Efimosfermin for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis (MASH): Mechanism of Action, Clinical Development and Emerging Therapeutic Potential

Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD), the hepatic manifestation of metabolic syndrome, has emerged as the leading cause of chronic liver disease worldwide. Its global prevalence estimated at 38% between 2016– 2019, representing a nearly 50% increase compared with 1990– 2006. A subset of patients with MASLD will develop Metabolic dysfunction-associated steatohepatitis (MASH), which can progress to cirrhosis and require transplantation. Until 2024, no therapy was available for the treatment of MASH. In 2024, resmetirom became the first drug approved for the treatment of MASH. The approval of semaglutide, a GLP-1 agonist for the treatment of MASH, followed this development. Besides these two drugs, multiple other pharmacologic therapies targeting metabolic and inflammatory pathways currently under active development. Fibroblast growth factor-21 (FGF-21) has emerged as a key endocrine regulator with physiological effects on glucose and lipid metabolism. Efimosfermin, a long-acting once-monthly FGF-21 analogue, is currently under development and represents a promising therapeutic option for MASLD, with the added advance of long-term adherence. Phase 2 clinical trials have reported efimosfermin to be beneficial in MASH resolution and fibrosis regression in patients with MASH and F2/F3 fibrosis. This review summarizes the biologic rationale, clinical development and emerging therapeutic role of efimosfermin in the treatment landscape of MASH. Keywords: MASH, efimosfermin, FGF-21, advanced fibrosis, cirrhosis, GLP-1, resmetirom