Efficacy and safety of zalfermin co-administered with semaglutide in participants with fibrosis and cirrhosis due to metabolic dysfunction-associated steatohepatitis: a phase 2, dose-ranging, double-blind, randomised controlled trial

Adding zalfermin 30 mg to semaglutide did not significantly increase the proportion of people with MASH and clinically significant fibrosis whose liver fibrosis improved without MASH worsening at week 52, compared with placebo. Semaglutide 2·4 mg alone showed a nominally significant effect versus placebo. Gastrointestinal adverse events were common, especially in the combination group.

Randomized controlled trial — Phase 2, double-blind, randomised controlled trial. Population: Adults aged 18+ with histologically confirmed MASH and clinically significant fibrosis (F2-F4c), including compensated cirrhosis, at 187 sites in 22 countries. Sample size: 698 participants. Follow-up: 52 weeks. Interventions: zalfermin 7·5 mg plus semaglutide 2·4 mg; zalfermin 15 mg plus semaglutide 2·4 mg; zalfermin 30 mg plus semaglutide 2·4 mg; zalfermin 30 mg; semaglutide 2·4 mg; cagrilintide 2·4 mg plus semaglutide 2·4 mg.

At week 52, 24 (24%) of 99 participants in the zalfermin 30 mg plus semaglutide 2·4 mg group achieved the primary endpoint versus 16 (16%) of 100 in the placebo group (EDP 7·98, 95% CI -3·82 to 19·79; p=0·19). In the semaglutide 2·4 mg group, 30 (30%) of 100 participants achieved the endpoint (EDP 14·05, 95% CI 1·88 to 26·23; p=0·024), whereas zalfermin 30 mg alone did not differ from placebo (22 [22%] of 101; p=0·39). Gastrointestinal adverse events were the most frequent, reported in 79 (80%) of 99 in the zalfermin 30 mg plus semaglutide group, 61 (60%) of 101 in the zalfermin 30 mg group, and 51 (51%) of 100 in the placebo group. Serious adverse events occurred in seven (7%), 13 (13%), and five (5%) participants in those groups, respectively; five deaths occurred overall, one possibly related to study drug.

This paper is relevant to researchers evaluating semaglutide and cagrilintide combinations in MASH fibrosis. It suggests semaglutide might warrant further study as a potential disease-modifying therapy in the F4c population, but it does not establish efficacy for adding zalfermin or for the cagrilintide plus semaglutide combination. The findings are hypothesis-generating rather than confirmatory.

Key findings

• Zalfermin 30 mg plus semaglutide 2·4 mg did not significantly improve the primary endpoint versus placebo (24% vs 16%; EDP 7·98, 95% CI -3·82 to 19·79; p=0·19).
• Semaglutide 2·4 mg alone achieved the primary endpoint in 30% versus 16% for placebo (EDP 14·05, 95% CI 1·88 to 26·23; p=0·024).
• Zalfermin 30 mg alone did not differ from placebo (22% vs 16%; EDP 4·99, 95% CI -6·51 to 16·49; p=0·39).
• Gastrointestinal adverse events occurred in 80% of the zalfermin 30 mg plus semaglutide group vs 51% with placebo.
• Serious adverse events were reported in 7% of the zalfermin 30 mg plus semaglutide group vs 5% with placebo; five deaths occurred, one possibly related to study drug.
• The trial randomised 698 participants across seven arms.

Limitations

• Phase 2 proof-of-concept trial, not confirmatory; the primary endpoint was not met for the zalfermin plus semaglutide combination.
• Nominal significance for semaglutide versus placebo was not adjusted for multiple comparisons.
• Follow-up was limited to 52 weeks, so no longer-term durability data are reported.
• The abstract reports no prespecified limitations.

The record

• Journal: The lancet. Gastroenterology & hepatology 11(9): 797-811
• Published: 2026-07-15
• PMID: 42456707 — DOI: 10.1016/s2468-1253(26)00123-8
• MeSH terms: Humans, Liver Cirrhosis, Peptide Hormones, Treatment Outcome, Drug Therapy, Combination, Double-Blind Method, Dose-Response Relationship, Drug, Adult, Aged, Middle Aged, Female, Male, Glucagon-Like Peptides, Non-alcoholic Fatty Liver Disease, Proof of Concept Study, Semaglutide
• Author countries: Australia, Belgium, Denmark, France, USA

Peptide profiles: Semaglutide, Cagrilintide.

All indexed evidence: Semaglutide trials & papers, Cagrilintide trials & papers.

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