Resmetirom for reducing liver volume

Abstract

The present disclosure describes methods for reducing liver volume in a cirrhotic or non-cirrhotic subject, comprising administering resmetirom, a prodrug thereof, or a pharmaceutically acceptable salt of resmetirom or a resmetirom prodrug. The present disclosure also describes methods for treating NASH in a cirrhotic subject in need of NASH treatment, comprising administering resmetirom, a prodrug thereof, or a pharmaceutically acceptable salt of resmetirom or a resmetirom prodrug to the subject.

Description

[Technical field]

[0001] Related Applications

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 248,634, filed September 27, 2021, the contents of which are incorporated herein by reference. [Background technology]

[0002]

[0002] Thyroid hormones are crucial for normal growth and development and for maintaining metabolic homeostasis. Circulating levels of thyroid hormones are tightly controlled by feedback mechanisms in the hypothalamic / pituitary / thyroid (HPT) axis. Thyroid dysfunction leading to hypo- or hyperthyroidism clearly demonstrates the profound effects of thyroid hormones on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle and behavior.

[0003]

[0003] The development of thyroid hormone analogs that maintain the beneficial effects of thyroid hormone while avoiding the undesirable effects of hyperthyroidism and hypothyroidism would open new treatment avenues for patients with metabolic diseases, such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, etc., as well as other disorders and diseases, such as fatty liver and nonalcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease, thyroid hormone insensitivity, etc., and related disorders and diseases.

[0004]

[0004] Subjects with NASH may also experience increased liver volume, which may be due to increased liver fat and fluid retention caused by the inflammatory process in NASH. As NASH progresses to cirrhosis, liver fat decreases as the liver becomes increasingly fibrotic. In subjects with cirrhosis, liver volume remains increased due to ongoing inflammation and venous congestion associated with portal hypertension. Reducing liver volume in cirrhotic subjects is important to maintain perfusion of diseased livers and inhibit disease progression. Reduction of liver volume in NASH and cirrhosis is associated with improved liver histopathology.

[0005]

[0005] Obesity is a common feature of both NASH and cirrhosis due to insufficient weight loss through diet and lifestyle modification, and this patient population is often indicated for surgical intervention procedures (e.g., bariatric surgery). Liver volume reduction immediately prior to surgery is aggressively pursued to improve surgical access to the stomach.

[0006]

[0006] The above and further features will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings. Summary of the Invention [Means for solving the problem]

[0007]

[0013] In some aspects, the disclosure provides a method of reducing liver volume in a subject, comprising administering to the subject (e.g., in a therapeutically effective amount) resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug.

[0008]

[0014] In some aspects, the disclosure provides resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug, for use in reducing liver volume in a subject.

[0009]

[0015] In some aspects, the disclosure provides for the use of resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug in the manufacture of a medicament for reducing liver volume in a subject.

[0010]

[0016] In some aspects, the disclosure provides a method of treating or preventing a disease, disorder, or condition in a subject, comprising administering to the subject (e.g., in a therapeutically effective amount) resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug.

[0011]

[0017] In some aspects, the disclosure provides resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug, for use in the treatment or prevention of a disease, disorder, or condition in a subject.

[0012]

[0018] In some aspects, the disclosure provides for the use of resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug in the manufacture of a medicament for treating or preventing a disease, disorder, or condition in a subject.

[0013]

[0019] In some embodiments, the disease, disorder or condition is obesity, hyperlipidemia, hypercholesterolemia, diabetes, nonalcoholic steatohepatitis (NASH), fatty liver, bone disease, thyroid axis alterations, atherosclerosis, cardiovascular disorders, tachycardia, hyperactive behavior, hypothyroidism, goiter, attention deficit hyperactivity disorder, learning disabilities, mental retardation, hearing loss, delayed bone age, neurological or psychiatric disorders, or thyroid cancer.

[0014]

[0020] In some aspects, the disclosure provides a method of treating or preventing NASH (e.g., cirrhotic NASH) in a subject, comprising administering to the subject (e.g., in a therapeutically effective amount) resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug.

[0015]

[0021] In some embodiments, the disclosure provides resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug for use in treating or preventing NASH (e.g., cirrhotic NASH) in a subject.

[0016]

[0022] In some embodiments, the disclosure provides for the use of resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug in the manufacture of a medicament for treating or preventing NASH (e.g., cirrhotic NASH) in a subject.

[0017]

[0023] In some aspects, the disclosure provides a method of treating or preventing portal hypertension in a subject, comprising administering to the subject (e.g., in a therapeutically effective amount) resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug.

[0018]

[0024] In some aspects, the disclosure provides resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug, for use in treating or preventing portal hypertension in a subject.

[0019]

[0025] In some aspects, the disclosure provides for the use of resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug in the manufacture of a medicament for treating or preventing portal hypertension in a subject.

[0020]

[0026] In some aspects, the disclosure provides a method of pretreating a subject having a disease, disorder, or condition for surgery (e.g., bariatric surgery), comprising administering to the subject resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug (e.g., in a therapeutically effective amount).

[0021]

[0027] In some embodiments, the disclosure provides resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug, for use in pretreatment of a subject having a disease, disorder, or condition for surgery (e.g., bariatric surgery).

[0022]

[0028] In some aspects, the disclosure provides for the use of resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug in the manufacture of a medicament for pretreating a subject having a disease, disorder, or condition for surgery (e.g., bariatric surgery). [Brief description of the drawings]

[0023] [Figure 1]

[0007] Figure 1 is a graph showing the correlation between reduction in liver volume and reduction in proton density fat fraction (PDFF) at 12 weeks in placebo- and resmetirom-treated patients. "PBO" represents placebo patients and "RES" represents resmetirom-treated patients. [Diagram 2]

[0008] Figure 1 shows changes in MRI-PDFF in several subgroups of patients treated with 100 mg resmetirom once daily for 52 weeks. "High SHBG" represents the two-thirds of study patients with the highest increase from baseline in sex hormone-binding globulin (SHBG), a biomarker of liver exposure to resmetirom. [Diagram 3]

[0009] Figure 1 is a graph showing changes in liver volume in several subgroups of patients treated with 100 mg resmetirom once daily for 52 weeks. "High SHBG" represents the two-thirds of study patients who had the highest increase from baseline in SHBG, a biomarker of liver exposure to resmetirom. [Figure 4]

[0010] Figure 1 is a graph showing resmetirom-mediated changes in MRI-PDFF and liver volume (LV) at 52 weeks. [Diagram 5]

[0011] Figure 1 is a graph showing the percentage of patients with a ≧10% decrease or ≧10% increase in spleen volume (SV) at 52 weeks. [Figure 6]

[0012] Figure 1 is a graph showing the correlation between change in liver volume and change in spleen volume over 52 weeks in patients who entered the study with a baseline PDFF < 8%. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Methods and Uses of Resmetirom

[0029] In some aspects, the disclosure provides a method of reducing liver volume in a subject, comprising administering to the subject (e.g., in a therapeutically effective amount) resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug.

[0025]

[0030] In some aspects, the disclosure provides resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug, for use in reducing liver volume in a subject.

[0026]

[0031] In some aspects, the disclosure provides for the use of resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug in the manufacture of a medicament for reducing liver volume in a subject.

[0027]

[0032] In some aspects, the disclosure provides a method of treating or preventing a disease, disorder, or condition in a subject, comprising administering to the subject (e.g., in a therapeutically effective amount) resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug.

[0028]

[0033] In some aspects, the disclosure provides resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug, for use in the treatment or prevention of a disease, disorder, or condition in a subject.

[0029]

[0034] In some aspects, the disclosure provides for the use of resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug in the manufacture of a medicament for treating or preventing a disease, disorder, or condition in a subject.

[0030]

[0035] In some embodiments, the disease, disorder or condition is obesity, hyperlipidemia, hypercholesterolemia, diabetes, nonalcoholic steatohepatitis (NASH), fatty liver, bone disease, thyroid axis alterations, atherosclerosis, cardiovascular disorders, tachycardia, hyperactive behavior, hypothyroidism, goiter, attention deficit hyperactivity disorder, learning disabilities, mental retardation, hearing loss, delayed bone age, neurological or psychiatric disorders, or thyroid cancer.

[0031]

[0036] In some aspects, the disclosure provides a method of treating or preventing NASH (e.g., cirrhotic NASH) in a subject, comprising administering to the subject (e.g., in a therapeutically effective amount) resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug.

[0032]

[0037] In some embodiments, the disclosure provides resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug for use in treating or preventing NASH (e.g., cirrhotic NASH) in a subject.

[0033]

[0038] In some embodiments, the disclosure provides for the use of resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug in the manufacture of a medicament for treating or preventing NASH (e.g., cirrhotic NASH) in a subject.

[0034]

[0039] In some aspects, the disclosure provides a method of treating or preventing portal hypertension in a subject, comprising administering to the subject (e.g., in a therapeutically effective amount) resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug.

[0035]

[0040] In some aspects, the disclosure provides resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug, for use in treating or preventing portal hypertension in a subject.

[0036]

[0041] In some aspects, the disclosure provides for the use of resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug in the manufacture of a medicament for treating or preventing portal hypertension in a subject.

[0037]

[0042] In some aspects, the disclosure provides a method of pretreating a subject having a disease, disorder, or condition for surgery (e.g., bariatric surgery), comprising administering to the subject resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug (e.g., in a therapeutically effective amount).

[0038]

[0043] In some embodiments, the disclosure provides resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug, for use in pretreatment of a subject having a disease, disorder, or condition for surgery (e.g., bariatric surgery).

[0039]

[0044] In some aspects, the disclosure provides for the use of resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug in the manufacture of a medicament for pretreating a subject having a disease, disorder, or condition for surgery (e.g., bariatric surgery). Targeted diseases, disorders and conditions

[0045] In some embodiments, the subject is a human.

[0040]

[0046] In some embodiments, the subject is cirrhotic (eg, the subject has cirrhosis of the liver).

[0041]

[0047] In some embodiments, the subject is non-cirrhotic (eg, the subject does not have cirrhosis).

[0042]

[0048] In some embodiments, the subject has an amount of liver fat characterized by a PDFF of 5% or less.

[0043]

[0049] In some embodiments, the subject has an amount of liver fat characterized by a PDFF of greater than 5%.

[0044]

[0050] In some embodiments, the disease, disorder or condition is NASH.

[0045]

[0051] In some embodiments, the disease, disorder or condition is cirrhotic or non-cirrhotic NASH.

[0046]

[0052] In some embodiments, the disease, disorder, or condition is cirrhotic NASH (eg, NASH associated with cirrhosis of the liver).

[0047]

[0053] In some embodiments, the disease, disorder, or condition is hepatitis.

[0048]

[0054] In some embodiments, the disease, disorder or condition is associated with increased liver volume.

[0049]

[0055] In some embodiments, the disease, disorder, or condition is portal hypertension.

[0050]

[0056] In some embodiments, the subject has a liver volume that is at least about 5% greater, at least about 10% greater, at least about 20% greater, at least about 30% greater, at least about 40% greater, at least about 50% greater, at least about 60% greater, at least about 70% greater, at least about 80% greater, at least about 90% greater, at least about 100% greater, at least about 150% greater, or at least about 200% greater, compared to a comparable subject that does not have the disease, disorder, or condition (e.g., does not have NASH (e.g., does not have cirrhotic NASH)).

[0051]

[0057] In some embodiments, the subject has a liver fat mass (e.g., as measured by proton density fat fraction (PDFF)) that is at least about 5% greater, at least about 10% greater, at least about 20% greater, at least about 30% greater, at least about 40% greater, at least about 50% greater, at least about 60% greater, at least about 70% greater, at least about 80% greater, at least about 90% greater, at least about 100% greater, at least about 150% greater, or at least about 200% greater, compared to a comparable subject that does not have the disease, disorder, or condition (e.g., does not have NASH (e.g., does not have cirrhotic NASH)).

[0052]

[0058] In some embodiments, the subject has a liver fat mass (e.g., as measured by proton density fat fraction (PDFF)) that is up to about 200% greater, up to about 150% greater, up to about 100% greater, up to about 90% greater, up to about 80% greater, up to about 70% greater, up to about 60% greater, up to about 50% greater, up to about 40% greater, up to about 30% greater, up to about 20% greater, up to about 10% greater, or up to about 5% greater, compared to a comparable subject that does not have the disease, disorder, or condition (e.g., does not have NASH (e.g., does not have cirrhotic NASH)).

[0053]

[0059] In some embodiments, the subject has a liver fat content (e.g., as measured by proton density fat fraction (PDFF)) that is about 50% or less, about 40% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, or about 1% or less.

[0054]

[0060] In some embodiments, the subject has a liver fat mass (eg, as measured by proton density fat fraction (PDFF)) that is about 5% or less.

[0055]

[0061] In some embodiments, the subject has a liver fat content (e.g., as measured by proton density fat fraction (PDFF)) of greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 40%, greater than about 50%, or greater than about 60%.

[0056]

[0062] In some embodiments, the subject has a liver fat mass (eg, as measured by proton density fat fraction (PDFF)) of greater than about 5%.

[0057]

[0063] In some embodiments, the subject has a spleen volume that is at least about 5% greater, at least about 10% greater, at least about 20% greater, at least about 30% greater, at least about 40% greater, at least about 50% greater, at least about 60% greater, at least about 70% greater, at least about 80% greater, at least about 90% greater, at least about 100% greater, at least about 150% greater, or at least about 200% greater, compared to a comparable subject that does not have the disease, disorder or condition (e.g., does not have portal hypertension). Resmetirom Administration

[0064] In some embodiments, resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug is administered to the subject.

[0058]

[0065] In some embodiments, a pharmaceutical composition comprising resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug is administered to the subject.

[0059]

[0066] In some embodiments, resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug is administered to the subject by oral administration.

[0060]

[0067] In some embodiments, resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug is administered daily.

[0061]

[0068] In some embodiments, resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug is administered once or twice daily.

[0062]

[0069] In some embodiments, resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug is administered once daily.

[0063]

[0070] In some embodiments, resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug is administered to a subject at a daily dosage of about 10 to about 250 mg, about 20 to about 200 mg, about 20 to about 150 mg, about 20 to about 100 mg, about 50 to about 200 mg, or about 50 to about 150 mg.

[0064]

[0071] In some embodiments, resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug is administered to a subject at a daily dosage of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 250 mg, about 500 mg, or about 1000 mg.

[0065]

[0072] In some embodiments, resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug is administered to a subject in a daily dosage of about 60±20 mg, about 60±15 mg, about 60±10 mg, about 60±5 mg, about 60±4 mg, about 60±3 mg, about 60±2 mg, or about 60±1 mg (e.g., about 60 mg).

[0066]

[0073] In some embodiments, resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug is administered to a subject in a daily dosage of about 60 mg.

[0067]

[0074] In some embodiments, resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug is administered to a subject in a daily dosage of about 80±20 mg, about 80±15 mg, about 80±10 mg, about 80±5 mg, about 80±4 mg, about 80±3 mg, about 80±2 mg, or about 80±1 mg (e.g., about 80 mg).

[0068]

[0075] In some embodiments, resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug is administered to a subject in a daily dosage of about 80 mg.

[0069]

[0076] In some embodiments, resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug is administered to a subject in a daily dosage of about 100±20 mg, about 100±15 mg, about 100±10 mg, about 100±5 mg, about 100±4 mg, about 100±3 mg, about 100±2 mg, or about 100±1 mg (e.g., about 100 mg).

[0070]

[0077] In some embodiments, resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug is administered to a subject in a daily dosage of about 100 mg.

[0071]

[0078] In some embodiments, resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug is administered without a drug holiday.

[0072]

[0079] In some embodiments, resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug is administered with one or more drug holidays.

[0073]

[0080] In some embodiments, resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug is administered for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, The compound is administered for about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, or about 52 weeks.

[0074]

[0081] In some embodiments, resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug is administered for greater than about 52 weeks. Possible outcomes depending on administration

[0082] In some embodiments, administration eliminates the disease, disorder, or condition, or reduces the severity of the disease, disorder, or condition.

[0075]

[0083] In some embodiments, administration reduces liver volume by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% (e.g., over a 12 or 52 week period).

[0076]

[0084] In some embodiments, administration reduces liver volume by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% over a 12 week period.

[0077]

[0085] In some embodiments, the administration reduces liver volume by at least about 10% over a 12 week period.

[0078]

[0086] In some embodiments, the administration reduces liver volume by at least about 15% over a 12 week period.

[0079]

[0087] In some embodiments, the administration reduces liver volume by at least about 20% over a 12 week period.

[0080]

[0088] In some embodiments, the administration reduces liver volume by at least about 25% over a 12 week period.

[0081]

[0089] In some embodiments, administration reduces liver volume by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% over a 52 week period.

[0082]

[0090] In some embodiments, the administration reduces liver volume by at least about 10% over a 52 week period.

[0083]

[0091] In some embodiments, the administration reduces liver volume by at least about 15% over a 52 week period.

[0084]

[0092] In some embodiments, the administration reduces liver volume by at least about 20% over a 52 week period.

[0085]

[0093] In some embodiments, prior to administration, the subject has a liver fat content (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces liver volume by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% (e.g., over a 12 or 52 week period).

[0086]

[0094] In some embodiments, prior to administration, the subject has a liver fat content (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces liver volume by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% over a 12 week period.

[0087]

[0095] In some embodiments, prior to administration, the subject has a liver fat content (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces liver volume by at least about 10% over a 12 week period.

[0088]

[0096] In some embodiments, prior to administration, the subject has a liver fat content (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces liver volume by at least about 15% over a 12 week period.

[0089]

[0097] In some embodiments, prior to administration, the subject has a liver fat content (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces liver volume by at least about 20% over a 12 week period.

[0090]

[0098] In some embodiments, prior to administration, the subject has a liver fat content (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces liver volume by at least about 25% over a 12 week period.

[0091]

[0099] In some embodiments, prior to administration, the subject has a liver fat content (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces liver volume by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% over a 52 week period.

[0092]

[0100] In some embodiments, prior to administration, the subject has a liver fat content (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces liver volume by at least about 10% over a 52 week period.

[0093]

[0101] In some embodiments, prior to administration, the subject has a liver fat content (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces liver volume by at least about 15% over a 52 week period.

[0094]

[0102] In some embodiments, prior to administration, the subject has a liver fat content (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces liver volume by at least about 20% over a 52 week period.

[0095]

[0103] In some embodiments, administration reduces liver fat content (e.g., as measured by MRI-PDFF) by about 60% or less, about 50% or less, about 45% or less, about 40% or less, about 35% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10% or less, or about 5% or less, compared to the subject's liver fat content before administration.

[0096]

[0104] In some embodiments, prior to administration, the subject has a liver fat mass (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces the liver fat mass (e.g., as measured by MRI-PDFF) by about 60% or less, about 50% or less, about 45% or less, about 40% or less, about 35% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10% or less, or about 5% or less, compared to the subject's liver fat mass prior to administration.

[0097]

[0105] In some embodiments, administration reduces liver fat content (e.g., as measured by MRI-PDFF) by about 20% or less, about 15% or less, about 10% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, or about 1% or less, compared to the subject's liver volume before administration.

[0098]

[0106] In some embodiments, prior to administration, the subject has a liver fat mass (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces the liver fat mass (e.g., as measured by MRI-PDFF) by about 60% or less, about 50% or less, about 45% or less, about 40% or less, about 35% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10% or less, or about 5% or less, compared to the subject's liver fat mass prior to administration, and administration reduces liver volume by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% (e.g., over 12 weeks or 52 weeks).

[0099]

[0107] In some embodiments, prior to administration, the subject has a liver fat mass (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces the liver fat mass (e.g., as measured by MRI-PDFF) by about 40% or less compared to the subject's liver fat mass prior to administration, and administration reduces liver volume by at least about 10% (e.g., over a 12 week or 52 week period).

[0100]

[0108] In some embodiments, prior to administration, the subject has a liver fat mass (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces the liver fat mass (e.g., as measured by MRI-PDFF) by about 35% or less compared to the subject's liver fat mass prior to administration, and administration reduces liver volume by at least about 10% (e.g., over a 12 week or 52 week period).

[0101]

[0109] In some embodiments, prior to administration, the subject has a liver fat mass (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces the liver fat mass (e.g., as measured by MRI-PDFF) by about 30% or less compared to the subject's liver fat mass prior to administration, and administration reduces liver volume by at least about 10% (e.g., over a 12 week or 52 week period).

[0102]

[0110] In some embodiments, prior to administration, the subject has a liver fat mass (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces the liver fat mass (e.g., as measured by MRI-PDFF) by about 40% or less compared to the subject's liver fat mass prior to administration, and administration reduces liver volume by at least about 15% (e.g., over a 12 week or 52 week period).

[0103]

[0111] In some embodiments, prior to administration, the subject has a liver fat mass (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces the liver fat mass (e.g., as measured by MRI-PDFF) by about 35% or less compared to the subject's liver fat mass prior to administration, and administration reduces liver volume by at least about 15% (e.g., over a 12 week or 52 week period).

[0104]

[0112] In some embodiments, prior to administration, the subject has a liver fat mass (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces the liver fat mass (e.g., as measured by MRI-PDFF) by about 30% or less compared to the subject's liver fat mass prior to administration, and administration reduces liver volume by at least about 15% (e.g., over a 12 week or 52 week period).

[0105]

[0113] In some embodiments, prior to administration, the subject has a liver fat mass (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces the liver fat mass (e.g., as measured by MRI-PDFF) by about 40% or less compared to the subject's liver fat mass prior to administration, and administration reduces liver volume by at least about 20% (e.g., over a 12 week or 52 week period).

[0106]

[0114] In some embodiments, prior to administration, the subject has a liver fat mass (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces the liver fat mass (e.g., as measured by MRI-PDFF) by about 35% or less compared to the subject's liver fat mass prior to administration, and administration reduces liver volume by at least about 20% (e.g., over a 12 week or 52 week period).

[0107]

[0115] In some embodiments, prior to administration, the subject has a liver fat mass (e.g., as measured by MRI-PDFF) that is about 5% or less, and administration reduces the liver fat mass (e.g., as measured by MRI-PDFF) by about 30% or less compared to the subject's liver fat mass prior to administration, and administration reduces liver volume by at least about 20% (e.g., over a 12 week or 52 week period).

[0108]

[0116] In some embodiments, the reduction in liver volume is dependent on liver fat content (eg, liver fat content prior to administration).

[0109]

[0117] In some embodiments, the reduction in liver volume is independent of liver fat content (eg, liver fat content prior to administration).

[0110]

[0118] In some embodiments, the reduction in liver volume is dependent on a reduction in liver fat content.

[0111]

[0119] In some embodiments, the reduction in liver volume is independent of a reduction in liver fat content.

[0112]

[0120] In some embodiments, the reduction in liver volume is greater than the reduction in liver fat content.

[0113]

[0121] In some embodiments, the reduction in liver volume is at least about 5% greater, at least about 10% greater, at least about 20% greater, at least about 30% greater, at least about 40% greater, at least about 50% greater, at least about 60% greater, at least about 70% greater, at least about 80% greater, at least about 90% greater, at least about 100% greater, at least about 150% greater, at least about 200% greater, at least about 300% greater, at least about 400% greater, at least about 500% greater, at least about 600% greater, at least about 700% greater, at least about 800% greater, at least about 900% greater, or at least about 1000% greater than the reduction in liver fat content.

[0114]

[0122] In some embodiments, the administration eliminates or reduces the severity of hepatitis.

[0115]

[0123] In some embodiments, the administration eliminates portal hypertension or reduces the severity of portal hypertension.

[0116]

[0124] In some embodiments, the administration reduces portal blood pressure in the subject.

[0117]

[0125] In some embodiments, administration reduces the subject's portal vein blood pressure by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% (e.g., over a 12 or 52 week period).

[0118]

[0126] In some embodiments, the administration reduces spleen volume in the subject.

[0119]

[0127] In some embodiments, administration reduces spleen volume by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% (e.g., over a 12 or 52 week period).

[0120]

[0128] In some embodiments, administration reduces spleen volume by at least about 10% or at least about 15% (eg, over a 12 week or 52 week period).

[0121]

[0129] In some embodiments, administration reduces spleen volume by at least about 10% or at least about 15% over a 12 week period.

[0122]

[0130] In some embodiments, administration reduces spleen volume by at least about 10% or at least about 15% over a 52 week period. Other Aspects

[0131] In some embodiments, the liver disease or disorder treated by the methods of the present disclosure is fatty liver disease.

[0123]

[0132] In some embodiments, the liver disease or liver injury treated by the method of the present disclosure is non-alcoholic fatty liver disease (NAFLD). Two types of NAFLD are simple fatty liver and NASH. NAFLD refers to a wide range of liver diseases, from simple fatty liver (steatosis) to NASH to cirrhosis. All stages of NAFLD have in common the accumulation of fat in liver cells. NASH is a form of NAFLD in which the subject also has hepatitis. More specifically in NASH, fat accumulation is associated with various degrees of inflammation (hepatitis) and scarring (fibrosis) of the liver. NAFLD and NASH occur in individuals who do not consume excessive amounts of alcohol. However, in many ways, the histology of biopsies of NAFLD is similar to that which can be seen in liver diseases caused by alcohol abuse. NAFLD and NASH are considered primary fatty liver diseases. Secondary fatty liver diseases include those that occur in other types of liver diseases. Thus, alcoholic liver disease (ALD) is the most common secondary fatty liver disease. Secondary fatty liver can also occur in chronic viral hepatitis C (HCV), chronic viral hepatitis B (HBV), chronic autoimmune hepatitis (AIH), and Wilson's disease.

[0124]

[0133] In some embodiments, the liver disease or disorder treated by the methods of the present disclosure is NASH.

[0125]

[0134] In some embodiments, the lipid disease or lipid disorder treated by the method of the present disclosure is dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, or high LDL.In some embodiments, the hypercholesterolemia is heterozygous familial hypercholesterolemia (HeFH) or homozygous familial hypercholesterolemia (HoFH).

[0126]

[0135] In some embodiments, the subject is a mammal.

[0127]

[0136] In some embodiments, the subject is a human.

[0128]

[0137] Resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug can be formulated for administration into a pharmaceutical composition, which can further include a pharma- ceutically acceptable carrier or excipient.

[0129]

[0138] The pharmaceutical compositions may be in a form suitable for oral use (e.g., as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (e.g., as a finely divided powder or liquid aerosol), for administration by insufflation (e.g., as a finely divided powder) or for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0130]

[0139] In some embodiments, the pharmaceutical composition is formulated into a gel.

[0131]

[0140] In some embodiments, the pharmaceutical composition is formulated into a tablet.

[0132]

[0141] In some embodiments, the pharmaceutical composition is formulated into a pill.

[0133]

[0142] In some embodiments, the pharmaceutical composition is formulated in a capsule.

[0134]

[0143] In some embodiments, the pharmaceutical composition is formulated in a solution. Exemplary embodiments

[0144] Exemplary embodiment 1. A method of reducing liver volume in a cirrhotic or non-cirrhotic subject with non-alcoholic steatohepatitis (NASH), comprising administering to the subject a therapeutically effective amount of resmetirom.

[0135]

[0145] Exemplary embodiment 2. The method of exemplary embodiment 1, wherein the subject is non-cirrhotic.

[0136]

[0146] Exemplary embodiment 3. The method of exemplary embodiment 1, wherein the subject has cirrhosis.

[0137]

[0147] Exemplary embodiment 4. The method of any one of exemplary embodiments 1 to 3, wherein liver volume is reduced by at least about 10% within a 12 week treatment period.

[0138]

[0148] Exemplary embodiment 5. The method of any one of exemplary embodiments 1 to 4, wherein liver volume is reduced by at least about 15% within a 12 week treatment period.

[0139]

[0149] Exemplary embodiment 6. The method of any one of exemplary embodiments 1 to 5, wherein the therapeutically effective amount of resmetirom is about 5 to 300 mg.

[0140]

[0150] Exemplary embodiment 7. The method of any one of exemplary embodiments 1 to 6, wherein the therapeutically effective amount of resmetirom is about 60 mg.

[0141]

[0151] Exemplary embodiment 8. The method of any one of exemplary embodiments 1 to 6, wherein the therapeutically effective amount of resmetirom is about 80 mg.

[0142]

[0152] Exemplary embodiment 9. The method of any one of exemplary embodiments 1 to 6, wherein the therapeutically effective amount of resmetirom is about 100 mg.

[0143]

[0153] Exemplary embodiment 10. The method of any one of exemplary embodiments 1 to 9, wherein resmetirom is administered daily.

[0144]

[0154] Exemplary Embodiment No. 11. The method of any one of exemplary embodiments 1 to 10, wherein resmetirom is administered once daily.

[0145]

[0155] Exemplary embodiment 12. The method of any one of exemplary embodiments 1 to 11, wherein the subject has an amount of liver fat characterized by a PDFF of 5% or less.

[0146]

[0156] Exemplary embodiment 13. A method of treating NASH in a cirrhotic subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of resmetirom.

[0147]

[0157] Exemplary embodiment 14. The method of exemplary embodiment 13, wherein the therapeutically effective amount of resmetirom is about 5-300 mg.

[0148]

[0158] Exemplary embodiment 15. The method of exemplary embodiment 13, wherein the therapeutically effective amount of resmetirom is about 60 mg.

[0149]

[0159] Exemplary embodiment 16. The method of exemplary embodiment 13, wherein the therapeutically effective amount of resmetirom is about 80 mg.

[0150]

[0160] Exemplary embodiment 17. The method of exemplary embodiment 13, wherein the therapeutically effective amount of resmetirom is about 100 mg.

[0151]

[0161] Exemplary embodiment 18. The method of exemplary embodiment 13, wherein resmetirom is administered daily.

[0152]

[0162] Exemplary embodiment 19. The method of exemplary embodiment 13, wherein resmetirom is administered once daily.

[0153]

[0163] Exemplary embodiment 20. The method of any one of exemplary embodiments 13 to 19, wherein the subject has an amount of liver fat characterized by a PDFF of 5% or less. definition

[0164] 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. The terms used in the description are intended to describe particular embodiments only and are not intended to limit the scope of the present invention.

[0154]

[0165] When a range of values ​​is listed, it is understood that the range includes the endpoints of the range, as well as all values ​​in between.

[0155]

[0166] As used in this specification and the appended claims, the articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article, unless the context clearly dictates otherwise. By way of example, "an ultrapure form" means one ultrapure form or more than one ultrapure form.

[0156]

[0167] The phrase "and / or" as used herein in the specification and claims should be understood to mean "either or both." Other elements may optionally be present other than the elements specifically specified by the "and / or" clause. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," can in one embodiment refer to only A (optionally including elements other than B), in another embodiment refer to only B (optionally including elements other than A), and in yet another embodiment refer to both A and B (optionally including other elements).

[0157]

[0168] Unless expressly specified otherwise, the terms "approximately" and "about" are synonymous. In some embodiments, "approximately" and "about" refer to the recited amount, value, dose or duration ±10%, ±8%, ±6%, ±5%, ±4%, ±2%, ±1% or ±0.5%. In some embodiments, "approximately" and "about" refer to the recited amount, value, dose or duration ±5%. In some embodiments, "approximately" and "about" refer to the recited amount, value, dose or duration ±2%. In some embodiments, "approximately" and "about" refer to the recited amount, value, dose or duration ±1%.

[0158]

[0169] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive, i.e., including at least one, but also including more than one, of a number or list of elements, and optionally including additional items not in the list. Only for terms clearly indicated to the contrary, such as "only one of" or "exactly one of," or "consisting of," when used in the claims, will the inclusion of exactly one element of a number or list of elements be referred to. In general, the term "or" as used herein should be interpreted as referring to exclusive alternatives (i.e., "one or the other, but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of."

[0159]

[0170] As used herein, the term "MRI-PDFF" refers to proton-density-fat-fraction determined by magnetic resonance imaging (MRI)-based quantification. MRI-PDFF is an MRI-based liver imaging biomarker developed to facilitate, by enhancing, patient recruitment to clinical trials for NASH. MRI-PDFF is a measure for assessing liver fat content and is proposed to be used as a non-invasive method to limit unnecessary liver biopsies by avoiding biopsies in patients with low likelihood of fatty liver. It is intended to be used as a pre-screening strategy in a population of adults with clinical signs or risk factors suggestive of non-alcoholic fatty liver disease (NAFLD). MRI-PDFF is an accurate, quantitative imaging biomarker that is highly repeatable and reproducible, and has provided results from MRI-PDFF testing and validation datasets compared to liver histology to indicate optimal MRI-PDFF cutoffs, thus reducing the number of unnecessary biopsies prior to clinical trial enrollment and identifying candidates most likely to meet the criteria for enrollment in clinical trials for NASH.

[0160]

[0171] As used herein, the term "portal hypertension" refers to increased pressure in the portal vein, the vein that carries blood from the digestive tract (large and small intestines, stomach, pancreas, spleen) to the liver. The increased pressure is caused by an obstruction to blood flow through the liver.

[0161]

[0172] As used herein, the term "cirrhosis" refers to the late scarring (fibrosis) of the liver caused by many forms of liver disease and conditions, such as hepatitis and chronic alcoholism.The liver fat of subjects with cirrhosis (e.g., as measured by MRI-PDFF) is 5% or less.

[0162]

[0173] As used herein, the terms "preventing" or "prevent" refer to reducing or eliminating the onset of symptoms or complications of such a disease, condition or disorder.

[0163]

[0174] As used herein, the term "pharmacologically acceptable" refers to compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals and are free of excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable risk-benefit ratio.

[0164]

[0175] As used herein, the term "dosage" or "daily dose" refers to the weight of resmetirom, a prodrug thereof, or a pharma- ceutically acceptable salt of resmetirom or a resmetirom prodrug.

[0165]

[0176] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in the preparation of formulations, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable excipient," as used in the specification and claims, includes both one such excipient and more than one such excipient.

[0166]

[0177] As used herein, the term "subject" includes human and non-human mammals, as well as cell lines, cell cultures, tissues and organs. In some embodiments, the subject is a mammal. The mammal can be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or pig. In some embodiments, the subject is a human.

[0167]

[0178] As used herein, the term "subject in need thereof" refers to a subject having a disease (to be treated) or at increased risk of developing a disease (to be prevented). A subject in need thereof may be one who has previously been diagnosed with or previously identified as having a disease or disorder disclosed herein. A subject in need thereof may also be one who has (e.g., suffers from) a disease or disorder disclosed herein. Alternatively, a subject in need thereof may be one who is at increased risk of developing such a disease or disorder compared to the overall population (i.e., a subject who is more susceptible to developing such a disorder compared to the overall population). A subject in need thereof may have a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that is not responding or has not yet responded to treatment). The subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, a subject in need thereof has undergone and failed all known effective treatments for a disease or disorder disclosed herein. In some embodiments, a subject in need thereof has undergone at least one previous treatment.

[0168]

[0179] It will be understood that resmetirom, its prodrugs, or pharma- ceutically acceptable salts of resmetirom or resmetirom prodrugs may be represented as different tautomers. It will also be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of a compound does not exclude any tautomeric form. It will be understood that certain tautomers may have a higher level of activity than others.

[0169]

[0180] As used herein, the term "treating" or "treat" refers to the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharma- ceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treat" can also include the treatment of an in vitro cell or animal model.

[0170]

[0181] As used herein, the term "salt" or "pharmaceutically acceptable salt" refers to a derivative of a compound of the present disclosure, in which the parent compound is modified by making its acid salt or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxyisobutyl acid, ethyl ... These include inorganic and organic acids selected from naphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, basic acetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluenesulfonic, and commonly occurring amino acids, such as those derived from glycine, alanine, phenylalanine, arginine, and the like. Other examples of pharma- ceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, and the like.The present disclosure also encompasses salts formed when acidic protons present in the parent compound are either replaced with metal ions, such as alkali metal ions, alkaline earth ions, or aluminum ions, or coordinate with organic bases, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1:3. It is understood that all references to pharma-ceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs), as defined herein, of the same salt.

[0171]

[0182] As used herein, "MGL-3196" is equivalent to "resmetirom," which is 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 (i.e.,

[0172] [ka] ), or any of its pharma- ceutically acceptable salts or solid forms, such as those disclosed in U.S. Pat. No. 9,266,861 and U.S. patent application Ser. No. 17 / 257,070, the contents of each of which are incorporated herein by reference.

[0173]

[0183] All percentages and ratios used herein are by weight unless otherwise specified. Other features and advantages of the present disclosure are apparent from the various examples. The examples provided illustrate various components and methods useful for carrying out the present disclosure. These examples do not limit the present disclosure as claimed. Based on this disclosure, a person skilled in the art can identify and use other components and methods useful for carrying out the present disclosure.

[0174]

[0184] All publications and patent documents cited herein are incorporated by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it grant any admission as to its contents or date. Although the invention has now been described in detail, those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the above description and the following examples are intended to be illustrative and not limiting of the scope of the claims that follow. EXAMPLES

[0175] Example 1. Reduction in Liver Volume in Non-cirrhotic and Cirrhotic NASH Patients Treated with Resmetirom

[0185] Hepatomegaly can cause symptoms (e.g., pain) in patients with NASH and is thought to be primarily induced by high liver fat content. Resmetirom (MGL-3196) is a liver-directed, orally active, highly selective THR-β agonist in Phase 3 development for the treatment of NASH with significant (stage 2-3) fibrosis. In a 36-week, Phase 2 sequential MRI-PDFF and liver biopsy study in adults with biopsy-confirmed NASH (NAS ≥ 4, F1-F3) and liver fat fraction ≥ 10%, patients treated with resmetirom showed a statistically significant reduction in liver fat associated with resolution of NASH on liver biopsy compared to placebo. The objective of this study was to evaluate the relationship between hepatic triglycerides measured by MRI-PDFF and liver volume (LV) in placebo- and resmetirom-treated patients.

[0176]

[0186] MRI-PDFF and liver volume (LV) were assessed in patients with at least baseline and one additional consecutive PDFF (n=117) and in the resmetirom-treated arm of NASH-cirrhosis activity (n=73) of MAESTRO-NAFLD-1. LV was assessed using a validated artificial intelligence model for segmenting the liver on standard MR images.

[0177]

[0187] Baseline LV was increased in patients with non-cirrhotic and cirrhotic NASH compared to literature values ​​in healthy controls and was greater than expected even after accounting for gender and weight. PDFF correlated with baseline LV in non-cirrhotic (r2=0.19, p<0.001) and less strongly in cirrhotic NASH (r2=0.079, p=0.01). Reduction in LV (CFB) correlated with reduction in PDFF at 12 (and 36 (not shown)) weeks in patients treated with placebo (r2=0.25, p=0.001) and resmetirom (r2=0.38, p<0.0001) (see e.g., Figure 1). LV declines were greater with resmetirom (-18.6% (1.1) and -20.5% (1.2)) compared with placebo (-0.4% (1.5) and 0.1% (1.9)) at 12 and 36 weeks of treatment, respectively (p<0.0001). A higher percentage of resmetirom patients (69.2%) compared with placebo patients (5.3%) had a decrease in liver volume ≥15% at week 12 (p<0.0001) and at week 36. The relationship between LV decline and PDFF decline was proportionally weaker in placebo compared with noncirrhotic NASH patients treated with resmetirom. In cirrhotic NASH patients treated with resmetirom (see Figure 1), LV reductions were significantly greater than would be expected based on the modest reduction in PDFF (LV mean %CFB, -16.3% vs. PDFF mean %CFB, -2.5% at week 16), particularly in patients with a PDFF <5% at baseline. All resmetirom-treated patients with biopsy-based resolution of NASH and / or reduction in fibrosis at week 36 had a reduction in PDFF ≥30% and / or LV reduction ≥15% at week 12.

[0178]

[0188] Without wishing to be bound by theory, the reduction in liver volume in patients treated with resmetirom may be explained in part by the reduction in hepatic triglycerides (measured by MRI-PDFF), but may also be driven by other changes related to its mechanism of action. The reduction in LV may be related to the histopathological improvement of NASH, which may be further evaluated by data from the Phase 3 MAESTRO-NASH trial.

[0179] Example 2. Biomarkers, Imaging, and Safety in the Completed, Open-Label Arm of the Resmetirom 52-Week Non-cirrhotic NASH Phase 3 Clinical Trial, MAESTRO-NAFLD-1

[0189] MAESTRO-NASH NCT03900429 and MAESTRO-NAFLD-1 NCT04197479 are 52-week, phase 3, registrational, double-blind, placebo-controlled clinical trials to test the efficacy of resmetirom in over 2,000 patients with NASH. The goal of MAESTRO-NAFLD-1, a 1,200-patient "real-life" NASH study, is to identify non-invasive markers that correlate with patient response to resmetirom treatment. The 169-patient, open-label (OL) arm of 100 mg completed the 52-week study in July 2021.

[0180]

[0190] Eligibility required at least three metabolic risk factors (metabolic syndrome), fibroscan kilopascals (kPa) consistent with a fibrosis stage of ≥F1, and an MRI-PDFF of ≥8%.The primary and key secondary endpoints of MAESTRO-NAFLD-1, including safety, MRI-PDFF (week 16), LDL cholesterol (LDL-C) (week 24), relative percent reduction in apolipoprotein B and triglycerides, fibroscan, and 52-week endpoints, were analyzed in the OL group.

[0181]

[0191] Mean age was 55.7 (11.5 (SD)), 69% were female, BMI 35.8 (6.0), diabetes 43%, hypertension 62%, dyslipidemia >70%, ASCVD score 11.5%, fibroscan (7.7 kPa (3.6)), and MRI-PDFF 17% (7%). Overall and in some subgroups, a statistically significant (p<0.0001) reduction in MRI-PDFF of -53% (3.3% (SE)) was observed at week 52 (see e.g., Figure 2). Liver volume (LV) was increased by approximately 50% (2202 cm) at baseline compared to normal controls. 3 (535)), which increased by approximately 15% after adjusting for BMI (Euro J of Radiol 106, 2018, pp. 32-37). Resmetirom reduced LV by -21% (1.0%) and -23% (1.0%) at weeks 16 and 52, respectively, in all demographic groups (p<0.0001) (see, e.g., Figure 3). The reduction in LV was 2-3 times greater than predicted by the % reduction in MRI-PDFF, a measure of liver fat content (Clin Gastroenterol Hepatol. 2015 13:561-568). The mean MRI-PDFF reduction corrected for LV was -63% (2.4%). Weight loss of ≥5% occurred in approximately 25% of patients and was associated with resmetirom exposure (SHBG). At week 52, compared to baseline, MRE (-0.34, p=0.03); Fibroscan CAP (-39(4.6)) and VCTE (-1.87;-20%) (p<0.0001) were reduced. LDL-C (-22%(1.9%)), apolipoprotein B (-24%(1.6%)) and triglycerides (-24%(2.6)) were statistically reduced (p<0.0001). Reductions from baseline in liver enzymes were ALT -20IU, AST -11IU, GGT -25IU (p<0.0001). Significant reductions in inflammatory and fibrotic biomarkers reverse T3, ELF and M30, as well as increases in adiponectin were observed. At 52 weeks, no safety flags were observed, blood pressure (systolic, diastolic) decreased by approximately 2 mmHg (p=0.02), and bone mineral density (DEXA) remained unchanged.

[0182]

[0192] In this 52-week Phase 3 OL trial, NASH patients who were noninvasively identified and treated with 100 mg per day of resmetirom for up to 52 weeks demonstrated rapid and sustained reductions in (1) liver fat and liver volume, (2) fibrosis as assessed by biomarkers, MRE and fibroscan, (3) LDL and atherogenic lipids, and (4) liver enzymes and inflammatory biomarkers, providing support for using noninvasive tests to monitor individual NASH patients' response to resmetirom treatment.

[0183] Example 3. Biomarkers, imaging and safety in a well-compensated NASH cirrhosis cohort treated with resmetirom, a thyroid hormone receptor beta agonist, for 52 weeks

[0193] MAESTRO-NAFLD-1 is a 52-week, >1200-patient, phase 3, randomized, double-blind, placebo-controlled NASH clinical trial to test the safety and biomarker effects of resmetirom, a selective thyroid hormone receptor beta agonist, in NASH patients with F1-F4 fibrosis identified using noninvasive biomarkers and imaging (NCT04197479). The goal of this "real-life" NASH trial is to identify noninvasive markers that correlate with individual patient response to resmetirom treatment. The study includes an open-label, active resmetirom treatment arm in patients with well-compensated NASH cirrhosis.

[0184]

[0194] Eligibility required at least three metabolic risk factors (metabolic syndrome) and NASH cirrhosis diagnosed by liver biopsy or according to accepted criteria. Primary and key secondary endpoints in the cirrhosis group included safety, MRI-PDFF (week 16), LDL cholesterol (LDL-C) (week 24), apolipoprotein B and triglycerides, and relative percent reduction in markers of fibrosis. Patients received resmetirom at daily doses of 80-100 mg for 52 weeks.

[0185]

[0195] 105 well-compensated patients with NASH cirrhosis were enrolled in the open-label arm, 2 / 3 of whom had liver biopsy-confirmed cirrhosis. Patient demographics included mean age 62.7 (9.0 (SD)), 64% female, BMI 35.4 (7.4), 70% diabetes, 77% hypertension, dyslipidemia >70%, mean ASCVD score 16.1%, 32.4% hypothyroidism, and 51% on statins. MRE, 5.7 kPa (2.1), fibroscan, 24.6 kPa (14.9), CAP, 318 (59), and mean MRI-PDFF, 8.1% (5). Cirrhosis stage was inversely correlated with baseline PDFF. At week 52, resmetirom reduced fibroscan CAP (-42 units, p<0.0001) and kPa (-7.6 kPa, p=0.02).

[0186]

[0196] In patients with baseline PDFF >5% (5%=UL normal), resmetirom reduced PDFF by 37% (p<0.0057). Resmetirom reduced MRE by 0.68 kPa at week 52, with 34% of patients experiencing a reduction in MRE ≥15%. GGT, -27%, p=0.04 and ALP, -18%, p=0.04 were reduced. Liver volume (LV), which was increased in patients with NASH cirrhosis at baseline, was reduced by -15.9% (7.7%) at week 16, independent of baseline PDFF (p<0.0001). 73% of patients experienced a reduction in LV ≥15% at week 52, independent of baseline cirrhosis severity (see Figure 4 for examples). PDFF reduction was associated with LV reduction only in patients with BL PDFF ≥5%. Changes in splenic volume (SV) were more variable than decreases in PDFF and LV and were therefore assessed as responder analyses (based on the percentage of patients with ≥10% decrease or ≥10% increase in SV). Exposure to resmetirom was strongly correlated with changes in LV and SV.

[0187]

[0197] Reductions in LV correlated with reductions in MRE, MRI-PDFF, TIMP, P3NP, and SHBG response to resmetirom (see Table 1 for examples). Resmetirom reduced LDL-C (20%), triglycerides (21%), ApoB (20%), and Lp(a) (30%), independent of cirrhosis stage. BP was reduced by 4-5 mm. Resmetirom was safe and well tolerated.

[0188] [Table 1]

[0189]

[0198] Treatment of patients with NASH cirrhosis with resmetirom for up to 52 weeks was safe and effective in reducing CV risk and markers of NASH fibrosis.

[0190] Equivalent

[0199] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The above-described embodiments are therefore to be considered in all respects as illustrative rather than limiting the invention described herein. The scope of the present invention is therefore to be specified by the appended claims rather than the above description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. Resmethylometh: 【Chemistry 1】 A pharmaceutical composition for use in a method of treating cirrhotic non-alcoholic steatohepatitis (NASH) in a subject, comprising a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, wherein the method for treating cirrhotic NASH in the subject is carried out by reducing the liver volume in the subject.

3. The pharmaceutical composition according to claim 2, which reduces liver volume by at least 5% over a period of 52 weeks.

4. The pharmaceutical composition according to claim 3, which reduces liver volume by at least 15% over a period of 52 weeks.

5. The pharmaceutical composition according to claim 1, wherein the subject has an increased liver volume at baseline compared to a comparable subject that does not have scirrhous NASH.

6. The pharmaceutical composition according to claim 5, wherein the subject has a liver volume at least 5% larger than that of a comparable subject that does not have cirrhotic NASH.

7. The pharmaceutical composition according to claim 1, wherein the resmethirome or a salt thereof is administered to the subject at a daily dose of 60 mg to 100 mg.

8. The pharmaceutical composition according to claim 7, wherein the resmethirome or a salt thereof is administered to the subject at a daily dose of 60 mg.

9. The pharmaceutical composition according to claim 7, wherein the resmethirome or a salt thereof is administered to the subject at a daily dose of 80 mg.

10. The pharmaceutical composition according to claim 7, wherein the resmethirome or a salt thereof is administered to the subject at a daily dose of 100 mg.

11. A pharmaceutical composition according to any one of claims 1 to 10, wherein resmethirome or a salt thereof is administered once daily.

12. The pharmaceutical composition according to claim 1, wherein the NASH in the cirrhosis is a well-compensated NASH in the cirrhosis, and resmethirome or a salt thereof is administered to the subject at a daily dose of 80 mg to 100 mg.

13. The pharmaceutical composition according to claim 1, wherein the method comprises treating portal hypertension in a subject.

14. The pharmaceutical composition according to claim 1, wherein the method includes reducing the severity of portal hypertension in a subject.

15. The pharmaceutical composition according to claim 1, wherein the resmethirome or a pharmaceutically acceptable salt thereof is resmethirome.

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