Metabolic Dysfunction-Associated Steatohepatitis (MASH)-Cirrhosis Clinical Trials: Lessons Learned and Future Directions

Metabolic dysfunction-associated steatohepatitis (MASH)-cirrhosis represents a critical and growing global health burden due to its progression to hepatic decompensation, hepatocellular carcinoma (HCC), and liver-related mortality. A growing number of MASH-related HCCs contribute to the increasing need for liver transplantation. Under current regulatory guidance, Phase 3 trials in compensated MASH cirrhosis compare drug versus placebo on time to a composite endpoint for outcomes. Composite endpoints are major adverse liver outcomes (MALO)—hepatic decompensation (ascites requiring treatment, variceal hemorrhage, hepatic encephalopathy, MELD ≥ 15), liver transplantation—and all‑cause mortality. Future trial sample size hinges on the annual event rate and expected effect size. From prior studies, event rates are ~ 3–20% higher with risk features. Progression to large gastroesophageal varices is now an accepted endpoint and will typically add a 3–5% yearly event rate to the baseline MALO event rate. Effect sizes on hard outcomes in metabolic chronic diseases often range from 0.70–0.85. Trials should enroll high‑risk patients (defined as those with clinically significant portal hypertension [CSPH], Child Turcotte Pugh A cirrhosis, and magnetic resonance elastography measurements > 6.5 kPa), plan 3–5 years of follow‑up and enroll using noninvasive criteria. Accelerated approval based on histologic reversal of cirrhosis is potentially possible; the SYMMETRY Phase 2b trial achieved F4 regression within 96 weeks with efruxifermin. Levers to increase regression include an upper limit for liver stiffness measurement(LSM), a platelet threshold (> 110,000/µL), limiting CSPH, and prespecified proportions with FIB‑4 > 3.5 or enhanced liver fibrosis (ELF) > 11.3. Ongoing studies include but are not limited to survodutide, a glucagon/GLP-1 receptor dual agonist targeting metabolic drivers, efruxifermin, an FGF21 analog, and a conditionally approved drug resmetirom, which is a selective thyroid hormone receptor β agonist.