptable salt thereof at a reduced dose for about one week, and if the patient tolerates the reduced dose, optionally increasing the dose by an amount equal to a second increment. In some embodiments, the first increment is the same as the second increment. In some embodiments, the first and second increments are different.

[0277] In some embodiments, the first increment value corresponds to approximately 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 23 mg, or 25 mg of compound 1. In some embodiments, the first increment value corresponds to approximately 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg of compound 1. In some embodiments, the first increment value corresponds to approximately 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, or 6 mg of compound 1. In some embodiments, the first increment corresponds to about 1 mg, about 2 mg, or about 3 mg of compound 1.

[0278] In some embodiments, the second increment value corresponds to approximately 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 23 mg, or 25 mg of compound 1. In some embodiments, the second increment value corresponds to approximately 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg of compound 1. In some embodiments, the second increment value corresponds to approximately 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, or 6 mg of compound 1. In some embodiments, the second increment corresponds to about 1 mg, about 2 mg, or about 3 mg of compound 1.

[0279] In some embodiments, the dose adjustment schedule is repeated until an optimized dose is obtained. The optimized dose provides therapeutic efficacy while minimizing side effects such as itching associated with FXR agonist treatment.

[0280] In some embodiments, the optimized dose corresponds to approximately 1 mg to approximately 30 mg of compound 1. In some embodiments, the optimized dose corresponds to approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 6 mg, approximately 7 mg, approximately 8 mg, approximately 9 mg, approximately 10 mg, approximately 11 mg, approximately 12 mg, approximately 13 mg, approximately 14 mg, approximately 15 mg, approximately 16 mg, approximately 17 mg, approximately 18 mg, approximately 19 mg, approximately 20 mg, approximately 21 mg, approximately 22 mg, approximately 23 mg, approximately 23 mg, approximately 25 mg, approximately 26 mg, approximately 27 mg, approximately 28 mg, approximately 29 mg, or approximately 30 mg of compound 1. In some embodiments, the optimized dose corresponds to approximately 1 mg, approximately 3 mg, approximately 5 mg, approximately 6 mg, approximately 12 mg, or approximately 25 mg of compound 1. In some embodiments, the optimized dose corresponds to approximately 3 mg of compound 1. In some embodiments, the optimized dose corresponds to approximately 6 mg of compound 1.

[0281] (Therapy based on biomarker detection) In some embodiments, administration of a pharmaceutical composition comprising at least one FXR agonist is based on the patient's circulating or tissue-based FGF-19 concentration. In some embodiments, administration of a pharmaceutical composition comprising a combination of at least one FXR agonist and an additional therapeutic agent is based on the patient's serum C4 (7α-hydroxy-4-cholesten-3-one) concentration. In some embodiments, administration of a pharmaceutical composition comprising a combination of at least one FXR agonist and an additional therapeutic agent is based on the patient's serum bile acid concentration. In some embodiments, administration of a pharmaceutical composition comprising a combination of at least one FXR agonist and an additional therapeutic agent is based on the patient's fecal bile acid concentration. In some embodiments, the additional therapeutic agent is any of the following: an anti-fibrotic therapeutic agent, an anti-inflammatory agent, a metabolic therapeutic agent, an anti-inflammatory agent, or other therapeutic agents described herein. In some embodiments, a composition comprising the combination therapy described herein is administered to a patient with abnormal concentrations of FGF-19, C4 (7α-hydroxy-4-cholesten-3-one), or bile acids. In some embodiments, compositions containing the combination therapies described herein are administered to patients with abnormal concentrations of FGF-19, C4 (7α-hydroxy-4-cholesten-3-one), or bile acids to treat any of the diseases or conditions described herein.

[0282] (Liver fat content as a marker to predict clinical response to FXR therapy in NASH patients) When evaluating treatments for NASH, it is difficult to demonstrate significant clinical benefit in all aspects of inflammation, hypertrophy, and fibrosis. Efficacy in clinical trials is usually demonstrated by showing improvement or resolution of NASH or reversal of fibrosis. Definitive assessment of both of these endpoints usually requires liver biopsy, but non-invasive imaging and biomarkers are increasingly being used for evaluation because they correlate with liver biopsy findings. Several studies have shown that in patients, a reduction of at least 30% from baseline in liver fat, as measured by non-invasive imaging, correlates with clinical improvement in liver biopsy. Therefore, non-invasive imaging is commonly used to assess changes in liver fat in early NASH clinical trials.

[0283] There is a need for the development of useful diagnostic tests to guide treatment strategies for NASH, including the administration of FXR agonists. In some embodiments, accurately evaluating NASH treatment strategies including FXR agonists provides useful information, including but not limited to the patient's response to FXR agonists, the appropriateness of treating NASH with FXR agonists, the maximum possible effect with FXR agonists, the dose of FXR agonist required for maximum effect, necessary dose adjustments of FXR agonists, the duration of treatment with FXR agonists, and / or whether combination therapy is desired or required in individual patients. Early prediction of the response to FXR agonists may guide long-term treatment strategies with FXR agonists.

[0284] In some embodiments, liver fat content (LFC) measurements using magnetic resonance imaging-proton density lipid fraction (MRI-PDFF) are used to predict the magnitude of long-term changes in liver fat content in NASH patients treated with FXR agonists. In some embodiments, changes in LFC are a significant predictor of response to treatment with FXR agonists. In some embodiments, changes in liver fat content (LFC) measurements using magnetic resonance imaging-proton density lipid fraction (MRI-PDFF) in combination with receiver operating characteristic area (AUC) analysis are used to predict long-term LFC changes in NASH patients treated with FXR agonists. In some embodiments, the FXR agonist is the FXR agonist described herein. In some embodiments, the FXR agonist is compound 1 or a pharmaceutically acceptable salt thereof.

[0285] In some embodiments, the reduction in liver fat content (LFC) after approximately 4 weeks of treatment with an FXR agonist accurately predicts the reduction in liver fat content (LFC) observed after approximately 12 weeks of treatment with an FXR agonist. In some embodiments, the predicted reduction in LFC at approximately 12 weeks is at least equal to the reduction in LFC observed at approximately 4 weeks of treatment. In some embodiments, the predicted reduction in LFC at approximately 12 weeks is greater than the reduction in LFC observed at approximately 4 weeks of treatment. In some embodiments, treatment with an FXR agonist comprises continuous daily dosing of the FXR agonist. In some embodiments, the FXR agonist is the FXR agonist described herein. In some embodiments, the FXR agonist is compound 1 or a pharmaceutically acceptable salt thereof.

[0286] (Combination therapy) In some cases, it is appropriate to administer at least one FXR agonist or a pharmaceutically acceptable salt thereof as described herein in combination with one or more other therapeutic agents.

[0287] In one embodiment, the therapeutic efficacy of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., the adjuvant itself has minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein together with another agent (including a therapeutic regimen) that also has a therapeutic benefit.

[0288] In one particular embodiment, the compound described herein or a pharmaceutically acceptable salt thereof is co-administered with a second therapeutic agent, where the compound described herein or a pharmaceutically acceptable salt thereof and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby resulting in a greater overall benefit than if either therapeutic agent were administered alone.

[0289] Regardless, the overall benefit experienced by the patient, regardless of the disease, disorder or condition being treated, is, in some embodiments, additive of the two therapeutic agents, or the patient experiences a synergistic benefit.

[0290] In certain embodiments, different dosages of the compounds disclosed herein are used in the preparation of pharmaceutical compositions and / or treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agents, such as additional drugs, adjuvants, etc. The dosages of drugs and other agents for use in combination treatment regimens are optionally determined by means similar to those described above for the active ingredients themselves. Furthermore, the preventive / therapeutic methods described herein include the use of metronome therapy, i.e., administering lower doses more frequently to minimize toxic side effects. In some embodiments, combination treatment regimens include treatment regimens in which the administration of the compounds disclosed herein or pharmaceutically acceptable salts thereof is initiated before, during, or after treatment with a second agent described herein and continues until any point during treatment with the second agent or until after the completion of treatment with the second agent. Combination treatment regimens also include treatments in which the compounds disclosed herein or pharmaceutically acceptable salts thereof and a second agent used in combination are administered simultaneously or at different times and / or at decreasing or increasing intervals during the treatment period. Combination therapy may also include regular treatments that are initiated and discontinued at various points to support the patient's clinical management.

[0291] In the combination therapies described herein, the dosage of the compound administered concurrently varies depending on the type of concomitant therapeutic agent used, the specific therapeutic agent used, and the disease or condition being treated. In additional embodiments, when administered concurrently with one or more other therapeutic agents, the compounds presented herein are administered simultaneously with or consecutively with one or more other therapeutic agents.

[0292] In combination therapy, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order, and in some cases simultaneously. When administered simultaneously, the multiple therapeutic agents are provided, for example, in a single integrated form or in multiple forms (e.g., as a single pill or as two separate pills).

[0293] The compounds described herein, or their pharmaceutically acceptable salts, and combination therapies are administered before, during, or after the onset of a disease or condition, and the timing of administration of compositions containing the compounds varies. Therefore, in one embodiment, the compounds described herein are used as prophylactic agents, continuously administered to mammals prone to developing a condition or disease in order to prevent the onset of the disease or condition. In another embodiment, the compounds and compositions are administered to mammals as soon as possible during or after the onset of symptoms.

[0294] In prophylactic use, compositions comprising the combination therapies described herein are administered to patients who are susceptible to, or otherwise at risk of, a particular disease, disorder, or condition. Such amounts are defined as “a prophylactically effective amount or dose.” In this use, the exact amount also depends on the patient’s health condition, weight, etc. When used in a patient, the amount effective for this use will vary depending on the severity and course of the disease, disorder, or condition, previous treatments, the patient’s health condition and response to the drug, and the judgment of the attending physician. In one embodiment, prophylactic treatment involves administering a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof to a mammal that has previously experienced at least one symptom of the disease being treated and is currently in remission, in order to prevent recurrence of symptoms of the disease or condition.

[0295] In certain embodiments, the FXR agonists and additional therapeutic agents described herein are administered at a lower dose than the dose at which either the FXR agonist or the additional therapeutic agent is typically administered as a monotherapy. In certain embodiments, the FXR agonists and additional therapeutic agents described herein are administered at a lower dose than the dose at which either the FXR agonist or the additional therapeutic agent is typically administered to exert an effect. In certain embodiments, when the FXR agonist is administered in combination with the additional therapeutic agent described herein, it is administered at a lower dose than the dose at which either the FXR agonist or the additional therapeutic agent is typically administered as a monotherapy. In certain embodiments, when the FXR agonist is administered in combination with the additional therapeutic agent described herein, it is administered at a lower dose than the dose at which either the FXR agonist or the additional therapeutic agent is typically administered to exert an effect.

[0296] In any of the embodiments described herein, the FXR agonist (e.g., Compound 1 or a pharmaceutically acceptable salt thereof) is used in a treatment regimen comprising one or more additional therapeutic agents. In any of the embodiments described herein, the FXR agonist is used in conjunction with any additional therapeutic agents described herein. For example, in some embodiments, the additional therapeutic agents are small molecules, polymers, oligonucleotides, viruses, bacteria, anti-inflammatory agents, immunomodulators, anticancer agents, weight loss agents, agents for treating NASH, diabetes agents, insulin resistance agents, statins, insulin sensitizers, vitamins, antifungal agents, antioxidants, corticosteroids, antitumor necrosis factor (TNF) agents, antibiotics, chemotherapeutic agents, biologics, radiotherapy agents, anti-obesity agents, nutritional supplements, radiotherapy, or agents for treating primary biliary cholangitis.

[0297] In some embodiments, the treatment of fatty liver disease (including, but not limited to, NAFLD and NASH) involves combination therapy with an FXR agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) and at least one additional agent used to treat fatty liver disease. Because FXR agonists address multiple pathogenic mechanisms of NASH, such as steatosis, inflammation, and fibrosis, and address both the metabolic and fibrous elements of fatty liver disease, FXR agonists are ideal foundational therapies to be used in combination with other treatments for fatty liver disease. For example, sodium-glucose cotransporter 2 (SGLT2) inhibitors are representative of a class of oral medications for treating diabetes that act on glucose transporters in the kidneys. Clinical trials have shown that SGLT2 inhibitors improve glucose regulation, improve insulin sensitivity, lead to weight loss, and reduce major adverse cardiovascular events. Furthermore, proof-of-concept studies with SGLT2 inhibitors have demonstrated their ability to improve hepatic fat and liver enzymes in diabetic NASH patients. In some embodiments, SGLT2 inhibitors can improve NASH in a complementary manner to the methods provided by FXR agonists.

[0298] In some embodiments, the FXR agonist is administered with a modulator of any one of the following target proteins: Cannabinoid receptor 1, Cannabinoid receptor 2, Peroxisome proliferator-activated receptor (PPAR) δ, PPARγ, PPARα, PPARα and PPARδ (double modulation), Smoothland (SMO), Hedgehog signaling effectors such as Gli-1 and Gli-2, Yes-related protein (YAP), Transcriptional coactivator with PDZ-binding motif (TAZ), Heat shock protein 47 (HSP47), Collagen type 1 α1 (COL1A1), Transforming growth factor (TGF)-β, α-5β-6 integrin, platelet-derived growth factor (PDGF), apical sodium-dependent bile acid transporter (ASBT), CC chemokine receptor type 2 (CCR2), CC chemokine receptor type 5 (CCR5), dual CC chemokine receptor type 2 / CC chemokine receptor type 5 (CCR2 / 5), lysophosphatidic acid receptor (LPA)-1, autotaxin, apoptosis signal-regulated kinase 1 (ASK1), NADPH oxidase 1 (NOX1), NADPH oxidase 4 (NOX4), NADPH Xidase 2 (NOX2), NADPH oxidase 5 (NOX5), dual oxidase 1 (DUOX1), dual oxidase 2 (DUOX2), caspase, galectin 3, pentraxin-2, acetyl-CoA carboxylase, glucagon-like peptide-1 (GLP-1), inducible nitric oxide synthase (iNOS), N-acetylcysteine, S-adenosylmethionine, lysyl oxidase (LOXL2), antiogensin 2 receptor, bromodomain-containing protein 4 (BRD4), eukaryotic translational development Initiating factor 4E (eIF4E), vascular endothelial growth factor (VEGF), fibroblast-activating protein, vitamin D receptor, Toll-like receptor 4 (TLR4), TIMP metallopeptidase inhibitor 1 (TIMP-1), CXC chemokine receptor type 3 (CXCR3), interleukin 13 (IL-13), IL-4, αvβ3 integrin, fibroblast growth factor 19, fibroblast growth factor 21, ABCA1 / SCD1, thyroid hormone receptor (THR)β, diacylglycerol acyltransferase 1 (DGAT-1),Diacylglycerol acyltransferase 2 (DGAT-2), discoidin domain receptor 1 (DDR1), discoidin domain receptor (DDR2), focal adhesion kinase (FAK), semicarbazide-sensitive amine oxidase (SSAO / VAP-1), 17b-HSD type 13, GPR84, protease-activated receptor (PAR-2), or retinoic acid receptor-associated orphan receptor γt (RORγt).

[0299] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a modulator of one of the following target proteins: cannabinoid receptor 1, cannabinoid receptor 2, peroxisome proliferator-activated receptor (PPAR)-δ, PPARγ, PPARα, PPARα and PPARδ (dual modulation), heat shock protein 47 (HSP47), fibroblast growth factor 19, fibroblast growth factor 21, transforming growth factor (TGF)-β, apical sodium-dependent bile acid transporter (ASBT), ABCA1 / SCD1, CC chemokine receptor type 2 (CCR2), CC chemokine receptor type 5 (CCR5), dual CC chemokine receptor type 2 / CC chemokine receptor type 5 (CCR2 / 5), lysophosphatidic acid receptor (LPA)-1, autotaxin, apoptosis signal-regulated kinase 1 (ASK1), caspase, acetyl-CoA carboxylase (ACC), and Lucagon-like peptide-1 (GLP-1), N-acetylcysteine, S-adenosylmethionine, lysyl oxidase (LOXL2), antiogensin II receptor, vascular endothelial growth factor (VEGF), fibroblast-activating protein, thyroid hormone receptor (THR)β, diacylglycerol acyltransferase 1 (DGAT-1), diacylglycerol acyltransferase 2 (DGAT2), discoidin domain receptor 1 (DDR1), discoidin domain receptor (DDR2), focal adhesion kinase (FAK), semicarbazide-sensitive amine oxidase (SSAO / VAP-1), 17b-HSD type 13, GPR84, protease-activated receptor (PAR-2), retinoic acid receptor-associated orphan receptor γt (RORγt).

[0300] In some embodiments, the FXR agonist is administered with one modulator of any of the following target proteins: angiotensin 2 receptor, ketohexokinase (KHK), mitochondrial uncoupler or protonophore, sodium-glucose cotransporter 2 (SGLT2), sodium-glucose cotransporter 1 (SGLT1), dihydroceramide desaturase 1 (DES-1), integrin aVb1, integrin aVb6, NOD-like receptor protein 3 (NLRP3), cyclophyllin, glucagon-like peptide-1 (GLP-1), 17-β-hydroxysteroid dehydrogenase 13 (17b-HSD13), thyroid hormone receptor β (THR-β), or a combination thereof.

[0301] In some embodiments, the FXR agonist is administered with one of the following: angiotensin 2 receptor agonists, KHK inhibitors, mitochondrial uncouplers or protonophores, SGLT2 inhibitors, SGLT1 / 2 coinhibitors, DES-1 inhibitors, integrin aVb1 inhibitors, integrin aVb6 inhibitors, NLRP3 inhibitors, cyclophyllin inhibitors, GLP-1 agonists, 17b-HSD13 inhibitors, THR-β agonists, or a combination thereof.

[0302] In any of the embodiments described herein, the additional therapeutic agent is a drug used to treat a metabolic disease or condition. In any of the embodiments described herein, the additional therapeutic agent is a drug used to treat a fibrous disease or condition. In some embodiments, the additional therapeutic agent used to treat a fibrous disease or condition is pirfenidone.

[0303] In some embodiments, additional therapeutic agents administered in combination with an FXR agonist in subjects requiring it as part of a method for treating or preventing liver diseases, including but not limited to fibrous liver disease or metabolic liver disease, are anti-fibrotic, anti-inflammatory, or metabolic therapeutic agents.

[0304] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is a cannabinoid receptor 1 antagonist, a smoothed receptor (SMO) antagonist, a Yes-related protein (YAP) antagonist, a PDZ-binding motif (TAZ) antagonist, a heat shock protein 47 (HSP47) antagonist, a collagen type 1 α1 (COL1a1) antagonist, a transforming growth factor-β (TGF-β) antagonist, an α-5β-6 integrin antagonist, a pirfenidone, or a platelet-derived growth factor (PDGF) antagonist, CC chemokine receptor type 2 and type 5 (CCR2 / CCR5) antagonist, lysophosphatidic acid receptor-1 (LPA-1) antagonist, autotaxin antagonist, apoptosis signal-regulated kinase 1 (ASK1) antagonist, glucagon-like peptide-1 (GLP-1) agonist, peroxisome proliferator-activated receptor (PPAR)-δ agonist, PPARγ agonist, PPARα agonist, PPARα and PPARδ dual agonist, acetyl-CoA carboxylase (ACC) inhibitors, fibroblast growth factor 19 analogs, fibroblast growth factor 21 analogs, ABCA1 / SCD1 modulators, thyroid hormone receptor (THR) β agonists, diacylglycerol acyltransferase 1 (DGAT-1) inhibitors, diacylglycerol acyltransferase 2 (DGAT-2) inhibitors, discoidin domain receptor 1 (DDR1) inhibitors, discoidin domain receptor (DDR2) inhibitors, focal adhesion kinase (FAK) inhibitors, semicarbazide-sensitive amine oxidase (SSAO / VAP-1 inhibitors, 17b-HSD type 13 inhibitors, GPR84 antagonists, protease-activated receptor (PAR-2) antagonists, or retinoic acid receptor-associated orphan receptor γt (RORγt) antagonists / reverse agonists, NADPH oxidase 1 (NOX1) antagonists, NOX2 antagonists, dual NOX1 / NOX4 antagonists, NOX5 antagonists, DUOX1 antagonists, DUOX2 antagonists, NOX4 antagonists, caspase antagonists, galectin 3 antagonists,It is administered in combination with inducible nitric oxide synthase (iNOS) antagonists, N-acetylcysteine, lysyl oxidase homolog 2 (LOXL2) antagonists, angiotensin II receptor antagonists, bromodomain-containing protein 4 (BRD4) inhibitors, eukaryotic translation initiation factor-4E (eIF4E) antagonists, cannabinoid receptor 2 agonists, vascular endothelial growth factor (VEGF) agonists, VEGF antagonists, fibroblast-activating protein antagonists, vitamin D receptor antagonists, Toll-like receptor 4 (TLR4) antagonists, metalloproteinase-1 (TIMP-1) antagonist tissue inhibitors, ursodiol, or non-ursodiol.

[0305] (In combination with chemokine receptor (CCR) inhibitors) Recruitment of inflammatory monocytes and macrophages via chemokine receptor type 2 (CCR2), and recruitment of lymphocytes and hepatic stellate cells via chemokine receptor type 5 (CCR5), promotes the progression of NASH to fibrosis.

[0306] Obesity-related macrophage infiltration in adipose and liver tissue is mediated by chemokine receptor type 2 (CCR2), where CCR2-positive, CD11b-positive, and F4 / 80-positive macrophages contribute to chronic inflammation and insulin resistance.

[0307] Several studies have highlighted the importance of CCR2 and CCR5 in inflammation and fibrosis. In some embodiments, inhibitors of CCR2 and / or CCR5 improve insulin sensitivity and glucose tolerance, reduce ALT levels and hepatic triglyceride content, improve insulin sensitivity, or induce a combination thereof compared to a control group.

[0308] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a CCR inhibitor. In some embodiments, the CCR inhibitor is a CCR2 inhibitor, a CCR5 inhibitor, or a dual inhibitor of CCR2 and CCR5.

[0309] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a CCR2 inhibitor, a CCR5 inhibitor, or a dual CCR2 and CCR5 inhibitor. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a CCR2 inhibitor. In some embodiments, the CCR2 inhibitor is CCX872. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a dual CCR2 and CCR5 inhibitor. In some embodiments, the dual CCR2 and CCR5 inhibitor is senicliviroc.

[0310] (In combination with ASK-1 inhibitors) Apoptosis signal-regulated kinase 1 (ASK-1) is an essential component of the MAP kinase signaling pathway. ASK-1 activates the downstream c-JunN-terminal kinase (JNK) and p38 MAP kinase, inducing the production of inflammatory cytokines and cellular apoptosis. In liver diseases such as NAFLD, ASK-1-mediated activation of JNK induces TGF-β-mediated apoptosis of hepatocytes. Therefore, blocking, inhibiting, reducing, or suppressing ASK-1 provides a method for treating or preventing liver disease in subjects where it is needed. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with an ASK-1 inhibitor. In some embodiments, the ASK-1 inhibitor is ceroncertib (Gilead), GS444217 (Gilead), or GS459679 (Gilead).

[0311] In some embodiments, the ASK-1 antagonist is ceroncertib (Gilead, 5-(4-cyclopropyl-1H-imidazole-1-yl)-2-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazole-3-yl)-2-pyridinyl]-4-methylbenzamide). In some embodiments, ceroncertib is administered orally once daily at doses of 2 mg, 6 mg, or 18 mg.

[0312] (In combination with LOXL2 Antagonist) Lysyl oxidase homolog 2 (LOXL2) is an extracellular matrix enzyme that promotes fibrosis through cross-linking of collagen and elastin fibers. LOXL2 promotes collagen accumulation and deposition in certain tissues. While LOXL2 is not significantly expressed in normal liver tissue, elevated levels of LOXL2 expression are seen in fibrotic liver disease. Increased LOXL2 expression in hepatocytes contributes to liver damage and causes hepatic fibrosis. Therefore, blocking, inhibiting, reducing, or suppressing LOXL2 provides a method for treating or preventing liver disease in subjects that require it. In some embodiments, a method for treating or preventing liver disease in subjects that require it includes administering a farnesoid X receptor (FXR) agonist and a LOXL2 antagonist to the subject.

[0313] In some embodiments, the LOXL2 antagonist is an antibody. In some embodiments, the FXR agonist is administered in combination with simtuzumab (Gilead) to subjects in need. In some embodiments, simtuzumab is administered at a dose of approximately 2 mg to 15 mg per kg of mammalian body weight. In some embodiments, simtuzumab is administered subcutaneously once a week at a dose of approximately 75 mg to 125 mg.

[0314] In some embodiments, the FXR agonist is administered in combination with PAT-1251 (Pharmakea) to subjects in need. In some embodiments, PAT-1251 is administered at a dose of approximately 1 mg to approximately 75 mg per kg of mammalian body weight. In some embodiments, PAT-1251 is administered orally daily at a dose of approximately 100 to 2000 mg. In some embodiments, PAT-1251 is administered orally daily at a dose of approximately 500 to 1000 mg.

[0315] In some embodiments, the FXR agonist is administered in combination with PXS-5382 (Pharmaxis) to subjects in need. PXS-5382 inhibits lysyl oxidase homolog 3 (LOXL3) in addition to lysyl oxidase homolog 2 (LOXL2). In some embodiments, PXS-5382 is administered in doses of approximately 0.1 mg to approximately 75 mg per kg of mammalian body weight. In some embodiments, PXS-5382 is administered orally daily in doses of approximately 25 to 200 mg. In some embodiments, PXS-5382 is administered orally daily in doses of approximately 50 to 100 mg.

[0316] (In combination with a TGF-β antagonist) Transforming growth factor-beta (TGF-β) is a multifunctional cytokine that plays a crucial role in tissue repair and wound healing. TGF-β is found in all tissues and generally stimulates the production of extracellular matrix proteins while also inhibiting their degradation. A balance of these functions is necessary to maintain tissue homeostasis. When the anti-inflammatory and immunosuppressive effects of TGF-β are disrupted, many disease processes occur in the liver. TGF-β is involved in all stages of chronic liver disease, from early liver injury to inflammation and fibrosis, and ultimately to cirrhosis and hepatocellular carcinoma. TGF-β is necessary for liver fibrosis to occur, and blunting TGF-β signaling alleviates liver fibrosis. Therefore, blocking, inhibiting, reducing, or suppressing TGF-β provides a method for treating or preventing liver disease in subjects that require it. In some embodiments, a method for treating or preventing liver disease in subjects requiring it involves administering a farnesoid X receptor (FXR) agonist and a TGF-β antagonist to the subject. In some embodiments, a method for treating or preventing liver disease in a subject in need thereof comprises administering a farnesoid X receptor (FXR) agonist and a TGF-β antagonist to the subject.

[0317] In some embodiments, the TGF-β antagonist is pirfenidone. In some embodiments, the TGF-β antagonist is 5-methyl-1-phenylpyridine-2(1H)-one. In some embodiments, the FXR agonist is administered in combination with pirfenidone to subjects who require it. In some embodiments, the FXR agonist is administered in combination with 5-methyl-1-phenylpyridine-2(1H)-one to subjects who require it. In some embodiments, pirfenidone is administered orally at a dose of approximately 250 mg to approximately 2500 mg per day. In some embodiments, pirfenidone is administered orally in the form of capsules. In some embodiments, pirfenidone is administered orally with food in the first week of treatment at a dose of approximately 267 mg per capsule, three capsules per day. In some embodiments, pirfenidone is administered orally with food at a dose of approximately 267 mg per capsule, two capsules three times daily, for a total of approximately 1602 mg per day, during the second week of treatment. In some embodiments, pirfenidone is administered orally with food at a dose of approximately 267 mg per capsule, three capsules three times daily, for a total of 2403 mg per day, starting from the first 15 days of treatment.

[0318] (In combination with metabolic therapeutic agents) In some embodiments, a method for treating or preventing liver disease in a subject requiring it includes administering a farnesoid X receptor (FXR) agonist and additional metabolic therapeutic agents to the subject. In some embodiments, a method for treating or preventing fibrous liver disease in a subject requiring it includes administering a farnesoid X receptor (FXR) agonist and additional metabolic therapeutic agents to the subject. In some embodiments, a method for treating or preventing metabolic liver disease in a subject requiring it includes administering a farnesoid X receptor (FXR) agonist and additional metabolic therapeutic agents to the subject.

[0319] (In combination with a PPARδ agonist) Peroxisome proliferator-activated receptor δ (PPARδ) is a nuclear hormone receptor involved in various chronic diseases such as diabetes, obesity, atherosclerosis, and cancer. Specifically, PPARδ is a key regulator of fatty acid metabolic pathways, glucose metabolism, and adipocyte proliferation, differentiation, and apoptosis. PPARδ agonists regulate glucose and fatty acid metabolism and alleviate insulin resistance. PPARδ agonists inhibit the formation of lipid deposits in hepatocytes and inhibit the development of hepatic steatosis. Therefore, activating or increasing PPARδ provides a method for treating or preventing liver disease in subjects that need it. In some embodiments, a method for treating or preventing liver disease in subjects that need it includes administering a farnesoid X receptor (FXR) agonist and a PPARδ agonist to the subject.

[0320] In some embodiments, the PPARδ agonist is KD-3010 (Kalypsys). In some embodiments, an FXR agonist is administered in combination with KD-3010 to subjects in need. In some embodiments, KD-3010 is administered orally at doses of approximately 5 mg to approximately 200 mg per day. In some embodiments, KD-3010 is administered orally in the form of capsules. In some embodiments, KD-3010 is administered orally once daily at doses of approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 60 mg, or approximately 80 mg.

[0321] In some embodiments, the PPARδ agonist is KD-3020 (Kalypsys).

[0322] (In combination with a PPARα agonist or a PPARδ / PPARα agonist) PPARα, also known as NR1C1 (nuclear receptor 1, group C, member 1), is a major regulator of lipid metabolism in the liver. PPARα is activated during energy deficiency. When activated, PPARα promotes fatty acid uptake and catabolism. PPARα expression decreases with high fat intake. PPARα agonists reduce hepatic steatohepatism by increasing mitochondrial β-oxidation and decreasing fatty acid synthesis. Administration of PPARα agonists also results in weight loss. Therefore, activating or increasing PPARα provides a method for treating or preventing liver disease in subjects that need it. In some embodiments, a method for treating liver disease in subjects that need it includes administering a farnesoid X receptor (FXR) agonist and a PPARα agonist to the subject. In some embodiments, a method for treating liver disease in subjects that need it includes administering a farnesoid X receptor (FXR) agonist and a PPARδ agonist to the subject. In some embodiments, a method for treating liver disease in a subject in need includes administering a farnesoid X receptor (FXR) agonist and a dual PPARδ / PPARα agonist to the subject.

[0323] In some embodiments, the PPARα agonist is a fibrate. In some embodiments, the PPARα agonist is fenofibrate. In some embodiments, the FXR agonist is administered in combination with a fibrate to subjects who require it. In some embodiments, the FXR agonist is administered in combination with fenofibrate to subjects who require it. In some embodiments, fenofibrate is administered orally at a dose of approximately 40 mg to approximately 200 mg per day. In some embodiments, fenofibrate is administered orally in the form of capsules. In some embodiments, fenofibrate is administered orally at a dose of approximately 150 mg once daily. In some embodiments, fenofibrate is administered orally at a dose of approximately 120 mg once daily.

[0324] In some embodiments, the PPARα agonist is a dietary supplement. In some embodiments, the PPARα agonist is fish oil. In some embodiments, the FXR agonist is administered in combination with fish oil to a subject in need. In some embodiments, the fish oil contains alpha-linoleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). In some embodiments, the fish oil is administered orally in doses ranging from approximately 100 mg to approximately 5000 mg per day. In some embodiments, the fish oil is administered orally in the form of capsules. In some embodiments, the fish oil is administered orally once daily in doses ranging from approximately 2000 mg. In some embodiments, the fish oil is administered orally once daily in doses ranging from approximately 4000 mg.

[0325] In some embodiments, the PPARδ / PPARα dual agonist is elafibranol (Genfit). In some embodiments, the FXR agonist is administered in combination with elafibranol to subjects in need. In some embodiments, elafibranol is administered orally at a dose of approximately 70 mg to approximately 130 mg per day. In some embodiments, elafibranol is administered orally in the form of capsules. In some embodiments, elafibranol is administered orally at a dose of approximately 80 mg once daily or approximately 120 mg once daily.

[0326] (In combination with an inhibitor of sodium-glucose cotransporter 1 (SGLT1)) SGLT1 is a member of the sodium-glucose cotransporter family. Inhibition of SGLT1 delays and reduces glucose absorption in the small intestine, thus improving postprandial glycemic control. SGLT1 is also found in the proximal tubules of the kidney, where it can mediate glucose reabsorption. SGLT1 is a low-volume, high-affinity glucose transporter. Therefore, inhibition of SGLT1 may be beneficial in patients with impaired renal function for whom SGLT2 inhibition is less effective.

[0327] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with an SGLT1 inhibitor.

[0328] (In combination with an inhibitor of sodium-glucose cotransporter 2 (SGLT2)) SGLT2 is a member of the sodium-glucose cotransporter family and is a sodium-dependent glucose transporter protein. SGLT2 is the primary transporter involved in glucose reabsorption in the kidneys. Inhibition of SGLT2 helps reduce the amount of glucose reabsorbed into the blood by the kidneys.

[0329] SGLT2 inhibitors have shown cardiovascular and renal protection in patients with type 2 diabetes mellitus (T2DM) with established cardiovascular disease. Increasing evidence suggests that SGLT2 inhibitors may protect the liver by reducing hepatic fat content.

[0330] In some embodiments, the SGLT2 inhibitor is canagliflozin, dapagliflozin, empagliflozin, luseogliflozin, ipragliflozin, tofogliflozin, erzgliflozin, ipragliflozin, remogliflozin, or remogliflozin etabone.

[0331] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is empagliflozin. In some embodiments, empagliflozin is administered orally once daily at a dose of approximately 10–25 mg. In some embodiments, empagliflozin is administered orally once daily at a dose of 10 mg. In some embodiments, empagliflozin is administered orally once daily at a dose of 25 mg.

[0332] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with empagliflozin and linagliptin.

[0333] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with empagliflozin and metformin.

[0334] In some embodiments, the SGLT2 inhibitor is canagliflozin. In some embodiments, canagliflozin is administered orally once daily at a dose of approximately 100-300 mg. In some embodiments, canagliflozin is administered orally once daily at a dose of 100 mg. In some embodiments, canagliflozin is administered orally once daily at a dose of 300 mg.

[0335] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with canagliflozin and metformin.

[0336] In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, dapagliflozin is administered orally once daily at a dose of approximately 5 to 10 mg. In some embodiments, dapagliflozin is administered orally once daily at a dose of 5 mg. In some embodiments, dapagliflozin is administered orally once daily at a dose of 10 mg.

[0337] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with dapagliflozin and metformin.

[0338] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with dapagliflozin and saxagliptin.

[0339] Another SGLT2 inhibitor is ertugliflozin. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with ertugliflozin. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with ertugliflozin and metformin. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with ertugliflozin and sitagliptin.

[0340] (Combination with dual inhibitors of both SGLT1 and SGLT2) In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with an agent that inhibits both the renal sodium-glucose cotransporter 2 and the intestinal SGLT1, thereby slowing glucose absorption and thus reducing postprandial glucose. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with an agent that inhibits both the renal sodium-glucose cotransporter 2 and the renal SGLT1. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with an agent that inhibits both the renal SGLT1, the renal SGLT2, and the intestinal SGLT1.

[0341] Examples of inhibitors for both SGLT1 and SGLT2 include, but are not limited to, sotagliflozin and licogliflozin.

[0342] In some embodiments, the dual SGLT1 / 2 inhibitor is sotagliflozin. In some embodiments, sotagliflozin is administered orally once daily at a dose of approximately 200 to approximately 400 mg. In some embodiments, sotagliflozin is administered orally once daily at a dose of 200 mg. In some embodiments, sotagliflozin is administered orally once daily at a dose of 400 mg.

[0343] In some embodiments, the dual SGLT1 / 2 inhibitor is licogliflozin. In some embodiments, licogliflozin is administered orally in doses of about 2.5 to about 300 mg. In some embodiments, licogliflozin is administered orally in doses of about 30 mg. In some embodiments, licogliflozin is administered orally in doses of about 300 mg.

[0344] (In combination with an acetyl-CoA carboxylase (ACC) inhibitor) Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA. ACC catalyzes the rate-limiting step in denominative fatty acid synthesis (DNL). Increased DNL contributes to the pathogenesis of non-alcoholic steatohepatitis (NASH). ACC inhibition improves steatosis, hepatitis, and hepatic fibrosis.

[0345] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with an ACC inhibitor. In some embodiments, the ACC inhibitor is GS-0976. In some embodiments, GS-0976 is administered orally once daily at a dose of approximately 5 to 20 mg. In some embodiments, GS-0976 is administered orally once daily at a dose of 5 mg. In some embodiments, GS-0976 is administered orally once daily at a dose of 20 mg.

[0346] (In combination with a GLP-1 agonist) Insulin resistance (IR) in both the liver and adipose tissue is considered a key factor in the pathogenesis of non-alcoholic steatohepatitis (NASH). Individuals with NASH exhibit severe adipose IR, in addition to increased hepatic IR and de novo fatty acid synthesis (DNL). Collectively, these contribute to excessive lipid accumulation in the liver, excessive efflux of non-esterified fatty acids (NEFAs), and the release of triglyceride-derived toxic metabolites from adipose tissue lipolysis, forming the major lipotoxic injury in the pathogenesis of NASH. In addition to promoting endogenous hepatic IR and inflammation, hepatic lipotoxicity is thought to further exacerbate the circulating pro-inflammatory environment and the IR state of NASH, which in turn contributes to a cycle of lipid dysfunction and worsening lipolysis.

[0347] Glucagon-like peptide-1 (GLP-1) agonists have been shown to improve glycemic control, contribute to weight loss, improve insulin sensitivity, enhance liver enzymes, and reduce hepatic glucose production. Improvement in hepatic steatohepatic disease has been observed after GLP-1 treatment, accompanied in some cases by a reduction in oxidative stress and fibrosis.

[0348] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a GLP1 agonist. In some embodiments, the GLP1 agonist is Victoza (liraglutide, Novo), semaglutide, exenatide (AstraZeneca), dulaglutide (Eli Lilly), lixisenatide (Sanofi), or albiglutide (GSK).

[0349] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a GLP1 agonist. In some embodiments, the GLP1 agonist is Victoza. In some embodiments, Victoza is administered by injection once daily at a dose of approximately 0.5–5 mg. In some embodiments, Victoza is administered by injection once daily at a dose of approximately 1–3 mg. In some embodiments, Victoza is administered by injection once daily at a dose of 0.6 mg. In some embodiments, Victoza is administered by injection once daily at a dose of 1.2 mg. In some embodiments, Victoza is administered by injection once daily at a dose of 1.8 mg.

[0350] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a GLP1 agonist. In some embodiments, the GLP1 agonist is semaglutide. In some embodiments, semaglutide is administered by injection once weekly at a dose of 0.25 mg. In some embodiments, semaglutide is administered by injection once weekly at a dose of 0.5 mg.

[0351] (In combination with DGAT inhibitors) NASH is characterized by excess triglycerides (TG) in the liver, simultaneously causing inflammation and cell damage. Diacylglycerol acyltransferase (DGAT) catalyzes the final step in TG synthesis from diacylglycerol and acyl-CoA. The reaction catalyzed by DGAT is the final and sole step in triglyceride synthesis and is considered essential for intestinal absorption (i.e., DGAT1) and adipose tissue formation (i.e., DGAT2). There are two isoforms, DGAT1 and DGAT2, with different protein sequences and potentially different physiological functions.

[0352] Triglycerides in food are not directly absorbed in the gastrointestinal tract, but are broken down into free fatty acids and monoglycerols by pancreatic lipases in the intestines. Once absorbed, the free fatty acids and glycerols are reconstituted into triglycerides at absorption sites called intestinal cells, packaged into chylomicron particles, and transported to the lymphatic system for use throughout the body. DGAT-1 is one of two enzymes that catalyze the process of triglyceride biosynthesis from monoacylglycerols or diacylglycerols and fatty acids, and is mainly distributed in the intestines, liver, and adipose tissue.

[0353] Inhibiting this enzyme has been shown in animal models and clinical trials to reduce fat accumulation and lead to weight loss.

[0354] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a DGAT1 inhibitor or a DGAT2 inhibitor. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a DGAT1 inhibitor. In some embodiments, the DGAT1 inhibitor is GSK3008356. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a DGAT2 inhibitor. In some embodiments, the DGAT2 inhibitor is PF-0685571.

[0355] (In combination with a bile acid pathway modulator) Bile acids bind to receptors in the colon that promote the release of intestinal hormones such as glucagon-like peptide-1 (GLP1). In the liver, bile acids bind to other receptors that regulate bile acid production from cholesterol in a negative feedback loop. Under normal conditions, bile acids bind to these receptors and inhibit the synthesis of new bile acids. When bile acid levels decrease, the liver needs to produce the necessary bile acids from cholesterol. This requires increased cholesterol uptake and, as a result, a decrease in cholesterol in the liver. A reduction in cholesterol accumulation in the liver mitigates liver damage in liver diseases, including but not limited to NASH and NAFLD.

[0356] After digestion is complete, bile acids are collected in the distal part of the small intestine known as the terminal ileum by the ileal bile acid transporter (also called IBAT, ASBT, or apical sodium-dependent bile acid transporter). IBAT initiates the transport of bile acids, which then flow through the portal vein and return to the liver in a process known as enterohepatic circulation.

[0357] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with an IBAT inhibitor. In some embodiments, the IBAT inhibitor is vorixibat (also known as SHP626), malalixibat (Shire), elobixibat (Albireo), or A4350 (Albireo). In some embodiments, the IBAT inhibitor is vorixibat.

[0358] (In combination with a fibroblast growth factor receptor modulator) In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a modulator of the fibroblast growth factor (FGF) 19 receptor or the fibroblast growth factor (FGF) 21 receptor. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with an FGF-19 variant or an FGF-21 variant.

[0359] The human hormone FGF-19 is a major regulator of bile acid synthesis in the liver and a crucial signaling molecule in metabolic processes involved in weight maintenance, including glucose homeostasis and triglyceride regulation. FGF-19 binds to the FGF-19 receptor and targets multiple pathogenic pathways in non-alcoholic steatohepatitis (NASH), leading to a reduction in liver fat content, improvement of hepatic steatosis, inflammation, and fibrosis, and ultimately improving liver function.

[0360] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a variant of human FGF-19. In some embodiments, the variant of human FGF-19 is a modified variant of the human hormone FGF-19. In some embodiments, the variant of human FGF-19 is NGM282 (NGM / Merck).

[0361] Fibroblast growth factor 21 (FGF-21) is a crucial metabolic regulator expressed in many tissues, including the liver. While many different metabolically active tissues express FGF-21, most of the hormone is produced in the liver. FGF-21 levels are regulated by metabolic stressors such as obesity, lack of exercise, and metabolic disorders such as type 2 diabetes. Conditions that show elevated circulating FGF-21 levels include obesity, type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH). These elevations may represent compensatory responses to protect the body from harmful metabolic conditions.

[0362] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a variant of human FGF-21. In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with PEGylated fibroblast growth factor (FGF) 21. In some embodiments, PEGylated fibroblast growth factor (FGF) 21 is BMS-986036 (Bristol Myers-Squibb).

[0363] (In combination with thyroid hormone beta-agonists) Thyroid hormone regulation of lipid metabolism affects a wide range of interconnected health parameters, from blood cholesterol and triglyceride concentrations to pathological accumulation of hepatic fat. In some embodiments, activation of selective thyroid hormone receptor β (THR-β) in the liver improves lipid metabolic dysregulation, resulting in reduced hepatic fat, decreased levels of several atherosclerotic lipids including LDL cholesterol and triglycerides, and resolution of NASH.

[0364] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a thyroid hormone β-agonist. In some embodiments, the thyroid hormone β-agonist is MGL-3196 (Madrigal Pharmaceuticals), MGL-3745 (Madrigal Pharmaceuticals), or VK2809 (Viking Therapeutics).

[0365] In some embodiments, the thyroid hormone β-agonist is MGL-3196. In some embodiments, MGL-3196 is administered orally once daily at doses of approximately 50 mg, 100 mg, or 200 mg. In some embodiments, the thyroid hormone β-agonist is VK2809. In some embodiments, VK2809 is administered orally once daily at doses of approximately 5 mg, 10 mg, or 20 mg.

[0366] (Other combinations) In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a hypoglycemic agent, an insulin secretagogue, an insulin sensitivity enhancer, a lipid-lowering agent, a compound that increases sympathetic nervous system activity, ethyl eicosapentaenoate, obeticholic acid, or a TGR5 agonist.

[0367] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a statin, an insulin sensitivity enhancer, an insulin secretagogue, an α-glucosidase inhibitor, a GLP agonist, a DPP-4 inhibitor (such as sitagliptin, vildagliptin, saxagliptin, linagliptin, anagliptin, teneligliptin, alogliptin, gemigliptin, or dutogliptin), a catecholamine (such as epinephrine, norepinephrine, or dopamine), a peroxisome proliferator-activated receptor (PPAR)-γ agonist (e.g., thiazolidinediones (TZDs) [ioglitazone, rosiglitazone, riboglitazone, or troglitazone], alleglitazar, falglitazar, mulaglitazar, or tesaglitazar), or a combination thereof. In some cases, statins are HMG-CoA reductase inhibitors. In other cases, additional therapeutic agents include fish oil, fibrates, vitamins such as niacin, retinoic acid (e.g., 9-cis-retinoic acid), nicotinamide ribonucleoside or its analogues, or combinations thereof. In some cases, NAD, a substrate for many enzymatic reactions including p450, which is a target of FXR. + There are nicotinamide ribonucleosides or their analogues that promote production (see, for example, Yang et al., J.Med.Chem. 50:6458-61, 2007).

[0368] In some embodiments, FXR agonists are administered in combination with additional therapeutic agents such as statins, insulin sensitivity enhancers, insulin secretagogues, alpha-glucosidase inhibitors, GLP agonists, DPP-4 inhibitors (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, anagliptin, teneligliptin, alogliptin, gemigliptin, or dutogliptin), catecholamines (e.g., epinephrine, norepinephrine, or dopamine), peroxisome proliferator-activated receptor (PPAR)-γ agonists (e.g., thiazolidinediones (TZDs) [ioglitazone, rosiglitazone, riboglitazone, or troglitazone], alleglitazar, falglitazar, mulaglitazar, or tesaglitazar), or combinations thereof, for the treatment of diabetes or diabetes-related disorders or conditions. In some embodiments, FXR agonists are administered in combination with additional therapeutic agents such as fish oil, fibrates, vitamins such as niacin, retinoic acid (e.g., 9-cis-retinoic acid), nicotinamide ribonucleoside or its analogues, or combinations thereof, for the treatment of diabetes or diabetes-related disorders or conditions.

[0369] In some embodiments, FXR agonists are administered in combination with statins such as HMG-CoA reductase inhibitors, fish oil, fibrates, niacin, or combinations thereof for the treatment of dyslipidemia.

[0370] In additional embodiments, FXR agonists are administered in combination with vitamins such as retinoic acid for the treatment of diabetes and diabetes-related disorders or conditions, e.g., for reducing increased body weight and / or lowering elevated blood glucose levels due to food intake.

[0371] In some embodiments, farnesoid X receptor agonists are administered in conjunction with at least one additional therapy. In some embodiments, at least one additional therapy is a glucose-lowering agent. In some embodiments, at least one additional therapy is an anti-obesity agent. In some embodiments, at least one additional therapy is selected from peroxisome proliferator-activated receptor (PPAR) agonists (γ, dual, or pan), dipeptidyl peptidase (IV) inhibitors, glucagon-like peptide-1 (GLP-I) analogs, insulin or insulin analogs, insulin secretagogues, sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucophages, human amyrin analogs, biguanides, α-glucosidase inhibitors, meglitinide, thiazolidinediones, and sulfonylureas. In some embodiments, at least one additional therapy is metformin, sitagliptin, saxagliptin, repaglinide, nateglinide, exenatide, liraglutide, insulin lispro, insulin aspart, insulin glargine, insulin detemir, isopheninsulin, and glucagon-like peptide 1, or any combination thereof. In some embodiments, at least one additional therapy is a lipid-lowering agent. In certain embodiments, at least one additional therapy is administered concurrently with the farnesoid X receptor agonist. In certain embodiments, at least one additional therapy is administered less frequently than the farnesoid X receptor agonist. In certain embodiments, at least one additional therapy is administered more frequently than the farnesoid X receptor agonist. In certain embodiments, at least one additional therapy is administered before the administration of the farnesoid X receptor agonist. In certain embodiments, at least one additional therapy is administered after the administration of the farnesoid X receptor agonist.

[0372] (In combination with bariatric surgery) The current best treatments for NAFLD and NASH include weight loss, but current options are lifestyle changes with or without medication, and bariatric surgery. Bariatric surgery is performed for severe obesity (body mass index 35 kg / m²). 2 This is an effective treatment option for individuals (as described above), resulting in long-term weight loss and resolution of obesity-related disorders in most patients. Regression and / or histological improvement of NASH have been reported after bariatric surgery.

[0373] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with bariatric surgery.

[0374] Bariatric surgery can be performed using a laparoscopic approach. One technique is adjustable gastric banding (AGB), in which an inflatable and adjustable silicone band is placed around the upper stomach near the gastroesophageal junction to create a 30 mL proximal gastric pouch. Postoperatively, a series of stepwise adjustments to deflate the band stoma are performed on an outpatient basis.

[0375] Another technique in bariatric surgery is Roux-en-Y gastric bypass (RYGB). This is a proximal gastric bypass. A small 30-50 mL proximal gastric pouch is created by separating it from the larger stomach using a stapler. The gastric pouch is then connected to the proximal jejunum in a Roux-en-Y style using various equally effective laparoscopic anastomosis techniques.

[0376] Another technique is sleeve gastrectomy (SG), in which the left portion of the gastric antrum, body, and fundus is separated from the medial portion. The "larger, extra stomach" is removed from the abdominal cavity, leaving a smaller, narrower stomach based on a left curvature, while maintaining the normal connection between the pylorus and the duodenum.

[0377] Another technique is biliary-pancreatic diversion with or without a duodenal switch (BPD) or with a duodenal switch (BPD-DS). In this method, a partial gastrectomy is performed in BPD, and a sleeve gastrectomy in BPD-DS, dividing the small intestine into two sections of similar length (gastrointestinal limb and biliary-pancreatic duct limb). The gastrointestinal limb is connected to the first part of the duodenum (BPD-DS) or the stomach (BPD). The biliary-pancreatic duct limb is anastomosed to the distal small intestine.

[0378] Another technique is non-adjustable vertical gastrectomy (VBG), which combines gastric stapling and gastric banding to create a small gastric pouch. After the stomach is incised, the sides of the incision are stapled, creating holes in the stomach for the bands to loop around. The stomach is then stapled over these holes.

[0379] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with bariatric surgery. In some embodiments, the bariatric surgery procedure is gastric banding, gastric bypass, sleeve gastrectomy, biliary-pancreatic diversion without duodenal switch or with duodenal switch, or vertical gastrectomy. In some embodiments, the bariatric surgery procedure is adjustable gastric banding (AGB), Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), biliary-pancreatic diversion without duodenal switch (BPD) or with duodenal switch (BPD-DS), or vertical gastrectomy (VBG).

[0380] In some embodiments, bariatric surgery is intake restriction, nutrient absorption inhibition, or a combination of both intake restriction and nutrient absorption inhibition. In some embodiments, intake restriction bariatric surgery includes, but is not limited to, vertical dissection gastroplasty, adjustable gastric banding, sleeve gastrectomy, intragastric balloon (gastric balloon), or gastric fold plasty. In some embodiments, nutrient absorption inhibition bariatric surgery includes, but is not limited to, biliary-pancreatic diversion, jejunoileal bypass, or intraluminal sleeve gastrectomy. In some embodiments, a combination of both nutrient absorption inhibition bariatric surgery and restriction bariatric surgery includes, but is not limited to, gastric bypass surgery, sleeve gastrectomy with duodenal switch, or implantable gastric stimulation.

[0381] (Combination with vitamins) In some embodiments, the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a vitamin. In some embodiments, the vitamin is administered parenterally or enterally. In some embodiments, the vitamin is tocopherol, α-tocopherol, vitamin E, γ-tocopherol, tocotrienol, β-tocopherol, or δ-tocopherol.

[0382] (Combination with bacteria) Microbial products have been shown to contribute to the development or maintenance of hepatic steatohepatitis and hepatitis, and significantly contribute to the development of NASH and NAFLD. The microbiome is influenced by many factors that contribute to inflammation and the development of hepatic steatohepatitis. The gut microbiota is thought to be involved in the pathogenesis of NASH for several reasons. First, the gut microbiota is known to have a significant impact on the digestion and absorption of nutrients. Second, the gut microbiota is involved in the development and homeostasis of the host's overall immune system. Thus, specific microbiota influence the development of hepatitis. The relationship between the gut microbiota and the host's immune system includes, but is not limited to, Toll-like receptors (TLRs) and short-chain fatty acids. In some embodiments, the innate immune system influences metabolic syndrome and obesity. Third, the gut microbiota influences the production of intestinal hormones such as glucagon-like peptide-1, which subsequently influence the host's overall metabolism. The liver appears as the first point of contact with bacterial and microbial components (and generates the first immune response to them), as well as other endogenous and exogenous toxins present in the portal blood. Given the liver's ability to regulate metabolism in a way that affects the entire body, distribute numerous substances to the intestines via bile and enterohepatic circulation, and modulate numerous hormonal and immune responses, the potential influence of the liver on intestinal function is readily apparent. The interaction between the intestines, diet, and liver is, naturally, bidirectional, with hormones, inflammatory mediators, and digestive and absorptive products all clearly influencing liver function.

[0383] In some embodiments, the microbiome is influenced by numerous factors that contribute to the development of inflammation and hepatic steatosis. Non-limiting examples of these factors include short-chain fatty acids (SCFAs) and lipopolysaccharides (LPS).

[0384] Changes in the gut microbiota can lead to obesity. This relationship is attributed to short-chain fatty acids (SCFAs). The amount of SCFAs in the gut of obese individuals is elevated compared to the SCFA concentration in the gut of healthy individuals. Obese individuals also have elevated levels of gut bacteria that are highly capable of gathering energy (e.g., Bacteroides / Firmicutes ratio). In other words, these bacteria can produce more SCFAs. Recently, changes in the gut microbiota have been linked to fatty liver disease. SCFAs have been shown to affect the liver through various mechanisms. Changes in the gut microbiota lead to increased calorie intake, and elevated SCFAs enhance intestinal absorption of nutrients. Both mechanisms contribute to the development of obesity, which is correlated with liver disease. Increased alcohol production by the gut microbiota is another mechanism by which changes in the gut microbiota affect the liver. For example, pediatric NASH patients have higher serum alcohol concentrations than healthy controls or non-NASH obese individuals. Alcohol produced by gut microbiota contributes to the development of NASH through a mechanism similar to that of alcoholic steatohepatitis.

[0385] Another mechanism by which changes in the gut microbiome correlate with NAFLD and NASH is due to elevated levels of microbial cellular components such as lipopolysaccharide (LPS) (i.e., endotoxin) found in Gram-negative bacteria. Levels of Gram-negative bacteria are elevated in the gut microbiota of NASH patients. NAFLD and NASH patients also exhibit elevated serum endotoxin levels. Furthermore, in vivo mouse studies have shown that elevated serum LPS levels are linked to metabolic syndrome.

[0386] In some embodiments, additional therapeutic agents administered in combination with the FXR agonists described herein are probiotics. In some embodiments, the probiotics have anti-fibrotic, metabolic, or anti-inflammatory effects. In some embodiments, the probiotics alter lipid metabolism. In some embodiments, a method for treating or preventing liver disease in a subject in need comprises administering a farnesoid X receptor (FXR) agonist and a probiotic to the subject. In some embodiments, the probiotics are microorganisms, spores, viruses, phages, or any combination thereof. In some embodiments, the probiotics include Streptococcus, Bifidobacterium, Lactobacillus, or any combination thereof. In some embodiments, the probiotics reduce alcohol production in the subject. In some embodiments, the probiotics reduce alcohol dehydrogenase activity. In some embodiments, the probiotics reduce LPS production. In some embodiments, the probiotics reduce Gram-negative bacteria present in the gut. In some embodiments, the probiotics regulate SCFA production. In some embodiments, the probiotics reduce SCFA production.

[0387] (A suitable combination for digestive disorders or conditions) In some embodiments, the FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with an anti-inflammatory agent, a monoclonal antibody, or a combination thereof.

[0388] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a 5-aminosalicylic acid agent, a corticosteroid, an immunomodulator, a TNFα inhibitor, an integrin inhibitor, an endothelial adhesion molecule (MAdCAM) inhibitor, a JAK kinase inhibitor, an IL-12 / 23 inhibitor, or an S1P1 selective agonist.

[0389] 5-aminosalicylic acid preparations include, but are not limited to, sulfasalazine, mesalamine, and orsalazine. Corticosteroids include, but are not limited to, prednisone, budesonide, prednisolone, and methylprednisolone. Immunomodulators include, but are not limited to, azathioprine, 6-mercaptopurine, and cyclosporine. TNFα inhibitors include, but are not limited to, adalimumab, infliximab, and golimumab. Integrin inhibitors include, but are not limited to, natalizumab, vedolizumab, and etrolizumab. Endothelial adhesion molecule (MAdCAM) inhibitors include, but are not limited to, PF-00547659. JAK kinase inhibitors include, but are not limited to, tofacitinib, baricitinib, filgotinib, and upadacitinib. IL-12 / 23 inhibitors include, but are not limited to, ustekinumab.

[0390] S1P1 selective agonists include, but are not limited to, ozanimod and etrasimodo.

[0391] (In combination with a JAK kinase inhibitor) Janus kinases (JAKs) are a family of intracellular non-receptor tyrosine kinases that transmit cytokine-mediated signals via the JAK-STAT pathway. Inhibition of JAK kinases has beneficial effects in patients with ulcerative colitis.

[0392] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a JAK kinase inhibitor. In some embodiments, the JAK kinase inhibitor is tofacitinib. In some embodiments, tofacitinib is administered orally at a dose of about 10 mg twice daily for 8 weeks, followed by an orally dose of 5 mg twice daily. In some embodiments, tofacitinib is administered orally at a dose of about 10 mg twice daily.

[0393] (In combination with interleukin-12 and interleukin-23 antagonists) Interleukin-12 (IL-12) is an interleukin spontaneously produced by dendritic cells, macrophages, neutrophils, and human B lymphoblastoid cells in response to antigen stimulation. IL-12 is involved in the differentiation of naive T cells into Th1 cells and is also involved in the activity of natural killer cells and T lymphocytes. IL-23 is an inflammatory cytokine. IL-23 has been shown to be an important cytokine for the maintenance and expansion of Th17 cells. Inhibitors of interleukins IL-12 and IL-23 are expected to inhibit the induction of inflammatory responses in the body through the suppression of specific cytokines and thus modulate the activation of specific T cells. Interleukin-12 and interleukin-23 antagonists are expected to be beneficial in patients with Crohn's disease. Interleukin-12 and interleukin-23 antagonists are expected to be beneficial in patients with active ulcerative colitis.

[0394] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with an interleukin-12 and interleukin-23 antagonist. In some embodiments, the interleukin-12 and interleukin-23 antagonists are ustekinumab. In some embodiments, ustekinumab is initially administered intravenously at a dose of approximately 260 mg, followed by 90 mg every 8 weeks. In some embodiments, ustekinumab is initially administered intravenously at a dose of approximately 390 mg, followed by 90 mg every 8 weeks. In some embodiments, ustekinumab is initially administered intravenously at a dose of approximately 520 mg, followed by 90 mg every 8 weeks.

[0395] In some cases, FXR agonists are administered in combination with additional therapeutic agents such as antibiotics, corticosteroids, or additional anti-inflammatory or immunomodulatory therapies for the treatment of inflammation-related bowel conditions. In some cases, FXR agonists are administered in combination with metronidazole, vancomycin, fidaxomicin, corticosteroids, or a combination thereof for the treatment of inflammation-related bowel conditions. In some embodiments, FXR agonists are administered in combination with pentoxifylline, an anti-inflammatory and vasodilator.

[0396] Inflammation may be associated with pseudomembranous colitis. In some cases, pseudomembranous colitis is associated with bacterial overgrowth (e.g., C. difficile overgrowth). In some embodiments, FXR agonists are administered in combination with antibiotics such as metronidazole, vancomycin, fidaxomicin, or a combination thereof, for the treatment of inflammation associated with bacterial overgrowth (e.g., pseudomembranous colitis). In some embodiments, FXR agonists are administered in combination with the ketolide antibiotic solithromycin (Cempra).

[0397] In some embodiments, an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with an opioid agonist, a bile acid chelating agent, an anticholinergic, a tricyclic antidepressant, a 5-HT3 antagonist, a mixed opioid receptor agonist / antagonist, an antimicrobial agent, a neurokinin antagonist, or a combination thereof.

[0398] In some embodiments, the opioid agonist is loperamide. In some embodiments, the bile acid chelating agent is cholestyramine, colestipol, or coleseveram. In some embodiments, the anticholinergic agent is dicyclomine. In some embodiments, the tricyclic antidepressant is amitriptyline, imipramine, desipramine, or nortriptyline. In some embodiments, the 5-HT3 antagonist is allosetron or ramosetron. In some embodiments, the mixed opioid receptor agonist / antagonist is erxadrine or ORP-101. In some embodiments, the antibacterial agent is rifaximin. In some embodiments, the neurokinin antagonist is ivodutant.

[0399] In some embodiments, any concomitant agent administered in combination with an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in the form of the pharmaceutically acceptable salt thereof.

[0400] (Kits and manufactured products) Kits and products for use in the therapeutic applications described herein are also described herein. In some embodiments, such a kit includes a carrier, package, or container partitioned to house one or more containers such as vials, tubes, etc., each of which contains one of the distinct elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In some embodiments, the containers are formed from a variety of materials such as glass or plastic.

[0401] The products presented herein include packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging materials suitable for the selected formulation and the intended mode of administration and treatment. The broad range of formulations of the compounds and compositions presented herein are considered to be various treatments for any one of the diseases or conditions presented herein that would benefit from FXR modulation.

[0402] Such kits may optionally include compounds having identifying descriptions, labels, or instructions for use relating to their use in the methods described herein.

[0403] The kit typically includes one or more additional containers, each containing one or more different materials (optionally concentrated forms of reagents, and / or devices, etc.) that are desirable from a commercial and user perspective with respect to the use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, and carriers, packages, containers, vials, and / or tube labels describing the contents and / or instructions for use, as well as accompanying documentation with instructions for use. A set of instructions is also usually included.

[0404] In some embodiments, the label is on or associated with the container. In some cases, the label is affixed to the container when the letters, numbers, or other characters forming the label are attached to, molded, or etched onto the container itself. In some cases, the label is associated with the container if it exists, for example, as an accompanying document within the receptacle or carrier that holds the container. In some cases, the label is used to indicate that the contents are to be used for a specific therapeutic purpose. In some cases, the label indicates how to use the contents, such as in the methods described herein.

[0405] In certain embodiments, a pharmaceutical composition comprising an FXR agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is provided in some cases in a pack or dispenser device containing one or more unit dosage forms. The pack in some cases includes metal or plastic foil, such as a blister pack. The pack or dispenser device is accompanied in some cases by instructions for administration. In some cases the pack or dispenser is also accompanied by a notice associated with a container of a form prescribed by a government agency that regulates the manufacture, use, or sale of the drug, which reflects the government agency's approval of the form of the drug for administration to humans or animals. Such notice is, for example, in some cases a label approved by the U.S. Food and Drug Administration for a prescription drug or approved product insert. Compositions containing the compounds described herein, formulated on a suitable drug carrier, are also prepared in some cases for the treatment of an intended condition, placed in an appropriate container, and labeled. [Examples]

[0406] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims presented herein.

[0407] (Example 1: NASH activity study (STZ model)) NASH is induced in male C57BL / 6 hamsters by subcutaneous injection of 200 μg of STZ on postnatal day 2, followed by free-flowing high-fat diet (HFD) at 4 weeks postnatal. While continuing the HFD, the FXR agonist combinations disclosed herein are administered for 4–8 weeks to determine their effect on NASH. Fasting blood glucose is measured throughout the study using a handheld blood glucose meter. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and triglycerides (TG) are measured by a clinical chemistry analyzer. TG content in liver tissue is measured using the Triglyceride E Test Kit (Wako, Tokyo, Japan). Histological analysis of liver sections is performed on tissue embedded in Tissue-Tec Optimal Cutting Temperature (OCT) compound, snap-frozen in liquid nitrogen, and stored at -80°C. Sections are cut (5 μm), air-dried, and fixed with acetone. For hematoxylin-eosin (H&E) staining, liver sections are pre-fixed with Bouin's solution and then stained with hematoxylin-eosin solution. The degree of hepatic fibrosis (zone-3) is assessed by Sirius red staining.

[0408] (Example 2: NASH activity study (AMLN model)) Male C57BL / 6 mice were induced to develop NASH by dietary induction using a GAN diet (DIO-NASH) (D09100310, Research Diet, USA) (40% fat, 22% fructose, and 2% cholesterol). The animals were fed the GAN diet for 29 weeks. After 35 weeks of dietary induction, liver biopsies were performed to histologically assess the baseline progression of the disease (hepatic steatosis and fibrosis), stratified according to the stage of hepatic fibrosis, steatosis score, and body weight, and randomized to the treatment group. Three weeks after biopsy, the mice were stratified to the treatment group and administered the FXR agonist combination disclosed herein orally daily for 8 weeks. At the end of the study, liver biopsies were performed to assess hepatic steatosis by examining H&E-stained tissue sections and fibrosis by examining Sirius Red-stained tissue sections. Triglyceride and total cholesterol content in liver homogenate is measured in a single measurement using a Cobas C-111 automated analyzer and a commercially available kit (Roche Diagnostics, Germany) according to the manufacturer's instructions.

[0409] Figure 1 shows that compound 1 improves NASH as measured by the change in NAS from baseline when administered at doses of 0.1 mg, 0.3 mg, and 1.0 mg per kg. The change in NAS for each mouse was derived from their baseline NAS values. Histological evaluation of the liver for fibrotic changes induced by compound 1 showed a statistically significant benefit at a dose of 1 mg / kg (Figure 2). Figures 3A and 3B show the liver triglyceride and liver cholesterol concentrations, respectively, of mice administered compound 1 at doses of 0.1 mg, 0.3 mg, and 1.0 mg per kg.

[0410] (Example 3: Intrahepatic cholestasis model) Experimental intrahepatic cholestasis induced by 17α-ethinylestradiol (EE2) treatment in rodents is a widely used in vivo model to investigate the mechanisms involved in estrogen-induced cholestasis. Intrahepatic cholestasis is induced in adult male mice by subcutaneous injection of 10 mg / kg of 17α-ethinylestradiol (EE2) daily for 5 days. The FXR agonist combinations disclosed herein are administered during EE2-induced cholestasis to perform tests. The cholestatic effect is quantified by evaluating the liver / body weight ratio and measuring serum total bile acids, and alkaline phosphatase concentrations are measured using reagents and controls (Diagnostic Chemicals Ltd.) and a Cobas Mira plus CC analyzer (Roche Diagnostics). For histological and mitotic measurements, liver samples from each mouse are fixed in 10% neutral buffered formalin. Slides are stained with hematoxylin and eosin using a standard protocol, and structural changes are examined under a microscope. Hepatocyte proliferation is assessed by immunohistochemical staining for Ki67.

[0411] (Example 4: Rat ANIT model) The combination of FXR agonists with the additional therapeutic agents described herein will be evaluated over a dose range of 0.01–10 mg / kg in a chronic treatment model for cholestasis. This model will be used to evaluate the combination therapies described herein for the treatment of cholestatic liver disorders such as bile acid malabsorption (e.g., primary or secondary biliary diarrhea), choleglycemic gastritis, collagenous colitis, lymphocytic colitis, fecal-flow diversion colitis, uncertain colitis, Alagille syndrome, biliary atresia, liver transplant rejection due to biliary hypoplasia, graft-versus-host disease associated with bone marrow or stem cell transplantation, cystic fibrotic liver disease, and parenteral nutrition-related liver disease.

[0412] Rats were treated with α-naphthyl isothiocyanate (ANIT) (0.1% w / w) in their diet for 3 days, and then treated with the compounds described herein at doses of 0.01–10 mg / kg ("Veh" group). The non-cholestasis control group was fed a standard diet without ANIT and served as the non-cholestasis control animals ("control" group). Fourteen days after oral administration, the concentration of the analytes in rat serum was analyzed. LLQ is the limit of quantification. Mean ± SEM, n=5. Levels of hepatobiliary injury indicators, including elevated concentrations of circulating aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, and bile acids, were measured in rat serum. Exposure to ANIT induces severe cholestasis and hepatocyte damage. Combinations of FXR agonists with additional therapeutic agents described herein that improve many of these indicators are useful in treating the aforementioned diseases or conditions.

[0413] (Example 5: DSS chronic colitis mouse model) The therapeutic potential of the combination therapies described herein for inflammatory bowel disease (IBD) will be tested using a dextran sulfate sodium (DSS)-induced chronic mouse model. Chronic colitis will be induced in mice by feeding them 2% DSS water for 5 days followed by normal water for 5 days, and this feeding cycle will be repeated two more times for a total of 3 cycles. Colitis will develop approximately after the first cycle of DSS feeding. Colitis will be monitored by weight loss, stool consistency, and rectal bleeding. The combination of an FXR agonist and the additional therapeutic agent described herein will be tested by administering it to the mice concurrently with the initiation of 2% DSS water. Alternatively, the combination therapy will be tested after the first feeding cycle of 2% DSS water and normal water. The therapeutic effect will be monitored by observing weight, stool consistency, and rectal bleeding during the period of administration of the combination therapy described herein to the mice. After euthanasia, the onset of the disease and the effects of the combination therapy described herein are further quantified by measuring the weight and length of the colon, histological examination of the colon by H&E staining for mucosal inflammation and structural changes, and the expression of disease-related genes (proteins and RNAs).

[0414] (Example 6: T cell adoptive transfer colitis mouse model) The T cell adoptive transfer colitis model is accepted as a relevant mouse model of human inflammatory bowel disease (IBD). To induce colitis in this model, a CD4 T lymphocyte population is isolated from the spleen of donor mice. Subsequently, a subpopulation of CD4+CD45RBhigh T cells is purified by cell sorting using flow cytometry. The purified CD4+CD45RBhigh T cells are injected into the peritoneal cavity of recipient severe combined immunodeficiency (SCID) mice. Colitis develops approximately 3 - 6 weeks after T cell transplantation and is monitored by weight loss. Testing of FXR agonists and additional therapeutic agents described herein is initiated 3 weeks after injecting the purified CD4+CD45RBhigh T cells into recipient SCID mice (at which point colitis has already developed in the model). Administration of the therapeutic agent is continued for 4 weeks prior to euthanasia. The therapeutic effect is monitored by observing the body weight during the period of administration of the FXR agonist and additional therapeutic agents described herein to the mice. After euthanasia, the onset and treatment effect of the disease are further quantified by measuring the weight and length of the colon and by the histological appearance of the colon by H&E staining of mucosal inflammation and structural changes associated with the disease.

[0415] Results: CD4+CD45RB hiT cell transfer resulted in a 13% decrease in body weight from baseline at the end of the study (p<0.0001). This was reversed by compound 1 and anti-IL-12 / 23 antibody. The colon weight-to-length ratio (colon W / L), a marker of colitis, increased 3.1-fold in the media group compared to control mice that did not receive T cell transplants (p<0.0001). Compared to the media, compound 1-treated mice had colon W / L reductions of 30%, 44%, and 36% at 0.1 mg / kg, 0.3 mg / kg, and 1 mg / kg, respectively (p<0.0001). Treatment with anti-IL-12 / 23 antibody improved colon W / L by 54% (p<0.0001). Mice treated with the media had mean histopathology scores of 3.2 for inflammation, 3.8 for hyperplasia, and 0.9 for glandular loss, with little to no erosion, and a mean total histopathology score of 7.9. Compound 1 at doses of 0.1 mg, 0.3 mg, and 1 mg per kg of body weight significantly reduced the total score by 33% (p<0.0001), 49% (p<0.0001), and 38% (p<0.0001), respectively. Anti-IL-12 / 23 antibody treatment showed a 58% reduction in the total score of colon histopathology (p<0.0001). Both Compound 1 and the anti-IL12 / 23 antibody showed similar improvement trends across all histopathological endpoints.

[0416] Histological analysis provides a detailed depiction of colon inflammation and injury. Histological indicators were used to assess inflammation, erosion, mucosal hyperplasia, and glandular loss. Treatment with compound 1 (0.1 mg / kg, 0.3 mg / kg, and 1.0 mg / kg) and anti-IL-12 / 23 antibody resulted in statistically significant improvements in colon histology (Figure 6). Representative histological images revealed that mice treated with compound 1 and anti-IL-12 / 23 antibody showed significantly less inflammatory infiltration in the mucosa and edema compared to animals treated with the appropriate medium. Compound 1, a non-bile acid FXR agonist, is effective in mitigating colitis in a T cell adoptive transfer model with a similar efficacy trend to anti-IL-12 / 23 antibody treatment.

[0417] (Example 7: CCl4 fibrosis model) In BALB / c male mice, fibrosis was induced by intraperitoneal injection of CCl4 every other week. CCl4 was prepared in oil in a 1:1 ratio and administered intraperitoneally at a dose of 1 mL / kg. Two to four weeks after fibrosis induction, a combination of an FXR agonist and the additional therapeutic agent described herein was administered orally daily for two to six weeks while continuing CCl4 administration. At the end of the study, the liver was fixed with formalin and stained with Sirius Red for histopathological evaluation of fibrosis. Total collagen content was measured by colorimetric quantification of hydroxyproline residues by acid hydrolysis of collagen. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured using a clinical chemistry analyzer.

[0418] (Example 8: 7-day pharmacodynamic study in non-human primates) Compound 1 was orally administered to male cynomolgus monkeys daily for 7 days at doses of 0 mg (medium), 0.3 mg, 1 mg, and 3 mg per kg of body weight. The pharmacokinetics and pharmacodynamics of Compound 1 were then investigated. Compound 1 was prepared in a medium solution of Solutol and 0.5% CMC at a 30 / 70 (v / v) ratio and administered at a dose of 5 mL / kg. Blood samples were collected at predetermined time intervals on days 1, 2, 4, and 7 into test tubes containing K2EDTA, and plasma was isolated by centrifugation. Partial samples were transferred to labeled polypropylene cluster tubes and stored below 80°C until analysis. Plasma samples were analyzed for Compound 1 and 7α-hydroxy-4-cholesten-3-one (C4).

[0419] Measurement of compound 1 in plasma.

[0420] A plasma calibration standard was prepared by serially diluting compound 1 in 10 mM DMSO with DMSO in a concentration range of 0.003 to 300 μM, and then spiking 3 μL of the serially diluted compound 1 in DMSO into 30 μL of blank cynomolgus monkey plasma so that the calibration standard range was 0.0003 to 30 μM. For plasma samples, 30 μL of plasma sample was combined with 3 μL of blank DMSO. The calibration standard and sample were extracted by protein precipitation using 150 μL of 100% ice acetonitrile containing the internal standard. The precipitated protein was removed by centrifugation, and the supernatant fraction for compound 1 was analyzed by LC / MS / MS.

[0421] Results: The plasma concentrations of compound 1 after 7 days of oral administration at 0.3 mg / kg, 1 mg / kg, and 3 mg / kg can be seen in Figure 7.

[0422] Measurement of 7α-hydroxy-4-cholesten-3-one (C4) in plasma.

[0423] A phosphate-buffered saline (PBS) calibration standard was prepared by serially diluting C4 in 10 mM DMSO with DMSO in a concentration range of 0.001 μM to 100 μM, and then spiking the serially diluted C4 in 5 μL of DMSO into 50 μL of PBS so that the calibration standard range was 0.0001 to 10 μM. For plasma samples, 25 μL of plasma sample was combined with 5 μL of blank DMSO and 25 μL of PBS (2-fold dilution). The PBS calibration standard and the 2-fold dilution sample were extracted by protein precipitation using 100% ice acetonitrile (250 μL) containing 1% formic acid and the internal standard (C4-d7). The precipitated protein was removed by centrifugation, and the supernatant fraction for C4 was analyzed by LC / MS / MS.

[0424] Results: Figure 8 shows the C4 plasma concentrations after 7 days of oral administration of compound 1 at approximately 0.3 mg / kg, 1 mg / kg, and 3 mg / kg.

[0425] Furthermore, compound 1 has an average elimination half-life of approximately 9.7 hours based on a single oral administration of a 10 mg tablet in non-human primates. No adverse effects were observed in rats at doses up to approximately 10 mg / kg over 28 days, and in non-human primates at doses up to approximately 50 mg / kg over 28 days.

[0426] (Example 9: Efficacy study on the treatment of cholangiocarcinoma and hepatocellular carcinoma (patient-derived xenograft model)) Tumor tissue derived from patients with cholangiocarcinoma or hepatocellular carcinoma is transplanted into immunodeficient mice to induce tumors that retain the histological / pathological structure, major driver mutations, and gene expression of the patient's tumor. The growth of these patient-derived xenografts (PDXs) is monitored to investigate the effect of the test product on tumor growth. Newly excised tumor fragments, 2-3 mm in diameter, from mice with established primary human tumor tissue are subcutaneously inoculated into the right flank of the mice. The tumors are allowed to establish, with an average tumor size of approximately 150 mm. 3 Once the target tumor volume is reached, mice are randomly divided into treatment groups and treated with daily oral administration of either the medium control or the test compound. Tumor volume is measured twice weekly in two dimensions using electronic calipers, and the volume is determined using the following formula: V = (L × W × W) / 2, where V is the tumor volume, L is the tumor length (longest tumor dimension), and W is the tumor width (longest tumor dimension perpendicular to L). Treatment of mice is continued for a maximum of 4 weeks, or until the tumor volume reaches 3000 mm². 3 Until it exceeds that, or until the animal's body weight decreases by more than 20%.

[0427] (Example 10: Efficacy study on the treatment of cholestasis and primary sclerosing cholangitis (Mdr2) - / - Mouse model)) Multidrug resistance 3 (MDR3) plays a role in transporting phospholipids into bile. Mutations in this transporter in humans can cause progressive familial intrahepatic cholestasis (PFIC3). Gene knockout of the mouse homolog MDR2 similarly causes cholestasis and fibrosis in mice (Fickert 2004 Gastroenterology 127 261). This model can be used to evaluate the efficacy of FXR agonists in reducing cholestasis and liver damage (Baghdasaryan 2011 Hepatology 54 1313).

[0428] 8-week-old MDR2 - / - Mice exhibit elevated serum bile acids and liver enzymes, indicating evidence of hepatic fibrosis and inflammation. To investigate the therapeutic effect of FXR agonists, the compound may be force-administered orally to 8-week-old knockout mice. Efficacy can be monitored by examining its effects on serum bile acids, liver enzymes (ALT, ALP), and bilirubin. Additional efficacy points may include histopathological analysis of the liver and scoring for inflammation, bile duct hyperplasia, and hepatic fibrosis.

[0429] (Example 11: In vitro FXR assay (TK)) (seeding) CV-1 cells were seeded at a density of 2,000,000 cells in a T175 flask containing DMEM + 10% charcoal double-removal BS, and incubated at 37°C for 18 hours (over-clocked) with 5% CO2.

[0430] (Transfection) After 18 hours of incubation, replace the culture medium in the T175 flask with fresh DMEM + 10% charcoal-exfoliated serum. Combine 2500 μL of OptiMEM (Life Technologies, catalog no. 31985-062) with the expression plasmids for hFXR, hRXR, TK-ECRE-luc, and pCMX-YFP in a polypropylene tube. Then, vortex the tube briefly and incubate at room temperature for 5 minutes. Add the transfection reagent (X-tremeGENE HP, catalog no. 06366236001, Roche) to the vortexed OptiMEM / plasmid mixture and incubate at room temperature for 20 minutes. After incubation, add the transfection reagent / DNA mixture complex to the cells in the T175 flask and incubate the cells at 37°C for 18 hours (O / N) in 5% CO2.

[0431] (Test compound) The compound is serially diluted with DMSO and added to transfected CV-1 cells. The cells are then incubated for 18 hours. The next day, the cells are lysed and their luminescence is examined.

[0432] (Example 12: Evaluation of PK / PD and safety of Compound 1 in healthy subjects) Objective: The objectives of this study are to evaluate the safety and tolerability of single and multiple oral doses of compound 1 or a pharmaceutically acceptable salt thereof for future research in patients; to characterize the pharmacokinetics (PK) of single and multiple oral doses of compound 1 or a pharmaceutically acceptable salt thereof; to characterize the pharmacodynamics (PD) of single and multiple oral doses of compound 1 or a pharmaceutically acceptable salt thereof; and to identify the recommended level of multiple oral doses of compound 1 or a pharmaceutically acceptable salt thereof. Further objectives of this study are to measure plasma concentrations of 7α-hydroxy-4-cholesten-3-one (C4), plasma concentrations of fibroblast growth factor 19 (FGF-19), and serum concentrations of total bile acids. This is a two-part, single-center, randomized, double-blind, placebo-controlled trial in healthy subjects. Part A is the single-dose escalation (SAD) portion, and Part B is the repeated-dose escalation (MAD) portion.

[0433] Selection criteria: BMI between 18.0 and 30.0 kg / m² 2 The target group is healthy men or women aged 18-50 who weigh more than 55 kg.

[0434] Participants: Part A included approximately 40 healthy men, and Part B included approximately 48 healthy men.

[0435] Investigational drug: Compound 1, formulated as an oral tablet.

[0436] Placebo: An oral tablet identical to the investigational drug, but without compound 1.

[0437] (variable) Safety: Adverse events, clinical tests, vital signs, 12-lead electrocardiogram, physical examination.

[0438] PK: Plasma PK parameter, which is the concentration of a compound in plasma.

[0439] Plasma concentration of PD:7α-hydroxy-4-cholesten-3-one (C4), plasma concentration of fibroblast growth factor 19 (FGF-19), and total bile acid concentration.

[0440] (Research design) (Part A: Single dose escalation [SAD]) A single dose of compound 1 will be administered to up to five groups of eight healthy men each. Two subjects in each group will receive a placebo, and the remaining six subjects in each group will receive compound 1.

[0441] (Part B: Repeated dose escalation [MAD]) Up to six groups of 10 healthy men each will be investigated to examine the safety, tolerability, pharmacokinetics (PK), and disease progression (PD) of compound 1 administered orally multiple times. All participants in each group will receive repeated-dose escalating doses of compound 1 or the corresponding placebo once daily from day 1 to day 14. Administration will be performed on a fasted basis on each administration day. Patients in each group will receive repeated oral doses of compound 1 at various oral dose levels ranging from approximately 2.5 mg to approximately 300 mg (e.g., approximately 2.5 mg, 5 mg, 15 mg, 30 mg, 40 mg, 50 mg, 80 mg, 100 mg, or 150 mg) once daily from day 1 to day 14 of the study. Eight participants in each group will receive compound 1, and two participants in each group will receive placebo.

[0442] (result) Both single doses (10 mg, 30 mg, 100 mg, 300 mg) and repeated doses (2.5 mg, 5 mg, 7.5 mg, 10 mg) of compound 1 were safe and well-tolerated. Compound 1 showed a sustained PK and PD profile with once-daily oral administration. A dose-dependent increase in maximum concentration was observed.

[0443] Figure 9 shows the plasma concentrations of compound 1 on day 14 after 14 days of oral administration of 5 mg and 10 mg of compound 1.

[0444] Figure 10 shows the C4 plasma concentrations on day 14 after 14 days of oral administration of 5 mg and 10 mg of compound 1.

[0445] Figure 11 shows the daily C4 plasma concentrations during 14 days of oral administration of Compound 1 at 2.5 mg, 5 mg, 7.5 mg, and 10 mg doses. Compound 1 reduced daily trough plasma C4 concentration and the area under the curve on day 14 (by approximately 55–95%) compared to placebo, and the reduction was observed over 24 hours post-administration.

[0446] Compound 1 did not cause two common adverse events in NASH patients: increased serum low-density lipoprotein cholesterol (LDL-C) and generalized pruritus.

[0447] (Example 13: Clinical trial of non-alcoholic steatohepatitis (NASH)) The following is a non-limiting example of a clinical trial of non-alcoholic steatohepatitis (NASH) in humans.

[0448] Objectives: The objectives of this study include: evaluating the safety and tolerability of compound 1 or a pharmaceutically acceptable salt thereof in patients with NASH; characterizing the pharmacokinetics (PK) of compound 1 or a pharmaceutically acceptable salt thereof; characterizing the pharmacodynamics (PD) of compound 1 or a pharmaceutically acceptable salt thereof; evaluating the pharmacological activity of compound 1 or a pharmaceutically acceptable salt thereof in patients with NASH using magnetic resonance imaging-proton density lipid fraction (MRI-PDFF); investigating the effects of compound 1 or a pharmaceutically acceptable salt thereof on serum concentrations of hepatic chemicals; and investigating the effects of compound 1 or a pharmaceutically acceptable salt thereof on non-invasive fibrosis biomarkers (e.g., pro-C3 and improved hepatic fibrosis [ELF] score).

[0449] Study Design: This is a double-blind, placebo-controlled, multicenter evaluation over 16 weeks (112 days) of two dose levels of compound 1 or a pharmaceutically acceptable salt thereof, or placebo. Approximately 180 participants will be randomly assigned in a 1:1:1 ratio to one of three treatment groups (6 mg of compound 1, 3 mg of compound 1, or the corresponding placebo). Additional doses of compound 1 may be considered. Individual dose adjustments during the study are not permitted.

[0450] Study Schedule: Screening (Day 28 to Day 1): Eligibility determination including screening / baseline MRI-PDFF. Treatment Period (Day 1 to Day 112): Randomization and daily administration for the following 112 days, with MRI-PDFF on Day 28 and Day 112 (end of treatment). Follow-up Period (Day 113 to Day 140): MRI-PDFF on Day 140.

[0451] Inclusion criteria: (1) Males and females aged 18 to 75 years at the time of signing the informed consent document; (2) Diagnosis of NASH based on one of the following criteria: histologically confirmed non-alcoholic steatohepatitis (NASH) within 12 months of screening with a NAFLD activity score (NAS) ≥ 4 and at least one point each of steatosis, inflammation, and hypertrophy, and magnetic resonance elastography (MRE) showing kPa ≥ 2.61; or multiparameter M2 showing iron-corrected T1 (cT1) > 830 milliseconds within 6 months of registration. (1) RI (i.e., liver multiscan), transient elastography (TE, FibroScan®) showing kPa ≥ 7.6 and control decay parameter (CAP) > 300 dB / m obtained within 3 months after enrollment, (2) liver fat content ≥ 10% as measured by MRI-PDFF during screening or 28 days prior to randomization, (3) ALT, ALP, AST, and total bilirubin stability, (4) additional laboratory values ​​at the time of screening must meet the following criteria: platelet count ≥ 150 × 10 9 / L, except for subjects currently taking anticoagulants, International Normalized Ratio (INR) < 1.4, Plasma Alanine Aminotransferase (ALT) ≥ 30 U / L, Plasma Aspartate Aminotransferase (AST) ≥ 20 U / L, (6) Estimated glomerular filtration rate (eGFR) ≥ 60 mL / min / 1.73 m² according to the formula of the Collaborative Study of Chronic Kidney Disease Epidemiology (CKD-EPI) 2 (1) The subjects must meet the following criteria: (2) There must be no clinically significant urinalysis findings (e.g., proteinuria, hematuria) at the time of screening; (3) The subject must not have received the investigational drug within 30 days (or 5 times the drug elimination half-life) prior to the first dose of the investigational drug; (4) Subjects taking SGLT-2 inhibitors must have been receiving them at a stable dose for at least 3 months prior to the first dose of the investigational drug; (5) Subjects may take vitamin E at a dose of less than 800 IU / day if the dose has been stable for at least 3 months prior to the first dose of the investigational drug; (6) Sexually active subjects must agree to use contraception during the treatment period and for 90 days after the last dose of the investigational drug.

[0452] Exclusion Criteria: Any of the following individuals will be excluded from participation in the study: (1) a history or presence of other active liver disease (e.g., alcoholic liver disease, viral hepatitis, etc.), (2) a history of liver transplantation, (3) the presence of cirrhosis on liver biopsy or evidence of possible cirrhosis, (4) a history of decompensated liver disease including ascites, hepatic encephalopathy, or variceal bleeding, (5) excessive alcohol consumption, (6) weight loss of more than 10% in the 6 months prior to screening, or weight loss of more than 5% during screening, (7) medications associated with the cause of NAFLD within the 12 months prior to screening (e.g., amiodarone, methotrexate, systemic glucocorticoids, tetrazodone (8) a history of continuous use of more than four weeks of lacycline, tamoxifen, estrogen, anabolic steroids, valproic acid, and other known hepatotoxins at doses higher than those used for hormone replacement; (9) use of GLP-1 analogues within three months of screening; (10) a serious medical condition, substance abuse, mental illness, or social circumstances that would impede compliance with the study; or (11) the presence of abnormal laboratory tests or concomitant use of drugs (e.g., potent or moderate CYP3A4 inhibitors, or P-gp substrates with a narrow therapeutic index range) that would put the subject at an unacceptable risk if they participate in the study.

[0453] Summary of Safety Assessment: Safety assessment includes collection of adverse events, vital signs and physical examination, 12-lead electrocardiogram, clinical laboratory evaluation, and validation of concomitant therapies. Clinical tests and procedures may be performed more frequently if clinically required.

[0454] Pharmacokinetic evaluation: Blood samples are collected according to the PK sampling schedule. PK parameters (C max t max t 1 / 2 , C trough、 CL ss / F, C avg(0-24h) AUC 0-tau AUC 0-t AUC 0-inf This is estimated by non-compartmental analysis.

[0455] Pharmacodynamic (PD) evaluation: Blood samples are collected according to the PD (C4, FGF-19, bile acids) sampling schedule.

[0456] Summary of pharmacological activity evaluation: The pharmacological activity of compound 1 is evaluated by quantitative analysis of liver fat using MRI-PDFF and blood-based NASH fibrosis biomarkers.

[0457] Biomarker assessment: Fibrosis assessment using the improved liver fibrosis (ELF) score derived from the measurement of hyaluronic acid, procollagen II amino-terminal peptide (PIIINP), and metalloproteinase 1 tissue inhibitor (TIMP-1) as biomarkers for fibrosis; the type III collagen propeptide (Pro-C3) as a biomarker for fibrosis; the NAFLD fibrosis score (NFS) to identify advanced fibrosis (age, hyperglycemia, BMI, platelet count, albumin, and AST / ALT ratio); and the FIB-4 score to classify the concentration of fibrosis (age, AST, ALT, and platelet count).

[0458] Bile acid composition: Serum bile acids (total and panel of 15 bile acids measured by LC-MS), specific ratios, and analytical methods.

[0459] Primary Objective: The objectives of this study include: evaluating the safety and tolerability of compound 1 in patients with NASH.

[0460] Secondary objectives: To characterize the pharmacokinetics (PK) of compound 1, to characterize the pharmacodynamics (PD) of compound 1, to evaluate the pharmacological activity of compound 1 in NASH patients using magnetic resonance imaging-proton density lipid fraction (MRI-PDFF), and to investigate the effect of compound 1 on the serum concentrations of hepatic chemicals.

[0461] Exploratory objective: To investigate the effect of compound 1 on non-invasive fibrosis biomarkers (e.g., pro-C3 and improved liver fibrosis [ELF] score).

[0462] (Example 14: Clinical trial for irritable bowel syndrome) The following are some non-exclusive examples of clinical trials for irritable bowel syndrome in humans.

[0463] Objective: The objective of this study is to characterize the safety, pharmacodynamics, and activity of compound 1 or a pharmaceutically acceptable salt thereof in subjects with diarrhea-predominant irritable bowel syndrome (IBS-D) with bile acid malabsorption (BAM).

[0464] Primary objective: To evaluate the effects of compound 1 or a pharmaceutically acceptable salt thereof, and placebo, on a composite endpoint of stool frequency and shape using the Bristol Stool Scale (BSFS).

[0465] Secondary objectives: To characterize the safety and tolerability of compound 1 or its pharmaceutically acceptable salts and placebo; to characterize the effects on total fecal BA and the proportion of primary BA in feces (% chenodeoxycholic acid [CDCA], % cholic acid [CA]); to characterize the effects on fecal fat content; to characterize the effects on each element of bowel function scoring (e.g., frequency of bowel movements, consistency, ease of defecation, feeling of completeness of defecation); to characterize the effects on the IBS Global Improvement Scale score; to characterize the effect on worst abdominal pain (WAP); to characterize the effect on the proportion of patients who received rescue medication; to characterize the effects on fasting serum concentrations of C4 and FGF-19; and to characterize the effect on colonic transit time (geometric centers at 24 and 48 hours) at selected research facilities.

[0466] Inclusion Criteria: Men and women aged 18–75 years meeting Rome III criteria for IBS-D. Evidence for BAM determined by one or more of the following criteria: currently receiving bile acid block therapy and symptom improvement; increased total fecal BA based on measurements over the past 60 days (fecal BA must be greater than 2337 μmol per 48 hours); fasting serum C4 concentration of at least 52 ng / mL at screening; women of childbearing potential must have a negative serum pregnancy test at screening, agree not to become pregnant during the study, and agree to use contraception throughout the study and for up to 3 months after the last dose of compound 1 or a pharmaceutically acceptable salt; men of childbearing potential must agree to use contraception (double barrier method) during the study and for up to 1 month after the last dose of compound 1 or a pharmaceutically acceptable salt.

[0467] Exclusion Criteria: Presence of other medical conditions known to cause diarrhea or constipation (e.g., bowel surgery, ulcerative colitis, Crohn's disease, constipation-predominant IBS), renal disease (e.g., serum creatinine ≥ 2.5 mg / dL), hepatic disease (e.g., aspartate transaminase > 2.5 ULN and / or alanine transaminase > 2.5 ULN), use of a new investigational drug within 30 days prior to screening (or 5 times the drug elimination half-life), active serious medical condition likely to result in a life expectancy of less than 2 years, active substance abuse or alcoholism in the year prior to screening, pregnancy, planning of pregnancy, possibility of pregnancy (e.g., unwillingness to use effective contraception during the study), or breastfeeding, as well as any other medical or social circumstances that, in the opinion of the researcher, would hinder compliance or completion of the study.

[0468] Investigational Treatment: Each participant will receive a daily dose of the investigational drug (placebo, or 5-300 mg of Compound 1 or a pharmaceutically acceptable salt thereof) orally once daily from days 1 to 28. The placebo or Compound 1 or a pharmaceutically acceptable salt thereof should be taken in the morning, at as close to the same time as possible each day, with at least 4 ounces of water, and should be taken 1 hour or 2 hours before a meal to minimize the potential influence of food on the absorption of Compound 1 or its pharmaceutically acceptable salt. If a morning dose of the placebo or Compound 1 or a pharmaceutically acceptable salt thereof is missed, it may be taken later on the same day (up to 12 hours from the planned dose time). However, if the entire daily dose is missed, an additional dose should not be taken the following day (this should be recorded as a missed dose).

[0469] Rescue medication: If necessary, loperamide 2 mg may be administered twice daily for uncontrolled diarrhea during the treatment period, defined as having at least three bowel movements per day with a BSFS of 6 or higher.

[0470] Effectiveness Assessment: Composite evaluation item of bowel movement frequency and consistency: Bowel movement frequency × stool consistency (BSFS1-7) = composite score / day. The composite score for a given week (7 days) from screening through the treatment period is compared. Percentage of total BA and primary BA in stool (%CDCA, %CA) (random spot stool collection): The mean total BA in stool from screening to week 4 is compared. The total percentage of mean CDCA and mean CA in stool from screening to week 4 is compared. Stool fat content (random spot stool collection). Colonic transit time: The mean geometric centers at 24 hours and 48 hours from screening to week 4 are compared for sites where this analysis can be performed. Bowel function: The total score of each element of the diary (number of bowel movements, consistency, ease of defecation, feeling of completion of defecation) for a given week (7 days) from screening through the treatment period is compared. IBS Global Improvement Scale Score: Participants are asked, "How would you rate your overall IBS symptoms over the past 7 days?" The mean scores on the IBS Global Improvement Scale (0=none, 1=mild, 2=moderate, 3=severe, and 4=very severe) for each week (7 days) from screening through the treatment period will be compared. Worst Abdominal Pain (WAP): Daily diaries will include a WAP pain scale, where 0=no pain and 10=worst pain imaginable. The mean weekly WAP scores for each week (7 days) from screening through the treatment period will be compared. Use of rescue medication: The proportion of subjects who received rescue medication during the treatment period will be compared.

[0471] Biomarkers: Fasting serum concentrations of C4 and FGF-19: Exploratory analyses will be conducted to evaluate the relationship between treatment and the concentration of each biomarker. Furthermore, the relationship between each biomarker and efficacy endpoints will be explored. Colonic passage will be considered if possible.

[0472] Primary endpoint: Average weekly composite score for stool frequency and consistency using BSFS from screening (7 days prior to randomization) to week 4.

[0473] Secondary endpoints: Mean weekly composite score for stool frequency and consistency using BSFS from screening (7 days prior to randomization) to weeks 1, 2, and 3; Mean weekly composite score for the two highest weekly values ​​of stool frequency and consistency using BSFS from screening (7 days prior to randomization) to weeks 1, 2, 3, and 4; Mean weekly composite score for bowel movement frequency from screening (7 days prior to randomization) to weeks 1, 2, 3, and 4; Mean weekly composite score for stool consistency using BSFS from screening (7 days prior to randomization) to weeks 1, 2, 3, and 4; Screen Weekly mean WAP scores from screening (7 days prior to randomization) to weeks 1, 2, 3, and 4; weekly mean scores on the IBS General Improvement Scale from screening (7 days prior to randomization) to weeks 1, 2, 3, and 4; mean total fecal BA and primary BA (% chenodeoxycholic acid [CDCA], % cholic acid [CA]) in stool from screening to week 4; mean total fecal fat content in stool from screening to week 4; correlation of fasting serum concentrations of C4 and FGF-19 with each efficacy assessment; mean total colonic transit time (geometric center at 24 hours and 48 hours) at screening and week 4, performed at selected research facilities.

[0474] (Example 15: Clinical trial for ulcerative colitis) The following is a non-limiting example of a clinical trial for ulcerative colitis in humans.

[0475] Objective: The objective of this study is to characterize the safety, pharmacodynamics, and activity of compound 1 or a pharmaceutically acceptable salt thereof in subjects with moderate to severe ulcerative colitis.

[0476] Primary objective: To evaluate the effect of compound 1 or a pharmaceutically acceptable salt thereof on UC by comparing the mean change in UC-100 score at week 12 with placebo.

[0477] Secondary objectives: To evaluate changes in the three-component Mayo score (score range 0-9 based on bowel movement frequency, rectal bleeding, and endoscopic findings); to evaluate the effect of compound 1 or a pharmaceutically acceptable salt and placebo on the endoscopic severity index of ulcerative colitis (UCEIS); to evaluate the effect of compound 1 or a pharmaceutically acceptable salt and placebo on the Roberts histological index (RHI); to evaluate changes in the total Mayo score; to evaluate changes in components of the Mayo score (bowel movement frequency, rectal bleeding, endoscopic score); and to evaluate clinical responses (rectal bleeding subscore of 0 or 1 or rectal bleeding subscore of 1 point or more). Assess the following: assess a decrease of 30% or more and a decrease of 3 points or more in the Mayo score from baseline, along with any decline in core scores; assess clinical remission (Mayo score of 2 points or less, along with no individual subscores exceeding 1 point); assess changes in histological indicators; assess the need for rescue medication; assess the impact on the Inflammatory Bowel Disease Questionnaire (IBDQ); and assess changes in fecal calprotectin concentration and serum C-reactive protein concentration, which are the effects on fasting serum concentrations of C4 and FGF-19, between compound 1 or a pharmaceutically acceptable salt of it and placebo at week 12.

[0478] Investigational treatment: Each participant will receive a daily dose of the investigational drug (placebo or compound 1 or a pharmaceutically acceptable salt thereof) orally once daily from day 1 to day 84. Permitted concomitant medications: If a patient is taking a stable dose of corticosteroids (up to 30 mg / day of prednisone or 6 mg / day of Entocort) at least two weeks prior to the screening endoscopy, the corticosteroid may be continued throughout the screening, treatment, and follow-up periods, unless the dose is adjusted. If a patient is taking a stable dose of oral aminosalicylates, azathioprine, 6-mercaptopurine, or methotrexate at least three weeks prior to the screening endoscopy, the drug therapy may be continued throughout the screening, treatment, and follow-up periods, unless the dose is adjusted. Prohibited medications: Patients must discontinue antitumor necrosis factor (TNF) therapy, ustekinumab, or vedolizumab at least eight weeks prior to the first dose. Patients must discontinue investigational drugs, UC medications (except permitted concomitant medications), or medications affecting bowel function at least eight weeks prior to the screening endoscopy (i.e., the washout period). These medications may not be administered during screening, treatment, and follow-up periods to avoid complicating data analysis.

[0479] Inclusion Criteria: Men and women aged 18–75 years diagnosed with UC at least 3 months prior to screening. Moderate to severe active UC is defined as a Mayo score of 6–12 on a scale of 0–12 and an endoscopic score of ≥2 on a scale of 0–3, with at least 15 cm of associated tissue during screening. Central readings of endoscopic scores are required. Participants with a history of previously receiving antitumor necrosis factor (TNF) therapy, ustekinumab, or vedolizumab must have discontinued these treatments at least 8 weeks prior to the first dose (i.e., baseline). Participants must be currently receiving or have a history of not responding to or being intolerant of at least one of the following: oral 5-aminosalicylic acid, oral corticosteroids, methotrexate, 6-mercaptopurine, and azathioprine. Women of childbearing age must have a negative serum pregnancy test during screening, agree not to become pregnant during the study, and agree to use some form of contraception for the entire study and until 3 months after the last dose of compound 1 or a pharmaceutically acceptable salt thereof. Male participants of childbearing potential must agree to use contraception (double barrier method) during the study and for up to one month after the last dose of compound 1 or a pharmaceutically acceptable salt thereof.

[0480] Exclusion criteria: Diagnosis of Crohn's disease or undetermined colitis, or presence or history of a fistula consistent with Crohn's disease, microscopic colitis, radiation colitis or ischemic colitis, presence of severe, widespread colitis likely to require surgical intervention within 12 weeks of screening, confirmed or suspected intestinal infection. Subjects may be re-examined if the infection is resolved. Renal disease (e.g., serum creatinine ≥ 2.5 mg / dL), liver disease (e.g., aspartate transaminase > 2.5 ULN and / or alanine transaminase > 2.5 ULN), active and serious medical condition that may result in a life expectancy of less than 2 years, active substance abuse or alcoholism in the year prior to screening, pregnancy, planning for pregnancy, possibility of pregnancy (e.g., unwillingness to use effective contraception during the study), or breastfeeding.

[0481] Efficacy evaluation: UC-100 score: A composite score based on endoscopy, histology, and bowel movement frequency. Endoscopic Severity Index of Ulcerative Colitis (UCEIS): Endoscopic scoring in three domains: vascular pattern (score 1-3), bleeding (score 1-4), erosion and ulcer (score 1-4). Mean change in score from baseline to week 12 will be compared between treatment groups. Robarts Histological Index (RHI): Histological scoring in four domains: chronic inflammatory infiltration (score 0-3), neutrophils in the lamina propria of the mucosa (score 0-3), neutrophils in the epithelium (score 0-3), erosion or ulcer (score 0-3). Mean change in score from baseline to week 12 will be compared between treatment groups. Mayo Score (MS): Total MS (score 1-12), divided into four domains: bowel movement frequency (score 0-3), rectal bleeding (score 0-3), endoscopy (score 0-3), and physician's overall assessment (score 0-3). Partial MS (score 0-9) does not include the endoscopy score. Endoscopic MS (score 0-3) is an endoscopic assessment of the mucosa. The mean change in each score from baseline to 12 weeks is compared between treatment groups. Proportion of subjects showing a clinical response: Defined as a total MS reduction of 3 to 30% from baseline, a rectal bleeding subscore reduction of 1 or more from baseline, or an absolute rectal bleeding subscore of 1 or less. This proportion is compared between treatment groups at 12 weeks. Proportion of subjects with clinical remission: Defined as MS ≤ 2 with individual subscores greater than 1. This proportion is compared between treatment groups at 12 weeks. Proportion of subjects with an endoscopic response: Defined as MS endoscopic subscore ≤ 1. This proportion is compared between treatment groups at 12 weeks. The proportion of subjects showing histological remission at week 12. Use of rescue medication: The proportion of subjects requiring each rescue medication during the treatment period is compared. Inflammatory Bowel Disease (IBDQ) score: A 10-question IBDQ. The mean change in score from baseline to week 12 is compared between treatment groups.

[0482] Biomarkers: Fasting serum concentrations of C4 and FGF-19. Exploratory analyses will be conducted to evaluate the relationship between treatment and the concentration of each biomarker. Furthermore, the relationship between each biomarker and efficacy endpoints will be explored.

[0483] Primary endpoint: Mean change in UC-100 at week 12

[0484] Secondary endpoints: Mean change in the three-component Mayo score (score range 0-9 based on bowel movement frequency, rectal bleeding, and endoscopic findings) at week 12; evaluation of the effect of compound 1 or a pharmaceutically acceptable salt and placebo on the endoscopic severity index of ulcerative colitis (UCEIS) at week 12; evaluation of the effect of compound 1 or a pharmaceutically acceptable salt and placebo on the Roberts histological index (RHI) at week 12; mean change in the total Mayo score at week 12; mean change in the endoscopic Mayo score at week 12; mean change in bowel movement frequency and rectal bleeding subscores of the Mayo score at week 12; The percentage of patients showing a clinical response as determined by the total Mayo score, the percentage of patients with clinical remission as determined by the total Mayo score at week 12, the mean change in histological indicators at week 12, the percentage of subjects showing histological remission at week 12, the percentage of subjects requiring each rescue medication during the treatment period, the mean change in Inflammatory Bowel Disease Questionnaire (IBDQ) score at week 12, the mean change in fasting serum concentrations of C4 and FGF-19 from baseline to week 12, the mean change in fecal calprotectin concentration from baseline to week 12, and the mean change in serum concentration of C-reactive protein from baseline to week 12.

[0485] (Example 16-A: Parenteral pharmaceutical composition) To prepare parenteral pharmaceutical compositions suitable for administration by injection (subcutaneous or intravenous), 1 to 100 mg of the compound specified herein or a pharmaceutically acceptable salt thereof is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. To adjust the pH, an appropriate buffer solution is optionally added, along with any acid or base. The mixture is then assembled into a dosage unit suitable for administration by injection.

[0486] (Example 16-B: Oral liquid formulation) To prepare a pharmaceutical composition for oral delivery, a sufficient amount of compound 1 or a pharmaceutically acceptable salt thereof is added to water (using any excipients, including but not limited to solubilizers, any buffers, and taste-masking excipients) to provide a solution of about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, or about 20 mg / mL.

[0487] (Example 16-C: Oral tablet) Tablets are prepared by mixing 1 to 40% by weight of the compound specified herein or a pharmaceutically acceptable salt thereof with 60 to 99% by weight of one or more suitable tableting excipients (e.g., microcrystalline cellulose, hydroxypropyl cellulose, magnesium stearate, etc.). Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100 to 500 mg.

[0488] (Example 16-D: Oral capsule) To prepare a pharmaceutical composition for oral delivery, 1 to 200 mg of the compound described herein or a pharmaceutically acceptable salt thereof is mixed with starch or other suitable powder blend. The mixture is then incorporated into an oral administration unit, such as a hard gelatin capsule, suitable for oral administration.

[0489] In another embodiment, 1 to 200 mg of the compound described herein or a pharmaceutically acceptable salt thereof is placed in a size 4 capsule or a size 1 capsule (hypromellose or hard gelatin), and the capsule is closed.

[0490] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes proposed to those skilled in the art should be included in the spirit and scope of this application and in the appended claims. The present invention may provide the following embodiments. [1] A method for treating or preventing a liver disease or condition, a lipid disorder or disorder, a metabolic inflammation-mediated disease or disorder, or a combination thereof, comprising administering a compound (compound 1) which is 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate or a pharmaceutically acceptable salt thereof to a subject in need. [2] The method according to [1] above, wherein the liver disease or condition is steatohepatitis, cholangitis, fatty liver disease, cholestasis, cirrhosis, fibrous liver disease, hepatitis, biliary atresia, Alagille syndrome, IFALD (intestinal insufficiency-associated liver disease), parenteral nutrition-associated liver disease (PNALD), hepatitis, hepatocellular carcinoma, cholangiocarcinoma, or a combination thereof. [3] The method according to [2] above, wherein the fatty liver disease is non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), or HIV-associated fatty liver disease. [4] The method according to [1] above, wherein the liver disease or condition is non-alcoholic steatohepatitis (NASH). [5] The method according to [4] above, wherein the liver disease or condition is NASH with hepatic fibrosis. [6] The method according to [4] above, wherein the liver disease or condition is NASH without hepatic fibrosis. [7] The method according to [2] above, wherein the cholangitis is primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC). [8] The method according to [2] above, wherein the fatty liver disease is non-alcoholic fatty liver disease (NAFLD) or alcohol-related fatty liver disease. [9] The method according to [2] above, wherein the cholestasis is intrahepatic cholestasis or extrahepatic cholestasis.

[10] The method according to [2] above, wherein the cholestasis is pregnancy-induced intrahepatic cholestasis or progressive familial intrahepatic cholestasis (PFIC).

[11] The method according to [2] above, wherein the cirrhosis is HIV-related cirrhosis.

[12] The method according to [1] above, wherein the metabolic inflammation-mediated disease or disorder is diabetes mellitus.

[13] The method according to

[12] above, wherein the diabetes is type 2 diabetes.

[14] The method according to [1] above, wherein the lipid disease or disorder is dyslipidemia.

[15] The method according to [2] above, wherein the fibrous liver disease is non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), hepatitis C virus (HCV), cirrhosis, Wilson's disease, HIV-associated steatohepatitis, HIV-associated cirrhosis, or a fibrous liver disease resulting from congenital liver fibrosis.

[16] The method according to [2] above, wherein the hepatitis is acute hepatitis, chronic hepatitis, fulminant hepatitis, viral hepatitis, bacterial hepatitis, parasitic hepatitis, toxic and drug-induced hepatitis, alcoholic hepatitis, autoimmune hepatitis, non-alcoholic steatohepatitis (NASH), neonatal hepatitis, or ischemic hepatitis.

[17] The method according to [2] above, wherein the hepatitis is autoimmune hepatitis.

[18] The method according to [2] above, wherein the liver disease or condition is Alagille syndrome.

[19] The method according to [2] above, wherein the liver disease or condition is bile duct atresia.

[20] The method according to [2] above, wherein the liver disease or condition is hepatocellular carcinoma.

[21] The method according to [2] above, wherein the liver disease or condition is cholangiocarcinoma.

[22] The method according to any one of the above [1] to

[21] , wherein treatment of the liver disease or condition, the lipid disease or disorder, the metabolic inflammation-mediated disease or disorder, or a combination thereof includes increasing serum FGF-19 concentration, decreasing serum 7α-hydroxy-4-cholesten-3-one (C4) concentration, decreasing serum bile acid concentration, or a combination thereof.

[23] A method for treating or preventing fatty liver disease in a subject, comprising administering a compound (compound 1) which is 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate or a pharmaceutically acceptable salt thereof to the subject having fatty liver disease.

[24] The method according to

[23] above, wherein the fatty liver disease is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or alcoholic steatohepatitis (ASH).

[25] The method described in

[23] or

[24] above, wherein the treatment of fatty liver disease includes a reduction in liver fat, improvement in liver tissue features, improvement in liver blood tests, improvement in cholestatic pruritus, or a combination thereof.

[26] The method according to any one of the above

[23] to

[25] , wherein the treatment of fatty liver disease includes increasing serum FGF-19 concentration, decreasing serum 7α-hydroxy-4-cholesten-3-one (C4) concentration, decreasing serum bile acid concentration, or a combination thereof.

[27] The method according to any one of the above

[23] to

[26] , wherein the subject is suffering from diabetes.

[28] The method according to

[27] above, wherein the diabetes is type 2 diabetes.

[29] A method for treating or preventing a gastrointestinal disorder or condition, comprising administering a compound (compound 1) which is 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate or a pharmaceutically acceptable salt thereof to a subject in need.

[30] The method according to

[29] above, wherein the gastrointestinal disease or condition is necrotizing enterocolitis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), gastroenteritis, radiation enteritis, pseudomembranous colitis, enteritis, celiac disease, postoperative inflammation of the intestine, graft-versus-host disease, bile acid reflux, or colorectal cancer.

[31] The method according to

[29] above, wherein the gastrointestinal disease or condition is inflammatory bowel disease (IBD).

[32] The method according to

[31] above, wherein the inflammatory bowel disease (IBD) is Crohn's disease or ulcerative colitis.

[33] The method according to

[30] above, wherein the irritable bowel syndrome (IBS) is diarrhea-predominant irritable bowel syndrome (IBS-D), constipation-predominant irritable bowel syndrome (IBS-C), mixed-type IBS (IBS-M), unclassifiable IBS (IBS-U), or biliary acid diarrhea (BAD).

[34] The method according to

[33] above, wherein the IBS-D is due to malabsorption of bile acids.

[35] The method according to

[29] above, wherein the gastrointestinal disease or condition is ulcerative colitis, microscopic colitis, or pseudomembranous colitis.

[36] The method according to

[30] above, wherein the enteritis is radiation enteritis or chemotherapy-induced enteritis.

[37] The method according to

[30] above, wherein the gastroenteritis is idiopathic gastroenteritis.

[38] The method according to

[29] above, wherein the gastrointestinal disorder or condition is bile acid reflux with gastroesophageal reflux disease (GERD).

[39] The method according to

[29] above, wherein the gastrointestinal disorder or condition is bile acid reflux without GERD.

[40] The method according to any one of the above

[29] to

[39] , wherein treatment of the gastrointestinal disease or condition includes increasing serum FGF-19 concentration, decreasing serum 7α-hydroxy-4-cholesten-3-one (C4) concentration, decreasing serum bile acid concentration, or a combination thereof.

[41] A method for treating or preventing a kidney disease or condition, comprising administering a compound (compound 1) which is 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate or a pharmaceutically acceptable salt thereof to a subject in need.

[42] The method according to

[41] above, wherein the kidney disease or condition is renal fibrosis, acute kidney injury, chronic kidney injury, ischemic nephropathy, diabetic nephropathy, tubulointerstitial nephritis / nephropathy, glomerulonephritis / nephropathy, or a combination thereof.

[43] A method for treating or preventing cancer, comprising administering a compound (compound 1) which is 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate or a pharmaceutically acceptable salt thereof to a subject in need.

[44] The method according to

[43] above, wherein the cancer is prostate cancer, colorectal cancer, cholangiocarcinoma, or hepatocellular carcinoma.

[45] The method according to any one of the above [1] to

[44] , wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to a mammal in a dose of about 1 mg to about 300 mg of compound 1.

[46] The method according to any one of the above [1] to

[44] , wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to a mammal in a dose of about 1 mg to about 30 mg of compound 1.

[47] The method according to any one of the above [1] to

[44] , wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to a mammal in a dose of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 12 mg, about 15 mg, about 20 mg, or about 25 mg.

[48] The method according to any one of the above [1] to

[44] , wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to a mammal in a dose of about 3 mg or about 6 mg.

[49] The method according to any one of the above [1] to

[48] , wherein compound 1 or a pharmaceutically acceptable salt thereof is administered systemically to the subject.

[50] The method according to any one of the above [1] to

[48] , wherein compound 1 or a pharmaceutically acceptable salt thereof is administered orally to the subject.

[51] The method according to

[50] above, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to a mammal in the form of an oral solution, oral suspension, powder, pill, tablet, or capsule.

[52] The method according to any one of the above

[29] to

[40] , wherein compound 1 or a pharmaceutically acceptable salt thereof is administered non-systemically to the subject.

[53] The method according to any one of the above [1] to

[52] , wherein compound 1 or a pharmaceutically acceptable salt thereof is administered daily to the mammal.

[54] The method according to any one of the above [1] to

[53] , wherein compound 1 or a pharmaceutically acceptable salt thereof is administered to the mammal once daily.

[55] The method according to any one of the above [1] to

[54] , wherein compound 1 or a pharmaceutically acceptable salt thereof is orally administered to the mammal according to a dose adjustment schedule.

[56] The method according to

[55] , wherein the dose adjustment schedule comprises administering an initial dose of compound 1 or a pharmaceutically acceptable salt thereof daily over an initial period, followed by administering a higher dose of compound 1 or a pharmaceutically acceptable salt thereof daily.

[57] The method according to

[56] above, wherein the initial period includes one day, about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, about nine weeks, about ten weeks, about eleven weeks, or about twelve weeks.

[58] The method according to

[55] , wherein the dose adjustment schedule comprises dose escalation or dose reduction of compound 1 or a pharmaceutically acceptable salt thereof, followed by any subsequent dose escalation.

[59] The method according to

[55] , wherein the dose adjustmen...

Claims

1. The use of a compound (Compound 1) or a pharmaceutically acceptable salt thereof, which is 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate, in the manufacture of a drug for treating or preventing a target gastrointestinal disease or condition, liver disease or condition, lipid disease or disorder, metabolic inflammation-mediated disease or disorder, or a combination thereof, (i) The treatment or prophylaxis comprises administering compound 1 or a pharmaceutically acceptable salt thereof to the subject at a dose of 1 mg to 300 mg of compound 1 once or twice daily, or (ii) Use wherein the treatment or prophylaxis comprises administering compound 1 or a pharmaceutically acceptable salt thereof to the subject at a dose of 1 mg to 30 mg of compound 1 once or twice daily.

2. The use according to claim 1 in the manufacture of a drug for treating or preventing the aforementioned gastrointestinal disease or condition.

3. The aforementioned gastrointestinal disease or condition is necrotizing enterocolitis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), gastroenteritis, radiation enteritis, pseudomembranous colitis, enteritis, celiac disease, postoperative inflammation of the intestines, graft-versus-host disease, bile acid reflux, or colorectal cancer. The use according to claim 2, wherein, optionally, the enteritis is radiation enteritis or chemotherapy-induced enteritis, or the gastroenteritis is idiopathic gastroenteritis.

4. (i) The gastrointestinal disease or condition is inflammatory bowel disease (IBD), and the inflammatory bowel disease (IBD) is Crohn's disease or ulcerative colitis, or (ii) The use according to claim 2, wherein the gastrointestinal disease or condition is ulcerative colitis, microscopic colitis, or pseudomembranous colitis.

5. The use according to claim 3, wherein the irritable bowel syndrome (IBS) is diarrhea-predominant irritable bowel syndrome (IBS-D), constipation-predominant irritable bowel syndrome (IBS-C), mixed-type IBS (IBS-M), unclassifiable IBS (IBS-U), or bile acid diarrhea (BAD), and optionally, IBS-D is due to bile acid malabsorption.

6. The use according to claim 2, wherein the gastrointestinal disease or condition is bile acid reflux accompanied by gastroesophageal reflux disease (GERD).

7. The aforementioned liver disease or condition is steatohepatitis, cholangitis, fatty liver disease, cholestasis, cirrhosis, fibrous liver disease, hepatitis, biliary atresia, Alagille syndrome, IFALD (intestinal failure-associated liver disease), parenteral nutrition-associated liver disease (PNALD), hepatitis, hepatocellular carcinoma, cholangiocarcinoma, or a combination thereof, and is at the discretion of the person concerned. (i) Whether the steatohepatitis is non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), or HIV-associated steatohepatitis, (ii) Whether the cholangitis is primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC), (iii) Whether the fatty liver disease is non-alcoholic fatty liver disease (NAFLD) or alcohol-related fatty liver disease, (iv) Whether the cholestasis is intrahepatic or extrahepatic, (v) The metabolic inflammation-mediated disease or disorder is diabetes mellitus, (vi) The lipid disease or disorder is dyslipidemia, (vii) Whether the fibrous liver disease is caused by non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), hepatitis C virus (HCV), cirrhosis, Wilson's disease, HIV-associated steatohepatitis, HIV-associated cirrhosis, or congenital liver fibrosis, (viiii) Whether the hepatitis is acute hepatitis, chronic hepatitis, fulminant hepatitis, viral hepatitis, bacterial hepatitis, parasitic hepatitis, toxic and drug-induced hepatitis, alcoholic hepatitis, autoimmune hepatitis, non-alcoholic steatohepatitis (NASH), neonatal hepatitis, or ischemic hepatitis, (ix) Whether the liver disease or condition is Alagille syndrome, (x) Whether the liver disease or condition is bile duct atresia, (xi) Whether the liver disease or condition is hepatocellular carcinoma or (xi) The use according to claim 1, wherein the liver disease or condition is cholangiocarcinoma.

8. The use according to claim 1, wherein the treatment or prevention comprises administering compound 1 or a pharmaceutically acceptable salt thereof to the subject in doses of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 15 mg, 20 mg, or 25 mg of compound 1 once or twice daily.

9. The use according to claim 1, wherein the treatment or prevention comprises systemic administration of compound 1 or a pharmaceutically acceptable salt thereof to the subject.

10. The use according to claim 1, wherein the treatment or prevention comprises orally administering compound 1 or a pharmaceutically acceptable salt thereof to the subject, optionally in the form of an oral liquid, oral suspension, powder, pill, tablet, or capsule.

11. The use according to claim 1, wherein the treatment or prevention comprises administering compound 1 or a pharmaceutically acceptable salt thereof to the subject on a daily basis.

12. The use according to claim 1, wherein the treatment or prevention further comprises administering at least one additional therapeutic agent to the subject in addition to compound 1 or a pharmaceutically acceptable salt thereof.

13. The use according to claim 12, wherein the at least one additional therapeutic agent is a 5-aminosalicylic acid agent, a corticosteroid, an immunomodulator, a TNFα inhibitor, an integrin inhibitor, an endothelial adhesion molecule (MAdCAM) inhibitor, a JAK kinase inhibitor, an IL-12 / 23 inhibitor, or an S1P1 selective agonist.

14. (i) The at least one additional therapeutic agent is an angiotensin 2 receptor agonist, a ketohexokinase (KHK) inhibitor, a mitochondrial uncoupler or protonophore, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a sodium-glucose cotransporter 1 / 2 (SGLT1 / 2) coinhibitor, a dihydroceramide desaturase 1 (DES-1) inhibitor, an integrin aVb1 inhibitor, an integrin aVb6 inhibitor, a NOD-like receptor protein 3 (NLRP3) inhibitor, a cyclophyllin inhibitor, a glucagon-like peptide-1 (GLP-1) agonist, a 17-β hydroxysteroid dehydrogenase 13 (17b-HSD13) inhibitor, a thyroid hormone receptor β (THR-β) agonist, or a combination thereof. (ii) The use according to claim 12, wherein the at least one additional therapeutic agent is a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a sodium-glucose cotransporter 1 / 2 (SGLT1 / 2) coinhibitor, a glucagon-like peptide-1 (GLP-1) agonist, or a combination thereof.

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