Survodutide Improved Liver Measures in MASH Even With Modest Weight Loss, Phase 2 Analysis Finds

Key Takeaways

• A post hoc analysis of a Phase 2 trial of survodutide in people with MASH and moderate to advanced fibrosis (F2 to F3) found improvements in liver endpoints at Week 48, including in participants who lost less than 5% of body weight.
• Liver improvements generally grew with the amount of weight lost, but the pattern was stronger for steatohepatitis-related measures than for fibrosis-related ones. The authors suggest the fibrosis findings may reflect a direct effect on the liver, which the analysis can’t confirm.
• The analysis included 170 participants, and the abstract was presented at The Liver Meeting, hosted by the American Association for the Study of Liver Diseases (AASLD).

Researchers led by Elisabetta Bugianesi of the University of Turin, with senior author Arun Sanyal of Virginia Commonwealth University, presented an analysis of how weight loss relates to liver outcomes with survodutide, an investigational once-weekly injection that activates both the glucagon and GLP-1 receptors. Survodutide is being studied in Phase 3 trials for MASH and for obesity. In the Phase 2 trial in people with biopsy-confirmed MASH and F1 to F3 fibrosis, it improved both steatohepatitis and fibrosis. The new analysis asks whether those liver benefits depend on how much weight a person loses.

The Phase 2 trial randomized 295 adults aged 18 to 80 to survodutide at 2.4, 4.8, or 6.0 mg or to placebo for 48 weeks. This analysis included 170 participants who had F2 or F3 fibrosis at baseline and liver biopsies at both baseline and the end of the trial. Of these, 54 received placebo and 116 received survodutide. Participants were grouped by weight loss at Week 48: less than 5%, 5% to less than 10%, 10% to less than 15%, and 15% or more. The liver endpoints included MASH resolution without worsening of fibrosis, at least one stage of fibrosis improvement without worsening of MASH, changes in blood markers of fibrosis (the enhanced liver fibrosis score and PRO-C3), liver fat measured by MRI, liver stiffness, and ALT and AST levels.

Among placebo participants, 85.2% lost less than 5% of their weight. Among survodutide participants, 16.4% (19) lost less than 5%, 29.3% (34) lost 5% to less than 10%, 22.4% (26) lost 10% to less than 15%, and 31.9% (37) lost 15% or more. Across those four groups, MASH resolution without worsening of fibrosis occurred in 36.8%, 55.9%, 69.2%, and 78.4%. Fibrosis improvement without worsening of MASH occurred in 47.4%, 41.2%, 53.8%, and 64.9%. A reduction in liver fat of more than 30% occurred in 31.6%, 72.7%, 100%, and 100%, and ALT fell by an average of 22.5%, 50.5%, 59.4%, and 42.0%.

The authors conclude that liver endpoints improved with survodutide at Week 48 even in the group with less than 5% weight loss, and that the improvements tended to increase with greater weight loss. They note that the gradient was steeper for steatohepatitis-related endpoints than for fibrosis-related ones. In their interpretation, the steatohepatitis improvements were largely associated with weight loss, consistent with the metabolic drivers of the disease, while the fibrosis improvements could reflect a direct effect of survodutide on the liver.