Mechanism Of Action:
Thyroid hormones, including free thyroxine (FT4) and free triiodothyronine (FT3), play a central role in regulating lipid metabolism in the liver. The thyroid hormone receptor-beta (THR-β) is the predominant thyroid hormone receptor isoform in hepatic tissue, and activation of this receptor has been shown to reduce intrahepatic triglyceride levels.
A substantial proportion of patients with non-alcoholic fatty liver disease (NAFLD) exhibit impaired thyroid function, particularly hypothyroidism, which is considered an important risk factor for NAFLD. Hypothyroidism is associated with dysregulated lipolysis in adipose tissue, leading to increased release of free fatty acids into the circulation and their subsequent delivery to the liver. This process promotes hepatic insulin resistance. In addition, elevated circulating pro-inflammatory adipokines may contribute to hepatic inflammation and fibrosis.
Resmetirom is a selective, partial agonist of THR-β that enhances lipophagy and stimulates hepatic fatty acid β-oxidation, resulting in reduced liver fat content. It demonstrates approximately 28-fold greater selectivity for THR-β compared with FT3, relative to thyroid hormone receptor-alpha (THR-α), which is primarily expressed in cardiac and bone tissue.
Indication:
Resmetirom is indicated, in combination with diet and exercise, for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) who have moderate to advanced liver fibrosis (corresponding to fibrosis stages F2 to F3). Its use is not recommended in patients with decompensated cirrhosis.
This indication has been granted accelerated approval based on evidence demonstrating improvement in NASH and liver fibrosis. Continued approval may depend on the confirmation and further characterization of clinical benefit in ongoing or subsequent confirmatory trials.
