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US-12616698-B2 - Methods for reducing liver fat and for treating fatty liver disorders

US12616698B2US 12616698 B2US12616698 B2US 12616698B2US-12616698-B2

Abstract

Applicant discloses methods and compositions for reducing liver fat and for treating fatty liver diseases (e.g., non-alcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) and nonalcoholic cirrhosis; alcohol related fatty liver diseases including, alcohol fatty liver disease (AFL), alcoholic steatohepatitis (ASH), and alcoholic cirrhosis; and liver fibrosis). Significant liver fat reductions were obtained in human patients after only between 30 to 44 days of administration of 600 mg/day or 900 mg/day of the cyclohexyl pyrimidine glucocorticoid receptor modulator miricorilant. Liver fat reductions ranged from 38.5% to 73.8% (magnetic resonance imaging measurements in 4 of 5 patients receiving miricorilant, measured between 16-64 days after cessation of miricorilant administration). A further effect of miricorilant was an increase in liver alanine amino transferase (ALT) and aspartate amino transferase (AST). Mouse studies showed that miricorilant reduced measures of NAFLD, body weight, liver weight, and liver collagen and galectin-3 levels.

Inventors

  • Ada Lee
  • Andreas Grauer
  • Joseph Belanoff

Assignees

  • CORCEPT THERAPEUTICS INCORPORATED

Dates

Publication Date
20260505
Application Date
20231122

Claims (11)

  1. 1 . A method of reducing liver fat in a patient in need thereof, comprising intermittently administering to the patient an effective amount of the nonsteroidal glucocorticoid receptor modulator (GRM) (E)-6-(4-Phenylcyclohexyl)-5-(3-trifluoromethylbenzyl)-1H-pyrimidine-2,4-dione (“miricorilant”), which has the structure: Wherein said intermittent administration comprises: Administering miricorilant two or three times per week for at least 2 weeks; Determining blood levels of ALT, AST, or both; Interrupting said administration of miricorilant for at least one week; and Resuming miricorilant administration two or three times per week for at least two weeks, effective to reduce the amount of liver fat in the patient.
  2. 2 . The method of claim 1 , wherein the patient suffers from a non-alcoholic fatty liver disease (NAFLD).
  3. 3 . The method of claim 2 , wherein the non-alcoholic fatty liver disease is selected from nonalcoholic steatohepatitis (NASH) and nonalcoholic cirrhosis.
  4. 4 . The method of claim 1 , wherein the patient suffers from an alcohol related fatty liver disease (ARLD).
  5. 5 . The method of claim 4 , wherein the alcohol related fatty liver disease is selected from alcohol fatty liver disease (AFL), alcoholic steatohepatitis (ASH), and alcoholic cirrhosis).
  6. 6 . The method of claim 1 , wherein the patient suffers from liver fibrosis.
  7. 7 . The method of claim 1 , wherein said miricorilant is administered orally.
  8. 8 . The method of claim 1 , wherein said miricorilant is administered at a dose selected from 50 mg, 100 mg, and 150 mg.
  9. 9 . The method of claim 1 , wherein said miricorilant is administered twice weekly.
  10. 10 . The method of claim 1 , wherein liver enzyme levels of said patient are measured, and administration of miricorilant is interrupted for at least one week if the levels of alanine aminotransferase (ALT) or of aspartate aminotransferase (AST) are found to be greater than 3 time the normal level of those enzymes.
  11. 11 . The method of claim 1 , wherein said liver disease characterized by abnormally high levels of liver fat is further characterized by abnormal or excessive levels of one or more of liver degeneration, liver weight, liver collagen, and liver galectin, wherein said treatment is effective to normalize or reduce said abnormal or excessive levels of liver degeneration, liver weight, liver collagen, or liver galectin.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of, and claims priority to and the benefit of, U.S. patent application Ser. No. 17/736,912, filed May 4, 2022, and claims priority to, and the benefit of, U.S. Provisional Application No. 63/184,694, filed May 5, 2021; U.S. Provisional Application No. 63/244,116, filed Sep. 14, 2021; and U.S. Provisional Application No. 63/271,861, filed Oct. 26, 2021, all of which applications are hereby incorporated by reference herein in their entireties. BACKGROUND Liver diseases are a significant cause of disease and death in the United States and abroad. Excessive liver fat, as compared to normal levels of liver fat, are indicative of, and may be a cause of, fatty liver diseases. However, although the incidence of liver diseases is increasing, treatments for these disorders are lacking. For example, non-alcoholic fatty liver disease (NAFLD) affects about 20% of people worldwide; however, there are no approved pharmacologic treatments for NAFLD. Liver disorders can be categorized in different groups of diseases, such as alcohol-induced (or alcohol-related) fatty liver disease (AFLD), nonalcoholic fatty liver disease (NAFLD; including, e.g., non-alcoholic steatohepatitis (NASH)), drug- or alcohol-related liver diseases, viral diseases, immune-mediated liver diseases, metabolic liver diseases, and complications associated with hepatic insufficiency and/or liver transplantation. Nonalcoholic fatty liver disease is a common hepatic disorder with histological features similar to those of alcohol-induced fatty liver disease, in individuals who consume little or no alcohol. Normal levels of liver fat are discussed in Pataja et al., Int. J. Mol. Sci. 2016, 17, 633 (e.g., about 5% by histological measurements, or by weight). Fatty liver disease is believed to be due to an abnormal retention of lipid (fats) within hepatocytes. High levels of liver fat, and fatty liver disease, may lead to liver fibrosis or cirrhosis of the liver. Normal levels of alanine aminotransferase (ALT) are known and ascertainable; upper limit of normal (ULN) for serum ALT level for healthy adults (per AASLD guideline) are 35 U/L for males and 25 U/L for females. Normal levels of aspartate aminotransferase (AST) are known and ascertainable; ULN for serum AST level for healthy adults are 20 U/L for males and 36 U/L for females. Reductions in liver fat have been reported following long-term (e.g., 24 weeks) experimental treatment (for review, see Loomba et al., Hepatology 2020 October; 72(4):1219-1229). A decline in liver fat of about 30% or more is believed to be clinically meaningful, and may be associated with clinical benefit including reduction of steatosis grade, histological improvement, and improvement in inflammation (Caussy et al., Hepatology. 2018 August; 68(2): 763-772). Treatments for fatty liver diseases are discussed, for example, in U.S. Pat. No. 10,238,659 and in U.S. Pat. No. 10,881,660. However, there remain need for additional methods for treating liver disorders related to high levels liver fat, and for managing fatty liver disease. Surprisingly, the present invention meets these and other needs. SUMMARY Applicant discloses herein rapid and extensive reduction in liver fat with a short duration of oral administration of a non-steroidal glucocorticoid receptor modulator (GRM). Reductions of liver fat ranged from 38.5% to 73.8% (as measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF)) in 4 of 5 patients receiving the GRM miricorilant; the duration of daily miricorilant administration for these patients ranged from between 30 to 44 days; liver fat percentage was measured between 16 and 64 days following cessation of miricorilant administration. A further effect of miricorilant was an increase in liver enzymes alanine amino transferase (ALT) and aspartate amino transferase (AST). Applicant discloses herein methods, uses, and compositions for reducing the level of fat in the liver of a patient, including methods for reducing high or excessive levels of liver fat, as compared to normal levels of liver fat, for treatment of patients in need thereof. Applicant discloses herein methods, uses, and compositions for reducing liver degeneration, or liver weight, or liver collagen, or liver galectin, or liver fibrosis, as compared to normal levels, or as compared to baseline values, for treatment of patients in need thereof. Reducing fat levels, including reducing the amount of liver fat, and reducing the relative amounts of fat in the liver of a patient as compared to other liver components, is useful for treating fatty liver diseases. Reducing liver degeneration, reducing liver weight, reducing liver collagen, reducing liver galectin, or reducing liver fibrosis is believed to be useful for treating fatty liver diseases. Fatty liver diseases which may be treated with the methods and compositions disclosed herein include, without limitation, no