Semaglutide 2.4 mg in MASH with F2 to F3 fibrosis. ESSENCE part 1 (NEJM 2025): 62.9% vs 34.3% MASH resolution at 72 weeks; basis for Wegovy's 2025 MASH approval.
Trial design
Phase 3 RCT of semaglutide 2.4 mg weekly vs placebo in 1,197 adults with biopsy-confirmed MASH and F2 to F3 fibrosis, planned to run 240 weeks. Part 1 is a planned 72-week analysis of the first 800 participants with two primary endpoints: MASH resolution without worsening fibrosis, and fibrosis improvement without worsening MASH.
Part 1 results (NEJM 2025)
In Sanyal et al., steatohepatitis resolved without worsening fibrosis in 62.9% on semaglutide 2.4 mg vs 34.3% on placebo at 72 weeks, and fibrosis improved in 36.8% vs 22.4%. Mean weight loss was 10.5% vs 2.0%. Gastrointestinal side effects were more common with semaglutide. Part 2, which looks at liver-related clinical outcomes, is still running.
Implications
On August 15, 2025, FDA granted Wegovy accelerated approval for noncirrhotic MASH with moderate to advanced fibrosis (F2 to F3) in adults, based on ESSENCE part 1. Continued approval depends on part 2. Tirzepatide has phase 2 MASH data (SYNERGY-NASH) but no FDA MASH indication as of October 16, 2026. Compounded semaglutide was not studied in ESSENCE and is not FDA-approved.