Methods of treating liver disorders or lipid disorders with thr-beta agonist

Abstract

To provide a method and a compound for treating a liver disorder or a lipid disorder.SOLUTION: A method comprises: (a) administering a first dose of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile ("Compound A") to a subject daily for a first period of time; (b) performing a test selected from the group consisting of a genetic test, a biomarker test, and a pharmacokinetic test on a biological sample obtained from the subject, a physical examination of the subject, and a combination thereof, to determine sensitivity of the subject to Compound A after step (a); and (c) administering a second dose of Compound A to the subject for a second period of time based on the sensitivity result from step (b).SELECTED DRAWING: Figure 1

Description

[Background technology]

[0001] This application claims priority to and the benefit of USSN 62 / 409,833, filed October 18, 2016, and USSN 62 / 516,594, filed June 7, 2017, the contents of each of which are incorporated herein by reference in their entirety.

[0002] Non-alcoholic steatohepatitis (NASH) is the most common chronic liver disease in the United States.NASH is the main cause of fatty inflammation of the liver and cirrhosis, fibrosis and liver failure.The disease is progressive, starting as steatosis or non-alcoholic fatty liver disease (NAFLD), progressing to inflammatory fatty liver (NASH), and finally leading to cirrhosis and fibrosis.The disease is generally asymptomatic until severe liver dysfunction occurs.

[0003] The prevalence of NAFLD in the US population is approximately 20-23% and can be as high as 33%, while the prevalence of NASH in the US population is approximately 2-3%. Some NASH patients progress to late-stage disease: approximately 15-50% of NASH patients progress to severe fibrosis, and approximately 7-16% progress to cirrhosis. The liver-specific mortality rate in NASH cirrhosis is approximately 10% per decade.

[0004] Currently, there is no specific treatment for NASH.

[0005] Despite advances in treatment, approximately 70% of high-risk cardiovascular (CV) patients do not achieve low-density lipoprotein cholesterol (LDL-C) targets, and as many as 10% of hypercholesterolemic patients are statin intolerant. Elevated LDL-C levels are associated with CV disease, including myocardial infarction and stroke, as well as drugs such as statins that lower LDL-C and also reduce CV morbidity and mortality.

[0006] Familial hypercholesterolemia is underdiagnosed and undertreated in the general population (see, e.g., BGNordestgaard et al., European Heart Journal, 2013, 34, 3478-3490). Heterozygous familial hypercholesterolemia (HeFH) and homozygous familial hypercholesterolemia (HoFH) are genetic disorders characterized by severe, debilitating dyslipidemia and early-onset CV disease. Individuals with HeFH typically have LDL-C levels approximately twice those of their unaffected siblings. HeFH is most commonly caused by mutations in the low-density lipoprotein receptor (LDLR) gene. If untreated, early-onset coronary artery disease is likely to develop in HeFH patients. The prevalence of HeFH is estimated to be 1 in 500, and may be as high as 1 in 200. Despite treatment with newer therapeutic agents (e.g., proprotein convertase subtilisin / kexin type 9 [PCSK9] inhibitors) and standard therapies (which include statins and ezetimibe), some HeFH patients do not achieve LDL-C goals. A recent retrospective study of HeFH patients followed over 20 years revealed that only 18.8% of patients receiving maximal therapy (i.e., a statin with an efficacy of >45% LDL-C reduction plus at least another lipid-lowering agent) achieved a target LDL-C level of <100 mg / dL (see, e.g., Atherosclerosis, May 2014, 234(1):136-41). [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] BGNordestgaard et al., European Heart Journal, 2013, 34, 3478~3490 [Non-patent document 2] Atherosclerosis, May 2014, 234(1):136~41 Summary of the Invention [Means for solving the problem]

[0008] (Abstract) The present disclosure provides a method of treating a liver disorder or a lipid disorder in a subject in need thereof, the method comprising: (a) administering a first dose of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (“Compound A”) to the subject daily for a first period of time; (b) conducting a test selected from the group consisting of a genetic test, a biomarker test, a pharmacokinetic test, a physical examination of the subject, and combinations thereof, on a biological sample obtained from the subject to determine the subject's sensitivity to Compound A after step (a); and (c) administering a second dose of Compound A to the subject for a second period of time based on the sensitivity result from step (b). In one embodiment, the test in step (b) is a biomarker test that measures the expression level of at least one biomarker. In one embodiment, the method further comprises: (d) performing a first biomarker test on a first biological sample obtained from the subject prior to step (a), wherein the first biomarker test measures the expression level of at least one biomarker to be measured in step (b); and (e) determining a change or degree of change in the expression level of the at least one biomarker based on the results of steps (b) and (d). In one embodiment, the method further comprises step (f) determining a second dose of Compound A based on the change or degree of change determined in step (e). In one embodiment, determining the second dose of Compound A in step (f) is further based on at least one demographic characteristic of the subject, the subject's medical history, the subject's physical information, or a combination thereof.

[0009] The present disclosure also provides a method of treating a liver disorder or a lipid disorder in a subject in need thereof, the method comprising: (a) conducting tests selected from the group consisting of genetic tests, biomarker tests, and pharmacokinetic tests on a biological sample obtained from the subject, a physical examination of the subject, and combinations thereof; (b) determining a therapeutically effective amount of Compound A for the subject based on the results of the tests; and (c) administering the therapeutically effective amount of Compound A to the subject. In one embodiment, a predictive algorithm is used in step (b) to determine the therapeutically effective amount of Compound A.

[0010] In one embodiment, the determination of the therapeutically effective amount of Compound A in step (b) is further based on at least one demographic characteristic of the subject, the subject's medical history, the subject's physical information, or a combination thereof.

[0011] In one embodiment, the liver disorder is NASH.

[0012] In one embodiment, the lipid disorder is hyperlipidemia or hypercholesterolemia.

[0013] In one embodiment, the genetic testing includes detecting polymorphisms in a polynucleotide encoding a drug transporter, a drug-metabolizing enzyme, or a thyroid axis hormone, a thyroid pathway gene, a lipid pathway gene, or a combination thereof. For example, the drug transporter may be a solute carrier transporter or an ATP-binding cassette transporter. For example, the ATP-binding cassette transporter may be selected from the group consisting of ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, ABCG2, and ABCB11. For example, the solute carrier transporter may be selected from the group consisting of SLC22A1, SLC22A2, SLC22A3, SLC22A6, SLC22A8, SLC22A11, SLC01B1, SLC01B3, SLC02B1, SLC47A1, and SLC47A2. In some embodiments, the drug-metabolizing enzyme is CYP2C8.

[0014] In one embodiment, the biomarker test comprises measuring the expression level of a biomarker selected from the group consisting of a thyroid axis hormone, thyroxine-binding globulin (TBG), sex hormone-binding globulin (SHBG), and a lipid biomarker. For example, the thyroid axis hormone can be triiodothyronine (free T3) or its metabolites, reverse T3 or its metabolites, free thyroxine (T4) or its metabolites, thyrotropin (TSH) or its metabolites, thyrotropin-releasing hormone (TRH) or its metabolites, or a combination thereof. For example, the lipid biomarker can be selected from the group consisting of total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, lipoprotein(a), apolipoprotein A1 (ApoA-1), apolipoprotein B (ApoB), and a combination thereof.

[0015] In one embodiment, the biological sample is a blood or serum sample.

[0016] In one embodiment, the first dose ranges from about 5 mg to 300 mg (e.g., about 40 mg, about 50 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg).

[0017] In one embodiment, the second dose is in the range of about 5 mg to 300 mg (e.g., about 40 mg, about 50 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg). For example, the second dose is administered daily in the range of about 5 mg to 300 mg (e.g., about 40 mg, about 50 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg).

[0018] In one embodiment, the effective amount is in the range of about 5 mg to 300 mg (e.g., about 40 mg, about 50 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg). For example, the effective amount is administered daily in the range of about 5 mg to 300 mg (e.g., about 40 mg, about 50 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg).

[0019] In one embodiment, the second dose is lower than the first dose.

[0020] In one embodiment, the second dose is the same as the first dose.

[0021] In one embodiment, the second dose is higher than the first dose.

[0022] In one embodiment, Compound A is in a crystalline form, eg, a form characterized by an X-ray powder diffraction pattern comprising peaks at about 10.5, 18.7, 22.9, 23.6, and 24.7 degrees 2θ.

[0023] In one embodiment, the first period of time ranges from 2 to 21 days (eg, about 1 week, about 2 weeks, or about 3 weeks).

[0024] In one embodiment, Compound A is formulated in a gel, tablet, pill, or capsule.

[0025] In one embodiment, Compound A is administered orally.

[0026] In one embodiment, Compound A is administered daily, for example, once daily, twice daily or three times daily.

[0027] In one embodiment, the subject is receiving or has received at least one other therapeutic agent.

[0028] In one embodiment, the at least one other therapeutic agent is a statin.

[0029] In one embodiment, the pharmacokinetic study includes measuring the level of a metabolite of Compound A in a biological sample at a predetermined time after administration of the first dose. For example, the predetermined time can be at least 20 minutes.

[0030] In one embodiment, the metabolite of Compound A has the following structure:

[0031] [ka] ("M1").

[0032] In one embodiment, the metabolites have a geometric mean maximum plasma concentration of about 100 ng / mL to 1000 ng / mL, for example, about 150 ng / mL to 800 ng / mL.

[0033] Unless otherwise defined, 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. As used herein, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not admitted to be prior art to the claimed invention(s). In the case of conflicts, the present specification, including definitions, will control. Additionally, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0034] Other features and advantages of the present disclosure will be apparent from the following detailed description and claims. [Brief explanation of the drawings]

[0035] [Figure 1]14C]-MGL-3196 concentration-time profiles in liver, bile, and plasma showing high hepatic uptake (compared to plasma) and biliary excretion in rats. [Figure 2A] 2A is a quantitative whole-body autoradiograph showing the tissue distribution of [C]-MGL-3196 in rats 4 hours after a single oral dose of 5 mg / kg (FIG. 2A). The autoradiograph shows selective uptake of MGL-3196 into the liver. [Figure 2B] 2B is a quantitative whole-body autoradiograph showing the tissue distribution of [C]-MGL-3196 in rats 24 hours after a single oral dose of 5 mg / kg. The autoradiograph shows selective uptake of MGL-3196 into the liver. [Figure 3] 1 is a graph of tissue to blood concentration ratios demonstrating selective uptake of MGL-3196 into the liver and kidney. The remaining organs / tissues have ratios that indicate MGL-3196 is restricted to the blood vasculature of these organs / tissues. DETAILED DESCRIPTION OF THE INVENTION

[0036] As used herein, the term "thyroid pathway gene" refers to any gene that encodes a protein involved in the thyroid pathway. Examples of thyroid pathway genes include DIO1 and DIO2.

[0037] As used herein, the term "lipid pathway gene" refers to any gene that encodes a protein involved in the lipid pathway. Examples of lipid pathway genes include the genes encoding MYLIP, ISC1, and HMG-CoA reductase.

[0038] As used herein, the term "sensitivity," when used in reference to a drug, refers to how well a subject responds to the drug. The present disclosure recognizes that one subject's sensitivity level to a drug may differ from another subject's sensitivity to the same drug. Sensitivity levels can be determined by genetic testing, biomarker testing, pharmacokinetic testing, physical examination, or a combination thereof, such as those described herein. For example, genetic testing can identify specific genetic profiles that can be used to stratify patient populations with respect to drug sensitivity. For example, after a first dose of compound A is administered to a subject over a period of time, a pharmacokinetic test can be performed on the subject to measure the drug exposure level, which is an indicator of drug sensitivity. If the drug exposure level is higher than the average drug exposure level, the subject is more sensitive to compound A than the average patient population. The second dose of compound A administered to the subject may be lower than the first dose.

[0039] As used herein, the term "sensitivity," when used in reference to a test (e.g., a genetic test, a biomarker test, a pharmacokinetic test, or a physical test of the present disclosure), refers to the ability of the test to detect a difference in the same object of interest in two or more samples when a difference actually exists. For example, the difference can be a difference in biomarker concentration.

[0040] As used herein, the term "specificity," when used in reference to a test (e.g., a genetic test, a biomarker test, a pharmacokinetic test, or a physical test of the present disclosure), refers to the probability of the test detecting an object of interest when the object of interest is actually present. For example, the object of interest may be a biomarker or polymorphism in a drug transporter or drug-metabolizing enzyme.

[0041] As used herein, "pharmaceutically acceptable excipient or carrier" means an excipient or carrier that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes excipients acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable excipient," as used in the specification and claims, includes both one and more than one such excipient. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field.

[0042] As used herein, a "subject" can be any mammal, e.g., a human, non-human primate, mouse, rat, dog, cat, cow, horse, pig, sheep, goat, camel. In a preferred embodiment, the subject is a human.

[0043] As used herein, a "subject in need of treatment" refers to a subject who has a liver disorder or a lipid disorder, or a subject who has an increased risk of developing a liver disorder or a lipid disorder relative to the population as a whole. In one embodiment, the subject in need of treatment has NASH. In another embodiment, the subject in need of treatment has hyperlipidemia or hypercholesterolemia. In another embodiment, the subject in need of treatment is or has been administered a drug other than Compound A to treat or prevent a liver disorder or a lipid disorder. For example, the subject in need of treatment is or has been administered atorvastatin.

[0044] As used herein, "treating" refers to the management and care of a patient for the purpose of combating a disease, condition, or disorder, including reducing or alleviating symptoms or complications, or eliminating the disease, condition, or disorder.

[0045] As used herein, "preventing" refers to halting the development of symptoms or complications of a disease, condition, or disorder.

[0046] As used herein, the term "salt" refers to a pharmaceutically acceptable salt, and may include acid addition salts, including hydrochloride, hydrobromide, phosphate, sulfate, hydrogensulfate, alkylsulfonate, arylsulfonate, acetate, benzoate, citrate, maleate, fumarate, succinate, lactate, and tartrate salts. Salts can also be formed between a cation and a negatively charged group on Compound A. Suitable cations include ammonium cations such as sodium, potassium, magnesium, calcium, and tetramethylammonium ions. Examples of some suitable substituted ammonium ions include those derived from ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine. Salts may also contain a quaternary nitrogen atom.

[0047] As used herein, "solvate" refers to a solvent addition form that contains either stoichiometric or non-stoichiometric amounts of solvent.Some compounds have the tendency to capture a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate.If the solvent is water, the solvate that is formed is a hydrate; if the solvent is alcohol, the solvate that is formed is an alcoholate.A hydrate is formed by the combination of one or more molecules of water with one molecule of a substance that water maintains its molecular state as HO.Hydrate refers to, for example, monohydrate, dihydrate, trihydrate, etc.

[0048] The term "therapeutically effective amount," as used herein, refers to an amount of a pharmaceutical agent that treats, ameliorates, or prevents an identified disease or condition, or that exhibits 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 on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation, which is within the skill and judgment of the clinician. In one embodiment, the disease or condition to be treated is NASH. In another embodiment, the disease or condition to be treated is a lipid disorder.

[0049] The term "single nucleotide polymorphism (SNP)" As used herein, the term "single nucleotide polymorphism" or "SNP" refers to a specific base position in a genome where alternative bases are known to distinguish one allele from another. In some embodiments, one or a small number of SNPs and / or CNPs are sufficient to distinguish complex genetic variants from one another, such that for analytical purposes, one or a set of SNPs and / or CNPs can be considered characteristic of a particular variant, trait, animal, line, breed, hybrid, or set thereof. In some embodiments, one or a set of SNPs and / or CNPs can be considered to define a particular variant, trait, animal, line, breed, hybrid, or set thereof.

[0050] The term "biological sample," as used herein, refers to a sample obtained or derived from a biological source of interest (e.g., a tissue or organism or cell culture) as described herein. In some embodiments, the source of interest comprises or consists of an organism, such as an animal or a human. In some embodiments, a biological sample comprises or consists of a biological tissue or fluid. In some embodiments, a biological sample may be or comprise bone marrow; blood; blood cells; serum; ascites; tissue or fine needle biopsy sample; cell-containing body fluids; free-floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological body fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as ductal lavage or bronchoalveolar lavage; aspirates; scrapings; tissue biopsy specimens; surgical specimens; other body fluids, secretions and / or excretions; and / or cells therefrom, etc. In some embodiments, a biological sample comprises or consists of cells obtained from an individual. In some embodiments, the obtained cells are or comprise cells from the individual from whom the sample is obtained. In some embodiments, a sample is a "primary sample" obtained directly from a source of interest by any suitable means. For example, in some embodiments, a primary biological sample is obtained by a method selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of bodily fluids (e.g., blood, lymph, stool, etc.), and the like. In some embodiments, as is clear from the context, the term "sample" refers to a preparation obtained by processing a primary sample (e.g., by removing one or more components of the primary sample and / or by adding one or more agents to the primary sample). For example, filtration using a semi-permeable membrane. Such a "processed sample" can include, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting the primary sample to techniques such as amplification or reverse transcription of mRNA, isolation, and / or purification of certain components. The terms "about," "approximately," or "approximate," when used in connection with numerical values, refer to a collection or range of included values.For example, "about X" includes a range of values that are ±20%, ±10%, ±5%, ±2%, ±1%, ±0.5%, ±0.2%, or ±0.1% of X, where X is a numerical value. In one embodiment, the term "about" refers to a range of values that are 5% greater or less than the specified value. In another embodiment, the term "about" refers to a range of values that are 2% greater or less than the specified value. In another embodiment, the term "about" refers to a range of values that are 1% greater or less than the specified value.

[0051] The use of the articles "a," "an," and "the," both in the following description and in the claims, should be construed to include both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "is," "including," and "containing," such as in "comprising," "being of," and "of the formula," should be construed as open terms (i.e., meaning "including but not limited to") unless otherwise noted. Additionally, whenever "comprising" or another open-ended term is used in an embodiment, it should be understood that the same embodiment could be more narrowly claimed using the intermediate term "consisting essentially of" or the closed term "consisting of."

[0052] As used herein, the phrases "for example," "for instance," "such as," or "including" are meant to introduce examples that further clarify their more general subject matter. These examples are provided solely as an aid to understanding the disclosure and are not meant to be limiting in any way.

[0053] In one aspect, the disclosure provides a method of treating a liver disorder or a lipid disorder in a subject in need thereof, the method comprising: (a) administering a first dose of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (“Compound A” or “MGL-3196”) to the subject daily for a first period of time; (b) conducting a test selected from the group consisting of a genetic test, a biomarker test, and a pharmacokinetic test on a biological sample obtained from the subject, a physical examination of the subject, and combinations thereof, to determine the subject's sensitivity to Compound A after step (a); and (c) administering a second dose of Compound A to the subject for a second period of time based on the sensitivity result from step (b). In one embodiment, the test in step (b) is a biomarker test that measures the expression level of at least one biomarker. In one embodiment, the method further comprises: (d) performing a first biomarker test on the first biological sample obtained from the subject prior to step (a), wherein the first biomarker test measures the expression level of at least one biomarker to be measured in step (b); and (e) determining a change or degree of change in the expression level of the at least one biomarker based on the results of steps (b) and (d). In one embodiment, the method further comprises step (f) determining a second dose of Compound A based on the change or degree of change determined in step (e). The change can be either an increase or a decrease in expression level.

[0054] In one aspect, the disclosure provides Compound A for use in a method for treating a liver disorder or a lipid disorder in a subject in need thereof, the method comprising: (a) administering a first dose of Compound A to the subject daily for a first period of time; (b) conducting a test selected from the group consisting of a genetic test, a biomarker test, and a pharmacokinetic test on a biological sample obtained from the subject, a physical examination of the subject, and combinations thereof, to determine the subject's sensitivity to Compound A after step (a); and (c) administering a second dose of Compound A to the subject for a second period of time based on the sensitivity result from step (b).

[0055] In one aspect, the disclosure provides use of Compound A in the manufacture of a medicament for use in a method of treating a liver disorder or a lipid disorder in a subject in need thereof, the method comprising: (a) administering a first dose of Compound A to the subject daily for a first period of time; (b) determining the subject's sensitivity to Compound A after step (a) by conducting a test selected from the group consisting of genetic testing, biomarker testing, and pharmacokinetic testing on a biological sample obtained from the subject, a physical examination of the subject, and combinations thereof; and (c) administering a second dose of Compound A to the subject for a second period of time based on the sensitivity results from step (b).

[0056] In one aspect, the present disclosure also provides a method of treating a liver disorder or a lipid disorder in a subject in need thereof, the method comprising: (a) conducting tests selected from the group consisting of genetic tests, biomarker tests, and pharmacokinetic tests on a biological sample obtained from the subject, a physical examination of the subject, and combinations thereof; (b) determining a therapeutically effective amount of Compound A for the subject based on the results of the tests; and (c) administering the therapeutically effective amount of Compound A to the subject. In one embodiment, a predictive algorithm is used in step (b) to determine the therapeutically effective amount of Compound A.

[0057] In one aspect, the disclosure provides Compound A for use in a method for treating a liver disorder or a lipid disorder in a subject in need thereof, the method comprising: (a) conducting a test selected from the group consisting of a genetic test, a biomarker test, and a pharmacokinetic test on a biological sample obtained from the subject, a physical examination of the subject, and combinations thereof; and (b) determining a therapeutically effective amount of Compound A for the subject based on the results of the test.

[0058] In one aspect, the disclosure provides use of Compound A in the manufacture of a medicament for use in a method of treating a liver disorder or a lipid disorder in a subject in need thereof, the method comprising: (a) conducting a test selected from the group consisting of a genetic test, a biomarker test, and a pharmacokinetic test on a biological sample obtained from the subject, a physical examination of the subject, and combinations thereof; and (b) determining a therapeutically effective amount of Compound A for the subject based on the results of the test.

[0059] Compound A is a thyroid hormone receptor (THR)-beta agonist and has the following structure:

[0060] [ka] It has.

[0061] In one embodiment, a single test (e.g., a genetic test, a biomarker test, a pharmacokinetic test, or a physical examination) can be performed for any of the methods disclosed herein. In one embodiment, a combination of two or more tests can be performed for any of the methods disclosed herein. For example, the tests can include one or more genetic tests optionally combined with one or more physical examinations, one or more biomarker tests optionally combined with one or more physical examinations, one or more pharmacokinetic tests optionally combined with one or more physical examinations, one or more genetic tests optionally combined with one or more biomarker tests, one or more genetic tests optionally combined with one or more pharmacokinetic tests or one or more biomarker tests optionally combined with one or more pharmacokinetic tests, or a combination of any three or four types of such tests (genetic tests, biomarker tests, pharmacokinetic tests, or physical examinations). In one embodiment, the physical examination includes measuring body mass index (BMI). For example, patients within different BMI ranges can be administered different doses of Compound A. For example, a patient with a BMI of 45 kg / m 2 For patients with a BMI less than 45 kg / m 2 For example, a lower dose of Compound A may be administered compared to patients with a BMI greater than 45 kg / m 2 For patients with a BMI less than 45 kg / m 2 In one embodiment, a higher dose of Compound A may be administered compared to patients with a BMI greater than 45 kg / m 2 Subjects with a BMI of less than about 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg or 250 mg of Compound A.

[0062] The test may have a specificity of at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.

[0063] The test may have a sensitivity of at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.

[0064] In one embodiment, the pharmacokinetic study comprises measuring the level of a metabolite of Compound A in a biological sample at a predetermined time after administration of the first dose. The metabolite of Compound A has the following structure:

[0065] [ka] ("M1"). In one embodiment, a metabolite of Compound A may be a positional isomer of M1.

[0066] In one embodiment, the predetermined time period may be at least 20 minutes, e.g., at least 40 minutes, at least 1 hour, at least 2 hours, at least 3 hours, or at least 6 hours. In one embodiment, the predetermined time period may be in the range of 20 minutes to 12 hours, e.g., 20 minutes to 10 hours, 20 minutes to 8 hours, 20 minutes to 6 hours, 1 hour to 6 hours, or 2 hours to 6 hours.

[0067] In one embodiment, the metabolites have a maximum plasma concentration (C) of about 100 ng / mL to 1000 ng / mL, e.g., about 100 ng / mL to 900 ng / mL, about 100 ng / mL to 800 ng / mL, or about 150 ng / mL to 800 ng / mL. max ) geometric mean.

[0068] In one embodiment, the liver disorder is nonalcoholic fatty liver disease (NAFLD). NAFLD refers to a broad spectrum of liver diseases ranging from simple fatty liver (steatosis) to nonalcoholic steatohepatitis (NASH) to cirrhosis. In one embodiment, the liver disorder is NASH. All stages of NAFLD share the accumulation of fat in liver cells. In NASH, fat accumulation is accompanied by varying degrees of liver inflammation (hepatitis) and scarring (fibrosis). NAFLD and NASH occur in individuals who do not consume excessive amounts of alcohol. However, in many respects, the histology of NAFLD biopsies is similar to that seen in liver disease caused by alcohol abuse. NAFLD and NASH are considered primary fatty liver diseases. Secondary fatty liver disease includes those occurring in other types of liver disease. Therefore, alcoholic liver disease (ALD) is the most frequent secondary fatty liver disease. Secondary fatty liver disease can also occur in chronic viral hepatitis C (HCV), chronic viral hepatitis B (HBV), chronic autoimmune hepatitis (AIH), and Wilson's disease.

[0069] Symptoms of NAFLD and NASH tend to be non-dramatic and non-specific (as can be observed in other diseases). Symptoms are minimal in most patients; however, they may occasionally experience vague abdominal pain in the upper right quadrant. This pain is characteristically dull and aching, with no predictable pattern of occurrence. It is not the sharp, sudden, and severe pain that can occur with, for example, gallstones. Abdominal pain in NAFLD and NASH is thought to be due to stretching of the liver capsule (membrane) when the liver is enlarged and / or inflamed. In contrast to ALD, hepatitis B, or hepatitis C, symptoms of severe acute liver failure (e.g., jaundice, severe fatigue, loss of appetite, nausea, vomiting, and confusion) are not observed in NAFLD or NASH. Obesity and related conditions (e.g., diabetes, hypertension) are frequently seen in people with NAFLD or NASH, and typical signs of insulin resistance often predominate on physical examination in NAFLD and NASH. Acanthosis nigricans, dark pigmentation of the skin in the armpits and neck, can be a sign of insulin resistance and is frequently seen in children with NASH. When the liver is palpated, it usually feels normal. However, if a large amount of fat accumulates in the liver, it may become quite large and have a soft, rounded outline that can be easily felt by a doctor.

[0070] In addition to the symptoms described above, the diagnosis of NAFLD or NASH is based on the following criteria: clinical and / or biochemical signs of insulin resistance; chronic elevation of ALT; ultrasound evidence of fatty liver; exclusion of other causes of elevated ALT and fatty liver.However, only liver biopsy can establish a definitive diagnosis and determine the severity of NAFLD or NASH.

[0071] In one embodiment, the lipid disorder is selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, and high LDL. For example, the hypercholesterolemia is heterozygous familial hypercholesterolemia (HeFH) or homozygous familial hypercholesterolemia (HoFH).

[0072] In one embodiment, the genetic testing used in the present disclosure involves detecting polymorphisms in polynucleotides encoding drug transporters, drug metabolizing enzymes, or thyroid axis hormones, thyroid pathway genes, lipid pathway genes, or combinations thereof. There are at least two drug transporter superfamilies: solute carrier (SLC) transporters and ATP-binding cassette (ABC) transporters. SLC transporters include SLC22A1 (also known as OCT1), SLC22A2 (also known as OCT2), SLC22A3 (also known as OCT3), SLC22A6 (also known as OAT1 or NKT), SLC22A8 (also known as OAT3 or ROCT), SLC22A11 (also known as OCT4), SLC01B1 (also known as OATP1B1), SLC01B3 (also known as OATP1B3), SLC02B1 (also known as OATP2B1), and members of the SLC47 family (e.g., SLC47A1 (also known as MATE1) or SLC47A2 (also known as MATE2)). ABC transporters include ABCC1 (also known as MRP1), ABCC2 (also known as MRP2), ABCC3 (also known as MRP3), ABCC4 (also known as MRP4), ABCC5 (also known as MRP5), ABCG2 (also known as BCRP), and ABCB11 (also known as BSEP). Additional information about drug transporters can be found, for example, in SK Nigam, Nat. Rev. Drug Discov. 2015, 14(1)29-44, the contents of which are incorporated herein by reference. In some embodiments, the drug transporter can be found in the liver. For example, drug transporters are concentrated in the liver. In some embodiments, the drug-metabolizing enzyme is CYP2C8.

[0073] Polymorphisms in drug transporters can have an effect on the handling of drugs by drug transporters. Coding or non-coding single nucleotide polymorphisms (SNPs) that result in clinical phenotypes have been reported for SLC22A6 and SLC22A8. Examples of polymorphisms for ABCG2 include C421A and Q141K. Examples of methods for detecting polymorphisms include, but are not limited to, selective oligonucleotide hybridization, selective amplification, selective primer extension, selective ligation, single-base extension, selective termination of extension, or invasive cleavage assays.

[0074] There are at least two types of drug-metabolizing enzymes: oxidative drug-metabolizing enzymes and conjugate drug-metabolizing enzymes. Oxidative drug-metabolizing enzymes include cytochrome P450 (e.g., CYP2D6, CYP2C19, CYP2E1, or CYP2C9) and flavin monooxygenase (e.g., FMO1, FMO2, FMO3, FMO4, FMO5, or FMO6). Coupling drug-metabolizing enzymes include UDP glycosyltransferases (e.g., UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B10, UGT2B11, or UGT2B15), glutathione transferases (e.g., GST A1-1, GST M1-1, or GST P1-1), sulfotransferases (e.g., SULT1A1, SULT1A2, SULT1A3, SULT1E, and SULT2A1), and N-acetyltransferases (e.g., NAT1 or NAT2). Polymorphisms in drug-metabolizing enzymes are known in the art, e.g., Pinto and Dolan, Current Drug Metabolism, 2011, 12, 487-497, the contents of which are incorporated herein by reference.

[0075] In one embodiment, the biomarker test used in the present disclosure comprises measuring the expression level of a biomarker selected from the group consisting of thyroid axis hormones, thyroxine-binding globulin (TBG), sex hormone-binding globulin (SHBG), and lipid biomarkers. In one embodiment, the biomarker test is a pharmacodynamic test. In one embodiment, the biomarker test can be used to measure the expression level of a metabolite of a biomarker. In another embodiment, the biomarker test can be used to measure the expression level of a biomarker and its metabolite. In one embodiment, the result of the biomarker test provides a ratio of the expression levels of two biomarkers.

[0076] Thyroid axis hormones are also referred to as hypothalamic pituitary thyroid (HPT) or HPT axis hormones. In one embodiment, thyroid axis hormones include triiodothyronine (free T3), reverse T3, total T3, free thyroxine (T4), total T4, thyrotropin (TSH), thyrotropin-releasing hormone (TRH), and combinations thereof. Total T3 refers to both bound T3 and free T3. Total T4 refers to both bound T4 and free T4. For example, thyroid axis hormones are free T3, free T4, and TSH. For example, thyroid axis hormones are TSH, TRH, total T3, and total T4. In one embodiment, the biomarker test measures the expression levels of free T3, free T4, and TSH, respectively. In another embodiment, the biomarker test measures the expression levels of free T3, free T4, and TSH in combination. In another embodiment, the biomarker test measures the expression levels of free T3, free T4, and TSH, respectively. In yet another embodiment, the biomarker test measures expression levels of TSH, TRH, total T3, and total T4 in combination.

[0077] The lipid biomarkers can be total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, lipoprotein(a), apolipoprotein A1 (ApoA-1), apolipoprotein B (ApoB), or a combination thereof. For example, the ApoB / ApoA-1 ratio can be used in the methods described herein.

[0078] In one embodiment, pharmacokinetic testing can be performed via biochemical analytical methods or mass spectrometry. Biochemical analytical methods can be used to construct concentration-time profiles. Chemical techniques are used to measure the concentration of a drug in a biological matrix, most often plasma. A suitable biochemical analytical method should be selective and sensitive. For example, microscale thermophoresis can be used to quantify how a biological matrix / fluid affects the affinity of a drug for its target. Pharmacokinetics can also be studied using mass spectrometry. The most common instrument used in this application is LC-MS using a triple quadrupole mass spectrometer. Tandem mass spectrometry is usually used for added specificity.

[0079] In certain embodiments of the present disclosure, a subject in need thereof is receiving or has been receiving another therapeutic agent different from Compound A (e.g., a lipid-lowering drug, a diabetes drug, an organic anion transporting polypeptide (OATP) inhibitor, an ABCG2 inhibitor, a CYP2C8 inhibitor, a drug that alters the pH of the gastrointestinal tract, an antacid, or a bile acid sequestrant). The different therapeutic agent can have an effect on the metabolism or absorption of Compound A. The therapeutic agent and Compound A can be administered simultaneously, sequentially, or alternately. For example, the therapeutic agent and Compound A can be administered simultaneously. For example, the therapeutic agent can be administered before administration of Compound A. For example, the therapeutic agent can be administered after administration of Compound A. For example, the therapeutic agent and Compound A are administered alternately. For example, the administration of the therapeutic agent and Compound A can be separated by a certain period of time, for example, several hours.

[0080] In one embodiment, the therapeutic agent other than Compound A may be a lipid-lowering drug. For example, the lipid-lowering drug may be a statin, fibrate, niacin, bile acid sequestrant, ezetimibe, lomitapide, phytosterol, or orlistat. Examples of statins include, but are not limited to, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0081] In one embodiment, the therapeutic agent different from Compound A may be a diabetes drug. Examples of diabetes drugs include, but are not limited to: (a) antioxidants such as vitamin E, vitamin C, isoflavones, zinc, selenium, ebselen, and carotenoids; (b) insulin or insulin analogs such as regular insulin, lente insulin, semilente insulin, ultralente insulin, NPH, or Humalog; (c) prazosin, doxazosin, phenoxybenzamine, terazosin, phentolamine, rauwolscine, yohimbine, tolazoline, tamsulosin, or (d) alpha-adrenergic receptor antagonists such as terazosin; (e) acebutolol, atenolol, betaxolol, bisoprolol, carteolol, esmolol, metoprolol, nadolol, penbutolol, pindolol, propanolol, timolol, dobutamine hydrochloride, alprenolol, bunolol, bupranolol, carazolol, epanolol, metoprolol, oxprenolol, pamatolol, talinolol, tiprenolol, tolamolol, or toliprolol; (e) nonselective adrenergic receptor antagonists such as carvedilol or labetolol; (f) first-generation sulfonylureas such as tolazamide, tolbutamide, chlorpropamide, and acetohexamide; (g) second-generation sulfonylureas such as glyburide, glipizide, and glimepiride; (h) biguanides such as metformin; (i) benzoic acid derivatives such as repaglinide; (j) α-glucosides such as acarbose and miglitol. (k) thiazolidinediones such as rosiglitazone, pioglitazone, or troglitazone; (l) phosphodiesterase inhibitors such as anagrelide, tadalafil, dipyridamole, dyphylline, vardenafil, cilostazol, milrinone, theophylline, or caffeine; (m) cholinesterase antagonists such as donepezil, tacrine, edrophonium, demecarium, pyridostigmine, zanapezil, phospholine, metrifonate, neostigmine, or galantamine;(n) Glutathione-increasing compounds such as N-acetylcysteine, cysteine esters, L-2-oxothiazolidine-4-carboxylate (OTC), gamma glutamylcysteine and its ethyl esters, glutathione ethyl esters, glutathione isopropyl esters, lipoic acid, cysteine, methionine, or S-adenosylmethionine; and (o) GLP and glucagon-like peptide analogs such as exenatide, DAC:GLP-1 (CJC-1131), liraglutide, ZP10, BIM51077, LY315902, LY307161 (SR).

[0082] In one embodiment, the therapeutic agent different from Compound A may be an OATP inhibitor. Examples of OATP inhibitors include, but are not limited to, gemfibrozil or cyclosporin A.

[0083] In one embodiment, the therapeutic agent different from compound A may be an ABCG2 inhibitor. Examples of ABCG2 inhibitors include, but are not limited to, afatinib, aripiprazole, axitinib, curcumin, cyclosporine, elacridar, erlotinib, fluvastatin, fumitremorgin C, gefitinib, ivermectin, ko143, lapatinib, nilotinib, novobiocin, pantoprazole, pitavastatin, ponatinib, quercetin, quizartinib, rabeprazole, regorafenib, rilpivirine, sulfasalazine, sunitinib, tacrolimus, teriflunomide, trametinib, trifluoperazine, and vismodegib.

[0084] In one embodiment, the therapeutic agent different from Compound A may be a CYP2C8 inhibitor. Examples of CYP2C8 inhibitors include, but are not limited to, gemfibrozil, clopidogrel, fluvoxamine, ketoconazole, fenofibrate, fenofibric acid, montelukast, nicardipine, quercetin, simvastatin, spironolactone, trimethoprim, and vilazodone.

[0085] In one embodiment, the therapeutic agent different from Compound A may be an antacid. Examples of antacids include, but are not limited to, aluminum carbonate, aluminum hydroxide, aluminum phosphate, aluminum hydroxycarbonate, dihydroxyaluminum sodium carbonate, aluminum magnesium glycinate, dihydroxyaluminum aminoacetate, dihydroxyaluminum aminoacetic acid, calcium carbonate, calcium phosphate, aluminum magnesium hydrated sulfate, magnesium aluminate, magnesium aluminosilicate, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, sclafalte, and sodium bicarbonate.

[0086] In one embodiment, the therapeutic agent different from Compound A may be a bile acid sequestrant. Examples of antacids include, but are not limited to, cholestyramine, colestipol, and colesevelam.

[0087] In one embodiment, a subject is administered a statin and Compound A. The statin can be administered simultaneously with Compound A. The statin can be administered prior to administration of Compound A. The statin can be administered after administration of Compound A. The administration of the statin and Compound A can be separated by a certain period of time, for example, about 1 to 24 hours, about 1 to 20 hours, about 1 to 16 hours, about 1 to 12 hours, or about 6 to 12 hours. For example, the administration of the statin and Compound A can be separated by about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours. In one embodiment, the statin is administered in the evening and Compound A is administered the following morning.

[0088] In one embodiment, a first dose of Compound A is administered to a population of patients for a first period (e.g., daily), and testing is subsequently performed on these patients to determine their respective sensitivity levels to Compound A. For example, the sensitivity level can be determined based on a change or degree of change in the expression level of at least one of the biomarkers disclosed herein; or the sensitivity level can be determined based on a combination of the expression level change and the results of another type of test (e.g., a genetic test, a physical examination, or a combination thereof). The period can range from about 2 to 21 days (e.g., 5, 7, 10, or 14 days). Based on the sensitivity level, patients can be divided into at least three subpopulations: The first subpopulation consists of patients with a normal or average sensitivity level to Compound A. The second subpopulation consists of patients with a sensitivity level to Compound A above the normal or average sensitivity level (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% above the normal or average sensitivity level). The third subpopulation consists of patients with a sensitivity level below the normal or average sensitivity level (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% below the normal or average sensitivity level). These stratified patient subpopulations can be used as a basis for determining a therapeutically effective dose for an individual patient.

[0089] In one embodiment, based on the results of the tests described herein for an individual patient (with or without prior treatment with Compound A), a caring person such as a physician can determine which subpopulation the individual patient belongs to and prescribe a therapeutically effective dose of Compound A according to the determination. In one embodiment, based on the results of the test, a predictive algorithm is used to determine a therapeutically effective dose of Compound A. Additional information, such as at least one demographic characteristic of the subject (e.g., race, ethnicity, age, or sex), the subject's medical history (e.g., whether the subject is receiving or has received at least one other therapeutic agent), and the subject's physical information (e.g., weight, height, blood pressure, or heart rate), can be used for the determination. For example, the effective dose can maintain the effectiveness of the drug in an individual patient while minimizing its side effects for the individual patient. For example, the effective dose for patients belonging to the second subpopulation is lower than the effective dose for patients belonging to the first subpopulation; and the effective dose for patients belonging to the third subpopulation is higher than the effective dose for patients belonging to the first subpopulation.

[0090] Depending on the results of testing for an individual patient, an effective amount of Compound A ranges from about 5 mg to 300 mg, about 10 mg to 250 mg, about 20 mg to 200 mg, about 20 mg to 150 mg, about 20 mg to 100 mg, about 50 mg to 200 mg, or about 50 mg to 150 mg. An effective amount may be about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, or 250 mg. For example, an effective amount of Compound A ranges from about 5 mg to 300 mg, about 10 mg to 250 mg, about 20 mg to 200 mg, about 20 mg to 150 mg, about 20 mg to 100 mg, about 50 mg to 200 mg, or about 50 mg to 150 mg daily. An effective amount may be about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, or 250 mg daily.

[0091] In another embodiment, a first dose of Compound A is administered to a subject daily for a first period of time, and then testing (e.g., selected from the group consisting of genetic testing, biomarker testing, and pharmacokinetic testing on a biological sample obtained from the subject, a physical examination of the subject, and combinations thereof) is used to determine the subject's sensitivity level to Compound A. The first period of time may be about 2 to 21 days (e.g., about 5 days, about 7 days, about 10 days, or about 14 days). The sensitivity level allows a caring person, such as a physician, to determine a second dose of Compound A for the subject for a second period of time. For example, if the subject's sensitivity level is above the average sensitivity level, the second dose is lower than the first dose; if the subject's sensitivity level is the same as the average sensitivity level, the second dose is the same as the first dose; or if the subject's sensitivity level is below the average sensitivity level, the second dose is higher than the first dose. The second period of time can continue for as long as the subject requires the treatment. For example, the second period of time may be about 7 days to 365 days. In some embodiments, the second period of time may be from about 1 month to 36 months, for example, from 3 months to 24 months.

[0092] For example, the first dose of Compound A may be a dose that is expected to have an effect on at least one of the biomarkers disclosed herein. In one embodiment, a multi-dose study can be conducted in a population of subjects divided into cohorts, where different doses of Compound A are administered to different cohorts of subjects, and the expression level of at least one biomarker is monitored after administration. For a cohort of subjects administered a particular dose of Compound A, a statistically significant change in the expression level of at least one biomarker is an indication that the particular dose has an effect on at least one biomarker. For example, a statistically significant change in the expression level of at least one biomarker may be a statistically significant reduction in the level of T4 or LDL-cholesterol. More information regarding dose studies of Compound A can be found, for example, in Taub et al., Atherosclerosis, 2013, 373-380, the contents of which are incorporated herein by reference.

[0093] For example, the first dose of Compound A can be determined based on the patient stratification methods described herein. For example, the first dose of Compound A can be in the range of about 5 mg to 300 mg, about 10 mg to 250 mg, about 20 mg to 200 mg, about 20 mg to 150 mg, about 20 mg to 100 mg, about 50 mg to 200 mg, or about 50 mg to 150 mg. The first dose can be about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, or 250 mg. In one embodiment, Compound A is administered once daily, twice daily or three times daily.

[0094] For example, a first biomarker test is performed on a first biological sample obtained from the subject before the first dose of Compound A is administered to measure the expression level of at least one biomarker. A second biomarker test is performed on a second biological sample obtained from the subject after the first dose of Compound A has been administered for a first period of time to measure the expression level of the same biomarker. The first and second biological samples are of the same type. Based on the results of the first and second biomarker tests, it can be determined whether there is a change and the degree of change in the expression level of one or more biomarkers. The biomarkers can be of the same type or different types. For example, the biomarkers can include at least one thyroid axis hormone and at least one lipid biomarker; the biomarkers can include at least one thyroid axis hormone and sex hormone-binding globulin; the biomarkers can include at least one lipid biomarker and sex hormone-binding globulin; or the biomarkers can include at least one lipid biomarker, sex hormone-binding globulin, and at least one thyroid axis hormone. For example, the biomarker may be LDL-C, ApoB, SHBG, T4, or a combination thereof. For example, depending on the subject's sensitivity to compound A, the expression level of one or more biomarkers may be increased, decreased, or unchanged after the administration of the first dose of compound A. The second dose is adjusted according to the change in expression level. For example, an algorithm can be implemented to determine the second dose based on the change and the degree of change. In one embodiment, genetic testing, pharmacokinetic testing, physical examination, or a combination thereof is performed in conjunction with biomarker testing to determine the second dose. For example, the physical examination can determine whether there is a change and the degree of change in the subject's BMI, which may be a factor in adjusting the second dose.Additional information, such as at least one demographic characteristic of the subject (e.g., race, ethnicity, age, or sex), the subject's medical history (e.g., whether the subject is receiving or has received at least one other therapeutic agent), and the subject's physical information (e.g., weight, height, blood pressure, or heart rate), can be used to adjust the second dose. For example, the degree of change can be about 10% to 500% compared to the original test data, e.g., 10% to 400%, 10% to 300%, 10% to 200%, 10% to 100%, 20% to 200%, or 50% to 100% compared to the original test data. For example, the degree of change can be about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200% when compared to the original test data.

[0095] For example, depending on the change and the degree of change, the second dose of Compound A may be lower or higher than the first dose. The second dose may be the same as the first dose. For example, the second dose may be in the range of about 5 mg to 200 mg, about 10 mg to 200 mg, about 20 mg to 200 mg, about 20 mg to 150 mg, about 20 mg to 100 mg, about 50 mg to 200 mg, or about 50 mg to 150 mg. The second dose may be about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg. In one embodiment, the second dose of Compound A is administered daily (e.g., once daily, twice daily, or three times daily), once every two days, twice weekly, or once weekly.

[0096] In one embodiment, the test can further include an algorithm, for example, to provide a quantitative result based on the test. The algorithm can also be used in situations where the subject is receiving or has previously received another therapeutic agent other than Compound A (e.g., a lipid-lowering drug, an antidiabetic drug, an organic anion transporting polypeptide (OATP) inhibitor, an ABCG2 inhibitor, a CYP2C8 inhibitor, a drug that alters the pH of the gastrointestinal tract, an antacid, or a bile acid sequestrant). Such a therapeutic agent can play a role in determining the dose of Compound A for the subject (e.g., via its effect on the metabolism or absorption of Compound A). The algorithm can take the effect into account when determining a therapeutically effective amount of Compound A for the subject.

[0097] In one embodiment, the algorithm is a predictive algorithm, such as a support vector machine (SVM), linear discriminant analysis (LDA), K-nearest neighbors (KNN), or naive Bayes (NB). The algorithm can process data generated in one or more tests to make a prediction regarding the subject's sensitivity to compound A. For example, the data generated in one or more tests can be the change in expression level or degree of change of one or more biomarkers in response to administration of a therapeutic agent to the subject. For example, the one or more biomarkers tested can be selected from thyroid axis hormones, thyroxine-binding globulin (TBG), sex hormone-binding globulin (SHBG), lipid biomarkers, and combinations thereof. The biomarkers can be of the same type or different types. For example, the biomarkers can include at least one thyroid axis hormone and at least one lipid biomarker; the biomarkers can include at least one thyroid axis hormone and SHBG; the biomarkers can include at least one lipid biomarker and SHBG; or the biomarkers can include at least one lipid biomarker, SHBG, and at least one thyroid axis hormone. For example, the biomarkers may be LDL-C, ApoB, SHBG, T4, or a combination thereof.

[0098] In vivo data confirm that Compound A exhibits interesting tissue uptake behavior. Specifically, while Compound A has high uptake in the liver, it has little uptake in tissues outside the liver, such as the heart, bone / cartilage, or brain. Therefore, Compound A can be safely administered without the need for clinical monitoring. One aspect of the present disclosure relates to a method for treating a liver disorder or a lipid disorder in a subject in need thereof, comprising administering to the subject an effective amount of Compound A daily, wherein the subject does not require clinical monitoring after administration. In one embodiment, the effective amount is in the range of 5 mg to 300 mg (e.g., about 5 mg, about 20 mg, about 40 mg, about 50 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg). In one embodiment, the effective amount is in the range of 5 mg to 300 mg (e.g., about 5 mg, about 20 mg, about 40 mg, about 50 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg) per day, e.g., via oral administration. In one embodiment, the clinical monitoring is selected from the group consisting of a bone scan, a heart scan, and a brain scan.

[0099] In one aspect, the present disclosure provides Compound A for use in treating a liver disorder or a lipid disorder in a subject in need thereof, wherein the subject does not require clinical monitoring following administration of Compound A.

[0100] In yet another aspect, the present disclosure provides the use of Compound A in the manufacture of a medicament for use in a method of treating a liver disorder or a lipid disorder in a subject in need thereof, wherein the subject does not require clinical monitoring after administration of the medicament.

[0101] Compound A can have a purity of greater than 85%, e.g., greater than 86%, greater than 90%, greater than 92.5%, greater than 95%, greater than 96%, greater than 97%, greater than 97.5%, greater than 98%, greater than 98.5%, greater than 99%, greater than 99.2%, greater than 99.5%, or greater than 99.8%.

[0102] All references to Compound A herein include all pharmaceutically acceptable salts and all solvates, and alternative physical forms thereof, unless otherwise specified. All dosages quoted herein for Compound A are based on the molecular weight of Compound A itself, rather than its pharmaceutically acceptable salts, solvate hydrates, or any excipients in the composition, unless otherwise specified.

[0103] For therapeutic administration according to the present disclosure, Compound A may be used in the form of its free base or in the form of a pharmaceutically acceptable salt.

[0104] In one embodiment, Compound A is crystalline, e.g., in a form (Form I) characterized by an X-ray powder diffraction pattern comprising peaks at about 10.5, 18.7, 22.9, 23.6, and 24.7 degrees 2θ. In one embodiment, Compound A Form I has a purity of greater than 85%, e.g., greater than 86%, greater than 90%, greater than 92.5%, greater than 95%, greater than 96%, greater than 97%, greater than 97.5%, greater than 98%, greater than 98.5%, greater than 99%, greater than 99.2%, greater than 99.5%, or greater than 99.8%. More information about this particular form is disclosed in US Pat. No. 9,266,861, the contents of which are incorporated herein by reference in their entirety.

[0105] In one embodiment, Compound A is in a morphological form different from Form I. In certain embodiments, Compound A is in the form of a solvate, e.g., a hydrate (such as a dihydrate), a dimethylacetamide (DMAC) solvate, or a methyl isobutyl ketone (MIBK) solvate. See U.S. Pat. No. 9,266,861. The solvate has a purity of greater than 85%, e.g., greater than 86%, greater than 90%, greater than 92.5%, greater than 95%, greater than 96%, greater than 97%, greater than 97.5%, greater than 98%, greater than 98.5%, greater than 99%, greater than 99.2%, greater than 99.5%, or greater than 99.8%.

[0106] Compound A, or a pharmaceutically acceptable salt, prodrug, analog, or derivative thereof, can be incorporated into a pharmaceutical composition suitable for administration. Such a composition typically comprises Compound A and a pharmaceutically acceptable excipient or carrier.

[0107] Pharmaceutically acceptable carriers include solid carriers such as lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Illustrative liquid carriers include syrup, peanut oil, olive oil, and water. Similarly, carriers or diluents can include time-delay materials known in the art, such as glyceryl monostearate or glyceryl distearate, alone or with waxes, ethylcellulose, hydroxypropylmethylcellulose, or methyl methacrylate. Other fillers, excipients, flavoring agents, and other additives known in the art can also be included in pharmaceutical compositions according to this disclosure. Liposomes and non-aqueous vehicles, such as fixed oils, can also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, its use in the composition is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0108] In one embodiment, Compound A, or a pharmaceutically acceptable salt, prodrug, analog, or derivative thereof, is administered in a suitable dosage form prepared by combining a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt, prodrug, analog, or derivative thereof (as the active ingredient) with a standard pharmaceutical carrier or diluent (i.e., by producing a pharmaceutical composition of the present disclosure) in accordance with conventional procedures. These procedures may involve mixing, granulating, and compressing or dissolving the ingredients as necessary to achieve the desired preparation.

[0109] The pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral, inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can contain the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetate, citrate, or phosphate, and agents for adjusting tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

[0110] Compound A or pharmaceutical compositions of the present disclosure can be administered to subject by many well-known methods.For example, the selected dosage should be sufficient to constitute effective treatment, but should not be so high as to cause unacceptable side effects.Preferably, the state of disease state and the health of patient should be closely monitored during and after treatment for a reasonable period.

[0111] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors that may be taken into consideration include the severity of the disease state, the subject's general health, the subject's age, weight, and sex, diet, time and frequency of administration, drug combination(s), and susceptibility and tolerance / response to treatment.

[0112] The pharmaceutical composition containing compound A of the present disclosure can be prepared in a generally known manner, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, mixing or lyophilizing processes.The pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, including excipients and / or auxiliaries that facilitate the processing of active compounds into pharmaceutically usable preparations.Of course, the appropriate formulation depends on the selected route of administration.

[0113] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microbial organisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

[0114] Sterile injectable solution can be prepared by incorporating active compound in the required amount in a suitable solvent with one or combination of the components listed above, and then, if necessary, by filtration sterilization.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle that contains a basic dispersion medium and other components that are required from the components listed above.In the case of sterile powder for preparing sterile injectable solution, the method of preparation is vacuum drying and freeze-drying, which can obtain the powder of active compound plus any additional desired components from this pre-sterilized-filtered solution.

[0115] Oral compositions generally contain an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, where the compound in the fluid carrier is orally applied, swished in the mouth, and expectorated or swallowed. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate or orange flavoring.

[0116] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0117] Systemic administration can also be via transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be achieved through the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams as generally known in the art.

[0118] In one embodiment, the active compound is prepared with a pharmaceutically acceptable carrier that protects the compound against rapid elimination from the body, such as a controlled-release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid may be used. Methods for preparing such formulations will be apparent to those skilled in the art. Materials may also be commercially obtained from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells using monoclonal antibodies against viral antigens) may also be used as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0119] It is particularly advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.Dosage unit form as used herein refers to a physically discrete unit that is suitable as a unitary dosage for the subject to be treated; each unit contains a predetermined amount of active compound calculated to produce desired therapeutic effect in association with required pharmaceutical carrier.The specification for dosage unit form of the present disclosure is determined and directly depends on the unique characteristics of active compound and the specific therapeutic effect to be achieved.

[0120] Compound A or a pharmaceutical composition thereof can be included in a container, pack, or dispenser together with instructions for administration.

[0121] Compound A or a pharmaceutical composition thereof can be administered once daily, twice daily, three times daily, once every other day, or once weekly.

[0122] All patents, patent applications, and publications mentioned herein are hereby incorporated by reference in their entirety. However, when a patent, patent application, or publication containing express definitions is incorporated by reference, it should be understood that those express definitions apply to the incorporated patent, patent application, or publication in which they are found, and not to the remainder of the text of this application, and in particular to the claims of this application.

[0123] All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the present disclosure will be apparent from the different examples. The examples provided illustrate different components and methodologies useful in practicing the present disclosure. The examples do not limit the claimed invention. Based on the present disclosure, a skilled artisan can identify and use other components and methodologies useful in practicing the present disclosure. [Example]

[0124] [Example 1] 14 Excretory mass balance, pharmacokinetics, and tissue distribution by quantitative whole-body autoradiography in rats after a single oral dose of [C]MGL-3196 (Compound A) The study utilized two groups of male SD rats (groups 1 and 2) and one group of male LE rats (group 3), which were obtained from Hilltop Lab Animals, Inc. (Scottdale, PA). Group 1 was used for the evaluation of excretory mass balance; group 2 was used for the evaluation of plasma total radioactivity PK; and group 3 was used for the evaluation of tissue distribution of total radioactivity. All rats were 14They received a single PO dose of [C]MGL-3196. The target dose was 5 mg / kg using a formulation prepared in 4% DMSO / 96% 2% Klucel, 0.1% Tween-80, 0.09% methylparaben, and 0.01% propylparaben in a purified MilliQ water vehicle.

[0125] In Group 1 rats 14 The primary route of excretion of radioactivity after a single PO dose of [C]MGL-3196 was via feces, which accounted for an average of 68.6% of the administered dose. An average of 16.2% of the administered dose was recovered in urine. An average of 1.3% of the administered dose was recovered in cage residues, and an average of 1.1% of the administered dose was recovered in the carcass. The average total recovery of radioactivity in Group 1 rats was 87.2% of the administered dose.

[0126] Excretion data showed that after a single PO dose, 14 C) demonstrated that the majority of MGL-3196-induced radioactivity was recovered in the feces after 72 hours in male SD rats.

[0127] In group 2, 14 Mean C of total plasma radioactivity after a single PO dose of [C]MGL-3196 max is 4 hours after administration (T max The mean plasma radioactivity concentration was 2230 ng equiv / mL at t 1 / 2 The mean AUC of total plasma radioactivity decreased over time. inf obs was 25,346 ng equiv·h / mL.

[0128] In group 3LE males, 14 C of total blood radioactivity (by LSC) after a single PO dose of [C]MGL-3196 max is 8 hours after administration (T max The blood radioactivity level was 645 ng equiv / g at t 1 / 2 The AUC of total blood radioactivity decreased slowly over time. inf obs The mean serotonin concentration in males of group 3LE was 54,361 ng equiv·h / g. 14C of plasma total radioactivity (by LSC) after a single PO dose of [C]MGL-3196 max is 4 hours after administration (T max The plasma radioactivity concentration was 1078 ng equiv / mL at t 1 / 2 The AUC of plasma total radioactivity decreased slowly over time. inf obs was 20,430 ng equiv·h / mL.

[0129] The blood to plasma radioactivity concentration ratio ranged from 0.57 to 0.98 over 24 hours after administration and from 1.52 to 5.62 from 48 to 168 hours after administration.

[0130] Drug-induced radioactivity was rapidly absorbed and widely distributed throughout the body of male LE rats, with quantifiable concentrations present in many tissues (17 of 40 tissues) over 768 hours.

[0131] In general, concentrations in most tissues of pigmented rats were lower or similar to those in the blood (cardiac). max is 8 hours after administration (T max ) was observed. C max Tissue concentrations >700 ng equiv / g at C were found in the following tissues: liver, kidney cortex, cecum, bladder, kidney medulla, small intestine, esophagus, cardiac blood, pigmented skin, and non-pigmented skin. max Tissue concentrations of <100 ng equiv / g at 1392 hours post-dose were observed in the brain (medulla, cerebellum, cerebrum), eye lens, spinal cord, and bone. Radioactivity concentrations of >7.90 ng equiv / g were observed 1392 hours post-dose in 7 of 40 tissues (blood, liver, Harderian gland, pancreas, pigmented skin, lung, and eye lens), but all tissues were close to the lower limit of quantification for radioactivity, suggesting near complete elimination.

[0132] The tissue to plasma (i.e., distribution phase) ratios determined for all tissues up to 8 hours post-dose, indicating tissue penetration, were [ 14These results suggest that [C]MGL-3196-induced radioactivity penetrated the liver, kidneys, and cecum several times more than could be explained by the presence of radioactivity in the blood vasculature of the organs. The ratios for all tissues except the liver, kidneys, bladder, and cecum were <1 throughout the distribution phase, suggesting much lower penetration into most other tissues. Together, the data suggest that MGL-3196 was taken up more specifically by the liver, kidneys, and cecum.

[0133] The highest concentrations of radioactivity in male LE rats were found in non-tissues in the gastrointestinal contents, bile, and bladder contents.

[0134] Tissue concentration versus time profiles for male LE rats showed that most tissues had a slow elimination / tissue release phase occurring from 24 to 768 hours. The longest reliable half-life (t 1 / 2 Tissues with ) values (>400.0 h) were: Harderian gland, lung, pancreas, cardiac blood, skeletal muscle, bone marrow, and stomach. 1 / 2 Values were determined for 21 of the 40 tissues. t for the concentration-time curves of the remaining tissues. 1 / 2 is due to insufficient time point data and / or the 2 It could not be determined because the value was <0.85.

[0135] [ 14 The primary route of excretion of radioactivity in intact SD rats (Group 1) after a PO dose of [C]MGL-3196 was in the feces (68.6%), with less recovery in the urine (16.2%). A mean total of 87.2% of the dose was recovered over 168 hours.

[0136] [ 14 [C]MGL-3196-induced radioactivity was quantifiable in the plasma of male SD rats over 48 hours (the final time point for this group). max The mean plasma total radioactivity in SD rats was 2230 ng equiv / mL at 4 hours. 1 / 2The mean AUC of total plasma radioactivity in SD rats was 9.6 hours. inf obs was 25,346 ng equiv·h / mL.

[0137] [ 14 [C]MGL-3196-induced radioactivity was quantifiable in the blood of male LE rats over 768 hours. 1 / 2 The AUC of total blood radioactivity in LE rats was 447.6 hours. inf obs was 54361ng equiv·h / g. 14 [C]MGL-3196-induced radioactivity was quantifiable in the plasma of male LE rats over 168 hours, and 1 / 2 The longer t obtained in Group 3 rats was 54.6 hours. 1 / 2 The values are likely due to the inclusion of low plasma concentrations at later time points following tissue release. AUC of total plasma radioactivity in LE rats inf obs was 20430 ng equiv·h / mL, which is similar to that observed in SD rats in Group 2.

[0138] The blood-to-plasma radioactivity concentration ratio ranged from 0.57 to 0.98 over 24 hours, suggesting that most of the radioactivity in the blood was in the plasma fraction. The blood-to-plasma ratio ranged from 1.52 to 5.62 from 48 to 168 hours after administration, suggesting that most of the radioactivity was distributed to the cellular portion of the blood at later time points.

[0139] [ 14 [C]MGL-3196-induced radioactivity was widely distributed throughout the body of pigmented male rats after a single PO dose. 14 The liver AUC of [C]MGL-3196 was approximately 10-fold higher than in plasma, and the kidney cortex AUC was approximately 3-fold higher than in plasma, while the skeletal and cardiac muscle AUCs and most other tissues were lower or similar to the plasma and blood AUCs (blood was approximately 2-fold higher than plasma). Liver: Plasma AUC allThe ratio was 10.5, and the volume fraction of plasma in the liver was approximately 0.06-0.14 (i.e., half the volume fraction of blood in the liver). Together, these data suggested that the selective uptake of MGL-3196 into the liver and kidney cortex, as well as concentrations in other tissues, were primarily due to concentrations present in the plasma and / or blood in the vasculature of the remaining tissues.

[0140] Example 2: Hepatic uptake and preclinical ADME of Compound A The following studies were performed: (a) in vitro drug protein-coupled transporters (organic anion transporting polypeptide [OATP], P-glycoprotein [P-gp], breast cancer-associated protein [BCRP], and multidrug resistance protein 1 [MDR1]) and cytochrome P-450 enzyme assays to investigate absorption, distribution, and excretion; (b) in vivo MGL-3196 rat and dog oral PK and bioavailability studies; (c) in vivo 14 (c) MGL-3196 rat and dog oral pharmacokinetics, absorption, excretion, and tissue distribution by quantitative whole-body autoradiography (QWBA) study; and (d) hepatic disposition of MGL-3196 using an in vitro sandwiched hepatocyte model system (B-CLEAR® Science and Technology) in canine (SCDH) and human (SCHH) hepatocytes. Tables 1A-1B show: 14 1 shows the C-MGL-3196 rat ADME study design.

[0141] [Table 1]

[0142] [Table 2]

[0143] Tables 2A-2B show 14 1 shows the C-MGL-3196 canine ADME study design.

[0144] [Table 3]

[0145] [Table 4]

[0146] Qualyst transporter solution was used to evaluate the hepatic uptake of MGL-3196 in sandwich-cultured human hepatocytes (SCHH). MGL-3196 was evaluated at 30 μM after 20 minutes of incubation (based on pilot uptake studies) in the presence of a physiological concentration of bovine serum albumin (BSA, approximately 4%). The experiment was performed in a 24-well format using one lot of Transporter Certified™ human hepatocytes (N=1). Each test condition was performed in three wells, providing triplicate data. Sample preparation and LC / MS / MS analysis of cell lysates to determine MGL-3196 concentration were performed at QTS according to the analytical assay methodology and analytical standards provided by Madrigal Pharmaceuticals. The following parameters were determined for the test article: (a) total accumulation (hepatic uptake), (b) cellular accumulation (intracellular concentration), (c) biliary excretion index (hepatic outflow), (d) Kp value (hepatic accumulation), (e) in vitro biliary clearance (prediction of in vivo biliary clearance), and (f) media accumulation (supernatant after incubation).

[0147] Determined parameters: Bile accumulation = total accumulation プラス(+)緩衝液 -Cell accumulation マイナス(-)緩衝液

[0148]

number

[0149]

number

[0150] Plasma protein binding of MGL-3196 was >99% in all species.

[0151] In vitro drug transporter & cytochrome P-450 enzyme assays are shown in Table 3.

[0152] [Table 5]

[0153] MGL-3196 is a weak substrate for MDR1 and is not a substrate for MRP2. MGL-3196 is not an inhibitor of: MDR1, MRP2, OCT2, CYP2C19, CYP1A2, CYP2A6, CYP2B6, CYP2D6, and CYP3A4 / 5.

[0154] Rat and dog PK / bioavailability studies were also performed. MGL-3196 reached maximum plasma concentrations in 2-6 hours and 1-8 hours after oral dosing in rats and dogs, with mean elimination half-lives of 2.5-7 hours and 3-5.5 hours, respectively. Mean bioavailability ranged from 45-98% and 11-135% in rats and dogs, respectively.

[0155] rat 14 The absorption, distribution, and excretion of C-MGL-3196 were studied. MGL-3196 has good liver penetration, high bile concentration, and excretion in the gastrointestinal tract, with low renal uptake and renal excretion. 14 Liver exposure of C-MGL-3196 was approximately 10X higher than that of plasma on average. MGL-3196 penetration into other tissues, including brain, heart, and bone, was low and could not be explained by blood flow. Tables 4-6 show the relevant results.

[0156] [Table 6]

[0157] [Table 7]

[0158] [Table 8]

[0159] Dog 14 C-MGL-3196 absorption, distribution, and excretion were studied. A canine C-MGL-3196 mass balance study (100 mg / kg) showed that at least 92% of the recovered radioactivity was in the feces and 2.7% in the urine (approximately 83% of the total administered dose was recovered in the feces and 2.5% in the urine). At 4 hours post-dose, high levels of MGL-3196 were present in the liver and bile, with bile concentrations approximately 80-fold and 250-fold higher than those in the liver and plasma, respectively. Liver to plasma ratios at 4 and 24 hours (100 mg / kg) were 3.1-fold and 267-fold higher, respectively, indicating that clearance from plasma was more rapid than that from the liver. Tables 7 and 8 show the relevant results.

[0160] [Table 9]

[0161] [Table 10]

[0162] The hepatic disposition of MGL-3196 was studied using an in vitro sandwiched canine and human hepatocyte model system. The data suggested that MGL-3196 accumulated in human and canine hepatocytes via active uptake and was excreted in the bile. Tables 9 and 10 show the relevant results.

[0163] [Table 11]

[0164] [Table 12]

[0165] MGL-3196 and its metabolite, MGL-3196-M1 (M1), were evaluated in sandwich-cultured human hepatocytes (SCHH) to assess the effects of temperature and concentration on total accumulation. Incubations were performed over multiple concentrations (3 μM, 10 μM, 30 μM, and 100 μM) in the presence of 4% bovine serum albumin (BSA) for 20 minutes at 37°C and 4°C. Following hepatic accumulation studies, interspecies comparisons of hepatobiliary disposition of MGL-3196 (30 μM) and its metabolite, M1, were assessed in SCHH and sandwich-cultured canine hepatocytes (SCDH) in the presence of 4% BSA.

[0166] Total accumulation of MGL-3196 (hepatocytes + bile) was demonstrated to be temperature dependent, suggesting that MGL-3196 accumulation (≥72.8%) was mediated by an active uptake process in SCHH. M1 accumulation was reduced by ≥65% upon incubation at 4°C in SCHH across all MGL-3196 exposure levels tested. These results suggested that M1 accumulation / formation was temperature dependent, consistent with a metabolically dependent mechanism.

[0167] An interspecies comparison of hepatobiliary disposition of MGL-3196 was performed in SCHH and SCDH. Total accumulation reflects the hepatic accumulation potential of the test article. Total accumulation of MGL-3196 (30 μM) in SCDH was approximately 81% lower than that observed in SCHH following 20 min of exposure. Accumulation of M1 was below the limit of detection (BLQ) in SCDH, whereas accumulation of M1 (0.67% of total parent accumulation) was observed in SCHH. M1 was BLQ in the cell culture medium following 20 min of exposure to MGL-3196 (30 μM) in both species.

[0168] The biliary excretion index (BEI) describes the movement of molecules from the inside of hepatocytes into the bile pocket, quantifying the biliary efflux potential of a test article. The BEI (%) of MGL-3196 was greater in SCDH (48.7%) than in SCHH (33.7%). In comparison, the BEI of d8-TCA, a model bile acid excreted extensively in bile, typically ranges from 30-50% and 50-75% in SCDH and SCHH, respectively.

[0169] Thus, these results suggested that MGL-3196 accumulation was mediated by an active uptake process in hepatocytes. M1 accumulation / formation was observed only in SCDH and was temperature-dependent, consistent with a metabolically dependent mechanism. M1 was BLQ in the cell culture medium following 20 min of exposure to MGL-3196 (30 μM) in both species. MGL-3196 biliary excretion was slightly greater in canine hepatocytes than in humans. However, the estimated biliary clearance of MGL-3196 was approximately 46% lower in canine hepatocytes than in humans. The lower biliary clearance was attributed to the significantly lower uptake of MGL-3196 observed in SCDH (81% lower total accumulation). Overall, these results suggested that MGL-3196 has the potential to be excreted into the bile of both species tested.

[0170] Human in vitro and animal in vivo analyses following dosing demonstrate that MGL-3196 is actively taken up into the liver and excreted via the bile. Distribution studies in rats and dogs showed that MGL-3196 localized to the liver with little or no penetration into other tissues.

Claims

1. 1. A method of treating a liver disorder or a lipid disorder in a subject in need thereof, comprising: (a) administering to a subject a first dose of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (“Compound A”) daily for a first time period; (b) performing a test selected from the group consisting of genetic testing, biomarker testing and pharmacokinetic testing on a biological sample obtained from the subject, a physical examination of the subject, and combinations thereof to determine the subject's sensitivity to Compound A after step (a); and (c) administering a second dose of Compound A to the subject for a second period of time based on the susceptibility result from step (b). A method comprising:

2. 10. The method of claim 1, wherein the test in step (b) is a biomarker test that measures the expression level of at least one biomarker.

3. (d) performing a first biomarker test on a first biological sample obtained from the subject prior to step (a), wherein the first biomarker test measures the expression level of at least one biomarker to be measured in step (b); (e) determining the change or degree of change in the expression level of at least one biomarker based on the results in steps (b) and (d); and (f) determining a second dose of Compound A based on the change or degree of change determined in step (e); The method of claim 1 or 2, further comprising:

4. 4. The method of claim 3, wherein determining the second dose of Compound A is further based on at least one demographic characteristic of the subject, a medical history of the subject, physical information of the subject, or a combination thereof.

5. 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile ("Compound A") for use in a method for treating a liver disorder or a lipid disorder in a subject in need thereof, said method comprising: (a) administering a first dose of Compound A to a subject daily for a first period of time; (b) performing a test selected from the group consisting of genetic testing, biomarker testing and pharmacokinetic testing on a biological sample obtained from the subject, a physical examination of the subject, and combinations thereof to determine the subject's sensitivity to Compound A after step (a); and (c) administering a second dose of Compound A to the subject for a second period of time based on the susceptibility result from step (b). 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile ("Compound A"),

6. 6. Compound A for use according to claim 5, wherein the test in step (b) is a biomarker test that measures the expression level of at least one biomarker.

7. The method comprises: (d) performing a first biomarker test on a first biological sample obtained from the subject prior to step (a), wherein the first biomarker test measures the expression level of at least one biomarker to be measured in step (b); (e) determining the change or degree of change in the expression level of at least one biomarker based on the results in steps (b) and (d); and (f) determining a second dose of Compound A based on the change or degree of change determined in step (e); 7. Compound A for use according to claim 5 or 6, further comprising:

8. 8. The compound A for use according to claim 7, wherein determining the second dose of compound A is further based on at least one demographic characteristic of the subject, the subject's medical history, the subject's physical information, or a combination thereof.

9. 1. Use of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile ("Compound A") in the manufacture of a medicament for use in a method of treating a liver disorder or a lipid disorder in a subject in need thereof, said method comprising: (a) administering a first dose of Compound A to a subject daily for a first period of time; (b) determining the subject's sensitivity to Compound A after step (a) by performing a test selected from the group consisting of genetic testing, biomarker testing and pharmacokinetic testing on a biological sample obtained from the subject, a physical examination of the subject, and combinations thereof; and (c) administering a second dose of Compound A to the subject for a second period of time based on the susceptibility result from step (b). Including, use.

10. 10. The use of claim 9, wherein the test in step (b) is a biomarker test that measures the expression level of at least one biomarker.

11. The method comprises: (d) performing a first biomarker test on a first biological sample obtained from the subject prior to step (a), wherein the first biomarker test measures the expression level of at least one biomarker to be measured in step (b); (e) determining the change or degree of change in the expression level of at least one biomarker based on the results in steps (b) and (d); and (f) determining a second dose of Compound A based on the change or degree of change determined in step (e); 11. The use according to claim 9 or 10, further comprising:

12. 12. The use of claim 11, wherein determining the second dose of compound A is further based on at least one demographic characteristic of the subject, the subject's medical history, the subject's physical information, or a combination thereof.

13. 1. A method of treating a liver disorder or a lipid disorder in a subject in need thereof, comprising: (a) conducting tests selected from the group consisting of genetic tests, biomarker tests and pharmacokinetic tests on a biological sample obtained from the subject, a physical examination of the subject, and combinations thereof; (b) determining a therapeutically effective amount of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (“Compound A”) for the subject based on the results of the test; and (c) administering to the subject a therapeutically effective amount of Compound A. A method comprising:

14. 14. The method of claim 13, wherein a predictive algorithm is used in step (b) to determine a therapeutically effective amount of Compound A.

15. 15. The method of claim 13 or 14, wherein determining the therapeutically effective amount of Compound A is further based on at least one demographic characteristic of the subject, the subject's medical history, the subject's physical information, or a combination thereof.

16. 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile ("Compound A") for use in a method for treating a liver disorder or a lipid disorder in a subject in need thereof, said method comprising: (a) conducting tests selected from the group consisting of genetic tests, biomarker tests and pharmacokinetic tests on a biological sample obtained from the subject, a physical examination of the subject, and combinations thereof; and (b) determining a therapeutically effective amount of Compound A for the subject based on the results of the test; 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile ("Compound A"),

17. 17. Compound A for use according to claim 16, wherein a predictive algorithm is used in step (b) to determine a therapeutically effective amount of compound A.

18. 18. The compound A for use according to claim 16 or 17, wherein determining the therapeutically effective amount of compound A is further based on at least one demographic characteristic of the subject, the subject's medical history, the subject's physical information, or a combination thereof.

19. 1. Use of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile ("Compound A") in the manufacture of a medicament for use in a method of treating a liver disorder or a lipid disorder in a subject in need thereof, said method comprising: (a) conducting tests selected from the group consisting of genetic tests, biomarker tests and pharmacokinetic tests on a biological sample obtained from the subject, a physical examination of the subject, and combinations thereof; and (b) determining a therapeutically effective amount of Compound A for the subject based on the results of the test; Including, use.

20. 20. The use of claim 19, wherein a predictive algorithm is used in step (b) to determine a therapeutically effective amount of compound A.

21. 21. The use of claim 19 or 20, wherein determining the therapeutically effective amount of Compound A is further based on at least one demographic characteristic of the subject, the subject's medical history, the subject's physical information, or a combination thereof.

22. The method, compound A for use, or use according to any one of claims 1 to 21, wherein the liver disorder is non-alcoholic steatohepatitis.

23. 22. The method, compound A for use, or use according to any one of claims 1 to 21, wherein the lipid disorder is hyperlipidemia or hypercholesterolemia.

24. 24. The method, compound A for use, or use of any one of claims 1 to 23, wherein the genetic testing comprises detecting a polymorphism in a polynucleotide encoding a drug transporter, a drug metabolizing enzyme, or a thyroid axis hormone, a thyroid pathway gene, a lipid pathway gene, or a combination thereof.

25. The method, compound A for use, or use according to any one of claims 1 to 24, wherein the drug transporter is a solute carrier transporter or an ATP-binding cassette transporter.

26. 26. The method, compound A for use, or use according to claim 25, wherein the ATP-binding cassette transporter is selected from the group consisting of ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, ABCG2 and ABCB11.

27. 26. The method, compound A for use, or use according to claim 25, wherein the solute carrier transporter is selected from the group consisting of SLC22A1, SLC22A2, SLC22A3, SLC22A6, SLC22A8, SLC22A11, SLCO1B1, SLCO1B3, SLCO2B1, SLC47A1 and SLC47A2.

28. 28. The method, compound A for use, or use of any one of claims 1 to 27, wherein the biomarker test comprises measuring the expression level of a biomarker selected from the group consisting of thyroid axis hormones, thyroxine-binding globulin (TBG), sex hormone-binding globulin (SHBG), and lipid biomarkers.

29. 29. The method, compound A for use, or use according to claim 28, wherein the thyroid axis hormone is triiodothyronine (free T3) or a metabolite thereof, reverse T3 or a metabolite thereof, free thyroxine (T4) or a metabolite thereof, thyrotropin (TSH) or a metabolite thereof, thyrotropin-releasing hormone (TRH) or a metabolite thereof, or a combination thereof.

30. 29. The method, compound A for use, or use according to claim 28, wherein the lipid biomarker is selected from the group consisting of total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, lipoprotein(a), apolipoprotein A1 (ApoA-1), and apolipoprotein B (ApoB).

31. The method, compound A for use, or use according to any one of claims 1 to 30, wherein the biological sample is a blood or serum sample.

32. 32. The method, the use or the compound A according to any one of claims 1 to 31, wherein the effective amount is in the range of 5 mg to 300 mg.

33. 33. The method, compound A for use, or use according to any one of claims 1 to 32, wherein the effective amount is about 40 mg, about 50 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg.

34. 34. The method, compound A for use, or use according to any one of claims 1 to 33, wherein the first dose is in the range of about 5 mg to 300 mg.

35. 35. The method, compound A for use, or use according to any one of claims 1 to 34, wherein the first dose is about 40 mg, about 50 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg.

36. 36. The method, the compound A for use or the use according to any one of claims 1 to 35, wherein the second dose is lower than the first dose.

37. 36. The method, the compound A for use, or the use according to any one of claims 1 to 35, wherein the second dose is the same as the first dose.

38. 36. The method, the compound A for use or the use according to any one of claims 1 to 35, wherein the second dose is higher than the first dose.

39. 39. The method, the compound A for use, or the use according to any one of claims 1 to 38, wherein the second dose is in the range of about 5 mg to 300 mg.

40. 40. The method, compound A for use, or use according to any one of claims 1 to 39, wherein the second dose is about 40 mg, about 50 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg.

41. 41. The method, compound A for use, or use of any one of claims 1 to 40, wherein compound A is in a form characterized by an X-ray powder diffraction pattern comprising peaks at about 10.5, 18.7, 22.9, 23.6, and 24.7 degrees 2θ.

42. 42. The method, compound A for use or use according to any one of claims 1 to 41, wherein the first period of time is in the range of 2 to 21 days.

43. 43. The method, compound A for use, or use according to any one of claims 1 to 42, wherein compound A is formulated in a gel, tablet, pill, or capsule.

44. 44. The method, compound A for use, or use according to any one of claims 1 to 43, wherein compound A is administered orally.

45. 45. The method, compound A for use or use according to any one of claims 1 to 44, wherein compound A is administered daily.

46. 46. The method, compound A for use, or use according to any one of claims 1 to 45, wherein the lipid disorder is heterozygous familial hypercholesterolemia (HeFH) or homozygous familial hypercholesterolemia (HoFH).

47. The method, compound A for use, or use according to any one of claims 1 to 46, wherein the drug metabolizing enzyme is an oxidative drug metabolizing enzyme or a conjugate drug metabolizing enzyme.

48. 48. The method, compound A for use, or use according to any one of claims 1 to 47, wherein compound A is administered once daily, twice daily, or three times daily.

49. 49. The method, compound A for use or use according to any one of claims 1 to 48, wherein the subject is administered or has been administered at least one other therapeutic agent.

50. 50. The method, use or use of Compound A according to claim 49, wherein the at least one other therapeutic agent is a statin.

51. 51. The method, Compound A for use, or use according to any one of claims 1 to 50, wherein the pharmacokinetic testing comprises measuring the level of a metabolite of Compound A in a biological sample at predetermined times after administration of the first dose.

52. A metabolite of Compound A has the following structure: 【Chemical 1】 52. The method, compound A for use, or use of claim 51, comprising M1 having the formula:

53. 53. The method, use or use of compound A according to claim 51 or 52, wherein the predetermined period of time is at least 20 minutes.

54. 54. The method, compound A for use, or use according to any one of claims 51 to 53, wherein the metabolites have a geometric mean maximum plasma concentration of about 100 ng / mL to 1000 ng / mL.

55. 55. The method, compound A for use, or use according to claim 54, wherein the geometric mean of the maximum plasma concentration is between about 150 ng / mL and 700 ng / mL.

56. 1. A method for treating a liver disorder or a lipid disorder in a subject in need thereof, comprising administering to the subject an effective amount of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile daily, wherein the subject does not require clinical monitoring following administration of the medication.

57. 57. The method of claim 56, wherein the effective amount is in the range of 5 mg to 300 mg.

58. 58. The method of claim 56 or 57, wherein the clinical monitoring is selected from the group consisting of a bone scan, a heart scan, and a brain scan.

59. 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile ("Compound A") for use in treating a liver disorder or a lipid disorder in a subject in need thereof, wherein the subject does not require clinical monitoring following administration of the medication.

60. 60. Compound A for use according to claim 59, wherein the clinical monitoring is selected from the group consisting of a bone scan, a heart scan and a brain scan.

61. 1. Use of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile ("Compound A") in the manufacture of a medicament for use in a method of treating a liver disorder or a lipid disorder in a subject in need thereof, wherein the subject does not require clinical monitoring following administration of the medicament.

62. 62. The use of claim 61, wherein the clinical monitoring is selected from the group consisting of a bone scan, a heart scan, and a brain scan.

Images