The trial
SYNERGY-NASH, presented at EASL 2024 and published in NEJM on June 8, 2024, randomized 190 patients with biopsy-confirmed MASH to tirzepatide 5/10/15 mg weekly vs placebo over 52 weeks. Primary endpoint: steatohepatitis resolution without worsening of hepatic fibrosis.
The results
MASH resolution: 44% (5 mg), 56% (10 mg), 62% (15 mg) vs 10% on placebo. At least 1-stage hepatic fibrosis improvement without MASH worsening: 55% (15 mg) vs 30% placebo. Simultaneous weight loss: 16.4% at 52 weeks in the 15 mg arm.
Versus Rezdiffra
In March 2024 the FDA approved Rezdiffra (resmetirom) as the first MASH-specific drug, with 25-30% resolution in the MAESTRO-NASH trial. Tirzepatide almost doubles that number and adds significant weight loss — a combo Rezdiffra doesn't deliver.
Implications
Lilly will prepare the regulatory dossier to extend the Mounjaro/Zepbound label to MASH in 2026-2027. If successful, MASH would stop being a Madrigal market (maker of Rezdiffra) and integrate into the dominant GLP-1 ecosystem. Madrigal stock fell -23% the day SYNERGY-NASH was published.