Combination therapy for the treatment of liver disease

Abstract

The present invention relates to pharmaceutical compositions comprising at least one fatty acid-bile acid conjugate (FABAC) or a pharmaceutically acceptable salt thereof and at least one thyroid hormone receptor agonist or thyroid hormone analog or a pharmaceutically acceptable salt thereof, and uses of said pharmaceutical compositions for treating, stabilizing, or reducing the severity or progression of liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, and their co-morbidities.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition, and more particularly to a pharmaceutical composition comprising at least one fatty acid-bile acid conjugate (FABAC) or a pharmaceutically acceptable salt thereof, and at least one thyroid hormone receptor agonist or thyroid hormone mimetic or a pharmaceutically acceptable salt thereof, and the use of the above pharmaceutical composition for treating, stabilizing or reducing the severity or progression of liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, and their co-morbidities.

Background Art

[0002] Fatty liver is one of the most common liver diseases currently known. Fatty liver develops due to excessive accumulation of fat in the liver. This is histologically proven by the presence of various amounts of micro-fat droplets and / or micro-vesicular fat droplets in liver tissue. Fatty liver can be caused by drugs, chemicals, diseases, bacteria, etc., but the main cause is excessive dietary intake that leads to obesity (mainly in the trunk) and insulin resistance. Since the prevalence of obesity is increasing in affluent societies, the prevalence of fatty liver is rising. Fatty liver may progress to steatohepatitis and cirrhosis, in which case the morbidity and mortality also increase. The best treatment for diet-induced fatty liver is sustained weight loss. However, it is well known that this is rarely achieved.

[0003] The term non-alcoholic fatty liver disease (NAFLD) refers to a range of liver diseases from simple fatty liver (steatosis) to non-alcoholic steatohepatitis (NASH) with progressive fibrosis and liver failure. NAFLD shows histological features of alcohol-induced liver disease in patients who do not consume large amounts of alcohol. In NASH, fat accumulation is associated with varying degrees of inflammation and fibrosis. What is common to all stages of NAFLD is the accumulation of fat in hepatocytes.

[0004] Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) that leads to further liver damage. The progression of NASH involves multiple parallel "hits" or injuries to the body, including, for example, steatosis, oxidative stress, mitochondrial dysfunction, apoptosis, inflammation, hepatic stellate cell activation, and collagen production.

[0005] Fibrosis refers to the formation of excessive fibrous connective tissue in an organ or tissue during a repair or reaction process. This can be a reactive, benign, or pathological condition. When fibrous connective tissue is deposited in an organ and / or tissue, the structure and function of the organ or tissue beneath it are lost. Fibrosis is thus a pathological condition of excessive fibrous tissue deposition, and is also a process of connective tissue deposition during healing.

[0006] The burden of liver disease, coupled with the lack of effective, approved therapeutic interventions for NAFLDs such as NASH, represents an unmet medical need.

[0007] The background technology includes U.S. Patent Publication No. 2018 / 0125862A, "Farrell and Larter, Hepatology, 243:S99-S112 (2006)", and "Palekar, et al., Liver int., 26(2): 151-6 (2006)".

[0008] Many patients do not respond to existing treatments for fatty liver disease. Furthermore, long-term treatment is limited by toxicity and side effects. Developing safe and effective treatments for liver diseases such as fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and liver disease-related comorbidities would be highly beneficial. [Overview of the project] [Means for solving the problem]

[0009] In one embodiment, the present invention provides a pharmaceutical composition comprising at least one fatty acid-bile acid conjugate (FABAC) or a pharmaceutically acceptable salt thereof, at least one thyroid hormone analog or thyroid hormone receptor agonist or a pharmaceutically acceptable salt thereof, and a carrier.

[0010] In another embodiment, the present invention provides a method for treating, stabilizing, or reducing the severity or progression of liver disease, comprising the step of co-administering a therapeutically effective amount of at least one fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone analog or thyroid hormone receptor agonist or a salt thereof to a subject in need thereof. [Modes for carrying out the invention]

[0011] The following detailed description includes numerous specific details to provide a complete understanding of the invention. However, it will be understood by those skilled in the art that the invention may be carried out without using these specific details. In other examples, well-known methods, procedures, and components are not described in detail so as not to obscure the invention.

[0012] Embodiments of the present invention relate to a pharmaceutical composition comprising at least one fatty acid-bile acid conjugate (FABAC) or a pharmaceutically acceptable salt thereof and at least one thyroid hormone receptor agonist or thyroid hormone analog or a pharmaceutically acceptable salt thereof, and to the use of the above-mentioned pharmaceutical composition for treating, stabilizing, or alleviating the severity or progression of liver diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, and their comorbidities.

[0013] Before describing at least one embodiment in detail, it should be understood that the present invention is not necessarily limited to its application to the structural and arrangement details of the components and / or methods described herein. Other embodiments are possible, or the invention can be carried out in various ways. The terms and expressions used herein are for illustrative purposes only and should not be considered limiting.

[0014] According to one aspect of several embodiments of the present invention, a composition is provided comprising a therapeutically effective amount of at least one fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog.

[0015] In some embodiments, at least one fatty acid-bile acid conjugate (FABAC) is represented by the following formula (I). WXG (Formula I) During the ceremony G is a bile acid or bile salt radical, W is one or two fatty acid radicals. X is (i) one binding member between a bile acid or bile salt radical and one fatty acid radical, or (ii) two binding members between two fatty acid radicals and two positions of a bile acid or bile salt radical. The bonding members are -NH, -O, or direct bonds.

[0016] In some embodiments, at least one fatty acid-bile acid conjugate (FABAC) is 3-β-arachidylamide-7-α,1-2α-dihydroxy-5-β-colan-24-acid (Aramcol™). In this specification, "TM" means trademark.

[0017] In some embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog comprises a selective thyroid hormone receptor β-agonist selected from the group consisting of (GC-1), (VK2809), and the compound represented by (Formula II) below.

[0018]

Chem.

[0019]

Chem.

[0020]

Chem.

[0021] In the formula, R1 is alkyl-COOH, an amino acid,

[0022]

Chem.

[0023] and R2 and R2' are, independently of each other, alkyl or halide, Q is O, alkyl, S, or SO2, R3 is H or alkyl, The compound represented by the above (Formula II) includes its pharmaceutically acceptable salts, or a mixture containing any combination thereof in any ratio.

[0024] In some embodiments, R1 in formula II is alkyl-COOH. In other embodiments, R1 in formula II is (CH2)n-COOH, where n is 1 to 6. In other embodiments, R1 in formula II is CH2-COOH. In other embodiments, R1 in formula II is CH2-CH2-COOH. In other embodiments, R1 in formula II is CH2-CH2-CH2-COOH. In other embodiments, R1 in formula II is CH2-CH2-CH2-CH2-COOH. In other embodiments, R1 in formula II is CH2-CH2-CH2-CH2-CH2-COOH. In other embodiments, R1 in formula II is CH2-CH2-CH2-CH2-CH2-CH2-COOH.

[0025] In some embodiments, R1 in formula II is an amino acid, linked by its side chain. In some embodiments, the amino acid is alanine. In other embodiments, the amino acid is arginine. In other embodiments, the amino acid is asparagine. In other embodiments, the amino acid is aspartic acid. In other embodiments, the amino acid is cysteine. In other embodiments, the amino acid is glutamic acid. In other embodiments, the amino acid is glutamine. In other embodiments, the amino acid is glycine. In other embodiments, the amino acid is histidine. In other embodiments, the amino acid is hydroxyproline. In other embodiments, the amino acid is isoleucine. In other embodiments, the amino acid is leucine. In other embodiments, the amino acid is lysine. In other embodiments, the amino acid is methionine. In other embodiments, the amino acid is phenylalanine. In other embodiments, the amino acid is proline. In other embodiments, the amino acid is pyroglutamic acid. In other embodiments, the amino acid is serine. In other embodiments, the amino acid is threonine. In other embodiments, the amino acid is tryptophan. In other embodiments, the amino acid is tyrosine. In other embodiments, the amino acid is valine.

[0026] In some embodiments, R2 is an alkyl group. In other embodiments, R2 is a halide.

[0027] In some embodiments, R2' is an alkyl group. In other embodiments, R2' is a halide.

[0028] In some embodiments, Q is O. In other embodiments, Q is alkyl. In other embodiments, Q is S. In other embodiments, Q is SO2.

[0029] In some embodiments, R3 is H. In other embodiments, R3 is alkyl.

[0030] In some embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog comprises a selective thyroid hormone receptor β-agonist selected from the group consisting of compounds represented by (GC-1), (VK2809), (Formula II) below, pharmaceutically acceptable salts thereof, and mixtures comprising any combination thereof in any ratio.

[0031] [ka]

[0032] [ka]

[0033] [ka]

[0034] In the compound represented by (Formula II) above, R1, R2, R2', Q, and R3 are as listed in the table below.

[0035] [Table 1]

[0036] In some embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog is selected from the group consisting of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), 2-[4-[[4-hydroxy-3-(1-methylethyl)phenyl]methyl]-3,5-dimethylphenoxy]acetic acid (GC1), 2-((3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl)-4-(3-chlorophenyl)-2-oxide(1,3,2)dioxaphosphonan (VK2809), and any combination thereof.

[0037] In some embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog comprises MGL-3196. In some such embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog consists essentially of MGL-3196.

[0038] In some embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog comprises levothyroxine (L-thyroxine). In some such embodiments, levothyroxine (L-thyroxine) comprises levothyroxine (L-thyroxine) sodium. In some embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog comprises dextrothyroxine. In some such embodiments, dextrothyroxine comprises dextrothyroxine sodium. In some embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog comprises dried thyroid gland. In some embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog comprises thyroid extract. In some embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog comprises liothyronine. In some such embodiments, liothyronine comprises liothyronine sodium. In some embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog comprises liotrix.

[0039] In some embodiments, the fatty acid-bile acid conjugate (FABAC) comprises Aramcol™, and the at least one thyroid hormone receptor agonist or thyroid hormone analog comprises MGL-3196.

[0040] According to one aspect of several embodiments of the present invention, a pharmaceutical composition is provided comprising the composition disclosed herein and at least one pharmaceutically acceptable excipient.

[0041] According to one aspect of several embodiments of the present invention, a liver-effective composition is provided comprising a pharmaceutical composition disclosed herein, wherein at least one fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog contained in the pharmaceutical composition disclosed herein are present in the liver-effective composition in a synergistically effective amount.

[0042] In some embodiments of compositions effective for the liver, administration of a synergistically effective amount of at least one fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog provides at least one therapeutic improvement selected from the group consisting of (a), (b), and (c) below, compared to administration of at least one composition comprising at least one fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog in the absence of the other of the two. (a) At least one fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog are present in a low dose. (b) A shorter treatment schedule. (c) Reduced incidence and severity of side effects.

[0043] In some embodiments of the liver-effective composition, at least one fatty acid-bile acid conjugate (FABAC) comprises Alamcol™, and at least one thyroid hormone receptor agonist or thyroid hormone analog comprises MGL-3196. Furthermore, the synergistically effective dose of at least one fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog is at least one of MGL-3196 in amounts greater than 0 mg and less than 50 mg (e.g., about 0.2 mg, about 0.5 mg, about 1 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 45 mg) and at least one of Alamcol™ in amounts greater than 0 mg and less than 400 mg (e.g., about 0.2 mg, about 0.5 mg, about 1 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 95 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 395 mg).

[0044] In some such embodiments, Alamcol™ is present in the liver-effective composition in an amount greater than 0 mg and less than 300 mg.

[0045] In some such embodiments, Alamcol™ is present in the liver-effective composition in an amount greater than 0 mg and less than 100 mg.

[0046] According to one aspect of several embodiments of the present invention, the use of the compositions disclosed herein in the treatment of liver disease is provided.

[0047] According to one aspect of several embodiments of the present invention, the use of the composition disclosed herein in the manufacture of a pharmaceutical composition for treating liver disease is provided.

[0048] In the compositions or embodiments of use of the present disclosure, the liver disease is selected from the group consisting of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), emerging cirrhosis, non-cirrodegenerative liver fibrosis, and liver fibrosis.

[0049] In some such embodiments, hepatic fibrosis is associated with at least one disease selected from the group consisting of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and emerging cirrhosis.

[0050] In some such embodiments, liver fibrosis includes non-cirrodegenerative liver fibrosis.

[0051] In some embodiments of the compositions or their use, the subject (subject) has a disease or condition selected from the group consisting of human immunodeficiency virus (HIV) infection, HIV and HCV co-infection, viral hepatitis, type 2 diabetes mellitus (T2DM), metabolic syndrome (MS), or any combination thereof.

[0052] In some such embodiments, viral hepatitis is HBV (hepatitis B virus) infection or HCV (hepatitis C virus) infection.

[0053] In some embodiments of the compositions or their use, at least one fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog are present in the composition in a synergistically effective amount.

[0054] In some such embodiments, administration of a synergistically effective amount of at least one fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog provides at least one therapeutic improvement selected from the group consisting of (a), (b), and (c) below, compared to administration of at least one composition comprising at least one fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog in the absence of the other of the fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog. (a) At least one fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog are present in a low dose. (b) A shorter treatment schedule. (c) Reduced incidence and severity of side effects.

[0055] In some embodiments of the compositions or uses of the present disclosure, at least one fatty acid-bile acid conjugate (FABAC) comprises Alamcol™, and at least one thyroid hormone receptor agonist or thyroid hormone analog comprises MGL-3196. Furthermore, the synergistically effective dose of at least one fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog is at least one of MGL-3196 in amounts greater than 0 mg and less than 50 mg (e.g., about 0.2 mg, about 0.5 mg, about 1 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 45 mg) and at least one of Alamcol™ in amounts greater than 0 mg and less than 400 mg (e.g., about 0.2 mg, about 0.5 mg, about 1 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 95 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 395 mg).

[0056] In some such embodiments, Alamcol™ is present in the liver-effective composition in an amount greater than 0 mg and less than 300 mg.

[0057] In some such embodiments, Alamcol™ is present in the liver-effective composition in an amount greater than 0 mg and less than 100 mg.

[0058] According to one aspect of several embodiments of the present invention, a method is provided for treating, stabilizing, or reducing the severity or progression of liver disease, comprising the step of co-administering a therapeutically effective amount of at least one fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog or salt thereof to a subject in need thereof.

[0059] In some embodiments of the methods of the present disclosure, at least one fatty acid-bile acid conjugate (FABAC) is represented by the following formula (I). WXG (Formula I) During the ceremony G is a bile acid or bile salt radical, W is one or two fatty acid radicals. X is (i) one binding member between a bile acid or bile salt radical and one fatty acid radical, or (ii) two binding members between two fatty acid radicals and two positions of a bile acid or bile salt radical. The bonding members are -NH, -O, or direct bonds.

[0060] In some embodiments of the methods disclosed herein, at least one fatty acid-bile acid conjugate (FABAC) is 3-β-arachidylamide-7-α, 12 It is α-dihydroxy-5-β-colan-24-acid (Aramcol™).

[0061] In some embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog comprises a selective thyroid hormone receptor β-agonist selected from the group consisting of (GC-1), (VK2809), and the compound represented by (Formula II) below.

[0062] [ka]

[0063] [ka]

[0064] [ka]

[0065] During the ceremony, R1 is alkyl-COOH, amino acid,

[0066] [ka]

[0067] And, R2 and R2' are independently alkyl or halide compounds. Q is O, alkyl, S, or SO2. R3 is either H or alkyl. The compound represented by (Formula II) above includes its pharmaceutically acceptable salts, or mixtures containing any combination thereof in any ratio.

[0068] In some embodiments, R1 in formula II is alkyl-COOH. In other embodiments, R1 in formula II is (CH2)n-COOH, where n is 1 to 6. In other embodiments, R1 in formula II is CH2-COOH. In other embodiments, R1 in formula II is CH2-CH2-COOH. In other embodiments, R1 in formula II is CH2-CH2-CH2-COOH. In other embodiments, R1 in formula II is CH2-CH2-CH2-CH2-COOH. In other embodiments, R1 in formula II is CH2-CH2-CH2-CH2-CH2-COOH. In other embodiments, R1 in formula II is CH2-CH2-CH2-CH2-CH2-CH2-COOH.

[0069] In some embodiments, R1 in formula II is an amino acid, linked by its side chain. In some embodiments, the amino acid is alanine. In other embodiments, the amino acid is arginine. In other embodiments, the amino acid is asparagine. In other embodiments, the amino acid is aspartic acid. In other embodiments, the amino acid is cysteine. In other embodiments, the amino acid is glutamic acid. In other embodiments, the amino acid is glutamine. In other embodiments, the amino acid is glycine. In other embodiments, the amino acid is histidine. In other embodiments, the amino acid is hydroxyproline. In other embodiments, the amino acid is isoleucine. In other embodiments, the amino acid is leucine. In other embodiments, the amino acid is lysine. In other embodiments, the amino acid is methionine. In other embodiments, the amino acid is phenylalanine. In other embodiments, the amino acid is proline. In other embodiments, the amino acid is pyroglutamic acid. In other embodiments, the amino acid is serine. In other embodiments, the amino acid is threonine. In other embodiments, the amino acid is tryptophan. In other embodiments, the amino acid is tyrosine. In other embodiments, the amino acid is valine.

[0070] In some embodiments, R2 is an alkyl group. In other embodiments, R2 is a halide.

[0071] In some embodiments, R2' is an alkyl group. In other embodiments, R2' is a halide.

[0072] In some embodiments, Q is O. In other embodiments, Q is alkyl. In other embodiments, Q is S. In other embodiments, Q is SO2.

[0073] In some embodiments, R3 is H. In other embodiments, R3 is alkyl.

[0074] In some embodiments of the methods of the present disclosure, at least one thyroid hormone receptor agonist or thyroid hormone analog comprises a selective thyroid hormone receptor β-agonist selected from the group consisting of compounds represented by (GC-1), (VK2809), (Formula II) below, pharmaceutically acceptable salts thereof, and mixtures comprising any combination thereof in any ratio.

[0075] [ka]

[0076] [ka]

[0077] [ka]

[0078] In the compound represented by (Formula II) above, R1, R2, R2', Q, and R3 are as listed in the table below.

[0079] [Table 1]

[0080] In some embodiments of the methods of the present disclosure, at least one thyroid hormone receptor agonist or thyroid hormone analog is selected from the group consisting of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), 2-[4-[[4-hydroxy-3-(1-methylethyl)phenyl]methyl]-3,5-dimethylphenoxy]acetic acid (GC1), 2-((3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl)-4-(3-chlorophenyl)-2-oxide(1,3,2)dioxaphosphonan (VK2809), and any combination thereof.

[0081] In some embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog comprises levothyroxine (L-thyroxine). In some such embodiments, levothyroxine (L-thyroxine) comprises levothyroxine (L-thyroxine) sodium. In some embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog comprises dextrothyroxine. In some such embodiments, dextrothyroxine comprises dextrothyroxine sodium. In some embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog comprises dried thyroid gland. In some embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog comprises thyroid extract. In some embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog comprises liothyronine. In some such embodiments, liothyronine comprises liothyronine sodium. In some embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog comprises liotrix.

[0082] In some embodiments of the methods disclosed herein, at least one thyroid hormone receptor agonist or thyroid hormone analog comprises MGL-3196.

[0083] In some embodiments of the methods of the present disclosure, at least one fatty acid-bile acid conjugate (FABAC) comprises Alamcol™, and at least one thyroid hormone receptor agonist or thyroid hormone analog comprises MGL-3196.

[0084] In some embodiments of the method of the present disclosure, the step of co-administering to the subject a therapeutically effective amount of the at least one fatty acid-bile acid conjugate (FABAC) and the at least one thyroid hormone receptor agonist or thyroid hormone analog or a salt thereof further comprises administering at least one pharmaceutically acceptable excipient.

[0085] In some embodiments of the method of the present disclosure, the step of co-administering a therapeutically effective amount of the at least one fatty acid-bile acid conjugate (FABAC) and the at least one thyroid hormone receptor agonist or thyroid hormone analog or salt thereof to the subject includes co-administering a therapeutically effective amount of the at least one fatty acid-bile acid conjugate (FABAC) and the at least one thyroid hormone receptor agonist or thyroid hormone analog or salt thereof in a synergistically effective amount.

[0086] In some such embodiments, administration of a synergistically effective amount of at least one fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog provides at least one therapeutic improvement selected from the group consisting of (a), (b), and (c) below, compared to administration of at least one composition comprising at least one fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog in the absence of the other of the fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog. (a) At least one fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog are present in a low dose. (b) A shorter treatment schedule. (c) Reduced incidence and severity of side effects.

[0087] In some embodiments of the methods of the present disclosure, at least one fatty acid-bile acid conjugate (FABAC) comprises Alamcol™, and at least one thyroid hormone receptor agonist or thyroid hormone analog comprises MGL-3196. Furthermore, the synergistically effective dose of at least one fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog is at least one of MGL-3196 in amounts greater than 0 mg and less than 50 mg (e.g., about 0.2 mg, about 0.5 mg, about 1 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 45 mg) and at least one of Alamcol™ in amounts greater than 0 mg and less than 400 mg (e.g., about 0.2 mg, about 0.5 mg, about 1 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 95 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 395 mg).

[0088] In some such embodiments, Alamcol™ is present in the liver-effective composition in an amount greater than 0 mg and less than 300 mg.

[0089] In some such embodiments, Alamcol™ is present in the liver-effective composition in an amount greater than 0 mg and less than 100 mg.

[0090] In some embodiments of the methods of the present disclosure, the liver disease is selected from the group consisting of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), emerging cirrhosis, non-cirrodegenerative liver fibrosis, and liver fibrosis.

[0091] In some such embodiments, hepatic fibrosis is associated with at least one disease selected from the group consisting of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and emerging cirrhosis.

[0092] In some such embodiments, liver fibrosis includes non-cirrodegenerative liver fibrosis.

[0093] In some embodiments of the methods of this disclosure, the subjects have a disease or condition selected from the group consisting of human immunodeficiency virus (HIV) infection, HIV and HCV co-infection, viral hepatitis, type 2 diabetes mellitus (T2DM), metabolic syndrome (MS), or any combination thereof.

[0094] In some such embodiments, viral hepatitis is HBV (hepatitis B virus) infection or HCV (hepatitis C virus) infection.

[0095] In some embodiments of the methods of the present disclosure, co-administration includes simultaneous administration, sequential administration, overlapping administration, combined administration, interval administration, continuous administration, simultaneous administration, or any combination thereof. In some embodiments of the methods of the present disclosure, sequential administration is performed in any order.

[0096] In some embodiments of the methods of the present disclosure, a fatty acid-bile acid conjugate (FABAC) is administered orally, and at least one thyroid hormone receptor agonist or thyroid hormone analog is administered orally or parenterally, for example, by intravenous, intra-arterial, intramuscular, subcutaneous, intraosseous, intrathecal, or any combination thereof.

[0097] In some such embodiments, fatty acid-bile acid conjugates (FABACs) are formulated as orally administered compositions.

[0098] In some embodiments of the methods of this disclosure, the fatty acid-bile acid conjugate (FABAC) is administered once daily.

[0099] In some embodiments of the methods of the present disclosure, at least one thyroid hormone receptor agonist or thyroid hormone analog is formulated as an orally administered composition.

[0100] In some embodiments of the methods of the present disclosure, a fatty acid-bile acid conjugate (FABAC) and at least one thyroid hormone receptor agonist or thyroid hormone analog are provided as a single composition.

[0101] In some embodiments of the methods of the present disclosure, at least one thyroid hormone receptor agonist or thyroid hormone analog is administered once daily. In some embodiments, at least one thyroid hormone receptor agonist or thyroid hormone analog is administered twice daily, three times daily, four times daily, every other day, every three days, once a week, or twice a week.

[0102] In some embodiments of the method disclosed herein, the administration is carried out in one or more treatment cycles, such as one, two, three, four, or more treatment cycles.

[0103] In some embodiments of the method of the present disclosure, each treatment cycle includes co-administration over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or more than 40 days. In some embodiments, there may be an interval of one day or more between the completion of one treatment cycle and the start of the next treatment cycle, for example, one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or longer.

[0104] According to one aspect of several embodiments of the present invention, a kit is provided comprising (a) at least one dose of at least one fatty acid-bile acid conjugate (FABAC) and (b) at least one dose of at least one thyroid hormone receptor agonist or thyroid hormone analog.

[0105] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which this invention pertains. In case of any conflict, this specification, including definitions, shall prevail.

[0106] As used herein, the indefinite articles "a" and "an" mean "at least one" or "one or more" unless the context clearly indicates otherwise.

[0107] When used herein, if the term “approximately” precedes a number, the term “approximately” is intended to include all values ​​that have substantially the same effect as the reference value or that provide substantially the same results. Therefore, the range encompassed by the term “approximately” depends on the context in which the term is used, for example, the parameters related to the reference value. Thus, depending on the context, “approximately” may include, for example, a range of ±15%, ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, or less than ±1% of the reference value.

[0108] As used herein, the term “pharmaceutically acceptable” means a material or method that can be used in medicine or pharmaceuticals for human or veterinary purposes, such as administration to an object.

[0109] As used herein, the term "salt" includes both acid addition salts and base addition salts.

[0110] As used herein, the term “acid addition salt” refers to a salt formed by inorganic and organic acids that retains the biological efficacy and properties of a free base and is not biologically or otherwise undesirable.

[0111] As used herein, the term “base addition salt” refers to a salt formed by the addition of an inorganic or organic base to a free acid, which preserves the biological efficacy and properties of the free acid and is not biologically or otherwise undesirable.

[0112] As used herein, the term “pharmaceutical composition” means a composition comprising one or more compounds or mixtures of the present disclosure and a medium commonly accepted in the art for delivering a biologically active compound to a mammal, such as a human. Such mediums include all pharmaceutically acceptable carriers, diluents, or excipients.

[0113] As used herein, the term “treat” includes improving, alleviating, preventing worsening, and reducing the condition or symptoms of a disease or condition.

[0114] As used herein, the term “administer” includes any form of administration, such as oral, subcutaneous, sublingual, transmucosal, parenteral, intravenous, intra-arterial, oral cavity, sublingual, topical, transvaginal, transrectal, transocular, transaural, transaural, transaural, transaural, inhalation, intramuscular, intraosseous, intrathecal, and transdermal, or any combination thereof. “Administer” also includes providing another compound that, when ingested or delivered as described above, necessarily transforms into the compound to be administered, and this type of “different compound” is often referred to as a “prodrug.” “Administer” may also include formulating or compounding a preparation containing a particular compound. “Administer” may also include providing instructions for carrying out a method that includes the step of administering a particular compound or a preparation containing it.

[0115] As used herein, the term “therapeutic dose” means an amount of an active substance sufficient to have a beneficial effect on a disease, disorder, or other undesirable medical condition when administered to a subject for the treatment of that disease, disorder, or other undesirable medical condition. The therapeutic dose varies depending on the chemical identity and formulation of the active substance, the disease or condition and its severity, and the age, weight, and other relevant characteristics of the patient being treated. Determining the therapeutic dose of a particular active substance is within the scope of those skilled in the art and usually requires only a series of experiments.

[0116] As used herein, the term “liver disease” refers to any liver dysfunction that causes disease. Liver disease is also referred to herein as “liver disorder.”

[0117] It should be understood that the text of all journal articles, patents, patent applications, publications, etc., described herein is intended to be included in this application to the extent relevant to the purpose of citation. All numerical ranges should be understood to include all numerical points within the range, and all numerical points should be interpreted as being listed individually. The endpoints of all ranges relating to the same component or property are comprehensive and are intended to be able to be combined independently.

[0118] While specific features of the present invention have been illustrated and described herein, various modifications, substitutions, alterations, and equivalents may be conceivable to those skilled in the art. Therefore, it should be understood that the appended claims are intended to encompass all such modifications and alterations that fall within the scope of the present invention.

[0119] Examples

[0120] To facilitate a more complete understanding of the present invention, examples are provided below. The following examples illustrate exemplary embodiments of the preparation and implementation of the present invention. However, the scope of the present invention is not limited to the specific embodiments disclosed in these examples, which are for illustrative purposes only.

[0121] Example 1:

[0122] A double-blind, placebo-controlled, randomized trial was designed to evaluate the safety and efficacy of co-administration of Alamcol™ and MGL-3196 in patients aged 18–75 years with non-alcoholic steatohepatitis (NASH) confirmed by liver biopsy performed 6 months prior to the start of the trial.

[0123] Study patient eligibility criteria

[0124] Male or female between the ages of 18 and 75.

[0125] BMI 25 kg / m² 2 ~40kg / m 2The range, or waist circumference, must be between 88cm and 200cm for women and between 102cm and 200cm for men.

[0126] You must be diagnosed with type 2 diabetes or prediabetes according to the American Diabetes Association. Prediabetes must meet one of the following three criteria: fasting plasma glucose > 100 mg / dl (5.5 mmol / l), PG > 140 mg / dl (7.8 mmol / l) 2 hours after a 75g OGTT, or HbA1c > 5.7%.

[0127] Steatohepatitis must be histologically demonstrated by a diagnostic liver biopsy performed during the screening period or within 6 months prior to the screening visit, and confirmed by slide interpretation in the central laboratory (Steatosis ≥ 1 + Inflammation ≥ 1 + Ballooning ≥ 1). The total active NAS score must be 4 or higher.

[0128] The liver fat concentration must be 5.5% or higher, as measured by NMRS.

[0129] The active NAS score obtained by biopsy must be 4 or higher.

[0130] Synthetic liver function should be normal (serum albumin > 3.2 g / dl, INR 0.8-1.2, conjugated bilirubin < 35 μmol / L).

[0131] Understand the details of the clinical trial and sign the consent form.

[0132] For women of childbearing potential, a negative pregnancy test result is required at the time of application for the clinical trial.

[0133] For women of childbearing potential, reliable contraception (including oral contraceptives) must be used during the trial period, and a negative pregnancy test result at the start of the trial.

[0134] For patients with hypertension, their blood pressure should be well controlled with a stable dose of antihypertensive medication for at least two months prior to screening.

[0135] In patients with a history of treatment with vitamin E (>400 IU / day), polyunsaturated fatty acids (>2 g / day), or ursodeoxycholic acid or fish oil, it is a condition that such treatment be discontinued at least 3 months prior to diagnostic liver biopsy, or that at least a stable dose is maintained (and that such treatment is not initiated during the study). These therapeutic doses are acceptable if they have been stable for at least 12 months prior to biopsy and remain stable throughout the study period.

[0136] For patients with type 2 diabetes, blood glucose levels must be controlled (glycosylated hemoglobin A1c ≤ 9%) and the change in HbA1c over the six months prior to enrollment must not exceed 1.5%. If the patient is self-managing their blood glucose levels, treatment with antidiabetic drugs (excluding those listed in exclusion criterion 16) is permitted. HbA1c may be measured repeatedly at the discretion of the principal investigator.

[0137] Exclusion criteria

[0138] Patients who, at the time of randomization, have other active (acute or chronic) liver disease other than NASH (e.g., viral hepatitis (unless it has been eradicated at least 3 years prior to screening), hereditary hemochromatosis, Wilson's disease, α1-antitrypsin deficiency, alcoholic liver disease, drug-induced liver disease).

[0139] Patients with clinically or histologically proven cirrhosis of the liver.

[0140] Anyone who has been found to have abused or been dependent on alcohol and / or other drugs in the past five years.

[0141] If a patient is found to have a history of or is currently suffering from any of the following clinically significant cardiovascular disease, gastrointestinal disease, metabolic disease other than diabetes, neurological disease, pulmonary disease, endocrine disease, psychiatric disorder, neoplastic disease, or nephrotic syndrome, they may be excluded from the clinical trial at the discretion of the principal investigator.

[0142] Patients with familial (i.e., hereditary) hypertriglyceridemia and familial (i.e., hereditary) hypercholesterolemia.

[0143] Individuals with a history of or current condition of having a disease or condition known to inhibit the absorption, distribution, metabolism, or excretion of drugs containing bile salt metabolites (e.g., inflammatory bowel disease (IBD)), bowel (ileal or colon) surgery, chronic pancreatitis, celiac disease, vagus nerve transection, or ongoing chronic constipation.

[0144] A patient who has a pacemaker (i.e., an implanted neurological device) in their heart or brain.

[0145] Individuals who have undergone surgery involving the placement of a metal stent (e.g., in the knee, buttocks, etc.) within three months prior to screening.

[0146] Individuals who experienced a weight loss of more than 5% within the six months prior to randomization.

[0147] Individuals with a history of obesity treatment within the five years prior to liver biopsy.

[0148] Individuals with uncontrolled arterial hypertension.

[0149] Pregnant women and breastfeeding women.

[0150] Individuals with diabetes other than type II (type I, endocrine disorders, hereditary syndromes, etc.).

[0151] A patient with HIV infection.

[0152] Depending on their medical history, individuals whose daily alcohol intake (on average) is >20g / day for women and >30g / day for men.

[0153] Patients receiving treatment with other antidiabetic drugs (GLP-1 receptor agonists and thiazolidinediones (TZDs)). However, this excludes cases where treatment was initiated at least 12 months prior to the biopsy and administered at a stable dose for 6 months. If discontinuation of GLP-1 receptor agonists is necessary, it should be done at least 6 months prior to the biopsy, depending on the patient's medical history.

[0154] Individuals receiving SGLT-2 inhibitors, metformin, fibrates, statins, insulin, DPP-4 inhibitors, or sulfonylurea. However, this excludes cases where the prescribed dosage has been stable for at least six months prior to the biopsy.

[0155] Individuals who have received treatment with valproic acid, tamoxifen, methotrexate, or amiodarone within 12 months prior to the screening visit, or who have received long-term treatment with anticholinergics, corticosteroids, high-dose estrogen, or tetracycline.

[0156] Individuals receiving long-term treatment with antibiotics (e.g., rifaximin).

[0157] Individuals receiving homeopathic and / or alternative therapies. During the screening period, any treatment will be discontinued at least 48 hours prior to randomization.

[0158] Individuals with uncontrolled hypothyroidism, defined as thyroid-stimulating hormone levels exceeding twice the upper limit of normal (ULN). Screening is permitted if thyroid dysfunction has been controlled for at least six months prior to the screening.

[0159] Patients with renal impairment whose eGFR is less than 40.

[0160] Individuals with unexplained serum creatine phosphokinase (CPK) levels exceeding three times the upper limit of normal (UNL). Patients with a known reason for elevated CPK may have their CPK levels re-tested before randomization. If the CPK retest exceeds three times the ULN, the patient will be excluded.

[0161] Patients who are not suitable for NMRS (as determined by the PI or MRI facility).

[0162] Individuals with hypersensitivity to Alamcol™ or any excipients contained in the tablets.

[0163] Individuals with hypersensitivity to cholic acid adsorbents or bile acid adsorbents.

[0164] intervention

[0165] According to the protocol in Table 1, administer the tablet orally to the subject in the morning, within 30 minutes after breakfast, with a glass of water (250cc).

[0166] The subjects are eligible to omit the administration of the investigational drug for up to three consecutive days during the clinical trial period.

[0167] Details of the patient inclusion criteria, exclusion criteria, and protocol for such clinical trials are described in U.S. Patent Publication No. 2018 / 0125862, which is incorporated herein by reference as if it were fully described herein.

[0168] In short, the subjects will be administered Aramcol™, MGL-3196, and a placebo in tablet form according to the table below.

[0169] treatment group

[0170] [Table 2]

[0171] Treatment group 1 (negative control): One placebo tablet matching Alamcol™ and one placebo tablet matching MGL-3196.

[0172] Treatment group 2 (positive control): One 400 mg tablet of Alamcol™ and one placebo tablet of MGL-3196.

[0173] Treatment group 3 (positive control): One placebo tablet of Alamcol™ and one 50mg tablet of MGL-3196.

[0174] Treatment group 4 (known dose): One 400 mg tablet of Alamcol™ and one 50 mg tablet of MGL-3196.

[0175] Treatment group 5 (low MGL-3196 dose): One 400 mg tablet of Alamcol™ and one 35 mg tablet of MGL-3196.

[0176] Treatment group 6 (low MGL-3196 dose): One 400 mg tablet of Alamcol™ and one 25 mg tablet of MGL-3196.

[0177] Treatment group 7 (low MGL-3196 dose): One 400 mg tablet of Alamcol™ and one 10 mg tablet of MGL-3196.

[0178] Treatment group 8 (low Alamcol™ dose): One 350 mg tablet of Alamcol™ and one 50 mg tablet of MGL-3196.

[0179] Treatment group 9 (low Alamcol™ dose): One 250 mg tablet of Alamcol™ and one 50 mg tablet of MGL-3196.

[0180] Treatment group 10 (low Alamcol™ dose): One 150 mg tablet of Alamcol™ and one 50 mg tablet of MGL-3196.

[0181] result

[0182] Combination therapy with Alamcol™ 400 mg and MGL-3196 50 mg (treatment group 4) was found to provide at least one of the following improvements compared to administration of Alamcol™ 400 mg in the absence of MGL-3196 (treatment group 2) and administration of MGL-3196 50 mg in the absence of Alamcol™ (treatment group 3). • Decreased liver triglyceride ratio • Decreased liver triglycerides, improved insulin sensitivity, and lower blood glucose levels. • A statistically significant increase in the proportion of subjects with reduced fibrosis. • A statistically significant increase in the percentage of subjects whose NAS scores improved. • Statistically significant increase in the proportion of subjects with improved SAF activity scores. • A statistically significant increase in the proportion of patients whose NASH has resolved. • Prevention of decrease, worsening, or improvement of the target liver fibrosis score. • A decrease of at least approximately 20% in the levels of the prohormone free thyroxine (Free T4). • Statistically significant decrease in LDL cholesterol (non-high-density lipoprotein cholesterol) • Increased testosterone • Increase in sex hormone-binding globulin (SHBG)

[0183] Combination therapy with Alamcol™ 400 mg and less than 50 mg of MGL-3196 (treatment groups 5-7) was found to provide at least one of the following improvements compared to administration of Alamcol™ 400 mg alone in the absence of MGL-3196 (treatment group 2) and administration of MGL-3196 50 mg alone in the absence of Alamcol™ (treatment group 3). • Equivalent efficacy compared to monotherapy with MGL-3196 50mg (treatment group 3). • Compared to monotherapy with MGL-3196 50mg (treatment group 3), the side effect profile was reduced.

[0184] Combination therapy with less than 400 mg of Alamcol™ and 50 mg of MGL-3196 (treatment groups 8-10) was found to provide at least one improvement compared to administration of 400 mg of Alamcol™ in the absence of MGL-3196 (treatment group 2) and administration of 50 mg of MGL-3196 in the absence of Alamcol™ (treatment group 3). • Equivalent efficacy compared to monotherapy with Alamcol™ 400 mg (treatment group 2). • Reduced side effect profile compared to monotherapy with Alamcol™ 400 mg (treatment group 2).

[0185] It should be understood that some features of the present invention described in separate embodiments for clarity may be combined with each other to be provided as a single embodiment. Conversely, various features of the present invention described in relation to a single embodiment for brevity may be provided separately, in any suitable partial combination, or appropriately in any other embodiment of the present invention. Certain features described in the context of various embodiments are not considered essential features to those embodiments unless the embodiment would not function without those features.

[0186] Although the present invention has been described in conjunction with its specific embodiments, various alternative, modified, and variant forms will be apparent to those skilled in the art. Therefore, it is intended to encompass all such alternative, modified, and variant forms that fall within the spirit and broad scope of the appended claims.

[0187] The citation or specification of any document in this application should not be construed as an admission that such document is available as prior art to the invention.

Claims

1. Essentially Fatty acid-bile acid conjugates (FABACs) or their pharmaceutically acceptable salts, A thyroid hormone receptor agonist or thyroid hormone analog, or a pharmaceutically acceptable salt thereof, Carrier and It consists of, The aforementioned fatty acid-bile acid conjugate (FABAC) essentially consists of 3-β-arachidylamide-7-α,12α-dihydroxy-5-β-colan-24-acid (Aramcol®), The thyroid hormone receptor agonist or thyroid hormone analog is essentially composed of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), The amount of Aramcol (trademark) is greater than 0 mg and 400 mg or less. A pharmaceutical composition in which the amount of MGL-3196 is greater than 0 mg and less than or equal to 50 mg.

2. A pharmaceutical composition according to claim 1, The amount of Aramcol (trademark) is greater than 0 mg and less than 400 mg. A pharmaceutical composition in which the amount of MGL-3196 is greater than 0 mg and less than 50 mg.

3. A pharmaceutical composition according to claim 1 or 2, A pharmaceutical composition for use in subjects requiring treatment, stabilization, or alleviation of the severity or progression of liver disease.

4. A pharmaceutical composition according to claim 3, The amount of Aramcol (trademark) is greater than 0 mg and less than 400 mg. A pharmaceutical composition in which the amount of MGL-3196 is greater than 0 mg and less than 50 mg.

5. A pharmaceutical composition according to claim 3, The aforementioned treatment, stabilization, or reduction of the severity or progression of liver disease is, Compared to administering a composition comprising the fatty acid-bile acid conjugate (FABAC) and either the thyroid hormone receptor agonist or thyroid hormone analog in the absence of the other of the fatty acid-bile acid conjugate (FABAC) and the thyroid hormone receptor agonist or thyroid hormone analog, (a) At least one of the fatty acid-bile acid conjugate (FABAC) and the thyroid hormone receptor agonist or thyroid hormone analog is administered in a low dose. (b) A shorter treatment schedule, and (c) The incidence and severity of side effects will decrease, A pharmaceutical composition comprising at least one therapeutic improvement selected from the group consisting of the following.

6. A pharmaceutical composition according to claim 3, The aforementioned liver disease is selected from the group consisting of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), emerging cirrhosis, non-cirrodegenerative liver fibrosis, and liver fibrosis, and is used in the pharmaceutical composition.

7. A pharmaceutical composition according to claim 3, The subject is a pharmaceutical composition having a disease or condition selected from the group consisting of human immunodeficiency virus (HIV) infection, HIV and HCV co-infection, viral hepatitis, type 2 diabetes mellitus (T2DM), metabolic syndrome (MS), or any combination thereof.

8. A pharmaceutical composition according to claim 3, A pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient.

9. Essentially (a) At least one dose of fatty acid-bile acid conjugate (FABAC), (b) A kit comprising at least one dose of a thyroid hormone receptor agonist or thyroid hormone analog, The aforementioned fatty acid-bile acid conjugate (FABAC) is essentially 3-β-arachidylamide-7-α,12α-dihydroxy-5-β-colan-24-acid (Aramcol®) It consists of, The amount of Aramcol (trademark) is greater than 0 mg and 400 mg or less. The thyroid hormone receptor agonist or thyroid hormone analog is essentially composed of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), The kit contains an amount of MGL-3196 that is greater than 0 mg and less than or equal to 50 mg.

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