Zalfermin Plus Semaglutide Misses Fibrosis Endpoint in Phase 2 MASH Trial

Key Takeaways

• The zalfermin-plus-semaglutide combination did not significantly improve the primary endpoint versus placebo.
• Semaglutide monotherapy was associated with a nominally significant signal on the same endpoint at week 52.
• Adverse events were mostly non-serious and mild to moderate, gastrointestinal events were the most common, and five deaths occurred across the trial, with one death in the zalfermin-alone group considered possibly related.

This phase 2, dose-ranging, double-blind, randomized controlled trial was published in The Lancet Gastroenterology & Hepatology. Researchers screened 2,420 people and randomized 698 at 187 sites across 22 countries between August 2021 and March 2025. Eligible participants were adults with metabolic dysfunction-associated steatohepatitis and clinically significant fibrosis, defined as F2 through F4c without decompensation, with F4c indicating compensated cirrhosis. Seven weekly injection regimens were tested for 52 weeks, including three zalfermin-plus-semaglutide doses, zalfermin 30 mg alone, semaglutide 2.4 mg alone, exploratory cagrilintide plus semaglutide, and placebo. The primary endpoint was at least one stage of fibrosis improvement on the NASH CRN scale without worsening of steatohepatitis at week 52.

In the zalfermin 30 mg and semiglutide 2.4 mg combination arm, 24% of patients met the primary endpoint, versus 16% with placebo at week 52. The estimated difference from placebo was not statistically significant at 7.98 percentage points, with a 95% confidence interval from -3.82 to 19.79, p=0.19. Zalfermin 30 mg alone arm also did not reach statistical significance compared to placebo. The lower-dose combination arms and the exploratory cagrilintide-plus-semaglutide arm were not substantially different from placebo. On the other hand, 30% of patients in the semaglutide 2.4 mg alone arm reached the endpoint, for a significant difference of 14.05 percentage points compared to placebo, with a 95% confidence interval from 1.88 to 26.23, p=0.024.

Adverse events were mostly non-serious and mild to moderate, and gastrointestinal events were the most frequent. Gastrointestinal event rates were 80% with the combination, 73% with semaglutide alone, 60% with zalfermin alone, and 51% with placebo, while serious adverse event rates were 7%, 10%, 13%, and 5%, respectively. Five deaths occurred across the trial, with one heart-failure death in a participant receiving zalfermin alone considered possibly related to study drug. Semaglutide's current FDA liver-disease approval applies to noncirrhotic MASH with moderate-to-advanced fibrosis rather than cirrhosis. The authors described the trial as proof-of-concept and dose-ranging, and it was not powered to detect differences between individual dose levels.