FGF21 Analogues Lead Efficacy Signals in Challenging MASH Compensated Cirrhosis Drug Development

Metabolic dysfunction-associated steatohepatitis (MASH)-related compensated cirrhosis represents a critical and growing global health burden, yet no approved treatments exist. This advanced stage of liver disease is characterized by concurrent metabolic dysfunction, persistent inflammation, stabilized fibrosis, and portal hypertension, making therapeutic development exceptionally complex. Current standard-of-care primarily focuses on managing complications, leaving a major unmet need for disease-modifying therapies that can halt or reverse progression to hepatic decompensation, hepatocellular carcinoma (HCC), and liver-related mortality.

This comprehensive review synthesizes recent progress in drug development for MASH-related compensated cirrhosis, evaluating the efficacy and safety of major investigational agents that have advanced into this challenging population. The authors discuss key barriers to successful development, including limitations of current endpoint frameworks, challenges in patient stratification, and trial design complexities. Furthermore, the review outlines future directions for the field, such as precision stratification, the adoption of composite endpoints, utilization of noninvasive assessment tools, exploration of combination strategies, and the importance of earlier screening and intervention.

Several agents initially developed for non-cirrhotic MASH have progressed to trials in compensated cirrhosis, including fibroblast growth factor 21 (FGF21) analogues, glucagon-like peptide-1 receptor (GLP-1R)/glucagon receptor (GR) dual agonists, and thyroid hormone receptor-beta (THR-beta) agonists. Among these, FGF21 analogues have demonstrated the most encouraging efficacy signals to date. However, the majority of candidates have not shown clear histological or clinical benefit in this specific patient population. The predominance of negative trials suggests that limited progress stems not only from insufficient drug efficacy but also from the inherent complexity of the disease, marked patient heterogeneity, and the limitations of current endpoint frameworks. Key challenges identified include the difficulty in demonstrating significant changes in histological endpoints and the need for better noninvasive biomarkers. > FGF21 analogues have shown the most encouraging efficacy signals among the investigational agents for MASH-related compensated cirrhosis.