WO2023220404A1 - Traitement de stéatohépatite non-alcoolique - Google Patents

Traitement de stéatohépatite non-alcoolique Download PDF

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WO2023220404A1
WO2023220404A1 PCT/US2023/022093 US2023022093W WO2023220404A1 WO 2023220404 A1 WO2023220404 A1 WO 2023220404A1 US 2023022093 W US2023022093 W US 2023022093W WO 2023220404 A1 WO2023220404 A1 WO 2023220404A1
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compound
pharmaceutically acceptable
patient
acceptable salt
msec
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PCT/US2023/022093
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English (en)
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Cara Nelson
Christopher T. Jones
Erin K. QUIRK
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Terns Pharmaceuticals, Inc.
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Publication of WO2023220404A1 publication Critical patent/WO2023220404A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine

Definitions

  • This disclosure relates to methods and compositions for treating liver disorder in a patient.
  • FLD Fatty liver disease
  • NAFLD non-alcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • NASH non-alcoholic steatohepatitis
  • 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.
  • FXR Famesoid X Receptor
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • compound (1) is administered as a free acid (e.g., non-salt form).
  • hepatic fibrosis is reduced without increasing the low-density lipoprotein cholesterol (LDL-C) levels in the blood of the patient.
  • hepatic fibrosis is reduced without decreasing the high-density lipoprotein cholesterol (HDL-C) levels in the blood of the patient.
  • 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.
  • compound (1) or a pharmaceutically acceptable salt thereof can be administered to NASH patients for long durations of time.
  • 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.
  • compound (1) or a pharmaceutically acceptable salt thereof is administered to the patient throughout the lifetime of the patient.
  • the pharmaceutical composition comprises a substantially amorphous form of compound (1).
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • the THR[3 agonist administered to the patient in need thereof is resmetirom (MGL-3196).
  • the THR[3 agonist is administered to the patient in need thereof VK2809 (by Viking Therapeutics).
  • the THRP agonist administered to the patient in need thereof is sobetirome.
  • the THR[3 agonist administered to the patient in need thereof is eprotirome.
  • 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).
  • 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).
  • an antihistamine an immunosuppressant, a steroid, rifampicin, an opioid antagonist, or a selective serotonin reuptake inhibitor (SSRI).
  • SSRI selective serotonin reuptake inhibitor
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • the NASH patients undergoing treatment have an iron- corrected T1 mapping (cTl) value of greater than 900 msec prior to treatment.
  • the cTl mapping score of the patients prior to treatment is between about 925 msec to about 1,100 msec.
  • 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).
  • 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.
  • 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.
  • the NAFLD Activity Score 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.
  • 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.)
  • a sufficient period of time e.g., from about 12 weeks to about 72 weeks.
  • 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.
  • the reduction of NAS score is accompanied by a decrease in cTl from about 60 msec to about 100 msec.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • FIG. 8 shows disposition, demographics and baseline characteristics of NASH patients being evaluated in studies described in Examples 1-3.
  • FIG. 9 shows disposition, demographics and baseline characteristics of NASH patients being evaluated in substudy designed to evaluate pharmacokinetics following administration of compound (1).
  • 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.
  • 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.
  • 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.
  • a compound of formula (I) or (II) can be administered in combination therapy with another agent in accordance with the present invention.
  • excipient 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.
  • 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.
  • 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.
  • “Pharmaceutically acceptable” refers to safe and non-toxic, preferably for in vivo, more preferably, for human administration.
  • “Pharmaceutically acceptable salt” refers to a salt that is pharmaceutically acceptable. A compound described herein may be administered as a pharmaceutically acceptable salt.
  • Salt refers to an ionic compound formed between an acid and a base.
  • salts include, without limitation, alkali metal, alkaline earth metal, and ammonium salts.
  • 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.
  • 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.
  • “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.
  • Treatment refers to an approach for obtaining beneficial or desired results including clinical results.
  • 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.
  • 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.
  • delay 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.
  • 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.
  • 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).
  • 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.
  • Compounds and compositions described herein may in some aspects be used in treating patients with advanced NASH, characterized by extensive liver fibrosis.
  • 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.
  • compound (1) can be safely administered to NASH patients with high levels of hepatic fibrosis and significantly reduce steatosis, inflammation and hepatic fibrosis.
  • 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.
  • 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.
  • the level of expression of one or more markers for fibrosis is reduced.
  • 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.
  • the level of collagen is reduced.
  • the level of collagen fragments is reduced.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • liver cTl liver cTl and hepatic fibrosis score.
  • 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.
  • stage F4 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).
  • the NASH patients undergoing treatment have an iron- corrected T1 mapping (cTl) value of greater than 900 msec prior to treatment.
  • the cTl mapping score of the patients prior to treatment is between about 925 msec to about 1,100 msec.
  • 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).
  • 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).
  • 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.
  • 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.
  • 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).
  • 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.
  • the reduction of NAS score is accompanied by a decrease in cTl from about 60 msec to about 100 msec.
  • 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.
  • 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.
  • 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 .
  • 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.
  • 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.).
  • advanced stage hepatic fibrosis e.g., a patient with a fibrosis score of F2, F3 or F4.
  • 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.
  • 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.
  • 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.
  • compound (1) is administered as a free acid (e.g., non-salt form).
  • hepatic fibrosis is reduced without increasing the low-density lipoprotein cholesterol (LDL-C) levels in the blood of the patient.
  • LDL-C low-density lipoprotein cholesterol
  • the Cmax of compound 1 in the plasma does not exceed 325 ng/mL.
  • the Cmax of compound 1 in the plasma does not exceed 250 ng/mL.
  • the Cmax of compound 1 in the plasma is from about 175 ng/mL to about 325 ng/mL.
  • compound (1) or a pharmaceutically acceptable salt thereof can be administered in amorphous form.
  • the amorphous form is administered in the form of a solid dispersion, as described below.
  • compound (1) is administered as a free acid (i.e., non-salt form).
  • NASH characterized by advanced fibrosis
  • 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.
  • 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.
  • NASH non-alcoholic steatohepatitis
  • 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.
  • the once daily dose of compound (1) or a pharmaceutically acceptable salt thereof is about 10 mg.
  • the once daily dose of compound (1) or a pharmaceutically acceptable salt thereof is about 15 mg.
  • the once daily dose of compound (1) or a pharmaceutically acceptable salt thereof is about 20 mg.
  • 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.
  • 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.
  • 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
  • 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.
  • 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).
  • 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.
  • 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.
  • the patient is 65 or more years old, such as 70 or more, 80 or more, or 90 or more.
  • 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.
  • treatment in accordance with the methods provided herein results in a reduced NAFLD Activity (NAS) score in a patient.
  • NAS NAFLD Activity
  • steatosis, inflammation, and/or ballooning is reduced upon treatment.
  • the methods of treatment provided herein reduce liver fibrosis.
  • the methods reduce serum triglycerides.
  • the methods reduce liver triglycerides.
  • 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).
  • 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.
  • the reduction of NAS score is accompanied by a decrease in cTl from about 60 msec to about 100 msec.
  • 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).
  • the patient is at risk of developing an adverse effect prior to the administration in accordance with the methods provided herein.
  • the adverse effect is an adverse effect which affects the kidney, lung, heart, and/or skin.
  • the adverse effect is pruritus.
  • the patient has had one or more prior therapies.
  • the liver disorder progressed during the therapy.
  • 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).
  • an antihistamine such as a corticosteroid
  • a steroid such as a corticosteroid
  • rifampicin such as a corticosteroid
  • opioid antagonist such as a selective serotonin reuptake inhibitor (SSRI).
  • SSRI selective serotonin reuptake inhibitor
  • 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.
  • the compounds are administered simultaneously.
  • compound (1), or a pharmaceutically acceptable salt thereof, and the THR agonist can be provided in a single pharmaceutical composition.
  • compound (1), or a pharmaceutically acceptable salt thereof, and the THRp agonist are administered sequentially.
  • dosing regimens for administering compound (1) or a pharmaceutically acceptable salt thereof are also provided herein.
  • 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).
  • the treatment period generally can be one or more weeks.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • about 1 mg to about 25 mg of compound (2) or a pharmaceutically acceptable salt thereof is administered to the individual.
  • about 1 mg to about 15 mg of compound (2), or a pharmaceutically acceptable salt thereof is administered to the individual.
  • about 2 mg to about 10 mg of compound (2) or a pharmaceutically acceptable salt thereof is administered to the individual.
  • about 2 mg of compound (2) or a pharmaceutically acceptable salt thereof is administered to the individual.
  • 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).
  • compound (1) or a pharmaceutically acceptable salt thereof and the THR[3 agonist are administered to the individual once per day for at least seven days.
  • both compounds are administered to the individual once per day for at least 14 days.
  • both compounds are administered to the individual once per day for a period of between 1 and 4 weeks.
  • both compounds are administered to the individual once per day for a period of between 4 and 12 weeks.
  • both compounds are administered to the individual once per day for a period of between 4 and 52 weeks.
  • both compounds are administered to the individual once per day for a period of between 1 year and 10 years.
  • both compounds are administered for the lifetime of the individual.
  • a therapeutic dose of the compound to a human patient is typically from about 3 mg to about 90 mg daily administered orally.
  • compound (2) or a pharmaceutically acceptable salt thereof when administered in combination with compound (1) 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.
  • compound (2) or a pharmaceutically acceptable salt thereof when administered in combination with compound (1) 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.
  • administration with the combination of compound (1) or a pharmaceutically acceptable salt thereof and a THR[3 agonist decreases serum total cholesterol in the individual.
  • 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.
  • 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)).
  • methods of treatment detailed herein 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.
  • administration with the combination of compound (1) or a pharmaceutically acceptable salt thereof and the THRp agonist 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.
  • 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.
  • 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.
  • methods of treatment detailed herein 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.
  • kits for 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).
  • the genes are fibroblast genes.
  • the genes are selected from Collal, Col3al, and Lgals3.
  • the patient has liver fibrosis.
  • compositions comprising Compound (1) or a pharmaceutically acceptable salt thereof.
  • Compound (1) 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.
  • a composition containing compound (1) as detailed herein or a salt thereof is in substantially pure form.
  • 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.
  • 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.
  • a composition of substantially pure compound (1) or a salt thereof is provided wherein the composition contains no more than 25% impurity.
  • a composition of substantially pure compound (1) or a salt thereof is provided wherein the composition contains or no more than 20% impurity.
  • a composition of substantially pure compound (1) or a salt thereof is provided wherein the composition contains or no more than 10% impurity.
  • a composition of substantially pure compound (1) or a salt thereof is provided wherein the composition contains or no more than 5% impurity.
  • compositions of substantially pure compound (1) or a salt thereof wherein the composition contains or no more than 3% impurity.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 1% impurity.
  • a composition of substantially pure compound (1) or a salt thereof is provided wherein the composition contains or no more than 0.5% impurity.
  • the compounds herein are synthetic compounds prepared for administration to an individual such as a human.
  • compositions are provided containing a compound (1) in substantially pure form.
  • the invention embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier or excipient.
  • methods of administering a compound are provided.
  • 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.
  • suitable carriers 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 (poultice
  • 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.
  • 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.
  • 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.
  • 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.
  • compound (1), or a pharmaceutically acceptable salt thereof is substantially amorphous.
  • the substantially amorphous compound (1), or a pharmaceutically acceptable salt thereof is dispersed in a polymer.
  • amorphous compound (1) is in its free acid form (i.e., non-salt form).
  • 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.
  • more than about 96% by weight of compound (1) in the pharmaceutical composition 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.
  • compound (1) or a pharmaceutically acceptable salt thereof is dispersed in a hydrophilic polymer.
  • 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.
  • vinyl lactams e.g., homopolymers and copolymers of vinylpyrrolidone or vinylcaprolactam
  • polyethylene glycols celluloses, cellulose esters and cellulose ethers (e.g., methylcellulose, hydroxypropyl methylcellulose,
  • 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).
  • vinylpyrrolidone -vinyl acetate copolymer e.g., the product sold under the trademark Kollidon® VA64.
  • the polymer is a homopolymer or a copolymer of vinylcaprolactam (e.g., poly(vinylcaprolactam) or vinylcaprolactam-vinyl acetate-ethylene glycol copolymer).
  • the polymer is vinylcaprolactam-vinyl acetate-ethylene glycol copolymer (e.g., the product sold under the trademark Soluplus®).
  • the polymer is vinylpyrrolidone-vinyl acetate copolymer or vinylcaprolactam-vinyl acetate-ethylene glycol copolymer.
  • the vinylcaprolactam-vinyl acetate-ethylene glycol copolymer is a vinylcaprolactam-vinyl acetate-ethylene glycol graft copolymer.
  • 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.
  • 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.
  • the pharmaceutical compositions comprising a solid dispersion of compound (1), or a pharmaceutically acceptable salt thereof, further comprise a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient comprises a diluent.
  • 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.
  • 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.
  • the diluent comprises microcrystalline cellulose.
  • 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 60%, between about 60% and about 90%, between about 60% and about 80%, between about 60% and about 50%, between about 50% and about 60%, between about 60% and about 80%, between about 60% and about 70%, between about 60%
  • 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.
  • the pharmaceutical composition comprises the diluent in the amount of about 10% by weight.
  • the pharmaceutical composition comprises the diluent in the amount of about 15% by weight.
  • the pharmaceutical composition comprises the diluent in the amount of about 20% by weight.
  • the pharmaceutical composition comprises the diluent in the amount of about 25% by weight.
  • 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.
  • 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.
  • the pharmaceutically acceptable excipient comprises a disintegrant.
  • 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.
  • 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.
  • the disintegrant comprises crospovidone.
  • 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.
  • 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.
  • the pharmaceutical composition comprises the disintegrant in the amount of about 10% by weight.
  • the pharmaceutical composition comprises the disintegrant in the amount of about 15% by weight.
  • 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.
  • 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.
  • the glidant comprises colloidal silicon dioxide.
  • 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.
  • 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.
  • the pharmaceutically acceptable excipient comprises a lubricant.
  • 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).
  • the lubricant comprises magnesium stearate.
  • the pharmaceutical composition comprises the lubricant in the amount of about 0.1% and about 1% by weight.
  • 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.
  • 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.
  • a pharmaceutically acceptable excipient may contain a diluent, a disintegrant, a glidant, and/or a lubricant.
  • 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.
  • the method for preparing the solid dispersion comprises hot-melt extruding compound (1), or a pharmaceutically acceptable salt thereof, and a polymer.
  • compound (1) is in a crystalline form before extrusion.
  • compound (1) is in a non-crystalline form before extrusion.
  • the polymer is a homopolymer or a copolymer of vinylpyrrolidone or vinylcaprolactam.
  • 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.
  • vinylpyrrolidone e.g, poly(vinylpyrrolidone) or vinyl pyrrolidone-vinyl acetate copolymer.
  • the polymer is vinylpyrrolidone-vinyl acetate copolymer.
  • the vinylcaprolactam-vinyl acetate-ethylene glycol copolymer is a vinylcaprolactam-vinyl acetate-ethylene glycol graft copolymer.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • Trough pharmacokinetic (PK) and 7aC4 were collected at baseline and Weeks 2, 4, 6, 8, and 12 in all patients.
  • 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.
  • ANCOVA analysis of covariance
  • 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.
  • 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
  • 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.
  • 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.
  • Corrected T1 (cTl) relaxation time 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.
  • cTl 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.
  • 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).
  • 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).
  • AUCtau compound (1) exposures
  • Impurities in various samples were determined by High-performance Liquid Chromatography (HPLC). The results are provided in Table 2.

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Abstract

L'invention concerne des méthodes et des compositions pour le traitement de la stéatohépatite non alcoolique (NASH) chez un patient en ayant besoin, la NASH du patient étant caractérisée par une fibrose hépatique de stade avancé. Les procédés comprennent l'administration au patient le composé (1) ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2023/022093 2022-05-13 2023-05-12 Traitement de stéatohépatite non-alcoolique WO2023220404A1 (fr)

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Cited By (1)

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WO2024183471A1 (fr) * 2023-03-08 2024-09-12 甘莱制药有限公司 Comprimé, et son procédé de préparation et son utilisation

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US11168079B2 (en) * 2017-11-01 2021-11-09 Bristol-Myers Squibb Company Alkene compounds as farnesoid x receptor modulators
US20220135540A1 (en) * 2020-10-15 2022-05-05 Eli Lilly And Company Polymorphs of an fxr agonist
WO2022152770A1 (fr) * 2021-01-14 2022-07-21 Enyo Pharma Effet synergique d'un agoniste de fxr et d'ifn pour le traitement d'une infection par le virus de l'hépatite b

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US20100152166A1 (en) * 2007-07-16 2010-06-17 Eli Lilly And Company Compounds and methods for modulating fxr
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WO2022152770A1 (fr) * 2021-01-14 2022-07-21 Enyo Pharma Effet synergique d'un agoniste de fxr et d'ifn pour le traitement d'une infection par le virus de l'hépatite b

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Publication number Priority date Publication date Assignee Title
WO2024183471A1 (fr) * 2023-03-08 2024-09-12 甘莱制药有限公司 Comprimé, et son procédé de préparation et son utilisation

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