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EP-4739301-A1 - COMPOSITIONS CONTAINING, AND COMBINATION THERAPIES USING BEMPEDOIC ACID AND A GLP-1 RECEPTOR AGONIST

EP4739301A1EP 4739301 A1EP4739301 A1EP 4739301A1EP-4739301-A1

Abstract

Provided herein are methods of treating hepatic steatosis and/or liver fibrosis by administering a combination of a GLP-1 receptor agonist and bempedoic acid. Also provided herein are methods of modulating glycemic control, the level of hemoglobin A1C, the body weight, systolic and/or diastolic blood pressure, liver fat, hepatocellular ballooning, and/or lobular inflammation of a subject by administering a combination of a GLP-1 receptor agonist and bempedoic acid.

Inventors

  • PINKOSKY, STEPHEN L.
  • STEINBERG, GREGORY R.
  • DESJARDINS, Eric Marc-Andre

Assignees

  • Esperion Therapeutics, Inc.

Dates

Publication Date
20260513
Application Date
20240703

Claims (20)

  1. 1. A method of treating hepatic steatosis in a subject in need thereof, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.
  2. 2. A method of treating liver fibrosis in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.
  3. 3. A method of modulating glycemic control in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.
  4. 4. A method of reducing the level of hemoglobin A1C (HbAlc) in blood or serum of a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.
  5. 5. A method of reducing the body weight of a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.
  6. 6. A method of reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.
  7. 7. A method of reducing liver fat in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.
  8. 8. A method of reducing hepatocellular ballooning in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.
  9. 9. A method of reducing lobular inflammation in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.
  10. 10. The method of any one of claims 1-9, wherein the hepatic steatosis is non-alcoholic steatohepatitis (NASH).
  11. 11. The method of any one of claims 1-10, wherein administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid lowers the level of hbAlc in blood or serum of the subject below that of a subject with hepatic steatosis, and not receiving the effective amounts of the GLP- 1 receptor agonist and bempedoic acid or receiving (a) the effective amount of the GLP-1 receptor agonist or (b) the effective amount of bempedoic acid.
  12. 12. The method of any one of claims 1-11 wherein administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid results in the subject exhibiting a greater reduction in body weight compared to a subject with hepatic steatosis, and not receiving the effective amounts of the GLP- 1 receptor agonist and bempedoic acid or receiving (a) the effective amount of the GLP- 1 receptor agonist or (b) the effective amount of bempedoic acid.
  13. 13. The method of any one of claims 1-12, wherein administration of the effective amounts of the GLP- 1 receptor agonist and bempedoic acid results in the subject exhibiting a greater reduction in liver fat compared to a subject with hepatic steatosis, and not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid or receiving (a) the effective amount of the GLP- 1 receptor agonist or (b) the effective amount of bempedoic acid.
  14. 14. The method of any one of claims 1-13, wherein administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid results in the subject exhibiting a greater reduction in liver fibrosis compared to a subject with hepatic steatosis, and not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid, or receiving (a) the effective amount of the GLP- 1 receptor agonist or (b) the effective amount of bempedoic acid.
  15. 15. The method of any one of claims 1-14, wherein the GLP-1 receptor agonist is selected from the group consisting of semaglutide, liraglutide, exenatide, dulaglutide, albiglutide, and lixisenatide.
  16. 16. The method of any one of claims 1-15, wherein administering an effective amount of a GLP-1 receptor agonist comprises administering to the subject about 0.25 mg to about 14 mg semaglutide.
  17. 17. The method of any one of claims 1-16, wherein administering an effective amount of a GLP-1 receptor agonist comprises administering parenterally to the subject about 0.25 mg to about 1 mg semaglutide.
  18. 18. The method of any one of claims 1-16, wherein administering an effective amount of a GLP-1 receptor agonist comprises administering orally to the subject about 3 mg to about 14 mg semaglutide.
  19. 19. The method of any one of claims 1- 15, wherein administering an effective amount of a GLP-1 receptor agonist comprises administering parenterally to the subject about 0.6 mg to about 1.8 mg liraglutide.
  20. 20. The method of any one of claims 1-15, wherein administering an effective amount of a GLP-1 receptor agonist comprises administering parenterally to the subject about 2 mg to about 10 mg exenatide.

Description

COMPOSITIONS CONTAINING, AND COMBINATION THERAPIES USING BEMPEDOIC ACID AND A GLP-1 RECEPTOR AGONIST CROSS REFERENCE TO RELATED APPLICATIONS [001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63/512,395, filed on July 7, 2023, the disclosure of which is hereby incorporated by reference in its entirety for all purposes. BACKGROUND [002] It is estimated that non-alcoholic fatty liver disease (NAFLD) affects between 30 and 40 percent of adults in the United States (Spengler et al. Recommendations for Diagnosis, Referral for Liver Biopsy, and Treatment of Nonalcohol Fatty Liver Disease and Nonalcoholic Slealohepatilis. Mayo Clin. Proc. 2015. 90 (9): 1233-1246). Although the majority of NAFLD cases have little risk progression, about 20 percent of adults with NAFLD have non-alcoholic steatohepatitis (NASH), a more serious form of NAFLD that represents a greater cause for concern (Spengler et al.). Associated complications and comorbidities of NASH include, but are not limited to, fibrosis and cirrhosis of the liver, liver cancer, and liver failure (National Institutes of Health). Moreover, currently there are few approved drug therapies available for the treatment of NASH. As such, NASH represents a significant health concern. [003] Glucagon-like protein- 1 (GLP-1) receptor agonists are a class of drugs, several members of which are FDA-approved (e.g., dulaglutide, exenatide, semaglutide, liraglutide, albiglutide, lixisenatide), that lower blood sugar in patients and are useful for the treatment of type 2 diabetes. The GLP-1 receptor agonist semaglutide, the only drug of its class currently approved for oral administration, has been investigated in the context of treating NASH (Newsome et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. New Eng. J. of Med. 2020). However, semaglutide has not been shown to have a beneficial effect in the management of liver fibrosis (Newsome et al.). [004] Despite the efforts made to date, there is an unmet need for drug therapies that treat NASH while also improving liver fibrosis. SUMMARY [005] The present disclosure provides combination drug therapies comprising bempedoic acid and a GLP- 1 receptor agonist (semaglutide, liraglutide, exenatide, dulaglutide, albiglutide, or lixisenatide). The disclosure additionally provides methods of using the combination drug therapies described herein to treat hepatic steatosis (e.g., non-alcoholic steatohepatitis (NASH)) in a subject in need thereof. The combination drug therapies described herein are also useful for one or more of treating liver fibrosis, modulating glycemic control, reducing the level of hemoglobin A1C (HbAlc) in blood or serum, reducing body weight, reducing the systolic and/or diastolic blood pressure, reducing liver fat, reducing hepatocellular ballooning, and reducing lobular inflammation in a subject with hepatic steatosis. The methods generally comprise administering to the subject an effective amount of bempedoic acid and an effective amount of a GLP- 1 receptor agonist described herein. [006] In one aspect, provided herein is a method of treating hepatic steatosis in a subject in need thereof, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid. [007] In another aspect, provided herein is a method of treating liver fibrosis in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid. [008] In another aspect, provided herein is a method of modulating glycemic control in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid. [009] In another aspect, provided herein is a method of reducing the level of hemoglobin A1C (HbAlc) in blood or serum of a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid. [010] In another aspect, provided herein is a method of reducing the body weight of a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid. [011] In another aspect, provided herein is a method of reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid. [012] In another aspect, provided herein is a method of reducing liver fat in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bemped