KR-20260066042-A - Combination therapy of thyroid hormone receptor agonists and FASN inhibitors

Abstract

A therapeutic combination of a fatty acid synthesis regulator and a thyroid hormone receptor agonist is provided. The combination may be used to treat disorders involving metabolic and liver disorders, such as non-alcoholic steatohepatitis/metabolic dysfunction-associated steatohepatitis (NASH/MASH).

Inventors

• 오’파렐, 앤-마리
• 켐블, 조지
• 차이, 웬-웨이

Assignees

• 새지메트 바이오사이언시스, 인코포레이티드

Dates

Publication Date

20260512

Application Date

20240620

Priority Date

20230620

Claims (20)

1. A method for treating fatty liver disease in a subject requiring treatment, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.
2. A method for treating non-alcoholic steatohepatitis/metabolic dysfunction-associated steatohepatitis (NASH/MASH) in a subject requiring treatment, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.
3. A method according to paragraph 2, wherein treating non-alcoholic steatohepatitis/metabolic dysfunction-associated steatohepatitis (NASH/MASH) prevents the progression of at least one symptom of non-alcoholic steatohepatitis/metabolic dysfunction-associated steatohepatitis (NASH/MASH).
4. A method according to claim 2 or 3, wherein the symptoms are selected from elevated levels of AST; elevated levels of ALT; elevated levels of GGT; elevated levels of liver triglycerides; elevated levels of cholesterol; liver steatosis; liver inflammation; liver ballooning; liver fibrosis; and NAFLD activity score.
5. A method for treating non-alcoholic fatty liver disease/metabolic dysfunction-associated fatty liver disease (NAFLD/MASLD) in a subject requiring treatment, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.
6. A method for treating metabolic syndrome in a subject requiring treatment, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.
7. A method for treating type 2 diabetes in a subject requiring treatment, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.
8. A method for treating atherosclerosis in a subject requiring treatment, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.
9. A method for treating liver cirrhosis in a subject requiring treatment, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.
10. A method for treating liver cancer in a subject requiring treatment, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.
11. In paragraph 10, the method wherein the liver cancer arose from NAFLD/MASLD or NASH/MASH.
12. In paragraph 11, the method wherein the liver cancer is a hepatocellular carcinoma.
13. In paragraph 12, the method wherein the hepatocellular carcinoma arises from NAFLD/MASLD or NASH/MASH.
14. In Clause 11, the method wherein the liver cancer is a cholangiocarcinoma.
15. A method for treating a disease or pathological condition in which interleukin 1 beta (IL1β) levels are elevated in a subject requiring treatment, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.
16. In paragraph 15, the above disease or condition is familial Mediterranean fever (FMF), suppurative arthritis, pyoderma gangrene, acne (PAPA), cryopyrin-related periodic syndrome (CAPS), hyper-IgD syndrome (HIDS), adult and pediatric Still's disease, Schnitzler syndrome, TNF receptor-related periodic syndrome (TRAPS), Blau syndrome; A method selected from Sweet syndrome, IL-1 receptor antagonist deficiency (DIRA), recurrent idiopathic pericarditis, macrophage activation syndrome (MAS), urticarial vasculitis, antisynthetic enzyme syndrome, recurrent chondritis, Behcet's disease, Erdheim-Chester syndrome (histiocytosis), synovitis, acne, pustulosis, hypertrophy, osteitis (SAPHO), rheumatoid arthritis, cyclic fever, aphthous stomatitis, pharyngitis, adenitis syndrome (PFAPA), ureate crystalline arthritis (gout), type 2 diabetes, smoldering multiple myeloma, heart failure after myocardial infarction, osteoarthritis, transfusion-associated acute lung injury, ventilator-induced lung injury, pulmonary fibrosis including idiopathic, chronic obstructive pulmonary disease and asthma.
17. A method for treating a disease or pathological condition in which regulatory T cells (T reg ) are reduced or suppressed in a subject requiring treatment, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to said subject.
18. In paragraph 17, a method in which T reg cells are inhibited.
19. A method for treating a disease or pathological condition in which t-helper (Th h ) cell levels are elevated in a subject requiring treatment, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.
20. In claim 19, the method wherein the elevated t-helper cell is T h 1, T h 2, T h 9, or T h 17.

Description

Combination therapy of thyroid hormone receptor agonists and FASN inhibitors Cross-reference regarding related applications This application claims priority and interest to U.S. provisional application No. 63/509,267 filed on June 20, 2023, the contents of which are incorporated herein by reference in their entirety. field The present disclosure generally relates to a therapeutic combination of a fatty acid synthase inhibitor and a thyroid hormone receptor agonist for the treatment of liver disease. background Metabolic Dysfunction-Associated Fatty Liver Disease (MASLD) (formerly known as Non-Alcoholic Liver Disease (NAFLD)), a pathological condition in which the liver contains more than 5% by weight of fat and is not caused by excessive alcohol consumption, currently affects approximately 20–30% of the population in the United States and the general Western world. It is associated with a significantly increased risk of morbidity extending beyond the liver to cardiovascular disease (i.e., carotid atherosclerosis and endothelial dysfunction), chronic kidney disease, and malignancies. Obesity, type 2 diabetes, and metabolic syndrome are three major risk factors for NAFLD/MASLD characterized by an imbalance between energy utilization and storage. This imbalance leads to inflammatory responses that induce uncontrolled metabolic pathways and further alterations resulting in liver damage and comorbidities. With the progression of metabolic syndrome, NAFLD/MASLD begins with metabolic dysfunction-associated steatohepatitis (MASH) (formerly known as non-alcoholic steatohepatitis (NASH)) and leads to more advanced liver disease, which can then progress to significant cirrhosis and hepatocellular carcinoma. In 2023, global liver disease medical societies and patient groups formalized the decision to rename non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MASLD) and non-alcoholic steatohepatitis (NASH) to metabolic dysfunction-associated steatohepatitis (MASH). Additionally, the comprehensive term steatohepatic liver disease (SLD) was established to encompass various types of liver diseases associated with fat accumulation in the liver. The synthesis of fatty acids in the liver, via a pathway named hepatic lipogenesis (DNL), is increased in subjects with metabolic syndrome and NAFLD/MASLD (Donnelly, K. L, et. al., "Sources of fatty acids stored in the liver and secreted via lipoproteins in patients with non-alcoholic fatty liver disease", J. Clin. Invest . 115 (5). 2005, 1343-51; Lambert, J. E, et. al., "Increased lipogenesis is a unique characteristic of individuals with non-alcoholic fatty liver disease", Gastroenterology 146 (3).2014, 726-35). The DNL pathway not only generates fatty acids that contribute to increased hepatic triglyceride storage, but the generated fatty acids are saturated fatty acid species, primarily palmitates, which contribute to signaling events that increase liver inflammation (Wei, Y., "Saturated fatty acids induce endoplasmic reticulum stress and apoptosis in hepatocytes independently of ceramides", Am. J. Physio. Endocrinol. Metab . 291 (2): 2006, E275-81; Kakazu, E., et al., "Hepatocytes release ceramide-rich pro-inflammatory extracellular vesicles in an IRE1-alpha-dependent manner", Abstract 58. AASLD- The Liver Meeting, San Francisco, California, USA, November 13-17, 2015). One of the major enzymes in the DNL pathway is fatty acid synthase (FASN), which is responsible exclusively for palmitate synthesis. Therefore, DNL is an important pathway for therapeutic interventions to reduce outcomes associated with metabolic syndrome and NAFLD/MASLD. Inhibition of FASN has the potential to be a treatment for a wide range of diseases, including cancer, viral diseases, metabolic diseases, NAFLD/MASLD, NASH/MASH, and inflammatory diseases (i.e., rheumatoid arthritis, gout, pulmonary fibrosis, COPD, IBD, and transplant rejection). Additionally, FASN inhibition may provide therapeutic benefits in cardiovascular disease, atherosclerosis, type 2 diabetes, and metabolic syndrome. Successful treatment of these diseases remains a very important, unmet need. FASN inhibition not only reduces hepatic fat but also acts directly on immune and hepatic stellate cells to reduce inflammation and fibrosis. WO2012/122391, WO2014/008197, and WO2015/105860 describe heterocyclic FASN inhibitors, and WO2018/089904 describes the use of some of the aforementioned FASN inhibitors for the treatment of NAFLD/MASLD and NASH/MASH. The contents of the aforementioned referenced disclosures are incorporated herein by reference. Denifanstat (TVB-2640), one of the compounds described in the aforementioned referenced applications, is the first-in-class FASN inhibitor to demonstrate improvement in hepatic fat and biomarkers associated with inflammation and fibrosis in NASH/MASH trials. Thyroid hormone receptor beta (THRβ) agonists increase lipid oxidation, which reduces liver fat, and