WO2023220404A1

WO2023220404A1 - Treatment of non-alcoholic steatohepatitis

Info

Publication number: WO2023220404A1
Application number: PCT/US2023/022093
Authority: WO
Inventors: Cara Nelson; Christopher T. Jones; Erin K. QUIRK
Original assignee: Terns Pharmaceuticals, Inc.
Priority date: 2022-05-13
Filing date: 2023-05-12
Publication date: 2023-11-16

Abstract

Provided herein are methods and compositions for treating non-alcoholic steatohepatitis (NASH) in a patient in need thereof, wherein the NASH of the patient is characterized by advanced stage hepatic fibrosis. The methods comprise administering to the patient compound (1) or a pharmaceutically acceptable salt thereof.

Description

TREATMENT OF NON-ALCOHOLIC STEATOHEPATITIS

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to, and the benefit of, U.S. Provisional Patent Application No. 63/341,983 filed May 13, 2022, the disclosure of which is hereby incorporated by reference in its entirety for all purposes.

FIELD OF THE INVENTION

[0002] This disclosure relates to methods and compositions for treating liver disorder in a patient.

BACKGROUND

[0003] Fatty liver disease (FLD) encompasses a spectrum of disease states characterized by excessive accumulation of fat in the liver often accompanied with inflammation. FLD can lead to non-alcoholic fatty liver disease (NAFLD), which may be characterized by insulin resistance. If untreated, NAFLD can progress to a persistent inflammatory response or nonalcoholic steatohepatitis (NASH), progressive liver fibrosis, and eventually to cirrhosis. In Europe and the US, NAFLD is the second most common reason for liver transplantation. Accordingly, the need for treatment is urgent, but due to the lack of obvious symptoms to the patient, patients may lack the motivation to maintain treatment regimens, particularly burdensome treatment regimens, such as injected medicines, medications that are administered many times a day, or any that produce dangerous or irritating side effects. There is currently no approved treatment of NASH.

[0004] The majority of drugs that have advanced to clinical trials for the treatment of NASH have shown disappointing results. One of the problems encountered in the trials is that the patients taking the drugs failed to show an improvement in hepatic fibrosis. Patients with advanced NASH often suffer from severe hepatic fibrosis, which often results in cirrhosis and potentially life-threatening complications. The prevalence of advanced NASH has been rapidly increasing worldwide in the past three decades. Therefore, there exists an urgent need to develop effective treatments of NASH, particularly NASH that is characterized by an extensive degree of hepatic fibrosis. BRIEF SUMMARY

[0005] Provided herein are methods and compositions for treating non-alcoholic steatohepatitis (NASH) in a patient in need thereof, wherein the NASH of the patient is characterized by advanced stage hepatic fibrosis. The methods comprise administering to the patient a Famesoid X Receptor (FXR) agonist of the structure depicted below (compound (1)) or a pharmaceutically acceptable salt thereof.

[0006] Compound (1) is disclosed in US 2010/0152166, the content of which is incorporated by reference in its entirety, and specifically with respect to the compound (1) or a pharmaceutically acceptable salt thereof, as well as methods of making and using the foregoing.

[0007] In one aspect, the disclosure provides a method of treating non-alcoholic steatohepatitis (NASH) in a patient in need thereof, comprising administering a once daily oral dose of an oral pharmaceutical composition comprising compound (1) or a pharmaceutically acceptable salt thereof, wherein the once daily dose provides a steady state AUC(o-r) of from about 1,000 hr*ng/mL to about 3,500 hr*ng/mL, and wherein the NASH of the patient is characterized by advanced stage hepatic fibrosis. In some embodiments, the once daily oral dose of compound (1) or a pharmaceutically acceptable salt thereof provides a steady state AUC(O-T) of from about 1,000 hr*ng/mL to about 3,000 hr*ng/mL. In other embodiments, the once daily oral dose of compound (1) or a pharmaceutically acceptable salt thereof provides a steady state AUC(o-r) of from about 1,000 hr*ng/mL to about 2,500 hr*ng/mL. In some embodiments, the once daily oral dose of compound (1) or a pharmaceutically acceptable salt thereof provides a steady state AUC(o-r) of from about 1,300 hr*ng/mL to about 3,000 hr*ng/mL. In some embodiments, the once daily oral dose of compound (1) or a pharmaceutically acceptable salt thereof provides a steady state AU o-i) of from about 1,000 hr*ng/mL to about 2,000 hr*ng/mL. In some embodiments, the once daily oral dose of compound (1) or a pharmaceutically acceptable salt thereof provides a steady state AUC(o-r) of from about 1,300 hr*ng/mL to about 2,100 hr*ng/mL. In some embodiments, the once daily oral dose of compound (1) or a pharmaceutically acceptable salt thereof provides a steady state AUC(O-T) of from about 1,700 hr*ng/mL to about 3,000 hr*ng/mL. In some embodiments, the once daily oral dose of compound (1) or a pharmaceutically acceptable salt thereof is about 10 mg. In other embodiments, the once daily oral dose of compound (1) or a pharmaceutically acceptable salt thereof is about 15 mg. In some embodiments, compound (1) is administered as a free acid (e.g., non-salt form). In some embodiments, hepatic fibrosis is reduced without increasing the low-density lipoprotein cholesterol (LDL-C) levels in the blood of the patient. In some embodiments, hepatic fibrosis is reduced without decreasing the high-density lipoprotein cholesterol (HDL-C) levels in the blood of the patient. In some embodiments, the Cmax of compound 1 in the plasma does not exceed 325 ng/mL. In some embodiments, the Cmax of compound 1 in the plasma is from about 175 ng/mL to about 325 ng/mL.

[0008] It has been found that at levels where compound (1) or a pharmaceutically acceptable salt thereof reduces NASH and advanced fibrosis, side effects are minimal. Owing to its favorable therapeutic index, compound (1) or a pharmaceutically acceptable salt thereof can be administered to NASH patients for long durations of time. For instance, in some embodiments, compound (1) or a pharmaceutically acceptable salt thereof can be administered to a NASH patient (e.g., a NASH patient with advanced fibrosis) for at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years or at least 10 years. In some embodiments, compound (1) or a pharmaceutically acceptable salt thereof is administered to the patient throughout the lifetime of the patient.

[0009] In certain embodiments, the pharmaceutical composition comprises a substantially amorphous form of compound (1). For instance, more than 85% by weight of compound (1) can be present as an amorphous form in the pharmaceutical composition. In some embodiments, more than 90% (e.g., more than 92%, more than 95%, more than 98% or more than 99%) by weight is present as the amorphous form in the pharmaceutical composition. In some embodiments, the amorphous form of compound (1) is dispersed in polymer, for instance, a hydrophilic polymer. In some embodiments, the polymer is a homopolymer or a copolymer of a vinyl lactam. In other embodiments, the polymer is vinylpyrrolidone-vinyl acetate copolymer or vinylcaprolactam-vinyl acetate-ethylene glycol copolymer. In other embodiments, the polymer is vinylpyrrolidone-vinyl acetate copolymer. In other embodiments, the polymer is vinylcaprolactam-vinyl acetate-ethylene glycol copolymer. In other embodiments, the polymer is a homopolymer or a copolymer of vinylpyrrolidone or vinylcaprolactam. In some embodiments, the weight ratio of the compound of formula (I) to the polymer is from about 1 : 1 to about 1: 10. In some embodiments, the weight ratio of the compound of formula (I) to the polymer is from about l: l to about 1: 15. (e.g., about 1: 1, about 1:2, about 1:3, about 1:4 or about 1:5).

[0010] In another aspect, the disclosure provides methods of treating NASH in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a THR[3 agonist, wherein the NASH of the patient is characterized by advanced stage hepatic fibrosis. In some embodiments, compound (1) or a pharmaceutically acceptable salt thereof is administered as a once daily dose that provides a steady state AUC(o-r) of from about 1,000 hr.ng/mL to about 2,000 hr.ng/mL. In some embodiments, compound (1) or a pharmaceutically acceptable salt thereof is administered as a once daily dose that provides a steady state AUC(o-r) of from about 1,300 hr.ng/mL to about 3,000 hr.ng/mL. In some such embodiments, the once daily dose of compound (1) is about 10 mg or about 15 mg. In some such embodiments, hepatic fibrosis is reduced without increasing the low-density lipoprotein cholesterol (LDL-C) levels in the blood of the patient. In some embodiments, administration of compound (1) or a pharmaceutically acceptable salt thereof and the THR[3 agonist results in reduction of liver fibrosis and hepatic inflammation. In some embodiments, the THR[3 agonist has the structure depicted below (compound (2)), or is a pharmaceutically acceptable salt thereof.

[0011] Compound (2) is disclosed in US 2020/0190064, the content of which is incorporated by reference in its entirety, and specifically with respect to the compound (2) or a pharmaceutically acceptable salt thereof, as well as methods of making and using the foregoing. In some embodiments, the THR[3 agonist administered to the patient in need thereof is resmetirom (MGL-3196). In some embodiments, the THR[3 agonist is administered to the patient in need thereof VK2809 (by Viking Therapeutics). In some embodiments, the THRP agonist administered to the patient in need thereof is sobetirome. In some embodiments, the THR[3 agonist administered to the patient in need thereof is eprotirome. In some embodiments, the THRp agonist administered to the patient in need thereof is ALG- 055009 (by Aligo). In some embodiments, the THRp agonist administered to the patient in need thereof is CNPT- 101101. In some embodiments, the THRp agonist administered to the patient in need thereof is CNPT-101207. In some embodiments, the THRp agonist administered to the patient in need thereof is ASC41 (by Ascletis).

[0012] In some embodiments, the patient has a liver disorder and diabetes mellitus. In some embodiments, the patient has a liver disorder and a cardiovascular disorder. In some embodiments, the treatment period is the remaining lifespan of the patient. In some embodiments, the method does not comprise administering an antihistamine, an immunosuppressant, a steroid, rifampicin, an opioid antagonist, or a selective serotonin reuptake inhibitor (SSRI).

[0013] In some embodiments, the NASH patients undergoing treatment have bridging fibrosis (i.e., stage 3 (F3) fibrosis score based on the METAVIR scoring system). Stage 3 (F3) fibrosis is evidenced by fibrotic bridging that extends across lobules, between portal areas, and between portal areas and central veins. In other embodiments, the patients undergoing treatment have a stage 4 (F4) fibrosis score, based on the METAVIR scoring system, which is indicative or compensated cirrhosis or cirrhosis. Stage 4 fibrosis is associated with distortion of the liver architecture and formation of nodules. In certain embodiments, the fibrosis score of the patient is reduced following administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time. For instance, in certain embodiments, the fibrosis score of a patient with Stage 3 fibrosis can be reduced to Stage 2 fibrosis following administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time (e.g., 1-3 years). In other embodiments, the fibrosis score of a patient with Stage 4 fibrosis can be reduced to Stage 3 or Stage 2 fibrosis following administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time. In some embodiments, the time needed to reduce the fibrosis score can be accelerated when compound (1) is administered in combination with a THR[3 agonist, such as compound (2) or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the NASH patients undergoing treatment have an iron- corrected T1 mapping (cTl) value of greater than 900 msec prior to treatment. In particular embodiments, the cTl mapping score of the patients prior to treatment is between about 925 msec to about 1,100 msec. In certain embodiments, the cTl of the patient decreases by greater than 50 msec following once oral daily administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time (e.g., after 6 weeks, after 12 weeks, after 24 weeks or after 52 weeks), wherein the cTl is measured at the steady state concentration of compound (1). In other embodiments, the cTl of the patient decreases from about 50 msec to about 100 msec following once daily oral administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time. In other embodiments, the cTl of the patient decreases from about 60 msec to about 100 msec following once daily oral administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time. In other embodiments, the cTl of the patient decreases from about 60 msec to about 90 msec following once daily oral administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time. In other embodiments, the cTl of the patient decreases from about 70 msec to about 95 msec following once daily oral administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time. In other embodiments, the cTl of the patient decreases from about 70 msec to about 85 msec following once daily oral administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time.

[0015] The NAFLD Activity Score (NAS) represents the sum of scores for steatosis, lobular inflammation and ballooning. An NAS score of 5-8 is considered diagnostic for NASH. An NAS score of 6 or greater is often associated with significant levels of fibrosis and inflammation in the liver. In accordance with the disclosure, once daily oral administration of compound (1) or a pharmaceutically acceptable salt thereof to a NASH patient with an NAS score of between 6-8 can lead to reduction in the NAS score of at least 1 point (e.g.., a reduction of NAS score of 1 point, 2 points or 3 points) following administration for a sufficient period of time (e.g., from about 12 weeks to about 72 weeks.) For example, once daily oral administration of compound (1) or a pharmaceutically acceptable salt thereof to a NASH patient with a NAS score of 7 can reduce the NAS score to a score of 6, 5 or 4. In some embodiments, the reduction of NAS score is accompanied by a decrease in cTl from about 60 msec to about 100 msec. In some embodiments, the NAS score is lowered even further when compound (1) is administered in combination with a THR[3 agonist, such as compound (2) or a pharmaceutically acceptable salt thereof. In some embodiments, a time to reduce the NAS score is reduced when compound (1) is administered in combination with a THR[3 agonist, such as compound (2). In any of the foregoing embodiments, the reduction of NAS score and/or cTl value is achieved after 12 weeks of administration of compound (1) or a pharmaceutically acceptable salt thereof. In other of the foregoing embodiments, the reduction of NAS score and/or cTl value is achieved after 52 weeks of administration of compound (1) or a pharmaceutically acceptable salt thereof. In other of the foregoing embodiments, the reduction of NAS score and/or cTl value is achieved after 72 weeks of administration of compound (1) or a pharmaceutically acceptable salt thereof. In other of the foregoing embodiments, the reduction of NAS score and/or cTl value is achieved after 104 weeks of administration of compound (1) or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE FIGURES

[0016] FIG. 1 shows reduction of 7-alpha-hydroxy-4-cholestene-3-one (7aC4) levels at various times following once daily oral administration of oral 5 mg, 10 mg or 15 mg compound (1) to NASH patients. The 7aC4 levels are measured at the trough level (24 hours post dose) each day for 12 weeks.

[0017] FIG. 2 shows % change in 7aC4 levels as a function of exposure of compound (1) in the serum of NASH patients following 12 weeks of once daily administration of compound (1).

[0018] FIG. 3A shows reduction of 7-alpha-hydroxy-4-cholestene-3-one (7aC4) levels at various times (0 to 24 hours) following administration of oral 5 mg, 10 mg or 15 mg compound (1) to a subset of NASH patients. Maximum reduction in 7aC4 is achieved after approximately 6 hours post dosing. FIG. 3B shows a bar graph displaying reductions of 7aC4 at various doses of compound (1) six hours post dosing.

[0019] FIG. 4 shows the mean steady-state trough plasma concentration of compound (1) following once daily oral administration of oral 5 mg, 10 mg or 15 mg compound (1) to NASH patients. The mean trough plasma concentrations remained well below the ECso of compound (1) for all dose levels.

[0020] FIG. 5 A shows the change in cTl levels as a function of plasma exposure of compound (1) following once daily oral administration of compound (1) (5 mg, 10 mg or 15 mg) to NASH patients. FIG. 5B shows a bar graph showing cTl as a function of compound (1) exposure as measured by AUC(O-T). [0021] FIG. 6 shows changes in LDL cholesterol levels as a function of plasma exposure of compound (1) following once daily oral administration of oral 5 mg, 10 mg or 15 mg compound (1) to NASH patients.

[0022] FIG. 7 shows changes in HDL cholesterol levels as a function of plasma exposure of compound (1) following once daily oral administration of oral 5 mg, 10 mg or 15 mg compound (1) to NASH patients.

[0023] FIG. 8 shows disposition, demographics and baseline characteristics of NASH patients being evaluated in studies described in Examples 1-3.

[0024] FIG. 9 shows disposition, demographics and baseline characteristics of NASH patients being evaluated in substudy designed to evaluate pharmacokinetics following administration of compound (1).

DETAILED DESCRIPTION

Definitions

[0025] As used herein, the following definitions shall apply unless otherwise indicated. Further, if any term or symbol used herein is not defined as set forth below, it shall have its ordinary meaning in the art.

[0026] “Comprising” is intended to mean that the compositions and methods include the recited elements, but not exclude others. “Consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination. For example, a composition consisting essentially of the elements as defined herein would not exclude other elements that do not materially affect the basic and novel characteristic(s) of the claimed invention. “Consisting of’ shall mean excluding more than trace amount of, e.g., other ingredients and substantial method steps recited.

Embodiments defined by each of these transition terms are within the scope of this invention.

[0027] ‘Combination therapy” or “combination treatment” refers to the use of two or more drugs or agents in treatment, e.g., the use of a compound of formula (I) or (II) as utilized herein together with another agent useful to treat liver disorders, such as NAFLD, NASH, and symptoms and manifestations of each thereof is a combination therapy. Administration in “combination” refers to the administration of two agents (e.g., a compound of formula (I) or (II) as utilized herein, and another agent) in any manner in which the pharmacological effects of both manifest in the patient at the same time. Thus, administration in combination does not require that a single pharmaceutical composition, the same dosage form, or even the same route of administration be used for administration of both agents or that the two agents be administered at precisely the same time. Both agent can also be formulated in a single pharmaceutically acceptable composition. A non-limiting example of such a single composition is an oral composition or an oral dosage form. For example, and without limitation, it is contemplated that a compound of formula (I) or (II) can be administered in combination therapy with another agent in accordance with the present invention.

[0028] The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose de (de = “directly compressible”), honey de, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch de, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose de, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose de, sorbitol, sucrose de, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0029] ‘Patient” refers to mammals and includes humans and non-human mammals. Examples of patients include, but are not limited to mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, patient refers to a human. [0030] “Pharmaceutically acceptable” refers to safe and non-toxic, preferably for in vivo, more preferably, for human administration.

[0031] “Pharmaceutically acceptable salt” refers to a salt that is pharmaceutically acceptable. A compound described herein may be administered as a pharmaceutically acceptable salt.

[0032] ‘Salt” refers to an ionic compound formed between an acid and a base. When the compound provided herein contains an acidic functionality, such salts include, without limitation, alkali metal, alkaline earth metal, and ammonium salts. As used herein, ammonium salts include, salts containing protonated nitrogen bases and alkylated nitrogen bases.

Exemplary and non-limiting cations useful in pharmaceutically acceptable salts include Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids. When the compounds utilized herein contain basic functionality, such salts include, without limitation, salts of organic acids, such as carboxylic acids and sulfonic acids, and mineral acids, such as hydrogen halides, sulfuric acid, phosphoric acid, and the likes.

Exemplary and non-limiting anions useful in pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, mono-, di-, and tribasic phosphate, mesylate, tosylate, and the likes.

[0033] “Therapeutically effective amount” or dose of a compound or a composition refers to that amount of the compound or the composition that results in reduction or inhibition of symptoms or a prolongation of survival in a patient. The results may require multiple doses of the compound or the composition.

[0034] ‘Treatment” or “treating” refers to an approach for obtaining beneficial or desired results including clinical results. For purposes of this invention, beneficial or desired results include, but are not limited to, one or more of the following: decreasing one or more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g. , preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delaying or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and/or prolonging survival of a patient. Also encompassed by “treatment” is a reduction of pathological consequence of the disease or disorder. The methods of the invention contemplate any one or more of these aspects of treatment.

[0035] As used herein, "delaying" development of a disease means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease and/or slowing the progression or altering the underlying disease process and/or course once it has developed. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop clinical symptoms associated with the disease. A method that "delays" development of a disease is a method that reduces probability of disease development in a given time frame and/or reduces extent of the disease in a given time frame, when compared to not using the method, including stabilizing one or more symptoms resulting from the disease.

[0036] An individual who is “at risk” of developing a disease may or may not have detectable disease, and may or may not have displayed detectable disease prior to the treatment methods described herein. “At risk” denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease. An individual having one or more of these risk factors has a higher probability of developing the disease than an individual without these risk factor(s). These risk factors include, but are not limited to, age, sex, race, diet, history of previous disease, presence of precursor disease and genetic (i.e., hereditary) considerations. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

Methods of Treatment

[0037] Compounds and compositions described herein may in some aspects be used in treating patients with advanced NASH, characterized by extensive liver fibrosis. In particular embodiments, administration of compound (1) or a pharmaceutically acceptable salt thereof impedes or slows the progression of NASH. NASH can progress, e.g., to cirrhosis, end-stage liver disease and the need for liver transplantation. Accordingly, a major goal of therapeutic intervention is to reduce the severity of NASH and to delay the progression of NASH to one of these potentially life-threatening diseases of the liver. [0038] It has been surprisingly found that compound (1) can be safely administered to NASH patients with high levels of hepatic fibrosis and significantly reduce steatosis, inflammation and hepatic fibrosis. The reduction of hepatic fibrosis is particularly important given many of the recent failures in clinical trials with drugs targeting NASH. Moreover, hepatic fibrosis is the major determinant of whether NASH will progress to cirrhosis and other liver-related morbidities. Therefore, the observation that compound (1) can effectively reduce hepatic fibrosis in patient with advanced liver disease can provide significant benefits to a growing number of patients suffering from NASH.

[0039] In some embodiments, provided herein a method of reducing liver damage in a patient with advanced NASH characterized by extensive hepatic fibrosis, comprising administering compound (1) or a pharmaceutically acceptable salt thereof, to an individual in need thereof, wherein fibrosis is reduced. In some embodiments, the level of expression of one or more markers for fibrosis is reduced. In some embodiments, the level of Ccr2, Collal, Colla2, Colla3, Cxcr3, Den, Hgf, Illa, Inhbe, Lox, Loxll, Loxl2, Loxl3, Mmp2, Pdgfb, Plau, Serpinel, Perpinhl, Snai, Tgfbl, Tgfb3, Thbsl, Thbs2, Timp2, and/or Timp3 expression is reduced. In some embodiments the level of collagen is reduced. In some embodiments, the level of collagen fragments is reduced. In some embodiments, the level of expression of the fibrosis marker is reduced at least 2, at least 3, at least 4, or at least 5-fold. In some embodiments, the level of expression of the fibrosis marker is reduced about 2-fold, about 3- fold, about 4-fold, or about 5 -fold.

[0040] In some embodiments, once daily oral administration of compound (1) or a pharmaceutically acceptable salt to a patient with NASH characterized by advanced fibrosis results in a decrease in 7-alpha-hydroxy-4-cholestene-3-one (7aC4), an intermediate in bile synthesis. In some such embodiments, the administration of compound (1) or a pharmaceutically acceptable salt thereof results in a decrease in 7aC4 of at least 10% when measured 6 weeks or 12 weeks after onset of administration, where the the 7aC4 levels are measured at the trough levels (i.e., 24 hours after dosing). In other embodiments, the administration of compound (1) or a pharmaceutically acceptable salt thereof results in a decrease in 7aC4 of at least 20% when measured 6 weeks or 12 weeks after onset of administration. In other embodiments, the administration of compound (1) or a pharmaceutically acceptable salt thereof results in a decrease in 7aC4 of at least 30% when measured 6 weeks or 12 weeks after onset of administration. In other embodiments, the administration of compound (1) or a pharmaceutically acceptable salt thereof results in a decrease in 7aC4 of at least 40% when measured 6 weeks or 12 after onset of administration. In other embodiments, the administration of compound (1) or a pharmaceutically acceptable salt thereof results in a decrease in 7aC4 of at least 50% when measured 6 weeks or 12 weeks after onset of administration. In other embodiments, the administration of compound (1) or a pharmaceutically acceptable salt thereof results in a decrease in 7aC4 of from about 15% to about 60% when measured 6 weeks or 12 weeks after onset of administration. In other embodiments, the administration of compound (1) or a pharmaceutically acceptable salt thereof results in a decrease in 7aC4 of from about 20% to about 60% when measured ta the trough levels 6 weeks or 12 weeks after onset of administration. In other embodiments, the administration of compound (1) or a pharmaceutically acceptable salt thereof results in a decrease in 7aC4 of from about 30% to about 50% when measured ta the trough levels 6 weeks or 12 weeks after onset of administration.

[0041] In some embodiments, administering compound 1 or a pharmaceutically acceptable salt thereof to a NASH patient results in reduction of iron-corrected T1 mapping (cTl). cTl is an MRI -based diagnostic imaging biomarker of the liver. cTl is used as a proxy for inflammation in the liver and is used as a non-invasive method to limit the use of liver biopsies. cTl mapping is an indicator of regional tissue water content. cTl has been shown to be correlated with the pathological features of NASH including ballooning, fibrosis and NAFLD Activity Score (NAS) and has been shown to predict clinical outcomes. See Dennis, A., et al, Frontiers in Endocrinology, 2021, Jan 27; 11:575843. Importantly, there exists a high degree of correlation between liver cTl and hepatic fibrosis score. For instance, NASH patients with a fibrosis score of F3 generally have a cTl score of over 925 msec. NASH patients who have progressed to cirrhosis (stage F4) can have a cTl score of approximately 1,000 msec or above. As described in Example 3, NASH patients with high levels of fibrosis as measured by cTl mapping have reduced levels of hepatic fibrosis following once daily administration of compound (1).

[0042] In some embodiments, the NASH patients undergoing treatment have an iron- corrected T1 mapping (cTl) value of greater than 900 msec prior to treatment. In particular embodiments, the cTl mapping score of the patients prior to treatment is between about 925 msec to about 1,100 msec. In certain embodiments, the cTl of the patient decreases by greater than 50 msec following once daily oral administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time (e.g., after 6 weeks, after 12 weeks, after 24 weeks, after 52 weeks, after 72 weeks or after 104 weeks), wherein the cTl is measured at the steady state concentration of compound (1). In other embodiments, the cTl of the patient decreases by greater than 60 msec following administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time, wherein the cTl is measured at the steady state concentration of compound (1). In other embodiments, the cTl of the patient decreases by greater than 70 msec following administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time, wherein the cTl is measured at the steady state concentration of compound (1). In other embodiments, the cTl of the patient decreases by greater than 80 msec following administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time, wherein the cTl is measured at the steady state concentration of compound (1). In other embodiments, the cTl of the patient decreases by greater than 90 msec following administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time, wherein the cTl is measured at the steady state concentration of compound (1). In other embodiments, the cTl of the patient decreases from about 50 msec to about 100 msec following administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time. In other embodiments, the cTl of the patient decreases from about 60 msec to about 100 msec following administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time. In other embodiments, the cTl of the patient decreases from about 60 msec to about 90 msec following administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time. In other embodiments, the cTl of the patient decreases from about 70 msec to about 95 msec following administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time. In other embodiments, the cTl of the patient decreases from about 70 msec to about 85 msec following administration of compound (1) or a pharmaceutically acceptable salt thereof for a sufficient period of time.

[0043] Administration of a compound (1) or a pharmaceutically acceptable salt thereof to a NASH patient with an NAS score of between 6-8 can lead to reduction in the NAS score of at least 1 point (e.g., a reduction of NAS score of 1 point, 2 points or 3 points) following administration for a sufficient period of time (e.g., three months to one year). For example, administration of a compound (1) or a pharmaceutically acceptable salt thereof to a NASH patient with an NAS score of 7 can reduce the NAS score to a score of 6, 5 or 4. In some embodiments, the reduction of NAS score is accompanied by a decrease in cTl from about 60 msec to about 100 msec. In some embodiments, the NAS score is lowered even further when compound (1) is administered in combination with a THR[3 agonist, such as compound (2) or a pharmaceutically acceptable salt thereof. In some embodiments, the time to reduce the NAS score is reduced when compound (1) is administered in combination with a THR[3 agonist, such as compound (2) or a pharmaceutically acceptable salt thereof.

[0044] As shown in the Example 3, there is a correlation between the exposures of compound (1) in the plasma as measured by area under the curve (AUC), and the reduction of cTl. In Example 3, AUC is measured from 0 to time tau (the dosing interval) at steady state. For once daily administration, time tau is 24 hours. Steady state AUC(o-r) of compound (1) of greater than about 1,000 hr*ng/mL result in significant changes in cTl . As shown in FIG. 5B and FIG. 5B, reduction of cTl increases as the steady state AUC(o-i) of compound (1) rises above 2,000 hr.ng/mL. cTl reductions of 80 msec or greater are associated with a two-point change in NAS. See Dennis, A., et al, Frontiers in Endocrinology, 2021, Jan 27; 11:575843. As shown in FIG. 5 A, a statistically significant of NASH patients in the trial described in Example 3 show cTl reductions of greater than 80 msec.

[0045] Accordingly, the disclosure provides a method of treating NASH in a patient in need thereof, comprising administering a once daily dose of an oral pharmaceutical composition comprising compound (1) or a pharmaceutically acceptable salt thereof, wherein the once daily dose provides a steady state AUC(O-T) of compound (1) from about 1,000 hr*ng/mL to about 3,500 hr*ng/mL, and wherein the NASH of the patient is characterized by advanced stage hepatic fibrosis (e.g., a patient with a fibrosis score of F2, F3 or F4.). In some embodiments, the once daily dose of compound (1) or a pharmaceutically acceptable salt thereof provides a steady state AUC(o-r) of compound (1) from about 1,000 hr*ng/mL to about 3,000 hr*ng/mL. In some embodiments, the once daily dose of compound (1) or a pharmaceutically acceptable salt thereof provides a steady state AUC(o-i) of compound (1) from about 1,000 hr*ng/mL to about 2,500 hr*ng/mL. In some embodiments, the once daily dose of compound (1) or a pharmaceutically acceptable salt thereof provides a steady state AUC(o-r) of compound (1) from about 1,300 hr*ng/mL to about 2,100 hr*ng/mL. In some embodiments, the once daily dose of compound (1) or a pharmaceutically acceptable salt thereof provides a steady state AUC(o-r) of compound (1) from about 1,700 hr*ng/mL to about 3,000 hr*ng/mL. In some embodiments, the once daily dose of compound (1) or a pharmaceutically acceptable salt thereof provides a steady state AUC(O-T) of compound (1) from about 2,000 hr*ng/mL to about 3,000 hr*ng/mL. In some embodiments, the once daily dose of compound (1) or a pharmaceutically acceptable salt thereof provides a steady state AUC(o-i) of compound (1) from about 1,800 hr*ng/mL to about 2,400 hr*ng/mL. In some embodiments, the once daily dose of compound (1) or a pharmaceutically acceptable salt thereof provides a steady state AUC(o-r) of compound (1) from about 1,800 hr*ng/mL to about 2,500 hr*ng/mL. In some embodiments, the once daily dose of compound (1) or a pharmaceutically acceptable salt thereof provides a steady state AUC(o-r) of compound (1) from about 2,000 hr*ng/mL to about 2,400 hr*ng/mL. In some embodiments, the once daily dose of compound (1) or a pharmaceutically acceptable salt thereof is about 10 mg. In other embodiments, the once daily dose of compound (1) or a pharmaceutically acceptable salt thereof is about 15 mg. In some embodiments, compound (1) is administered as a free acid (e.g., non-salt form). In some embodiments, hepatic fibrosis is reduced without increasing the low-density lipoprotein cholesterol (LDL-C) levels in the blood of the patient. In some embodiments, the Cmax of compound 1 in the plasma does not exceed 325 ng/mL. In some embodiments, the Cmax of compound 1 in the plasma does not exceed 250 ng/mL. In some embodiments, the Cmax of compound 1 in the plasma is from about 175 ng/mL to about 325 ng/mL. In any of the foregoing embodiments, compound (1) or a pharmaceutically acceptable salt thereof can be administered in amorphous form. In some such embodiments, the amorphous form is administered in the form of a solid dispersion, as described below. In particular embodiments, compound (1) is administered as a free acid (i.e., non-salt form).

[0046] Trials conducted on NASH patients show that exposures of compound (1) that are effective in treating NASH (e.g., NASH characterized by advanced fibrosis) are not associated with significant rises in LDL cholesterol or significant decreases in HDL cholesterol. For instance, as shown in FIG. 6 and FIG. 7, AUC(O-T) of compound (1) from about 1,000 hr*ng/mL to about 3,000 hr*ng/mL leads to insignificant or minimal increases in LDL cholesterol and insignificant or minimal increases in HDL cholesterol. Therefore, the disclosure provides methods of effectively treating NASH patients with advanced fibrosis without significantly altering levels of LDL cholesterol levels or HDL cholesterol levels.

[0047] Additionally, in accordance with the disclosure, to the extent that administration of compound (1) or a pharmaceutically acceptable salt results in increases in LDL cholesterol levels and/or decreases in HDL cholesterol levels, these modifications in the lipid profile can be mitigated by conjoint administration with a THR[3 agonist such as compound (2) or a pharmaceutically acceptable salt thereof. Conjoint administration with a THR[3 agonist allows for even greater exposures of compound (1) without effecting the lipid profile (e.g. LDL cholesterol and HDL cholesterol levels). In some embodiments, the disclosure provides a method of treating non-alcoholic steatohepatitis (NASH) in a patient in need thereof, comprising administering a once daily dose of an oral pharmaceutical composition comprising compound (1) or a pharmaceutically acceptable salt thereof, in combination with a THR[3 agonist (e.g., compound (2) or a pharmaceutically acceptable salt thereof), wherein the once daily dose provides a steady state AUC(o-r) of compound (1) from about 1,000 hr*ng/mL to about 3,000 hr*ng/mL (e.g. from about 1,300 hr*ng/mL to about 2,400 hr*ng/mL) and wherein the NASH of the patient is characterized by advanced stage hepatic fibrosis (e.g., a patient with a fibrosis score of F2, F3 or F4.). In some such embodiments, the once daily dose provides an AUC(o-i) of compound (1) from about 1,000 hr*ng/mL to about 2,000 hr*ng/mL. In some of the foregoing embodiments, the once daily dose of compound (1) or a pharmaceutically acceptable salt thereof is about 10 mg. In other of the foregoing embodiments, the once daily dose of compound (1) or a pharmaceutically acceptable salt thereof is about 15 mg. In other of the foregoing embodiments, the once daily dose of compound (1) or a pharmaceutically acceptable salt thereof is about 20 mg.

[0048] Furthermore, the administration of compound (1) is not accompanied by significant pruritus. Pruritus is a well-documented adverse effect of several FXR agonists and can result in patient discomfort, a decrease in patient quality of life, and an increased likelihood of ceasing treatment. Pruritus is particularly burdensome for indications, such as those described herein, including NASH, for which chronic drug administration is likely.

[0049] In some embodiments, the administration of compound (1), or a pharmaceutically acceptable salt thereof, does not result in pruritus in the patient greater than Grade 2 in severity. In some embodiments, the administration does not result in pruritus in the patient greater than Grade 1 in severity. In some embodiments, the administration does not result in pruritus in the patient. The grading of adverse effects is known. According to Version 5 of the Common Terminology Criteria for Adverse Events (published November 27, 2017), Grade 1 pruritus is characterized as “Mild or localized; topical intervention indicated.” Grade 2 pruritus is characterized as “Widespread and intermittent; skin changes from scratching (e.g., edema, papulation, excoriations, lichenification, oozing/crusts); oral intervention indicated; limiting instrumental ADL.” Grade 3 pruritus is characterized as “Widespread and constant; limiting self care ADL or sleep; systemic corticosteroid or immunosuppressive therapy indicated.” Activities of daily living (ADL) are divided into two categories: “Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.,” and “Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.” Accordingly, provided herein are methods of treating a liver disorder in a patient in need thereof with an FXR agonist that does not result in detectable pruritus in the patient in need thereof.

[0050] In some embodiments, the patient is a human. Obesity is highly correlated with NASH, but lean people can also be affected by NASH. Accordingly, in some embodiments, the patient is obese. In some embodiments, the patient is not obese. Obesity can be correlated with or cause other diseases as well, such as diabetes mellitus or cardiovascular disorders. Accordingly, in some embodiments, the patient also has diabetes mellitus and/or a cardiovascular disorder. Without being bound by theory, it is believed that comorbidities, such as obesity, diabetes mellitus, and cardiovascular disorders can make NASH more difficult to treat. Conversely, the only currently recognized method for addressing NASH is weight loss, which would likely have little to no effect on a lean patient.

[0051] The risk for NASH increases with age, but children can also suffer from, with literature reporting of children as young as 2 years old (Schwimmer, et al., Pediatrics, 2006, 118: 1388-1393). In some embodiments, the patient is 2-17 years old, such as 2-10, 2-6, 2-4, 4- 15, 4-8, 6-15, 6-10, 8-17, 8-15, 8-12, 10-17, or 13-17 years old. In some embodiments, the patient is 18-64 years old, such as 18-55, 18-40, 18-30, 18-26, 18-21, 21-64, 21-55, 21-40, 21- 30, 21-26, 26-64, 26-55, 26-40, 26-30, 30-64, 30-55, 30-40, 40-64, 40-55, or 55-64 years old. In some embodiments, the patient is 65 or more years old, such as 70 or more, 80 or more, or 90 or more.

[0052] NASH are common causes of liver transplantation, but patients that already received one liver transplant often develop NAFLD and/or NASH again. Accordingly, in some embodiments, the patient has had a liver transplant.

[0053] In some embodiments, treatment in accordance with the methods provided herein results in a reduced NAFLD Activity (NAS) score in a patient. For example, in some embodiments, steatosis, inflammation, and/or ballooning is reduced upon treatment. In some embodiments, the methods of treatment provided herein reduce liver fibrosis. In some embodiments, the methods reduce serum triglycerides. In some embodiments, the methods reduce liver triglycerides.

[0054] In some embodiments, administration of a compound (1) or a pharmaceutically acceptable salt thereof to a NASH patient with an NAS score of between 6-8 can lead to reduction in the NAS score of at least 1 point (e.g., a reduction of NAS score of 1 point, 2 points or 3 points) following administration for a sufficient period of time (e.g., 3 months to 52 weeks or 6 months to 72 weeks). For example, administration of a compound (1) or a pharmaceutically acceptable salt thereof to a NASH patient with an NAS score of 7 can reduce the NAS score to a score of 6, 5 or 4. In some embodiments, the reduction of NAS score is accompanied by a decrease in cTl from about 60 msec to about 100 msec. In some embodiments, the NAS score is lowered even further when compound (1) is administered in combination with a THRp agonist, such as compound (2). In some embodiments, a time to reduce the NAS score is reduced when compound (1) is administered in combination with a THRp agonist, such as compound (2).

[0055] In some embodiments, the patient is at risk of developing an adverse effect prior to the administration in accordance with the methods provided herein. In some embodiments, the adverse effect is an adverse effect which affects the kidney, lung, heart, and/or skin. In some embodiments, the adverse effect is pruritus.

[0056] In some embodiments, the patient has had one or more prior therapies. In some embodiments, the liver disorder progressed during the therapy. In some embodiments, the patient suffered from pruritus during at least one of the one or more prior therapies.

[0057] In some embodiments, the methods described herein do not comprise treating pruritus in the patient. In some embodiments, the methods do not comprise administering an antihistamine, an immunosuppressant, a steroid (such as a corticosteroid), rifampicin, an opioid antagonist, or a selective serotonin reuptake inhibitor (SSRI).

[0058] As discussed above, the disclosure also provides methods of treating NASH characterized by advanced fibrosis in a patient in need thereof by administering to the patient compound (1) or a pharmaceutically acceptable salt thereof, in combination with a THR [3 agonist. In some embodiments comprising administering compound (1) or a pharmaceutically acceptable salt thereof and a THRp agonist, the compounds are administered simultaneously. In some such embodiments, compound (1), or a pharmaceutically acceptable salt thereof, and the THR agonist can be provided in a single pharmaceutical composition. In other embodiments, compound (1), or a pharmaceutically acceptable salt thereof, and the THRp agonist are administered sequentially. [0059] Also provided herein are dosing regimens for administering compound (1) or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of compound (1), or a pharmaceutically acceptable salt thereof, is from about 10 mg/day (e.g., 10 mg/day) to about 15 mg/day (e.g., 15 mg/day). In some embodiments, the therapeutically effective amounts is about 10 mg/day (e.g., 10 mg/day). In some embodiments, the therapeutically effective amounts is about 15 mg/day (e.g., 15 mg/day).

[0060] The treatment period generally can be one or more weeks. In some embodiments, the treatment period is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 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, 1 year, 2 years, 3 years, 4 years, 5 years, alO years or more. In some embodiments, the treatment period is for the lifetime of the patient. It will be understood that dosing amounts of compound (1) or a pharmaceutically acceptable salt can be reduced as patients begin showing improved NAS and fibrosis scores. In some embodiments, the treatment period is from about a week to about a month, from about a month to about a year, from about a year to about several years. In some embodiments, the treatment period at least any of about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 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, 1 year, 2 years, 3 years, 4 years, or more. In some embodiments, the treatment period is the remaining lifespan of the patient.

[0061] In some embodiments where compound (1) is administered in combination with a THRP agonist (such as compound (2) or a pharmaceutically acceptable salt thereof), about 0.5 mg to about 100 mg of the THR[3 agonist (such as compound (2) or a pharmaceutically acceptable salt thereof) is administered to the individual. In some embodiments, about 1 mg to about 25 mg of compound (2) or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, about 1 mg to about 15 mg of compound (2), or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, about 2 mg to about 10 mg of compound (2) or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, about 2 mg of compound (2) or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, about 5 mg of compound (2) or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, about 10 mg of compound (2), or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, about 15 mg of compound (2) or a pharmaceutically acceptable salt thereof, is administered to the individual. In some of the foregoing embodiments, compound (2) is administered to the patient as a potassium salt. It will be understood that in all embodiments, the weight of the compound (2) refers to the active portion of the molecule (free acid).

[0062] In some embodiments, compound (1) or a pharmaceutically acceptable salt thereof and the THR[3 agonist (such as compound (2) or a pharmaceutically acceptable salt thereof) are administered to the individual once per day for at least seven days. In some embodiments, both compounds are administered to the individual once per day for at least 14 days. In some embodiments, both compounds are administered to the individual once per day for a period of between 1 and 4 weeks. In some embodiments, both compounds are administered to the individual once per day for a period of between 4 and 12 weeks. In some embodiments, both compounds are administered to the individual once per day for a period of between 4 and 52 weeks. In some embodiments, both compounds are administered to the individual once per day for a period of between 1 year and 10 years. In some embodiments, both compounds are administered for the lifetime of the individual.

[0063] In embodiments wherein the THR[3 agonist is a compound (2) or a pharmaceutically acceptable salt thereof, a therapeutic dose of the compound to a human patient is typically from about 3 mg to about 90 mg daily administered orally. In particular embodiments, when administered in combination with compound (1) or a pharmaceutically acceptable salt thereof, compound (2) or a pharmaceutically acceptable salt thereof can be administered at an oral dose of from about 3 mg to about 90 mg (e.g., 3 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 90 mg) or can be administered at a lower dose. For instance, when administered in combination with compound (1) or a pharmaceutically acceptable salt thereof, compound (2) or a pharmaceutically acceptable salt thereof can be administered orally at a dose of from about 0.5 mg to about 30 mg daily, from about 0.5 mg to about 25 mg daily, from about 0.5 mg to about 20 mg daily, from about 0.5 mg to about 15 mg daily, from about 0.5 mg to about 10 mg daily, from about 0.5 mg to about 5 mg daily, from about 0.5 mg to about 3 mg daily, or from about 1 mg to about 3 mg daily.

[0064] In some embodiments, administration with the combination of compound (1) or a pharmaceutically acceptable salt thereof and a THR[3 agonist (such as the compound 2 or a pharmaceutically acceptable salt thereof) decreases serum total cholesterol in the individual. In some embodiments, administration with the combination decreases serum total cholesterol in the individual as compared to administration with a monotherapy of compound (1) or a pharmaceutically acceptable salt thereof or the THRp agonist. In some embodiments, administration with the combination decreases serum total cholesterol in the individual comparably as well as administration with a monotherapy of compound (1) or the THRp agonist (e.g., compound (2)). Thus it is understood that methods of treatment detailed herein, in some embodiments, comprise treating NASH characterized by advanced stage fibrosis in a patent in need thereof, wherein the NASH wherein treatment comprises either maintaining or reducing the serum cholesterol level.

[0065] In some embodiments, administration with the combination of compound (1) or a pharmaceutically acceptable salt thereof and the THRp agonist (such as compound (2) or a pharmaceutically acceptable salt thereof) decreases expression of one or more fibrosis- and/or inflammation-associated genes in the NASH patient. Genes associated with fibrosis and/or inflammation include, but are not limited to, Collal, Col3al, Mmp2, Lgals3, Cd68, and Ccr2. Methods of assessing expression are known to the skilled artisan and may include RNAseq. In some embodiments, administration with the combination decreases expression of at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 genes associated with fibrosis and/or inflammation. In some embodiments, administration with the combination decreases expression of at least 1, at least 2, at least 3, at least 4, or at least 5 genes selected from Collal, Col3al, Mmp2, Lgals3, Cd68, and Ccr2. In some embodiments, administration with the combination decreases expression of Collal, Col3al, Mmp2, Lgals3, Cd68, and Ccr2. In some embodiments, administration with the combination decreases expression of fibrosis- and/or inflammation-associated genes in the individual as compared to administration with a monotherapy of compound (1) or the THRp agonist. In some embodiments, administration with the combination decreases expression of fibrosis- and/or inflammation-associated genes in the individual comparably as well as administration with a monotherapy of compound (1) or the THRp agonist. Thus it is understood that methods of treatment detailed herein, in some embodiments, comprise treating NASH in a patient in need thereof, wherein treatment comprises decreasing expression of at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 genes associated with fibrosis and/or inflammation, such as Collal, Col3al, Mmp2, Lgals3, Cd68, and Ccr2.

[0066] In some embodiments, provided are methods of inhibiting expression of genes in a responsible for the production of collagen in the extracellular matrix of the liver in a NASH patient in need thereof, comprising administering to the patient a combination of compound (1) or a pharmaceutically acceptable salt thereof and the THRp agonist (such as compound (2) or a pharmaceutically acceptable salt thereof). In some embodiments, the genes are fibroblast genes. In some embodiments, the genes are selected from Collal, Col3al, and Lgals3. In some embodiments, the patient has liver fibrosis.

Pharmaceutically Acceptable Compositions and Formulations

[0067] Pharmaceutically acceptable oral compositions or simply “pharmaceutical compositions” of any of the compounds detailed herein are embraced by this invention. Thus, the invention includes pharmaceutical compositions comprising Compound (1) or a pharmaceutically acceptable salt thereof.

[0068] Compound (1), as detailed herein, may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising compound (1) as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing compound (1) as detailed herein or a salt thereof is in substantially pure form. In one variation, “substantially pure” intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than compound (1) comprising the majority of the composition or a salt thereof. For example, a composition of a substantially pure compound intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than compound (1) or a salt thereof. In one variation, a composition of substantially pure compound (1) or a salt thereof is provided wherein the composition contains no more than 25% impurity. In another variation, a composition of substantially pure compound (1) or a salt thereof is provided wherein the composition contains or no more than 20% impurity. In still another variation, a composition of substantially pure compound (1) or a salt thereof is provided wherein the composition contains or no more than 10% impurity. In a further variation, a composition of substantially pure compound (1) or a salt thereof is provided wherein the composition contains or no more than 5% impurity. In another variation, a composition of substantially pure compound (1) or a salt thereof is provided wherein the composition contains or no more than 3% impurity. In still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 1% impurity. In a further variation, a composition of substantially pure compound (1) or a salt thereof is provided wherein the composition contains or no more than 0.5% impurity. [0069] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual such as a human. In another variation, compositions are provided containing a compound (1) in substantially pure form. In another variation, the invention embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier or excipient. In another variation, methods of administering a compound are provided.

[0070] Compound (1) may be formulated for oral administration with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g, nasal spray or inhalers), gels, suspensions (e.g, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21^st ed. (2005), which is incorporated herein by reference.

[0071] Compound ( 1) may be administered to individuals (e.g. , a human) in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, com starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid polyols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.

[0072] In some embodiments, compound (1), or a pharmaceutically acceptable salt thereof, is substantially amorphous. In some such embodiments, the substantially amorphous compound (1), or a pharmaceutically acceptable salt thereof, is dispersed in a polymer. In some embodiments, amorphous compound (1) is in its free acid form (i.e., non-salt form).

[0073] As used herein, the term “substantially amorphous” means that more than about 50%, more than about 60%, more than about 70%, more than about 75%, more than about 80%, more than about 85%, more than about 90%, more than about 95%, more than about 96%, more than about 97%, more than about 98%, more than about 99%, or more than about 99.9% by weight of compound (1) in the pharmaceutical composition (e.g., solid dispersion) is amorphous. In some embodiments, more than about 90% of compound (1) in the pharmaceutical composition (e.g., solid dispersion) is amorphous. In some embodiments, more than about 95% by weight of compound (1) in the pharmaceutical composition (e.g., solid dispersion) is amorphous. In some embodiments, more than about 96% by weight of compound (1) in the pharmaceutical composition (e.g., solid dispersion) is amorphous. In some embodiments, more than about 97% by weight of compound (1) in the pharmaceutical composition (e.g., solid dispersion) is amorphous. In some embodiments, more than about 98% by weight of compound (1) in the pharmaceutical composition (e.g., solid dispersion) is amorphous. In some embodiments, more than about 99% by weight of compound (1) in the pharmaceutical composition (e.g., solid dispersion) is amorphous. In some embodiments, more than about 99.9% by weight of compound (1) in the pharmaceutical composition (e.g., solid dispersion) is amorphous. In some embodiments, the solid dispersion is substantially free of a crystalline form of compound 1.

[0074] In some embodiments, compound (1) or a pharmaceutically acceptable salt thereof, is dispersed in a hydrophilic polymer. Examples of hydrophilic polymers include, but are not limited to, homopolymers and copolymers of vinyl lactams (e.g., homopolymers and copolymers of vinylpyrrolidone or vinylcaprolactam); polyethylene glycols; celluloses, cellulose esters and cellulose ethers (e.g., methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, and hydroxypropyl methylcellulose phthalate); polyacrylates (e.g., ammonio methacrylate copolymer and polyacrylic acid); and mixtures thereof.

[0075] In some embodiments, the polymer is a homopolymer or a copolymer of a vinyl lactam. In some embodiments, the polymer is a homopolymer or a copolymer of vinylpyrrolidone or vinylcaprolactam. In some embodiments, the polymer is a homopolymer or a copolymer of vinylpyrrolidone (e.g., poly(vinylpyrrolidone) or vinyl pyrrolidone-vinyl acetate copolymer). In some embodiments, the polymer is a vinylpyrrolidone -vinyl acetate copolymer (e.g., the product sold under the trademark Kollidon® VA64). In some embodiments, the polymer is a homopolymer or a copolymer of vinylcaprolactam (e.g., poly(vinylcaprolactam) or vinylcaprolactam-vinyl acetate-ethylene glycol copolymer). In some embodiments, the polymer is vinylcaprolactam-vinyl acetate-ethylene glycol copolymer (e.g., the product sold under the trademark Soluplus®). In some embodiments, the polymer is vinylpyrrolidone-vinyl acetate copolymer or vinylcaprolactam-vinyl acetate-ethylene glycol copolymer. In some embodiments, the vinylcaprolactam-vinyl acetate-ethylene glycol copolymer is a vinylcaprolactam-vinyl acetate-ethylene glycol graft copolymer.

[0076] In some embodiments, the weight ratio of compound (1) to the polymer is between about 1: 1 and about 1:20, between about 1: 1 and about 1: 15, between about 1: 1 and about 1: 10, between about 1 : 1 and about 1 : 9, between about 1 : 1 and about 1:8, between about 1 : 1 and about 1:7, between about 1: 1 and about 1:6, between about 1: 1 and about 1:5, between about 1: 1 and about 1:4, between about 1: 1 and about 1:3, or between about 1: 1 and about 1:2. In some embodiments, the weight ratio of Compound I to the polymer is about 1: 1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1: 10, about 1 : 15, or about 1 : 20. In some embodiments, the weight ratio of compound (1) to the polymer is between about 1 : 1 and about 1 : 10. In some embodiments, the weight ratio of compound (1) to the polymer is about 1:3.

[0077] In some embodiments, the pharmaceutical compositions comprising a solid dispersion of compound (1), or a pharmaceutically acceptable salt thereof, further comprise a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable excipient comprises a diluent. As used herein, the term “diluent” refers to a substance that is used to dilute an active ingredient prior to delivery. Diluents can also serve to stabilize the active ingredient. Examples of diluents include, but are not limited to, starch, saccharides, disaccharides, sucrose, lactose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium or sodium carbonate, lactose monohydrate, dicalcium phosphate, compressible sugars, dibasic calcium phosphate dehydrate, mannitol, and tribasic calcium phosphate. In some embodiments, the diluent comprises microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of between about 10% and about 90%, between about 10% and about 80%, between about 10% and about 70%, between about 10% and about 60%, between about 10% and about 50%, between about 10% and about 40%, between about 10% and about 30%, between about 10% and about 20%, between about 20% and about 90%, between about 20% and about 80%, between about 20% and about 70%, between about 20% and about 60%, between about 20% and about 50%, between about 20% and about 40%, between about 20% and about 30%, between about 30% and about 90%, between about 30% and about 80%, between about 30% and about 70%, between about 30% and about 60%, between about 30% and about 50%, between about 30% and about 40%, between about 40% and about 90%, between about 40% and about 80%, between about 40% and about 70%, between about 40% and about 60%, between about 40% and about 50%, between about 50% and about 90%, between about 50% and about 80%, between about 50% and about 70%, between about 50% and about 60%, between about 60% and about 90%, between about 60% and about 80%, between about 60% and about 70%, between about 70% and about 90%, between about 70% and about 80%, or about 80% and about 90% by weight. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% by weight. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of about 10% by weight. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of about 15% by weight. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of about 20% by weight. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of about 25% by weight. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of about 30% by weight. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of about 35% by weight. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of about 40% by weight. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of about 45% by weight. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of about 50% by weight. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of about 55% by weight. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of about 60% by weight. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of about 65% by weight. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of about 70% by weight. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of about 75% by weight. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of about 80% by weight. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of about 85% by weight. In some embodiments, the pharmaceutical composition comprises the diluent in the amount of about 90% by weight.

[0078] In some embodiments, the pharmaceutically acceptable excipient comprises a disintegrant. As used herein, the term “disintegrant” refers to a substance which, upon addition to a solid formulation, facilitates its break-up or disintegration after administration and permits the release of an active ingredient as efficiently as possible to allow for its rapid dissolution. Examples of disintegrants include, but are not limited to, maize starch, sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, modified com starch, sodium carboxymethyl starch, povidone, pregelatinized starch, and alginic acid. In some embodiments, the disintegrant comprises crospovidone. In some embodiments, the pharmaceutical composition comprises the disintegrant in the amount of between about 10% and about 50%, between about 10% and about 40%, between about 10% and about 30%, between about 10% and about 20%, between about 20% and about 50%, between about 20% and about 40%, between about 20% and about 30%, between about 30% and about 50%, between about 30% and about 40%, or between about 40% and about 50% by weight. In some embodiments, the pharmaceutical composition comprises the disintegrant in the amount of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% by weight. In some embodiments, the pharmaceutical composition comprises the disintegrant in the amount of about 10% by weight. In some embodiments, the pharmaceutical composition comprises the disintegrant in the amount of about 15% by weight. In some embodiments, the pharmaceutical composition comprises the disintegrant in the amount of about 20% by weight. In some embodiments, the pharmaceutical composition comprises the disintegrant in the amount of about 25% by weight. In some embodiments, the pharmaceutical composition comprises the disintegrant in the amount of about 30% by weight. In some embodiments, the pharmaceutical composition comprises the disintegrant in the amount of about 35% by weight. In some embodiments, the pharmaceutical composition comprises the disintegrant in the amount of about 40% by weight. In some embodiments, the pharmaceutical composition comprises the disintegrant in the amount of about 45% by weight. In some embodiments, the pharmaceutical composition comprises the disintegrant in the amount of about 50% by weight. [0079] In some embodiments, the pharmaceutically acceptable excipient comprises a glidant. As used herein, the term “glidanf ’ refers to a substance used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anticaking effect. Examples of glidants include, but are not limited to, colloidal silicon dioxide, talc, fumed silica, starch, starch derivatives, and bentonite. In some embodiments, the glidant comprises colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises the glident in the amount of about 0. 1% and about 1% by weight. In some embodiments, the pharmaceutical composition comprises the glident in the amount of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1% by weight. In some embodiments, the pharmaceutical composition comprises the glident in the amount of about 0. 1% by weight. In some embodiments, the pharmaceutical composition comprises the glident in the amount of about 0.2% by weight. In some embodiments, the pharmaceutical composition comprises the glident in the amount of about 0.3% by weight. In some embodiments, the pharmaceutical composition comprises the glident in the amount of about 0.4% by weight. In some embodiments, the pharmaceutical composition comprises the glident in the amount of about 0.5% by weight. In some embodiments, the pharmaceutical composition comprises the glident in the amount of about 0.6% by weight. In some embodiments, the pharmaceutical composition comprises the glident in the amount of about 0.7% by weight. In some embodiments, the pharmaceutical composition comprises the glident in the amount of about 0.8% by weight. In some embodiments, the pharmaceutical composition comprises the glident in the amount of about 0.9% by weight. In some embodiments, the pharmaceutical composition comprises the glident in the amount of about 1% by weight.

[0080] In some embodiments, the pharmaceutically acceptable excipient comprises a lubricant. As used herein, the term “lubricant” refers to a substance which is added to a powder blend to prevent the compacted powder mass from sticking to the equipment during the tableting or encapsulation process. Examples of lubricants include, but are not limited to, magnesium stearate, stearic acid, silica, fats, talc, and solubilizers such as fatty acids (e.g., lauric acid and oleic acid). In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the pharmaceutical composition comprises the lubricant in the amount of about 0.1% and about 1% by weight. In some embodiments, the pharmaceutical composition comprises the lubricant in the amount of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1% by weight. In some embodiments, the pharmaceutical composition comprises the lubricant in the amount of about 0. 1% by weight. In some embodiments, the pharmaceutical composition comprises the lubricant in the amount of about 0.2% by weight. In some embodiments, the pharmaceutical composition comprises the lubricant in the amount of about 0.3% by weight. In some embodiments, the pharmaceutical composition comprises the lubricant in the amount of about 0.4% by weight. In some embodiments, the pharmaceutical composition comprises the lubricant in the amount of about 0.5% by weight. In some embodiments, the pharmaceutical composition comprises the lubricant in the amount of about 0.6% by weight. In some embodiments, the pharmaceutical composition comprises the lubricant in the amount of about 0.7% by weight. In some embodiments, the pharmaceutical composition comprises the lubricant in the amount of about 0.8% by weight. In some embodiments, the pharmaceutical composition comprises the lubricant in the amount of about 0.9% by weight. In some embodiments, the pharmaceutical composition comprises the lubricant in the amount of about l% by weight.

[0081] It is to be understood that a pharmaceutically acceptable excipient may contain a diluent, a disintegrant, a glidant, and/or a lubricant. As an example, in some embodiments, the pharmaceutical composition comprises a solid dispersion disclosed herein, a diluent such as microcrystalline cellulose, a disintegrant such as crospovidone, a glidant such as colloidal silicon dioxide, and a lubricant such as magnesium stearate.

[0082] Techniques known in the art for preparing solid dispersions may be used. Examples of techniques that can be used include, but are not limited to, hot-melt extrusion and spray-drying. In some embodiments, the method for preparing the solid dispersion comprises hot-melt extruding compound (1), or a pharmaceutically acceptable salt thereof, and a polymer. . In some embodiments, compound (1) is in a crystalline form before extrusion. In some embodiments, compound (1) is in a non-crystalline form before extrusion. I n some embodiments, the polymer is a homopolymer or a copolymer of vinylpyrrolidone or vinylcaprolactam. In some embodiments, the polymer is a homopolymer or a copolymer of vinylpyrrolidone (e.g, poly(vinylpyrrolidone) or vinyl pyrrolidone-vinyl acetate copolymer). In some embodiments, the polymer is vinylpyrrolidone-vinyl acetate copolymer. In some embodiments, the polymer is a homopolymer or a copolymer of vinylcaprolactam (e.g., poly(vinylcaprolactam) or vinylcaprolactam-vinyl acetate-ethylene glycol copolymer). In some embodiments, the polymer is vinylcaprolactam-vinyl acetate-ethylene glycol copolymer. In some embodiments, the vinylcaprolactam-vinyl acetate-ethylene glycol copolymer is a vinylcaprolactam-vinyl acetate-ethylene glycol graft copolymer. In some embodiments, the hot-melt extrusion is performed at a temperature of between about 120 °C and about 180 °C. In some embodiments, the hot-melt extrusion is performed at a temperature of about 120 °C, about 125 °C, about 130 °C, about 135 °C, about 140 °C, about 145 °C, about 150 °C, about 155 °C, about 160 °C, about 165 °C, about 170 °C, about 175 °C, or about 180 °C.

[0083] Compositions comprising two compounds (e.g., compound (1) and compound (2)) utilized herein are described. Any of the compounds described herein can be formulated in a tablet in any dosage form described herein.

[0084] The present disclosure further encompasses kits (e.g., pharmaceutical packages). The kit provided may comprise the pharmaceutical compositions or the compounds described herein and containers (e.g., drug bottles, ampoules, bottles, syringes and/or subpackages or other suitable containers). In some embodiments, the kit includes a container comprising compound (1) or a pharmaceutically acceptable salt thereof and optionally a THR[3 agonist (such as the compound of (II) or a pharmaceutically acceptable salt thereof).

EXAMPLES

Example 1 - Pharmacokinetic/Pharmacodynamic (PK/PD) Studies

[0085] A total of 100 patients (FIG. 8) were randomized and received at least one dose of study drug (compound (1)). The numbers (%) of patients completing the treatment period were 26 (100%), 24 (96%), 25 (96.2%), and 21 (91.3%) for the placebo, 5 mg, 10 mg, and 15 mg groups, respectively. A total of 26 patients participated in the PK/PD substudy (N = 7, 6, 7, and 6 for the placebo, 5 mg, 10 mg, and 15 mg groups, respectively) with all but one subject completing both the Week 0 and Week 12 visits (one subject in 10 mg group did not complete Week 12 visit). In general, demographics and baseline characteristics were similar between the PK/PD substudy (FIG. 9) and the study conducted with all patients (FIG. 8). Amorphous compound (1) was administered in a tablet (solid dispersion), as described herein.

[0086] Trough pharmacokinetic (PK) and 7aC4 were collected at baseline and Weeks 2, 4, 6, 8, and 12 in all patients. A PK/PD substudy was performed in a pre-specified subset of approximately 6 patients in each treatment group (N=~24 total) at Week 0/Day 1 and Week 12; serial samples of 7aC4, FGF19, and PK collected. Compound (1) plasma concentrations were determined using a validated LC-MS/MS bioanalytical assay. PK parameters for Compound (1) were estimated using a nonlinear mixed effects model (NONMEM). Pharmacodynamic (PD) endpoints were analyzed using an analysis of covariance (ANCOVA) model with percent change or change from baseline as the dependent variable including treatment group as a fixed effect and baseline as a covariate to compare placebo and each active Compound (1) treatment group.

[0087] All dose levels of Compound (1) were overall safe and well -tolerated, with no discontinuations due to adverse events. Pruritus, which was predominantly mild and transient, occurred in 15% of compound (1) treated patients overall, with no compound (1) dosedependent effect, and no patients in the placebo group. No patient discontinued or had dose adjustments of compound (1) due to pruritus or any other adverse effect.

[0088] FIG. 1 shows that reduction of 7-alpha-hydroxy-4-cholestene-3 -one (7aC4) levels at various times were observed following once daily oral administration of oral 5 mg, 10 mg or 15 mg compound (1) to NASH patients. Measurements of 7aC4 are described in Example 2.

[0089] As shown in FIG. 4, mean steady-state trough plasma concentration of compound (1) following once daily oral administration of oral 5 mg, 10 mg or 15 mg compound (1) to NASH patients remained well below the ECso of compound (1) for all dose levels.

[0090] As shown in FIG. 6, changes in LDL cholesterol levels as a function of plasma exposure of compound (1) following once daily oral administration of oral 5 mg, 10 mg or 15 mg compound (1) to NASH patients were minimal. As shown in FIG. 7 changes in HDL cholesterol levels as a function of plasma exposure of compound (1) following once daily oral administration of oral 5 mg, 10 mg or 15 mg compound (1) to NASH patients were minimal.

Example 2 - Measurement of 7aC4 Levels

[0091] Concentrations of 7a-C4 in human K2-EDTA plasma samples from clinical studies were determined using a validated analytical LC-MS/MS method. A total of 880 human K2- EDTA plasma samples were successfully analyzed for 7a-C4 by ultra-performance liquid chromatography with tandem mass spectrometric detection. The results from calibration samples and QC samples demonstrated acceptable stock solutions of 7a-C4 were prepared from individually weighed out aliquots of a reference standard. Calibration and QC samples were prepared from separate stock solutions. All stock solutions were stored at a nominal - 20°C with an expiry period of 330 days after preparation for 7a-C4 and 1 year after preparation for the internal standard.

[0092] The assay instructions describe the quantitative determination of 7a-C4 in human K2-EDTA plasma samples. Sample processing was performed by solid-phase extraction using a 200 pL sample volume. Separation between potential metabolites and interfering endogenous compounds was achieved by UPLC on a Waters Acquity CSH C18 column (2.1 x 50 mm, 1.7 pm particle size) at 45.0°C using 10 mM ammonium formate with 0.1% formic acid as mobile phase A and 50:50 acetonitrile methanol v/v as mobile phase B, operating under isocratic conditions for analyte elution and a post-elution gradient column wash with a 0.9 mL/min flow rate. A triple quadrupole mass spectrometer (Triple Quad 6500) equipped with a turbo ion spray source was used for detection in positive ion mode. Quantification was based on multiple reaction monitoring (MRM) of the transitions of m/z 401.4— >177.2 for 7a-C4 and

408.4— >177.1 for C4-d7 (internal standard). A linear calibration curve ranging from 0.500 to 200 ng/mL with a l/x2 weighting factor was used.

[0093] Plotting of chromatograms and determinations of peak areas were carried out using Analyst (AB Sciex, Concord, Canada) version 1.7.1. All calculations were done in Watson LIMS version 7.4.2 (Thermo Fisher Scientific) and Microsoft Excel using validated or tested and checked spreadsheets. The IDBS Laboratory Execution System was used for data collection of study supporting materials.

[0094] Each analytical run started with a test sample, a blank sample and a zero sample (blank matrix with internal standard). The calibration curve standards were analyzed prior to the study samples in ascending order, starting with the LLOQ and ending with the ULOQ sample. The QC samples were individually interspersed between the study samples (in the sequence of low-medium-high, low-medium-high). At least 2 replicates of each QC level was included on each batch (i.e. 96 well plate). The first QC sample was analyzed prior to the first study sample and the last QC sample was analyzed following the last study sample.

[0095] Diluted QC samples were analyzed in one set of three samples preceding the last undiluted QC sample. Three zero samples were placed immediately following the calibration sample at the highest concentration and all high QC samples. [0096] Results from the studies are shown in FIG. 1. Statistically significant declines in trough 7aC4 levels at multiple time points in the 10 mg and 15 mg groups. To generate FIG.

2, Compound (1) exposures (AUCtau) were pooled across groups and subjects were separated by quartile (see Table in FIG. 2) irrespective of the dose group. Percent change in 7a-C4 at week 12 associated with the subjects in each quartile was then plotted; box represents median with interquartile range and whiskers represent min to max.

[0097] FIG. 3A shows reduction of 7-alpha-hydroxy-4-cholestene-3-one (7aC4) levels at various times (0 to 24 hours) following administration of oral 5 mg, 10 mg or 15 mg compound (1) to a subset of NASH patients. Maximum reduction in 7aC4 is achieved after approximately 6 hours post dosing. FIG. 3B shows a bar graph displaying reductions of 7aC4 at various doses of compound (1) six hours post dosing.

Example 3 - cTl Analysis

[0098] Corrected T1 (cTl) relaxation time, measured in milliseconds (msec), is an MRI- based test that measures the signal from extracellular water, and is a composite biomarker of inflammation and fibrosis. See Baneijee R, et al., J Hepatol, 2014;61 (1): 69-77. cTl has been correlated with NAFLD activity score and fibrosis score on liver histology. A study to evaluate the relationship between compound (1) exposure and change in cTl was conducted.

[0099] Prior to administration of compound (1), cTl was collected at baseline. cTl was also collected at Week 6, and Week 12 following administration of compound (1). cTl change from baseline to Week 6 and to Week 12 by treatment group was calculated. cTl response was defined as a >80 msec decrease from baseline.

[00100] FIG. 8 shows that the mean cTl at baseline for NASH patients prior to treatment with Compound (1) was greater than 900 msec. These cTl values were indicative of high levels of fibroinflammation at baseline. Compound (1) treatment resulted in significant decreases in cTl as early as week 6 and through week 12, indicative of a potent anti- fibroinflammatory effect of compound (1).

[00101] FIG. 5 A shows the change in cTl levels as a function of plasma exposure of compound (1) following once daily oral administration of compound (1) (5 mg, 10 mg or 15 mg) to NASH patients. FIG. 5B shows a bar graph displaying cTl as a function of compound (1) exposure as measured by AUC(O-T). TO generate the data in FIG. 5B, compound (1) exposures (AUCtau) were pooled across different groups and subjects were separated by quartile (Table in FIG. 5B), irrespective of dose group. Change in cTl at Week 12 associated with the subjects in each quartile was then plotted; the box in FIG. 5B represents median with interquartile range and whiskers represent min to max. Not all subjects in the PK analysis set had a corresponding Week 12 cTl value. The data shows significant decreases in cTl in an exposure dependent manner.

Example 4 - Formulation Preparation

[00102] A mixture of 35 g Compound (1) and 105 g vinylpyrrolidone -vinyl acetate copolymer (sold under the trademark Kollidon® VA 64) (API: polymer, w/w = 1:3), a mixture of 35 g compound (1) and 105 g vinylcaprolactam-vinyl acetate-ethylene glycol copolymer (sold under the trademark Soluplus®) (API: polymer, w/w = 1:3), and a mixture of 35 g compound (1) and 105 g hydroxypropyl methylcellulose acetate succinate (HPMCAS-LG) (API: polymer, w/w = 1:3) were hot-melt extruded on a Leistritz (ZSE 18HP) extruder. The extrusion conditions and properties of the resulting solid dispersions are provided in Table 1.

TABLE 1

a: Transparent yellow solic b: Opaque white solid c: Opaque gray solid

[00103] The resulting extrudates were milled, sieved, and measured by differential scanning calorimetry (DSC). The DSC data suggests that compound (1) was substantially amorphous in those solid dispersions.

[00104] Impurities in various samples (compound (1); a physical mixture of compound (1) and Kollidon® VA 64; a physical mixture of compound (1) and Soluplus®; Compound I/Kollidon® VA 64 solid dispersion; and compound (1)/Soluplus® solid dispersion) were determined by High-performance Liquid Chromatography (HPLC). The results are provided in Table 2.

TABLE 2

Claims

1. A method of treating non-alcoholic steatohepatitis (NASH), in a patient in need thereof, comprising administering a once daily dose of an oral pharmaceutical composition comprising compound (1):

or a pharmaceutically acceptable salt thereof, wherein the once daily dose provides a steady state AUC(O-T) of compound (1) from about 1,000 hr*ng/mL to about 3,000 hr*ng/mL, wherein the NASH of the patient is characterized by advanced stage liver fibrosis.

2. The method of claim 1, wherein the once daily dose provides, a steady state AUC(o-r) of compound (1) from about 1,300 hr*ng/mL to about 2,500 hr*ng/mL.

3. The method of claim 1, wherein the once daily dose provides, a steady state AUC(o-r) of compound (1) from about 1,500 hr*ng/mL to about 2,000 hr*ng/mL.

4. The method of any one of claims 1-3, wherein the once daily dose is about 10 mg.

5. The method of any one of claims 1-3, wherein the once daily dose is about 15 mg.

6. The method of any one of claims 1-5, wherein the patient has stage 3 (F3) fibrosis.

7. The method of any one of claims 1-5, wherein the patient has stage 4 (F4) fibrosis.

8. The method of any one of claims 1-7, wherein the baseline corrected T1 (cTl) of the patient prior to treatment is greater than 900 msec.

9. The method of any one of claims 1-7, wherein the baseline cTl of the patient prior to treatment is from about 925 msec to about 1,100 msec.

10. The method of claim 8 or clam 9, wherein the cTl of the patient decreases by greater than 50 msec following administration of compound (1) or a pharmaceutically acceptable salt thereof for at least 52 weeks.

11. The method of claim 8 or clam 9, wherein the cTl of the patient decreases by greater than 80 msec following administration of compound (1) or a pharmaceutically acceptable salt thereof for at least 52 weeks.

12. The method of claim 8 or clam 9, wherein the cTl of the patient decreases by from about 50 msec to about 90 msec following administration of compound (1) or a pharmaceutically acceptable salt thereof for at least 52 weeks.

13. The method of claim 8 or clam 9, wherein the cTl of the patient decreases by from about 70 msec to about 90 msec following administration of compound (1) or a pharmaceutically acceptable salt thereof for at least 52 weeks.

14. The method of any one of claims 1-13, wherein NAFLD Activity Score (NAS) of the patient prior to treatment is between 6 and 8.

15. The method of claim 14, wherein the NAS of the patient prior to treatment is 7.

16. The method of claim 14 or claim 15, wherein the NAS is reduced by at least 1 point following administration of compound (1) for at least 52 weeks.

17. The method of claim 14 or claim 15, wherein the NAS is reduced by at least 2 points following administration of compound (1) for at least 72 weeks.

18. The method of any one of claims 1 to 17, wherein the Cmax of compound (1) does not exceed 325 ng/mL.

19. The method of any one of claims 1 to 17, wherein the Cmax of compound (1) is from about 175 ng/mL to about 325 ng/mL.

20. The method of any one of claims 1 to 19, wherein the administration does not result in an increase in LDL cholesterol.

21. The method of any one of claims 1 to 20, wherein the administration does not result in a decrease in HDL cholesterol.

22. The method of any one of claims 1 to 21, wherein compound (1), or pharmaceutically acceptable salt thereof, is administered to the patient over a cycle of at least 3 months.

23. The method of claim 22, wherein mean plasma concentration of compound (1) over the cycle is less than 100 ng/mL.

24. The method of claim 22, wherein mean plasma concentration of compound (1) over the cycle is less than 50 ng/mL.

25. The method of any one of claims 1-24, wherein compound (1), or a pharmaceutically acceptable salt thereof, is substantially amorphous.

26. The method of claim 25, wherein compound (1), or a pharmaceutically acceptable salt thereof, is dispersed in a polymer.

27. The method of any one of claims 1-26, wherein compound (1) is administered as a free acid.

28. The method of any one of claims 1-27, further comprising administering a THRp agonist to the patient.

29. The method of claim 28, wherein the THRp agonist is compound (2)

or a pharmaceutically acceptable salt thereof.

30. The method of claim 29, wherein about 1 mg to about 10 mg of compound (2), or a pharmaceutically acceptable salt thereof is administered orally once daily to the patient.

31. A method of achieving a reduction of the baseline corrected T1 (cTl) of a patient with

NASH of greater than 60 msec comprising administering a once daily dose of an oral pharmaceutical composition comprising compound (1):

or a pharmaceutically acceptable salt thereof, wherein the once daily dose provides a steady state AUC(O-T) of compound (1) from about 1,000 hr*ng/mL to about 2,400 hr*ng.

32. The method of claim 31, wherein the cTl of the patient prior to administration is greater than 900 msec.

33. The method of claim 31, wherein the baseline cTl of the patient prior to treatment is from about 925 msec to about 1,100 msec.

34 The method of any one of claims 31-33, wherein the once daily dose provides a reduction of cTl of at least 70 msec.

35. The method of any one of claims 31-33, wherein the once daily dose provides a reduction of cTl of at least 80 msec.

36. The method of any one of claims 31-33, wherein the once daily dose provides a reduction of cTl of from about 60 msec to about 90 msec.

37. The method of any one of claims 31-36, wherein the patient has advanced stage liver fibrosis.

38. The method of any one of claims 31-37, wherein compound (1), or a pharmaceutically acceptable salt thereof, is substantially amorphous.

39. The method of claim 38, wherein compound (1), or a pharmaceutically acceptable salt thereof, is dispersed in a polymer.

40. The method of any one of claims 1-39, wherein compound (1) is administered as a free acid.

41 The method of any one of claims 1-40, further comprising administering a THRp agonist to the patient.

42. The method of claim 41, wherein the THRp agonist is compound (2)

or a pharmaceutically acceptable salt thereof.