Study background and disease burden
Metabolic dysfunction-associated steatohepatitis (MASH), formerly recognized within the spectrum of nonalcoholic steatohepatitis (NASH), is an increasingly prevalent liver condition marked by hepatic inflammation, steatosis, and progressive fibrosis, often linked with metabolic comorbidities such as type 2 diabetes mellitus and obesity. Fibrosis progression in MASH drives the risk of cirrhosis, liver failure, and hepatocellular carcinoma, representing a significant clinical challenge with limited approved pharmacotherapies to date. Integral to MASH pathogenesis are mechanisms involving glycaemic dysregulation, chronic low-grade inflammation, and lipid metabolism abnormalities.
Free fatty acid receptors (FFARs), specifically FFAR1 and FFAR4, are G-protein coupled receptors expressed on multiple cell types including hepatocytes, immune cells, and pancreatic beta cells. They modulate glucose homeostasis, insulin sensitivity, and inflammatory responses, suggesting their dual role as attractive therapeutic targets in MASH. Icosabutate, an oral dual FFAR1/FFAR4 agonist, was developed to leverage these mechanisms to improve liver histology and systemic metabolic parameters.
