Treatment of liver disorders with a THR-beta agonist

Abstract

The present disclosure is directed to a method of monitoring treatment of metabolic dysfunction-associated steatohepatitis (MASH) in a patient by initiating a treatment by administering Compound 1: (Compound 1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof to the patient, determining percentage increase in the level of SHBG from baseline, and continuing administration of Compound 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof to the patient if the percentage increase in the level of SHBG is at least 50% from baseline.

Description

Attorney Docket No.: TRPH-057 / 001WO 346923-2825 TREATMENT OF LIVER DISORDERS WITH A THR-BETA AGONIST CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 650,536, filed May 22, 2024, the contents of which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION

[0002] The present invention relates to the field of monitoring and treating metabolic dysfunction-associated steatohepatitis (MASH). Particularly, the present invention relates tothe use of a compound that can serve as an agonist of THR- in treating MASH, andthe use of Sex Hormone Binding Globulin (SHBG), a simple blood-based, as a targetengagement marker for THR- .BACKGROUND

[0003] Thyroid hormone (TH) is synthesized in the thyroid gland in response to the thyroid stimulating hormone (TSH) secreted by the pituitary. Thyroxine plays a rather important role in regulating body growth, development, metabolism, and body balance. Thyroid hormones mainly include two types: 3,5,3’-triiodo-L-thyroxine (T3) and thyroxine (T4). Human bodies mainly secrete T4. In peripheral organs, T4 is transformed by deiodinase into T3 having greater activity. T3 and T4 produced by the thyroid gland are under negative feedback control. Thyrotropin (TSH) is responsible for the normal thyroid function and thyroid hormone secretion. Thyrotropin is synthesized in the anterior pituitary gland, and its secretion is controlled by the thyroid releasing hormone (TRH) synthesized in the hypothalamus.

[0004] Thyroid hormones function by binding to the thyroid hormone receptors (THR). The thyroid hormone receptor belongs to a family of nuclear receptors and regulates the target geneexpressions. Thyroid hormone receptors include two different subtypes, i.e., THR- -- function. The THR- cholesterol metabolism and thyrotropin secretion.

[0005] At normal levels, thyroid hormones THs maintain body weight, metabolic rate, body temperature, and mood, and are responsible for regulating serum cholesterol. Attempts have been made to use thyroid hormones to regulate serum cholesterol. However, given the possible side effects on the heart from taking natural thyroid hormone (e.g., tachycardia and arrhythmia, 1 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 heart failure, and thyroid axis function, muscle metabolism, and osteoporosis,) thyroid hormones are unsuitable for treating high cholesterol and obesity. Research results regarding the study of animals with selective knock-out of the THR gene, and research results of some selective THR ligands show that the side effects on the heart caused by these thyroid hormonescan be attributed to THR-

[0006] The pathway of the thyroid hormone receptor regulates metabolism of lipids, including cholesterol, triglyceride, and lipoprotein. It has been clinically shown that lowering the low- density cholesterol can reduce the incidence of cardiovascular diseases.

[0007] MASH, also known as “Non-Alcoholic SteatoHepatitis” (NASH), refers to a serious chronic condition of liver inflammation, progressive from the less serious simple fatty liver condition called steatosis. Simple steatosis (alcoholic fatty liver) is an early and reversible consequence of excessive alcohol consumption. In certain cases the fat accumulation can be associated with inflammation and scarring in the liver. This more serious form of the disease is termed MASH. MASH is associated with a risk of liver fibrosis and cirrhosis. Patients with MASH have increased risk for hepatocellular carcinoma.

[0008] Non-alcoholic fatty liver disease (NAFLD) is also a type of metabolic disorder disease caused by excessive accumulation of triglycerides in the liver. Given the thyroid hormone’s function of regulating the lipid metabolism, the thyroid receptor pathway becomes a potential target for the treatment of MASH and NAFLD. It has been proven in animal bodies that thyroid hormone analogues can significantly reduce fatty levels in animal livers.

[0009] Selective THR- conventional THR receptor agonists, and selectively to only activate THR- improving cell lipid metabolism, and achieve the function of lowering cholesterol and blood fat. However, selective THR- fatigue, osteoporosis, and other side effects. Therefore, it is desired to develop a method ofselecting patients for treatment of a liver disorder in a patient using a selective THR-SUMMARY

[0010] In some embodiments, the present disclosure provides a method of treating metabolic dysfunction-associated steatohepatitis (MASH) in a patient in need thereof comprising: (i) measuring a first level of sex hormone binding globulin (SHBG) in the patient prior to (ii); 2 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 (ii) administering a thyroid hormone receptor-(iii) after a first time period following (ii), measuring a second level of SHBG in the patient; (iv) determining a percentage increase between the first level of SHBG and the second level of SHBG; and (v) administering the thyroid hormone receptor- SHBG level has increased by a predetermined percentage.

[0011] In some embodiments, the present disclosure provides a method of treating metabolic dysfunction-associated steatohepatitis (MASH) in a patient in need thereof comprising: (i) measuring a first level of sex hormone binding globulin (SHBG) in the patient prior to (ii); (ii) administering a thyroid hormone receptor-(iii) after a first time period following (ii), measuring a second level of SHBG in the patient; (iv) determining a percentage increase between the first level of SHBG and the second level of SHBG; and (v) administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the patient if the SHBG level has increased by a predetermined percentage,Formula (I) wherein, R1 is selected from the group consisting of hydrogen, cyano, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C3-6cycloalkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C1-6alkoxy; 3 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 R2 and R3 are each independently selected from the group consisting of halogen atoms or substituted or unsubstituted C1-6 alkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C1-6alkoxy; ring A is a substituted or unsubstituted saturated or unsaturated C5-10aliphatic ring, or a substituted or unsubstituted C5-10 aromatic ring, the substituent being one or more substances selected from the group consisting of hydrogen, halogen atoms, hydroxy, -OCF3, -NH2, -NHC1-4alkyl, -N(C1-4alkyl)2, -CONH2, -CONHC1-4alkyl, -CON(C1-4alkyl)2, -NHCOC1-4alkyl, C1-6alkyl, C1-6 alkoxy, or C3-6 cycloalkyl, and when two substituents are contained, the two substituents can form a ring structure together with the carbon connected thereto; and the halogen atoms are selected from the group consisting of F, Cl, or Br.

[0012] In some embodiments, the present disclosure provides a method of monitoring treatment of MASH in a patient, the method comprising: (i) obtaining a first test sample from the patient, (ii) measuring level of SHBG in the first test sample, (iii) initiating a treatment by administering a thyroid hormone receptor- (also referredto as “thyroid hormone receptor- ”) agonist, or a pharmaceutical composition comprising thethyroid hormone receptor- to the patient,(iv) obtaining a second test sample from the patient after a first time period, (v) measuring the level of SHBG in the second test sample, (vi) determining percentage increase in the level of SHBG from baseline, and (vii) continuing administration of the thyroid hormone receptor- , or thepharmaceutical composition comprising the thyroid hormone receptor- to the patientif the percentage increase in the level of SHBG is at least 50% from baseline.

[0013] In some embodiments, the present disclosure provides a method of monitoring treatment of MASH in a patient, the method comprising: (i) obtaining a first test sample from the patient, (ii) measuring level of SHBG in the first test sample, 4 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 (iii) initiating a treatment by administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the patient,wherein, R1is selected from the group consisting of hydrogen, cyano, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-6 cycloalkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C1-6alkoxy; R2and R3are each independently selected from the group consisting of halogen atoms or substituted or unsubstituted C1-6 alkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C1-6alkoxy; ring A is a substituted or unsubstituted saturated or unsaturated C5-10aliphatic ring, or a substituted or unsubstituted C5-10 aromatic ring, the substituent being one or more substances selected from the group consisting of hydrogen, halogen atoms, hydroxy, -OCF3, -NH2, -NHC1-4alkyl, -N(C1-4alkyl)2, -CONH2, -CONHC1-4alkyl, -CON(C1-4alkyl)2, -NHCOC1-4alkyl, C1-6alkyl, C1-6 alkoxy, or C3-6 cycloalkyl, and when two substituents are contained, the two substituents can form a ring structure together with the carbon connected thereto; and the halogen atoms are selected from the group consisting of F, Cl, or Br, (iv) obtaining a second test sample from the patient after a first time period, (v) measuring the level of SHBG in the second test sample, (vi) determining percentage increase in the level of SHBG from baseline, and (vii) continuing administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the patient if the percentage increase in the level of SHBG is at least 50% from baseline. 5 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0014] In some embodiments, the treatment comprises the administration of Compound 1 or apharmaceutically acceptable salt thereof to the patient,(Compound 1), which has the chemical name 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile, and was described in International Application Publication WO 2020 / 123827, the contents of which are incorporated herein by reference.

[0015] In some embodiments, the present disclosure is directed to a method of monitoringtreatment of MASH in a patient, the method comprising: (i) obtaining a first test sample from the patient, (ii) measuring level of SHBG in the first test sample, (iii) initiating a treatment by administering Compound 1 or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition comprising Compound 1 or apharmaceutically acceptable salt thereof to the patient,(iv) obtaining a second test sample from the patient after a first time period, (v) measuring the level of SHBG in the second test sample, (vi) determining percentage increase in the level of SHBG from baseline, and (vii) continuing administration of Compound 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof to the patient if the percentage increase in the level of SHBG is at least 50% from baseline.

[0016] In some embodiments, the present disclosure is directed to monitoring treatment ofMASH in a patient, wherein the treatment comprises the administration of Compound 2 or a pharmaceutically acceptable salt thereof to the patient, 6 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825(Compound 2), which has the chemical name 6-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol- 4-ylmethoxy]-piperidin-1-yl}-1-methyl-1H-indole-3-carboxylic acid, and was described in International Application Publication WO 2009 / 012125, the contents of which are incorporated herein by reference.

[0017] In some embodiments, the THR-B agonist is Compound 1.

[0018] In some embodiments, the THR-B agonist is Compound 1 or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the first time period is about 6 weeks.

[0020] In some embodiments, the first time period is about 12 weeks.

[0021] In some embodiments, the first time period is between about 6 weeks and about 12 weeks.

[0022] In some embodiments, the percentage difference between the first level of SHBG and the second level of SHBG is at least 70%.

[0023] In some embodiments, the percentage difference between the first level of SHBG and the second level of SHBG is 70% - 100%.

[0024] In some embodiments, the predetermined percentage increase of SHBG level is at least 50%.

[0025] In some embodiments, the predetermined percentage increase of SHBG level is at least 60%.

[0026] In some embodiments, the predetermined percentage increase of SHBG level is at least 70%.

[0027] In some embodiments, the present disclosure is directed to monitoring treatment of MASH in a patient, wherein the treatment comprises the administration of a combination comprising Compound 1 or a pharmaceutically acceptable salt thereof and Compound 2 or a pharmaceutically acceptable salt thereof to the patient. 7 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0028] In some embodiments, the present disclosure is directed to monitoring treatment of MASH in a patient, wherein the treatment comprises the administration of a combination comprising Compound 1 and Compound 2 to the patient.

[0029] Uses of the compounds (e.g., the compound of Formula (I), Compound 1, and Compound 2, or a pharmaceutically acceptable salt thereof) or the pharmaceutical compositions as described herein for the treatment of the disclosed indications (e.g., MASH), as well as uses of the compounds (e.g., the compound of Formula (I), Compound 1, and Compound 2, or a pharmaceutically acceptable salt thereof) as decribed herein in the manufacture of a medicament for the treatment of the disclosed indications (e.g., MASH) also supported herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The accompanying drawings, which are incorporated into and form a part of the specification, illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure. The drawings are only for the purpose of illustrating an embodiment of the disclosure and are not to be construed as limiting the invention. Further objects, features and advantages of the invention will become apparent from the following detailed description taken in conjunction with the accompanying figures showing illustrative embodiments of the disclosure.

[0031] FIG.1 depicts the design of a study in which Compound 1 was administered to subjects and SHBG levels were measured.

[0032] FIG. 2 depicts the dose-dependent, significant liver fat reduction and SHBG increases observed after 12-weeks of treatment with Compound 1.

[0033] FIG. 3 depicts the receiver operating characteristic (ROC) curve.

[0034] FIGs. 4A and 4B depict results for patients (%) a relative reduction inMRI-PDFF at week 12 by SHBG cutoff at week 12. Results are based on pooled data from the Compound 1 at 3 mg and 6 mg groups only. baseline at Week 12 in SHBG; Low is defined as <70% or <120% increase from baseline at in MRI-PDFF at Week 12; N represents the number of patients who achieved the defined SHBG response criteria (“High” / ”Low”). 8 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0035] FIGs. 5A and 5B depict results for patients (%) a relative reduction inMRI-PDFF at week 12 by SHBG cutoff at week 6. Results are based on pooled data from the Compound 1 at 3 mg and 6 mg groups only. baseline at Week 12 in SHBG; Low is defined as <70% or <120% increase from baseline at in MRI-PDFF at Week 12; N represents the number of patients who achieved the defined SHBG response criteria (“High” / ”Low”). DETAILED DESCRIPTION

[0036] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0037] 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.

[0038] As used herein, the term “comprising” is intended to mean that the compositions and methods include the recited elements, but not excluding 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.

[0039] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” shall 9 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0040] As used herein, the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0041] As used herein, the term “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.

[0042] As used herein, the term “pharmaceutically acceptable” refers to safe and non-toxic, preferably for in vivo, more preferably, for human administration.

[0043] As used herein, the term “pharmaceutically acceptable salt” refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically-acceptable salts are well known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1–19.

[0044] Included in the present teachings are pharmaceutically acceptable salts of the compound of Formula (I), Compound 1, or Compound 2. Compounds having basic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of compounds include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic acid, benzenesulfonic, benzoic, ethanesulfonic, methanesulfonic, succinic, and trifluoroacetic acid acids). Compounds with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, 10 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).

[0045] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.

[0046] As used herein, the term “pharmaceutical composition” is a formulation containing the compound of Formula (I), Compound 1, or Compound 2 of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of the compound of Formula (I), Compound 1, or Compound 2 include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0047] It is to be understood that a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods. For example, a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment. 11 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0048] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy.

[0049] As used herein, the term “salt” refers to an ionic compound formed between an acid and a base.

[0050] As used herein, the term “treating” or “treatment” of a disease in a patient refers to 1) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease. As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: decreasing one 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, delay 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.

[0051] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0052] As used herein, the term “baseline” refers to the measurement of the level of SHBG or Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF) before the initiation of the treatment. 12 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0053] As used herein, the term “corrected T1” refers to an iron-corrected T1 mapping (cT1). cT1 is an MRI-based diagnostic imaging biomarker of the liver. cT1 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. cT1 mapping is an indicator of regional tissue water content.

[0054] As used herein, the term “optional” or “optionally” as used throughout the specification means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

[0055] This disclosure also includes all salts, such as pharmaceutically acceptable salts, of the compound of Formula (I), Compound 1, and Compound 2. All forms of the compound of Formula (I), Compound 1, and Compound 2 are also embraced by the invention, such as crystalline or non-crystalline forms of the compound of Formula (I), Compound 1, and Compound 2. Compositions comprising the compound of Formula (I), Compound 1, or Compound 2 of the invention are also intended, such as a composition of substantially pure compound of Formula (I), Compound 1, or Compound 2, including a specific stereochemical form thereof.

[0056] The terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of the compound(s), or composition(s) to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0057] Unless explicitly indicated otherwise, the terms “approximately” and “about” are synonymous. In one embodiment, “approximately” and “about” refer to the recited amount, value, or duration ± 10%.

[0058] As used herein, the phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple 13 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0059] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from anyone or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a nonlimiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0060] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow. 14 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0061] Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure. Methods of Use / Monitoring Treatments

[0062] Described herein is a method of treating a liver disease or disorder in a patient in need thereof comprising: (i) measuring a first level of sex hormone binding globulin (SHBG) in the patient prior to (ii); (ii) administering a thyroid hormone receptor-(iii) after a first time period following (ii), measuring a second level of SHBG in the patient; (iv) determining a percentage increase between the first level of SHBG and the second level of SHBG; and (v) administering the thyroid hormone receptor- to the patient if theSHBG level has increased.

[0063] Described herein is a method of treating a liver disease or disorder in a patient in need thereof comprising: (i) measuring a first level of sex hormone binding globulin (SHBG) in the patient prior to (ii); (ii) administering a thyroid hormone receptor-(iii) after a first time period following (ii), measuring a second level of SHBG in the patient; (iv) determining a percentage increase between the first level of SHBG and the second level of SHBG; and (v) administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the patient, 15 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825Formula (I) wherein, R1is selected from the group consisting of hydrogen, cyano, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-6 cycloalkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C1-6alkoxy; R2and R3are each independently selected from the group consisting of halogen atoms or substituted or unsubstituted C1-6 alkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C1-6alkoxy; ring A is a substituted or unsubstituted saturated or unsaturated C5-10aliphatic ring, or a substituted or unsubstituted C5-10 aromatic ring, the substituent being one or more substances selected from the group consisting of hydrogen, halogen atoms, hydroxy, -OCF3, -NH2, -NHC1-4alkyl, -N(C1-4alkyl)2, -CONH2, -CONHC1-4alkyl, -CON(C1-4alkyl)2, -NHCOC1-4alkyl, C1-6alkyl, C1-6 alkoxy, or C3-6 cycloalkyl, and when two substituents are contained, the two substituents can form a ring structure together with the carbon connected thereto; and the halogen atoms are selected from the group consisting of F, Cl, or Br.

[0064] Described herein is a method of treating a disease mediated by THR- need thereof comprising: (i) measuring a first level of sex hormone binding globulin (SHBG) in the patient prior to (ii); (ii) administering a thyroid hormone receptor-(iii) after a first time period following (ii), measuring a second level of SHBG in the patient; (iv) determining a percentage increase between the first level of SHBG and the second level of SHBG; and (v) administering the thyroid hormone receptor- to the patient if theSHBG level has increased. 16 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0065] Described herein is a method of treating a disease mediated by THR- need thereof comprising: (i) measuring a first level of sex hormone binding globulin (SHBG) in the patient prior to (ii); (ii) administering a thyroid hormone receptor-(iii) after a first time period following (ii), measuring a second level of SHBG in the patient; (iv) determining a percentage increase between the first level of SHBG and the second level of SHBG; and (v) administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the patient,Formula (I) wherein, R1is selected from the group consisting of hydrogen, cyano, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-6 cycloalkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C1-6 alkoxy; R2and R3are each independently selected from the group consisting of halogen atoms or substituted or unsubstituted C1-6 alkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C1-6 alkoxy; ring A is a substituted or unsubstituted saturated or unsaturated C5-10aliphatic ring, or a substituted or unsubstituted C5-10aromatic ring, the substituent being one or more substances selected from the group consisting of hydrogen, halogen atoms, hydroxy, -OCF3, -NH2, -NHC1-4alkyl, -N(C1-4alkyl)2, -CONH2, -CONHC1-4alkyl, -CON(C1-4alkyl)2, -NHCOC1-4alkyl, C1-6alkyl, C1-6alkoxy, or C3-6cycloalkyl, and when two substituents are contained, the two substituents can form a ring structure together with the carbon connected thereto; and the halogen atoms are selected from the group consisting of F, Cl, or Br. 17 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0066] Described herein is a method of treating MASH in a patient in need thereof comprising: (i) measuring a first level of sex hormone binding globulin (SHBG) in the patient prior to (ii); (ii) administering a thyroid hormone receptor-(iii) after a first time period following (ii), measuring a second level of SHBG in the patient; (iv) determining a percentage increase between the first level of SHBG and the second level of SHBG; and (v) administering the thyroid hormone receptor- to the patient if theSHBG level has increased.

[0067] Described herein is a method of treating MASH in a patient in need thereof comprising: (i) measuring a first level of sex hormone binding globulin (SHBG) in the patient prior to (ii); (ii) administering a thyroid hormone receptor-(iii) after a first time period following (ii), measuring a second level of SHBG in the patient; (iv) determining a percentage increase between the first level of SHBG and the second level of SHBG; and (v) administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the patient,Formula (I) wherein, R1is selected from the group consisting of hydrogen, cyano, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C3-6cycloalkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C1-6 alkoxy; 18 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 R2 and R3 are each independently selected from the group consisting of halogen atoms or substituted or unsubstituted C1-6 alkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C1-6alkoxy; ring A is a substituted or unsubstituted saturated or unsaturated C5-10aliphatic ring, or a substituted or unsubstituted C5-10 aromatic ring, the substituent being one or more substances selected from the group consisting of hydrogen, halogen atoms, hydroxy, -OCF3, -NH2, -NHC1-4alkyl, -N(C1-4alkyl)2, -CONH2, -CONHC1-4alkyl, -CON(C1-4alkyl)2, -NHCOC1-4alkyl,alkyl, C1-6 alkoxy, or C3-6 cycloalkyl, and when two substituents are contained, the two substituents can form a ring structure together with the carbon connected thereto; and the halogen atoms are selected from the group consisting of F, Cl, or Br.

[0068] Described herein is a treating method of monitoring treatment of MASH in a patient byinitiating a treatment by administering a thyroid hormone receptor- , or apharmaceutical composition comprising the thyroid hormone receptor- to the patient,determining percentage increase in the level of SHBG from baseline, and continuingadministration of the thyroid hormone receptor- , or the pharmaceutical compositioncomprising the thyroid hormone receptor- to the patient if the percentage increase inthe level of SHBG is at least 50% from baseline.

[0069] Described herein is a treating method of monitoring treatment of MASH in a patient by initiating a treatment by administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the patient, determining percentage increase in the level of SHBG from baseline, and continuing administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the patient if the percentage increase in the level of SHBG is at least 50% from baseline.

[0070] Described herein is a treating method of monitoring treatment of MASH in a patient by initiating a treatment by administering Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof to the patient, determining percentage increase in the level of SHBG from baseline, and continuing administration of Compound 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising Compound 1 or a pharmaceutically 19 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 acceptable salt thereof to the patient if the percentage increase in the level of SHBG is at least 50% from baseline.

[0071] In some embodiments, described herein is a method of monitoring treatment of MASH in a patient, the method comprising: (i) obtaining a first test sample from the patient, (ii) measuring level of SHBG in the first test sample, (iii) initiating a treatment by administering a thyroid hormone receptor- , or apharmaceutical composition comprising the thyroid hormone receptor- to the patient,(iv) obtaining a second test sample from the patient after a first time period, (v) measuring the level of SHBG in the second test sample, (vi) determining percentage increase in the level of SHBG from baseline, and (vii) continuing administration of the thyroid hormone receptor- , or thepharmaceutical composition comprising the thyroid hormone receptor- to the patientif the percentage increase in the level of SHBG is at least 50% from baseline.

[0072] In some embodiments, described herein is a method of monitoring treatment of MASH in a patient, the method comprising: (i) obtaining a first test sample from the patient, (ii) measuring level of SHBG in the first test sample, (iii) initiating a treatment by administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the patient,Formula (I) wherein, 20 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 R1 is selected from the group consisting of hydrogen, cyano, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-6 cycloalkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C1-6alkoxy; R2and R3are each independently selected from the group consisting of halogen atoms or substituted or unsubstituted C1-6 alkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C1-6alkoxy; ring A is a substituted or unsubstituted saturated or unsaturated C5-10aliphatic ring, or a substituted or unsubstituted C5-10 aromatic ring, the substituent being one or more substances selected from the group consisting of hydrogen, halogen atoms, hydroxy, -OCF3, -NH2, -NHC1-4alkyl, -N(C1-4alkyl)2, -CONH2, -CONHC1-4alkyl, -CON(C1-4alkyl)2, -NHCOC1-4alkyl, C1-6alkyl, C1-6 alkoxy, or C3-6 cycloalkyl, and when two substituents are contained, the two substituents can form a ring structure together with the carbon connected thereto; and the halogen atoms are selected from the group consisting of F, Cl, or Br, (iv) obtaining a second test sample from the patient after a first time period, (v) measuring the level of SHBG in the second test sample, (vi) determining percentage increase in the level of SHBG from baseline, and (vii) continuing administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the patient if the percentage increase in the level of SHBG is at least 50% from baseline.

[0073] In some embodiments, described herein is a method of monitoring treatment of MASH in a patient, the method comprising: (i) obtaining a first test sample from the patient, (ii) measuring level of SHBG in the first test sample, (iii) initiating a treatment by administering Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof to the patient, (iv) obtaining a second test sample from the patient after a first time period, (v) measuring the level of SHBG in the second test sample, 21 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 (vi) determining percentage increase in the level of SHBG from baseline, and (vii) continuing administration of Compound 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof to the patient if the percentage increase in the level of SHBG is at least 50% from baseline.

[0074] In some embodiments, described herein is a method of monitoring treatment of MASH in a patient, the method comprising: (i) obtaining a first test sample from the patient, (ii) measuring level of SHBG in the first test sample, (iii) initiating a treatment by administering a combination comprising Compound 1 or a pharmaceutically acceptable salt thereof and Compound 2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof and Compound 2 or a pharmaceutically acceptable salt thereof to the patient, (iv) obtaining a second test sample from the patient after a first time period, (v) measuring the level of SHBG in the second test sample, (vi) determining percentage increase in the level of SHBG from baseline, and (vii) continuing administration of the combination comprising Compound 1 or a pharmaceutically acceptable salt thereof and Compound 2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof and Compound 2 or a pharmaceutically acceptable salt thereof to the patient if the percentage increase in the level of SHBG is at least 50% from baseline.

[0075] In some embodiments, the first time period is 1 week.

[0076] In some embodiments, the first time period is 2 weeks.

[0077] In some embodiments, the first time period is 3 weeks.

[0078] In some embodiments, the first time period is 4 weeks.

[0079] In some embodiments, the first time period is 5 weeks.

[0080] In some embodiments, the first time period is 6 weeks. 22 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0081] In some embodiments, the first time period is 7 weeks.

[0082] In some embodiments, the first time period is 8 weeks.

[0083] In some embodiments, the first time period is 9 weeks.

[0084] In some embodiments, the first time period is 10 weeks.

[0085] In some embodiments, the first time period is 11 weeks.

[0086] In some embodiments, the first time period is 12 weeks.

[0087] In some embodiments, the first time period is 13 weeks.

[0088] In some embodiments, the first time period is 14 weeks.

[0089] In some embodiments, the first time period is 15 weeks.

[0090] In some embodiments, the first time period is 16 weeks.

[0091] In some embodiments, the first time period is 17 weeks.

[0092] In some embodiments, the first time period is 18 weeks.

[0093] In some embodiments, the first time period is 19 weeks.

[0094] In some embodiments, the first time period is 20 weeks.

[0095] In some embodiments, the predetermined percentage is a percentage increase between the first level of SHBG and the second level of SHBG.

[0096] In some embodiments, the percentage increase in the level of SHBG is at least about 50% from baseline.

[0097] In some embodiments, the percentage increase in the level of SHBG is at least about 55% from baseline.

[0098] In some embodiments, the percentage increase in the level of SHBG is at least about 60% from baseline.

[0099] In some embodiments, the percentage increase in the level of SHBG is at least about 65% from baseline.

[0100] In some embodiments, the percentage increase in the level of SHBG is at least about 70% from baseline. 23 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0101] In some embodiments, the percentage increase in the level of SHBG is at least about 75% from baseline.

[0102] In some embodiments, the percentage increase in the level of SHBG is at least about 80% from baseline.

[0103] In some embodiments, the percentage increase in the level of SHBG is at least about 85% from baseline.

[0104] In some embodiments, the percentage increase in the level of SHBG is at least about 90% from baseline.

[0105] In some embodiments, the percentage increase in the level of SHBG is at least about 95% from baseline.

[0106] In some embodiments, the percentage increase in the level of SHBG is at least about 100% from baseline.

[0107] In some embodiments, the percentage increase in the level of SHBG is at least about 105% from baseline.

[0108] In some embodiments, the percentage increase in the level of SHBG is at least about 110% from baseline.

[0109] In some embodiments, the percentage increase in the level of SHBG is at least about 115% from baseline.

[0110] In some embodiments, the percentage increase in the level of SHBG is at least about 120% from baseline.

[0111] In some embodiments, the percentage increase in the level of SHBG is at least about 125% from baseline.

[0112] In some embodiments, the percentage increase in the level of SHBG is at least about 130% from baseline.

[0113] In some embodiments, the percentage increase in the level of SHBG is at least about 135% from baseline.

[0114] In some embodiments, the percentage increase in the level of SHBG is at least about 140% from baseline. 24 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0115] In some embodiments, the percentage increase in the level of SHBG is at least about 145% from baseline.

[0116] In some embodiments, the percentage increase in the level of SHBG is at least about 150% from baseline.

[0117] In some embodiments, the percentage increase in the level of SHBG is from about 50% to about 150% from baseline.

[0118] In some embodiments, the percentage increase in the level of SHBG is from about 60% to about 150% from baseline.

[0119] In some embodiments, the percentage increase in the level of SHBG is from about 70% to about 150% from baseline.

[0120] In some embodiments, the percentage increase in the level of SHBG is from about 80% to about 150% from baseline.

[0121] In some embodiments, the percentage increase in the level of SHBG is from about 90% to about 150% from baseline.

[0122] In some embodiments, the percentage increase in the level of SHBG is from about 100% to about 150% from baseline.

[0123] In some embodiments, the percentage increase in the level of SHBG is from about 110% to about 150% from baseline.

[0124] In some embodiments, the percentage increase in the level of SHBG is from about 120% to about 150% from baseline.

[0125] In some embodiments, the percentage increase in the level of SHBG is from about 130% to about 150% from baseline.

[0126] In some embodiments, the percentage increase in the level of SHBG is from about 140% to about 150% from baseline.

[0127] In some embodiments, the percentage increase in the level of SHBG is from about 50% to about 140% from baseline.

[0128] In some embodiments, the percentage increase in the level of SHBG is from about 60% to about 140% from baseline. 25 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0129] In some embodiments, the percentage increase in the level of SHBG is from about 70% to about 140% from baseline.

[0130] In some embodiments, the percentage increase in the level of SHBG is from about 80% to about 140% from baseline.

[0131] In some embodiments, the percentage increase in the level of SHBG is from about 90% to about 140% from baseline.

[0132] In some embodiments, the percentage increase in the level of SHBG is from about 100% to about 140% from baseline.

[0133] In some embodiments, the percentage increase in the level of SHBG is from about 110% to about 140% from baseline.

[0134] In some embodiments, the percentage increase in the level of SHBG is from about 120% to about 140% from baseline.

[0135] In some embodiments, the percentage increase in the level of SHBG is from about 130% to about 140% from baseline.

[0136] In some embodiments, the percentage increase in the level of SHBG is from about 50% to about 130% from baseline.

[0137] In some embodiments, the percentage increase in the level of SHBG is from about 60% to about 130% from baseline.

[0138] In some embodiments, the percentage increase in the level of SHBG is from about 70% to about 130% from baseline.

[0139] In some embodiments, the percentage increase in the level of SHBG is from about 80% to about 130% from baseline.

[0140] In some embodiments, the percentage increase in the level of SHBG is from about 90% to about 130% from baseline.

[0141] In some embodiments, the percentage increase in the level of SHBG is from about 100% to about 130% from baseline.

[0142] In some embodiments, the percentage increase in the level of SHBG is from about 110% to about 130% from baseline. 26 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0143] In some embodiments, the percentage increase in the level of SHBG is from about 120% to about 130% from baseline.

[0144] In some embodiments, the percentage increase in the level of SHBG is from about 50% to about 120% from baseline.

[0145] In some embodiments, the percentage increase in the level of SHBG is from about 60% to about 120% from baseline.

[0146] In some embodiments, the percentage increase in the level of SHBG is from about 70% to about 120% from baseline.

[0147] In some embodiments, the percentage increase in the level of SHBG is from about 80% to about 120% from baseline.

[0148] In some embodiments, the percentage increase in the level of SHBG is from about 90% to about 120% from baseline.

[0149] In some embodiments, the percentage increase in the level of SHBG is from about 100% to about 120% from baseline.

[0150] In some embodiments, the percentage increase in the level of SHBG is from about 110% to about 120% from baseline.

[0151] In some embodiments, the percentage increase in the level of SHBG is from about 50% to about 110% from baseline.

[0152] In some embodiments, the percentage increase in the level of SHBG is from about 60% to about 110% from baseline.

[0153] In some embodiments, the percentage increase in the level of SHBG is from about 70% to about 110% from baseline.

[0154] In some embodiments, the percentage increase in the level of SHBG is from about 80% to about 110% from baseline.

[0155] In some embodiments, the percentage increase in the level of SHBG is from about 90% to about 110% from baseline.

[0156] In some embodiments, the percentage increase in the level of SHBG is from about 100% to about 110% from baseline. 27 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0157] In some embodiments, the percentage increase in the level of SHBG is from about 50% to about 100% from baseline.

[0158] In some embodiments, the percentage increase in the level of SHBG is from about 60% to about 100% from baseline.

[0159] In some embodiments, the percentage increase in the level of SHBG is from about 70% to about 100% from baseline.

[0160] In some embodiments, the percentage increase in the level of SHBG is from about 80% to about 100% from baseline.

[0161] In some embodiments, the percentage increase in the level of SHBG is from about 90% to about 100% from baseline.

[0162] In some embodiments, the percentage increase in the level of SHBG is from about 50% to about 90% from baseline.

[0163] In some embodiments, the percentage increase in the level of SHBG is from about 60% to about 90% from baseline.

[0164] In some embodiments, the percentage increase in the level of SHBG is from about 70% to about 90% from baseline.

[0165] In some embodiments, the percentage increase in the level of SHBG is from about 80% to about 90% from baseline.

[0166] In some embodiments, the percentage increase in the level of SHBG is from about 50% to about 80% from baseline.

[0167] In some embodiments, the percentage increase in the level of SHBG is from about 60% to about 80% from baseline.

[0168] In some embodiments, the percentage increase in the level of SHBG is from about 70% to about 80% from baseline.

[0169] In some embodiments, the percentage increase in the level of SHBG is from about 50% to about 70% from baseline.

[0170] In some embodiments, the percentage increase in the level of SHBG is from about 60% to about 70% from baseline. 28 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0171] In some embodiments, the percentage increase in the level of SHBG is from about 50% to about 60% from baseline.

[0172] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 50%.

[0173] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 55%.

[0174] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 60%.

[0175] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 65%.

[0176] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 70%.

[0177] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 75%.

[0178] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 80%.

[0179] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 85%.

[0180] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 90%.

[0181] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 95%.

[0182] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 100%.

[0183] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 105%.

[0184] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 110%. 29 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0185] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 115%.

[0186] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 120%.

[0187] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 125%.

[0188] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 130%.

[0189] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 135%.

[0190] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 140%.

[0191] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 145%.

[0192] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is at least about 150%.

[0193] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 50% to about 150%.

[0194] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 60% to about 150%.

[0195] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 70% to about 150%.

[0196] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 80% to about 150%.

[0197] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 90% to about 150%.

[0198] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 100% to about 150%. 30 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0199] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 110% to about 150%.

[0200] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 120% to about 150%.

[0201] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 130% to about 150%.

[0202] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 140% to about 150%.

[0203] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 50% to about 140%.

[0204] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 60% to about 140%.

[0205] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 70% to about 140%.

[0206] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 80% to about 140%.

[0207] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 90% to about 140%.

[0208] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 100% to about 140%.

[0209] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 110% to about 140%.

[0210] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 120% to about 140%.

[0211] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 130% to about 140%.

[0212] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 50% to about 130%. 31 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0213] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 60% to about 130%.

[0214] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 70% to about 130%.

[0215] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 80% to about 130%.

[0216] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 90% to about 130%.

[0217] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 100% to about 130%.

[0218] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 110% to about 130%.

[0219] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 120% to about 130%.

[0220] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 50% to about 120%.

[0221] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 60% to about 120%.

[0222] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 70% to about 120%.

[0223] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 80% to about 120%.

[0224] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 90% to about 120%.

[0225] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 100% to about 120%.

[0226] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 110% to about 120%. 32 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0227] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 50% to about 110%.

[0228] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 60% to about 110%.

[0229] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 70% to about 110%.

[0230] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 80% to about 110%.

[0231] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 90% to about 110%.

[0232] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 100% to about 110%.

[0233] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 50% to about 100%.

[0234] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 60% to about 100%.

[0235] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 70% to about 100%.

[0236] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 80% to about 100%.

[0237] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 90% to about 100%.

[0238] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 50% to about 90%.

[0239] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 60% to about 90%.

[0240] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 70% to about 90%. 33 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0241] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 80% to about 90%.

[0242] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 50% to about 80%.

[0243] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 60% to about 80%.

[0244] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 70% to about 80%.

[0245] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 50% to about 70%.

[0246] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 60% to about 70%.

[0247] In some embodiments, the percentage increase between the first level of SHBG and the second level of SHBG is from about 50% to about 60%.

[0248] In some embodiments, the thyroid hormone receptor- of about 1 mg.

[0249] In some embodiments, the thyroid hormone receptor- of about 3 mg.

[0250] In some embodiments, the thyroid hormone receptor- of about 6 mg.

[0251] In some embodiments, the thyroid hormone receptor- of about 10 mg.

[0252] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg.

[0253] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 3 mg.

[0254] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 6 mg. 34 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0255] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 mg.

[0256] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg.

[0257] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered at a dose of about 3 mg.

[0258] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered at a dose of about 6 mg.

[0259] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 mg.

[0260] In some embodiments, Compound 2 or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg.

[0261] In some embodiments, Compound 2 or a pharmaceutically acceptable salt thereof is administered at a dose of about 3 mg.

[0262] In some embodiments, Compound 2 or a pharmaceutically acceptable salt thereof is administered at a dose of about 6 mg.

[0263] In some embodiments, Compound 2 or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 mg.

[0264] In some embodiments, the method results in a decrease in Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF).

[0265] In some embodiments, the method results in a decrease in MRI-PDFF from baseline.

[0266] In some embodiments, the decrease in MRI-PDFF is at least 10% from baseline.

[0267] In some embodiments, the decrease in MRI-PDFF is at least 15% from baseline.

[0268] In some embodiments, the decrease in MRI-PDFF is at least 20% from baseline.

[0269] In some embodiments, the decrease in MRI-PDFF is at least 25% from baseline.

[0270] In some embodiments, the decrease in MRI-PDFF is at least 30% from baseline.

[0271] In some embodiments, the decrease in MRI-PDFF is at least 35% from baseline.

[0272] In some embodiments, the decrease in MRI-PDFF is at least 40% from baseline. 35 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0273] In some embodiments, the decrease in MRI-PDFF is at least 45% from baseline.

[0274] In some embodiments, the decrease in MRI-PDFF is at least 50% from baseline.

[0275] In some embodiments, the decrease in MRI-PDFF is from about 10% to about 50% from baseline.

[0276] In some embodiments, the decrease in MRI-PDFF is from about 10% to about 40% from baseline.

[0277] In some embodiments, the decrease in MRI-PDFF is from about 10% to about 30% from baseline.

[0278] In some embodiments, the decrease in MRI-PDFF is from about 10% to about 20% from baseline.

[0279] In some embodiments, the decrease in MRI-PDFF is from about 20% to about 50% from baseline.

[0280] In some embodiments, the decrease in MRI-PDFF is from about 20% to about 40% from baseline.

[0281] In some embodiments, the decrease in MRI-PDFF is from about 20% to about 30% from baseline.

[0282] In some embodiments, the decrease in MRI-PDFF is from about 30% to about 50% from baseline.

[0283] In some embodiments, the decrease in MRI-PDFF is from about 30% to about 40% from baseline.

[0284] In some embodiments, the decrease in MRI-PDFF is from about 40% to about 50% from baseline.

[0285] In some embodiments, the first time period is 4 weeks and the percentage increase in the level of SHBG is at least 50% from baseline.

[0286] In some embodiments, the first time period is 4 weeks and the percentage increase in the level of SHBG is at least 60% from baseline.

[0287] In some embodiments, the first time period is 4 weeks and the percentage increase in the level of SHBG is at least 70% from baseline. 36 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0288] In some embodiments, the first time period is 4 weeks and the percentage increase in the level of SHBG is at least 80% from baseline.

[0289] In some embodiments, the first time period is 4 weeks and the percentage increase in the level of SHBG is at least 90% from baseline.

[0290] In some embodiments, the first time period is 4 weeks and the percentage increase in the level of SHBG is at least 100% from baseline.

[0291] In some embodiments, the first time period is 4 weeks and the percentage increase in the level of SHBG is at least 110% from baseline.

[0292] In some embodiments, the first time period is 4 weeks and the percentage increase in the level of SHBG is at least 120% from baseline.

[0293] In some embodiments, the first time period is 4 weeks and the percentage increase in the level of SHBG is at least 130% from baseline.

[0294] In some embodiments, the first time period is 4 weeks and the percentage increase in the level of SHBG is at least 140% from baseline.

[0295] In some embodiments, the first time period is 4 weeks and the percentage increase in the level of SHBG is at least 150% from baseline.

[0296] In some embodiments, the first time period is 6 weeks and the percentage increase in the level of SHBG is at least 50% from baseline.

[0297] In some embodiments, the first time period is 6 weeks and the percentage increase in the level of SHBG is at least 60% from baseline.

[0298] In some embodiments, the first time period is 6 weeks and the percentage increase in the level of SHBG is at least 70% from baseline.

[0299] In some embodiments, the first time period is 6 weeks and the percentage increase in the level of SHBG is at least 80% from baseline.

[0300] In some embodiments, the first time period is 6 weeks and the percentage increase in the level of SHBG is at least 90% from baseline.

[0301] In some embodiments, the first time period is 6 weeks and the percentage increase in the level of SHBG is at least 100% from baseline. 37 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0302] In some embodiments, the first time period is 6 weeks and the percentage increase in the level of SHBG is at least 110% from baseline.

[0303] In some embodiments, the first time period is 6 weeks and the percentage increase in the level of SHBG is at least 120% from baseline.

[0304] In some embodiments, the first time period is 6 weeks and the percentage increase in the level of SHBG is at least 130% from baseline.

[0305] In some embodiments, the first time period is 6 weeks and the percentage increase in the level of SHBG is at least 140% from baseline.

[0306] In some embodiments, the first time period is 6 weeks and the percentage increase in the level of SHBG is at least 150% from baseline.

[0307] In some embodiments, the first time period is 8 weeks and the percentage increase in the level of SHBG is at least 50% from baseline.

[0308] In some embodiments, the first time period is 8 weeks and the percentage increase in the level of SHBG is at least 60% from baseline.

[0309] In some embodiments, the first time period is 8 weeks and the percentage increase in the level of SHBG is at least 70% from baseline.

[0310] In some embodiments, the first time period is 8 weeks and the percentage increase in the level of SHBG is at least 80% from baseline.

[0311] In some embodiments, the first time period is 8 weeks and the percentage increase in the level of SHBG is at least 90% from baseline.

[0312] In some embodiments, the first time period is 8 weeks and the percentage increase in the level of SHBG is at least 100% from baseline.

[0313] In some embodiments, the first time period is 8 weeks and the percentage increase in the level of SHBG is at least 110% from baseline.

[0314] In some embodiments, the first time period is 8 weeks and the percentage increase in the level of SHBG is at least 120% from baseline.

[0315] In some embodiments, the first time period is 8 weeks and the percentage increase in the level of SHBG is at least 130% from baseline. 38 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0316] In some embodiments, the first time period is 8 weeks and the percentage increase in the level of SHBG is at least 140% from baseline.

[0317] In some embodiments, the first time period is 8 weeks and the percentage increase in the level of SHBG is at least 150% from baseline.

[0318] In some embodiments, the first time period is 10 weeks and the percentage increase in the level of SHBG is at least 50% from baseline.

[0319] In some embodiments, the first time period is 10 weeks and the percentage increase in the level of SHBG is at least 60% from baseline.

[0320] In some embodiments, the first time period is 10 weeks and the percentage increase in the level of SHBG is at least 70% from baseline.

[0321] In some embodiments, the first time period is 10 weeks and the percentage increase in the level of SHBG is at least 80% from baseline.

[0322] In some embodiments, the first time period is 10 weeks and the percentage increase in the level of SHBG is at least 90% from baseline.

[0323] In some embodiments, the first time period is 10 weeks and the percentage increase in the level of SHBG is at least 100% from baseline.

[0324] In some embodiments, the first time period is 10 weeks and the percentage increase in the level of SHBG is at least 110% from baseline.

[0325] In some embodiments, the first time period is 10 weeks and the percentage increase in the level of SHBG is at least 120% from baseline.

[0326] In some embodiments, the first time period is 10 weeks and the percentage increase in the level of SHBG is at least 130% from baseline.

[0327] In some embodiments, the first time period is 10 weeks and the percentage increase in the level of SHBG is at least 140% from baseline.

[0328] In some embodiments, the first time period is 10 weeks and the percentage increase in the level of SHBG is at least 150% from baseline.

[0329] In some embodiments, the first time period is 12 weeks and the percentage increase in the level of SHBG is at least 50% from baseline. 39 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0330] In some embodiments, the first time period is 12 weeks and the percentage increase in the level of SHBG is at least 60% from baseline.

[0331] In some embodiments, the first time period is 12 weeks and the percentage increase in the level of SHBG is at least 70% from baseline.

[0332] In some embodiments, the first time period is 12 weeks and the percentage increase in the level of SHBG is at least 80% from baseline.

[0333] In some embodiments, the first time period is 12 weeks and the percentage increase in the level of SHBG is at least 90% from baseline.

[0334] In some embodiments, the first time period is 12 weeks and the percentage increase in the level of SHBG is at least 100% from baseline.

[0335] In some embodiments, the first time period is 12 weeks and the percentage increase in the level of SHBG is at least 110% from baseline.

[0336] In some embodiments, the first time period is 12 weeks and the percentage increase in the level of SHBG is at least 120% from baseline.

[0337] In some embodiments, the first time period is 12 weeks and the percentage increase in the level of SHBG is at least 130% from baseline.

[0338] In some embodiments, the first time period is 12 weeks and the percentage increase in the level of SHBG is at least 140% from baseline.

[0339] In some embodiments, the first time period is 12 weeks and the percentage increase in the level of SHBG is at least 150% from baseline.

[0340] In some embodiments, when the first time period is 12 weeks, the patient achieves a percentage increase in the level of SHBG of at least 70% from baseline and achieves a reduction in MRI-PDFF of at least 30% at week 12.

[0341] In some embodiments, when the first time period is 12 weeks, the patient achieves a percentage increase in the level of SHBG of at least 120% from baseline and achieves a reduction in MRI-PDFF of at least 30% at week 12.

[0342] In some embodiments, when the first time period is 6 weeks, the patient achieves a percentage increase in the level of SHBG of at least 70% from baseline after the 6 weeks and 40 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 achieves a reduction in MRI-PDFF of at least 30% at week 12 (i.e. 6 weeks after the first time period).

[0343] In some embodiments, when the first time period is 6 weeks, the patient achieves a percentage increase in the level of SHBG of at least 120% from baseline after the 6 weeks and achieves a reduction in MRI-PDFF of at least 30% at week 12 (i.e. 6 weeks after the first time period).

[0344] In some embodiments, the patient does not require imaging to monitor response to treatment.

[0345] In some embodiments, the patient does not require magnetic resonance-based imaging to monitor response to treatment.

[0346] In some embodiments, the method results in a decrease in liver fat content.

[0347] In some embodiments, level of SHBG is used to monitor the treatment on or after 6 weeks from initiating the treatment.

[0348] Furthermore, described herein is a treating method of monitoring treatment of a disease or disorder in a patient by initiating a treatment by administering a thyroid hormone receptor- ,or a pharmaceutical composition comprising the thyroid hormone receptor-to the patient, determining percentage increase in the level of SHBG from baseline, andcontinuing administration of the thyroid hormone receptor- , or the pharmaceuticalcomposition comprising the thyroid hormone receptor- to the patient if the percentageincrease in the level of SHBG is at least 50% from baseline.

[0349] In some embodiments, the method results in a decrease in corrected T1 (cT1).

[0350] In some embodiments, the MASH patients undergoing treatment have an iron-corrected T1 mapping (cT1) value of greater than 900 msec prior to treatment. In particular embodiments, the cT1 mapping score of the patients prior to treatment is between about 925 msec to about 1,100 msec. In certain embodiments, the cT1 of the patient decreases by greater than 50 msec following once oral daily administration of the compound of Formula (I), Compound 1, or Compound 2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I), Compound 1, or Compound 2 or a pharmaceutically acceptable salt thereof for a sufficient time period (e.g., after 6 weeks, after 12 weeks, after 24 weeks or after 52 weeks), wherein the cT1 is measured at the steady state concentration of the 41 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 compound of Formula (I), Compound 1, or Compound 2 or a pharmaceutically acceptable salt thereof. In other embodiments, the cT1 of the patient decreases from about 50 msec to about 100 msec following once daily oral administration of the compound of Formula (I), Compound 1, or Compound 2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I), Compound 1, or Compound 2 or a pharmaceutically acceptable salt thereof for a sufficient time period. In other embodiments, the cT1 of the patient decreases from about 60 msec to about 100 msec following once daily oral administration of the compound of Formula (I), Compound 1, or Compound 2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Formula (I), Compound 1, or Compound 2 or a pharmaceutically acceptable salt thereof for a sufficient time period. In other embodiments, the cT1 of the patient decreases from about 60 msec to about 90 msec following once daily oral administration of the compound of Formula (I), Compound 1, or Compound 2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I), Compound 1, or Compound 2 or a pharmaceutically acceptable salt thereof for a sufficient time period. In other embodiments, the cT1 of the patient decreases from about 70 msec to about 95 msec following once daily oral administration of the compound of Formula (I), Compound 1, or Compound 2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I), Compound 1, or Compound 2 or a pharmaceutically acceptable salt thereof for a sufficient time period. In other embodiments, the cT1 of the patient decreases from about 70 msec to about 85 msec following once daily oral administration of the compound of Formula (I), Compound 1, or Compound 2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I), Compound 1, or Compound 2 or a pharmaceutically acceptable salt thereof for a sufficient time period.

[0351] In some embodiments, the disease or disorder is diabetes, MASH, insulinoma, obesity, and / or hyperglycemia.

[0352] In some embodiments, the disease or disorder is obesity.

[0353] In accordance with the present application, a disease or condition to be treated and / or prevented is selected from the group consisting of cardiometabolic and associated diseases including diabetes (T1 D and / or T2DM, including pre-diabetes), idiopathic T1 D (Type 1 b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related 42 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea, obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain from use of other agents (e.g., from use of steroids and antipsychotics), excessive sugar craving, dyslipidemia (including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL cholesterol, and low HDL cholesterol), hyperinsulinemia, liver diseases such as NAFLD, steatosis, NASH, fibrosis, cirrhosis, and hepatocellular carcinoma, cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson’s Disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, Polycystic Ovary Syndrome and addiction (e.g., alcohol and / or drug abuse), prevention or treatment of Polycystic Ovary Syndrome and treatment of addiction (e.g., alcohol and / or drug abuse).

[0354] In some embodiments, the disease or disorder is a liver disorder. Exemplary liver disorders include, without limitation, liver inflammation, fibrosis, and steatohepatitis.

[0355] In some embodiments, the liver disorder is selected from the list consisting of primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, 43 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren’s syndrome, sarcoidosis, Wilson’s disease, Gaucher’s disease, hemochromatosis, and oti- antitrypsin deficiency.

[0356] In some embodiments, the liver disorder is selected from the list consisting of liver inflammation, liver fibrosis, alcohol induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH).

[0357] In some embodiments, the patient has had a liver biopsy. In some embodiments, the method further comprising obtaining the results of a liver biopsy.

[0358] The risk for MASH increases with age, but children can also suffer from MASH. 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.

[0359] MASH are common causes of liver transplantation, but patients that already received one liver transplant often develop MASH again. Accordingly, in some embodiments, the patient has had a liver transplant. Routes of Administration

[0360] The compounds or pharmaceutical compositions of the present disclosure may be administered alone as a sole therapy or can be administered in addition with one or more other substances and / or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.

[0361] For example, therapeutic effectiveness may be enhanced by administration of an adjuvant (i.e. by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, the benefit experienced by an individual may be increased by administering the compound of Formula (I), Compound 1, or Compound 44 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 2 or a pharmaceutically acceptable salt thereof with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[0362] The compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0363] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray or powder); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. Compositions

[0364] In some embodiments, the pharmaceutical compositions comprising a solid dispersion of the compound of Formula (I), Compound 1, or Compound 2, 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.

[0365] 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. 45 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 Examples of disintegrants include, but are not limited to, maize starch, sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, modified corn starch, sodium carboxymethyl starch, povidone, pregelatinized starch, and alginic acid. In some embodiments, the disintegrant comprises crospovidone.

[0366] In some embodiments, the pharmaceutically acceptable excipient comprises a glidant. As used herein, the term “glidant” refers to a substance used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anti-caking 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.

[0367] 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).

[0368] Compositions comprising two compounds (e.g., the compound of Formula (I), Compound 1, and Compound 2, or a pharmaceutically acceptable salt thereof) utilized herein are described. Any of the compounds described herein can be formulated in a tablet in any dosage form described herein. Exemplary Embodiments

[0369] The present disclosure is further described by the following embodiments. The features of each of the embodiments are combinable with any of the other embodiments where appropriate and practical.

[0370] Embodiment 1. A method of monitoring treatment of metabolic dysfunction-associated steatohepatitis (MASH) in a patient, the method comprising: (i) obtaining a first test sample from the patient, (ii) measuring level of sex hormone binding globulin (SHBG) in the first test sample, (iii) initiating a treatment by administering a thyroid hormone receptor- , or apharmaceutical composition comprising the thyroid hormone receptor- to the patient,46 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 (iv) obtaining a second test sample from the patient after a first time period, (v) measuring the level of SHBG in the second test sample, (vi) determining percentage increase in the level of SHBG from baseline, and (vii) continuing administration of the thyroid hormone receptor- , or thepharmaceutical composition comprising the thyroid hormone receptor- to the patientif the percentage increase in the level of SHBG is at least 50% from baseline.

[0371] Embodiment 2. A method of monitoring treatment of metabolic dysfunction-associated steatohepatitis (MASH) in a patient, the method comprising: (i) obtaining a first test sample from the patient, (ii) measuring level of sex hormone binding globulin (SHBG) in the first test sample, (iii) initiating a treatment by administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the patient,Formula (I) wherein, R1 is selected from the group consisting of hydrogen, cyano, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-6 cycloalkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C1-6alkoxy; R2 and R3 are each independently selected from the group consisting of halogen atoms or substituted or unsubstituted C1-6 alkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C1-6alkoxy; ring A is a substituted or unsubstituted saturated or unsaturated C5-10aliphatic ring, or a substituted or unsubstituted C5-10 aromatic ring, the substituent being one or more substances selected from the group consisting of hydrogen, halogen atoms, hydroxy, -OCF3, -NH2, -NHC1-4alkyl, -N(C1-4alkyl)2, -CONH2, -CONHC1-4alkyl, -CON(C1-4alkyl)2, -NHCOC1-4alkyl, C1-647 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 alkyl, C1-6 alkoxy, or C3-6 cycloalkyl, and when two substituents are contained, the two substituents can form a ring structure together with the carbon connected thereto; and the halogen atoms are selected from the group consisting of F, Cl, or Br, (iv) obtaining a second test sample from the patient after a first time period, (v) measuring the level of SHBG in the second test sample, (vi) determining percentage increase in the level of SHBG from baseline, and (vii) continuing administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the compound ofFormula (I) or a pharmaceutically acceptable salt thereof to the patient if the percentageincrease in the level of SHBG is at least 50% from baseline.

[0372] Embodiment 3. A method of monitoring treatment of metabolic dysfunction-associatedsteatohepatitis (MASH) in a patient, the method comprising: (i) obtaining a first test sample from the patient, (ii) measuring level of sex hormone binding globulin (SHBG) in the first test sample, (iii) initiating a treatment by administering Compound 1:(Compound 1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical compositioncomprising Compound 1 or a pharmaceutically acceptable salt thereof to the patient,(iv) obtaining a second test sample from the patient after a first time period, (v) measuring the level of SHBG in the second test sample, (vi) determining percentage increase in the level of SHBG from baseline, and 48 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 (vii) continuing administration of Compound 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof to the patient if the percentage increase in the level of SHBG is at least 50% from baseline.

[0373] Embodiment 4. The method of any one of embodiments 1-3, wherein the first time period is selected from 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or 20 weeks.

[0374] Embodiment 5. The method of any one of embodiments 1-4, wherein the percentage increase in the level of SHBG is at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 105%, at least about 110%, at least about 115%, at least about 120%, at least about 125%, at least about 130%, at least about 135%, at least about 140%, at least about 145%, or at least about 150% from baseline.

[0375] Embodiment 6. The method of any one of embodiments 1 and 4-5, wherein the thyroid hormone receptor- or about 10 mg.

[0376] Embodiment 7. The method of any one of embodiments 2 and 4-5, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg, about 3 mg, about 6 mg, or about 10 mg.

[0377] Embodiment 8. The method of any one of embodiments 3-5, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg, about 3 mg, about 6 mg, or about 10 mg.

[0378] Embodiment 9. The method of any one of embodiments 1-8, wherein the method results in a decrease in Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF).

[0379] Embodiment 10. The method of any one of embodiments 1-9, wherein the decrease in MRI-PDFF is at least 20% from baseline.

[0380] Embodiment 11. The method of any one of embodiments 1-10, wherein the decrease in MRI-PDFF is at least 30% from baseline. 49 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0381] Embodiment 12. The method of any one of embodiments 1-11, wherein the first time period is 6 weeks and the percentage increase in the level of SHBG is at least 70% from baseline.

[0382] Embodiment 13. The method of any one of embodiments 1-11, wherein the first time period is 6 weeks and the percentage increase in the level of SHBG is at least 120% from baseline.

[0383] Embodiment 14. The method of any one of embodiments 1-11, wherein the first time period is 12 weeks and the percentage increase in the level of SHBG is at least 70% from baseline.

[0384] Embodiment 15. The method of any one of embodiments 1-11, wherein the first time period is 12 weeks and the percentage increase in the level of SHBG is at least 120% from baseline.

[0385] Embodiment 16. The method of any one of embodiments 1-15, wherein the patient does not require imaging to monitor response to treatment.

[0386] Embodiment 17. The method of any one of embodiments 1-15, wherein the patient does not require magnetic resonance-based imaging to monitor response to treatment.

[0387] Embodiment 18. The method of any one of embodiments 1-17, wherein the method results in a decrease in liver fat content.

[0388] Embodiment 19. The method of any one of embodiments 1-17, wherein the method results in a decrease in corrected T1 (cT1).

[0389] Embodiment 20. The method of any one of embodiments 1-19, wherein level of SHBG is used to monitor the treatment on or after 6 weeks from initiating the treatment.

[0390] Embodiment 21. The method of any one of embodiments 1-9, wherein when the first time period is 12 weeks, the patient achieves a percentage increase in the level of SHBG of at least 70% from baseline and achieves a reduction in MRI-PDFF of at least 30% at week 12.

[0391] Embodiment 22. The method of any one of embodiments 1-9, wherein when the first time period is 12 weeks, the patient achieves a percentage increase in the level of SHBG of at least 120% from baseline and achieves a reduction in MRI-PDFF of at least 30% at week 12.

[0392] Embodiment 23. The method of any one of embodiments 1-9, wherein when the first time period is 6 weeks, the patient achieves a percentage increase in the level of SHBG of at 50 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 least 70% from baseline after the 6 weeks and achieves a reduction in MRI-PDFF of at least 30% at week 12 (i.e. 6 weeks after the first time period).

[0393] Embodiment 24. The method of any one of embodiments 1-9, wherein when the first time period is 6 weeks, the patient achieves a percentage increase in the level of SHBG of at least 120% from baseline after the 6 weeks and achieves a reduction in MRI-PDFF of at least 30% at week 12 (i.e. 6 weeks after the first time period). EXAMPLES

[0394] Example 1. Sex Hormone Binding Globulin as an Effective Predictor of TreatmentResponse to Compound 1, a Potent, Highly Selective Thyroid Hormone Receptor- Agonist:Post-Hoc Analyses From a 12-Week Phase 2a Trial

[0395] Thyroid hormone receptor- - , the major form of thyroid hormone receptor inthe liver, regulates key aspects of energy and lipid metabolism including liver fat removal via fatty acid oxidation. [Sinha R, et al. Nat Rev Endocrinol. 2018;14:259-269]. Compound 1 is apotent, highly selective THR- [Kirschberg et al. Journal of Hepatology 2020;73:S653-S915 (SAT066)].

[0396] In a 12-week, Phase 2a study, (FIG.1), in patients with clinically diagnosed or previous biopsy confirmed Metabolic Dysfunction-Associated Steatohepatitis (MASH), Compound 1 demonstrated significant, dose-dependent decreases in Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) baseline (FIG. 2) and a dose-dependent decrease in corrected T1 (cT1) with a favorable safety profile. [Noureddin et al. Hepatology. 79(2):E33-E85, February 2024 and Noureddin et al. Presented at AASLD The Liver Meeting 2023.] MRI- to histologic improvement in MASH. [Harrison et al. N Engl J Med. 2024;390:497-509].

[0397] Sex hormone binding globulin (SHBG), a protein produced in the liver in response toTHR- agonism, also significantly increased in a rapid, dose-dependent manner, demonstratingrobust target engagement (FIG. 2). [Noureddin et al. Hepatology. 79(2):E33- E85, February 2024 and Noureddin et al. Presented at AASLD The Liver Meeting 2023.] Both Compound 1 at 3 mg and 6 mg treatment groups have demonstrated statistically significant MRI-PDFF reduction and SHBG increase from baseline versus placebo.

[0398] -PDFF reduction in Phase 3 THR- agonist trials. [Harrison et al. N Engl J Med. 2024;390:497-51 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 509 and Harrison et al. Nat Med. 2023 Nov;29(11):2919-2928.] In this post-hoc analysis, the potential clinical utility of SHBG, a simple blood-based marker, in predicting or monitoring Compound 1’s efficacy as assessed or measured by MRI-PDFF was evaluated. i. Endpoints At Week 12

[0399] The primary endpoint is relative change in MRI-PDFF of Compound 1 versus placebo.a. ii. Key Entry Criteria Non-cirrhotic; presumed MASH Body Mass Index (BMI)2MRI-MRI-Hemoglobin A1c (HbA1c) Low Density Lipoprotein (LDL) <150 mg / dL; Triglycerides (TG) iii. Methods

[0400] MRI-PDFF was measured at baseline, week 6, and week 12 of the study. SHBG was measured at baseline, week 2, week 4, week 6, and week 12.

[0401] Receiver operating characteristic (ROC) curve was built to identify an optimal Compound 1 -PDFF reduction, a response criterion that has been linked to histologic improvement in MASH, at Week 12. Pooled data at Week 12 from the Compound 1 at 3 mg and 6 mg groups were used since both 3 mg and 6 mg groups demonstrated statistically significant MRI-PDFF reduction and SHBG increase from baseline versus placebo.

[0402] “High” category was defined as the subgroup who achieved the SHBG increase threshold. “Low” category was defined as those who did not achieve the SHBG increase threshold.

[0403] -PDFF reduction at Week 12 in “High” and “Low” subgroups was assessed using the following SHBG increase thresholds at Week 12: (a) the optimal SHBG increase threshold identified from the ROC curve, and (b) a previously 52 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 [Harrison et al. N Engl J Med. 2024;390:497- 509 and Harrison et al. Nat Med. 2023 Nov;29(11):2919-2928].

[0404] Since rapid SHBG increases were observed from DUET (as early as Week 6; FIG. 2), -PDFF reduction at Week 12 was also evaluated using the same SHBG increase thresholds at Week 6.

[0405] Finally, the performance of SHBG measured at Week 6 was evaluated as a predictor of MRI-PDFF response at Week 12. iv. Results

[0406] At Week 12, 39% (p<0.01) and 64% (p<0.001) of patients in the Compound 1 at 3mg MRI-PDFF reduction versus 4% of the patients in placebo.

[0407] MRI-PDFF reduction at Week 12 (sensitivity=80.7%; specificity=85.7%; AUROC=0.84) (FIG. 3).

[0408] -PDFF reduction at Week 12 compared to only 17% of patients with <70% SHBG increase (“Low”) (FIG. 4A). -PDFF reduction -PDFF reduction at Week 12 (FIG. 4B).

[0409] -PDFF reduction at Week 12 (FIG. 5A). -PDFF reduction at Week 12 compared to 30% of patients with <120% SHBG increase at Week 6 (FIG. 5B). v. Conclusions

[0410] Compound 1 led to significant, dose-dependent increases in SHBG indicating potentliver THR- target engagement and potential histologic improvement with Compound 1.

[0411] Treatment response to Compound 1 in patients with MASH may be effectively predicted or monitored, potentially as early as Week 6 with SHBG, a simple blood-based marker that measures Compound 1 target engagement. 53 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825

[0412] with Compound 1 treatment may not require MR-based imaging to monitor response to Compound 1 treatment.

[0413] Patients achieving a high SHBG increase with Compound 1 treatment may not require MR-based imaging to demonstrate liver fat reduction. EQUIVALENTS

[0414] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference.

[0415] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto. 54 319099089

Claims

Attorney Docket No.: TRPH-057 / 001WO 346923-2825 CLAIMS What is claimed is:

1. A method of treating metabolic dysfunction-associated steatohepatitis (MASH) in a patient in need thereof comprising: (i) measuring a first level of sex hormone binding globulin (SHBG) in the patient prior to (ii); (ii) administering a thyroid hormone receptor-(iii) after a first time period following (ii), measuring a second level of SHBG in the patient; (iv) determining a percentage increase between the first level of SHBG and the second level of SHBG; and (v) administering the thyroid hormone receptor- to the patient if theSHBG level has increased by a predetermined percentage.

2. A method of treating metabolic dysfunction-associated steatohepatitis (MASH) in a patient in need thereof comprising: (i) measuring a first level of sex hormone binding globulin (SHBG) in the patient prior to (ii); (ii) administering a thyroid hormone receptor-(iii) after a first time period following (ii), measuring a second level of SHBG in the patient; (iv) determining a percentage increase between the first level of SHBG and the second level of SHBG; and (v) administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the patient if the SHBG level has increased by a predetermined percentage,Formula (I) wherein, 55 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 R1 is selected from the group consisting of hydrogen, cyano, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-6 cycloalkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C1-6alkoxy; R2and R3are each independently selected from the group consisting of halogen atoms or substituted or unsubstituted C1-6 alkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C1-6alkoxy; ring A is a substituted or unsubstituted saturated or unsaturated C5-10aliphatic ring, or a substituted or unsubstituted C5-10 aromatic ring, the substituent being one or more substances selected from the group consisting of hydrogen, halogen atoms, hydroxy, -OCF3, -NH2, -NHC1-4alkyl, -N(C1-4alkyl)2, -CONH2, -CONHC1-4alkyl, -CON(C1-4alkyl)2, -NHCOC1-4alkyl, C1-6alkyl, C1-6 alkoxy, or C3-6 cycloalkyl, and when two substituents are contained, the two substituents can form a ring structure together with the carbon connected thereto; and the halogen atoms are selected from the group consisting of F, Cl, or Br.

3. A method of monitoring treatment of metabolic dysfunction-associated steatohepatitis (MASH) in a patient, the method comprising: (i) obtaining a first test sample from the patient, (ii) measuring level of sex hormone binding globulin (SHBG) in the first test sample, (iii) initiating a treatment by administering a thyroid hormone receptor- , or apharmaceutical composition comprising the thyroid hormone receptor- to the patient,(iv) obtaining a second test sample from the patient after a first time period, (v) measuring the level of SHBG in the second test sample, (vi) determining percentage increase in the level of SHBG from baseline, and (vii) continuing administration of the thyroid hormone receptor- , or thepharmaceutical composition comprising the thyroid hormone receptor- to the patientif the percentage increase in the level of SHBG is at least 50% from baseline.

4. A method of monitoring treatment of metabolic dysfunction-associated steatohepatitis (MASH) in a patient, the method comprising: (i) obtaining a first test sample from the patient, (ii) measuring level of sex hormone binding globulin (SHBG) in the first test sample, 56 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 (iii) initiating a treatment by administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the patient,Formula (I) wherein, R1is selected from the group consisting of hydrogen, cyano, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-6 cycloalkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C1-6alkoxy; R2and R3are each independently selected from the group consisting of halogen atoms or substituted or unsubstituted C1-6 alkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C1-6 alkoxy; ring A is a substituted or unsubstituted saturated or unsaturated C5-10aliphatic ring, or a substituted or unsubstituted C5-10 aromatic ring, the substituent being one or more substances selected from the group consisting of hydrogen, halogen atoms, hydroxy, -OCF3, -NH2, -NHC1-4alkyl, -N(C1-4alkyl)2, -CONH2, -CONHC1-4alkyl, -CON(C1-4alkyl)2, -NHCOC1-4alkyl,alkyl, C1-6 alkoxy, or C3-6 cycloalkyl, and when two substituents are contained, the two substituents can form a ring structure together with the carbon connected thereto; and the halogen atoms are selected from the group consisting of F, Cl, or Br, (iv) obtaining a second test sample from the patient after a first time period, (v) measuring the level of SHBG in the second test sample, (vi) determining percentage increase in the level of SHBG from baseline, and (vii) continuing administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the patient if the percentage increase in the level of SHBG is at least 50% from baseline.

5. A method of monitoring treatment of metabolic dysfunction-associated steatohepatitis (MASH) in a patient, the method comprising: (i) obtaining a first test sample from the patient, 57 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 (ii) measuring level of sex hormone binding globulin (SHBG) in the first test sample, (iii) initiating a treatment by administering Compound 1:(Compound 1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical compositioncomprising Compound 1 or a pharmaceutically acceptable salt thereof to the patient,(iv) obtaining a second test sample from the patient after a first time period, (v) measuring the level of SHBG in the second test sample, (vi) determining percentage increase in the level of SHBG from baseline, and (vii) continuing administration of Compound 1 or a pharmaceutically acceptable saltthereof, or the pharmaceutical composition comprising Compound 1 or a pharmaceuticallyacceptable salt thereof to the patient if the percentage increase in the level of SHBG is at least50% from baseline.

6. The method of any one of the previous claims, wherein the THR-B agonist is Compound 1, or a pharmaceutically acceptable salt thereof.

7. The method of any one of the previous claims, wherein the first time period is selected from 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or 20 weeks.

8. The method of any one of the previous claims, wherein the first time period is 6 weeks.

9. The method of any one of the previous claims, wherein the first time period is 12 weeks. 58 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 10. The method of any one of the previous claims, wherein the percentage increase between the first level of SHBG and the second level of SHBG is at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 105%, at least about 110%, at least about 115%, at least about 120%, at least about 125%, at least about 130%, at least about 135%, at least about 140%, at least about 145%, or at least about 150% from baseline.

11. The method of any one of the previous claims, wherein the percentage increase between the first level of SHBG and the second level of SHBG is at least 70%.

12. The method of any one of the previous claims, wherein the percentage increase between the first level of SHBG and the second level of SHBG is 70% to 100%.

13. The method of any one of the previous claims, wherein the thyroid hormonereceptor- about 3 mg, about 6 mg, or about10 mg.

14. The method of any one of the previous claims, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg, about 3 mg, about 6 mg, or about 10 mg.

15. The method of any one of the previous claims, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg, about 3 mg, about 6 mg, or about 10 mg.

16. The method of any one of the previous claims, wherein the method results in a decrease in Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF).

17. The method of any one of the previous claims, wherein the decrease in MRI- PDFF is at least 20% from baseline. 59 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 18. The method of any one of the previous claims, wherein the decrease in MRI- PDFF is at least 30% from baseline.

19. The method of any one of the previous claims, wherein the first time period is 6 weeks and the percentage increase in the level of SHBG is at least 70% from baseline.

20. The method of any one of the previous claims, wherein the first time period is 6 weeks and the percentage increase in the level of SHBG is at least 120% from baseline.

21. The method of any one of the previous claims, wherein the first time period is 12 weeks and the percentage increase in the level of SHBG is at least 70% from baseline.

22. The method of any one of the previous claims, wherein the first time period is 12 weeks and the percentage increase in the level of SHBG is at least 120% from baseline.

23. The method of any one of the previous claims, wherein the patient does not require imaging to monitor response to treatment.

24. The method of any one of the previous claims, wherein the patient does not require magnetic resonance-based imaging to monitor response to treatment.

25. The method of any one of the previous claims, wherein the method results in a decrease in liver fat content.

26. The method of any one of the previous claims, wherein the method results in a decrease in corrected T1 (cT1).

27. The method of any one of the previous claims, wherein level of SHBG is used to monitor the treatment on or after 6 weeks from initiating the treatment.

28. The method of any one of the previous claims, wherein when the first time period is 12 weeks, the patient achieves a percentage increase in the level of SHBG of at least 70% from baseline and achieves a reduction in MRI-PDFF of at least 30% at week 12. 60 319099089Attorney Docket No.: TRPH-057 / 001WO 346923-2825 29. The method of any one of the previous claims, wherein when the first time period is 12 weeks, the patient achieves a percentage increase in the level of SHBG of at least 120% from baseline and achieves a reduction in MRI-PDFF of at least 30% at week 12.

30. The method of any one of the previous claims, wherein when the first time period is 6 weeks, the patient achieves a percentage increase in the level of SHBG of at least 70% from baseline after the 6 weeks and achieves a reduction in MRI-PDFF of at least 30% at week 12 (i.e. 6 weeks after the first time period).

31. The method of any one of the previous claims, wherein when the first time period is 6 weeks, the patient achieves a percentage increase in the level of SHBG of at least 120% from baseline after the 6 weeks and achieves a reduction in MRI-PDFF of at least 30% at week 12 (i.e. 6 weeks after the first time period).

32. The method of any one of the previous claims, wherein the predetermined percentage increase of SHBG level is at least 50%.

33. The method of any one of the previous claims, wherein the predetermined percentage increase of SHBG level is at least 60%.

34. The method of any one of the previous claims, wherein the predetermined percentage increase of SHBG level is at least 70%. 61 319099089

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