Zalfermin Plus Semaglutide Misses Its Primary Endpoint in Phase 2 Liver Fibrosis Trial

A Phase 2 trial testing Novo Nordisk's investigational drug zalfermin in combination with semaglutide did not significantly improve liver fibrosis compared with placebo, according to results published online in The Lancet Gastroenterology & Hepatology on July 15, 2026. Semaglutide on its own showed a nominally significant benefit over placebo in the same trial, in a patient population that extended into compensated cirrhosis, a stage beyond the drug's currently approved liver-disease indication.

The trial, registered as NCT05016882 and sponsored by Novo Nordisk, enrolled adults with metabolic dysfunction-associated steatohepatitis (MASH) and clinically significant liver fibrosis, defined as stages F2 through F4c, the latter meaning compensated cirrhosis without decompensation. Of 2,420 people screened at 187 sites across 22 countries between August 2021 and March 2025, 698 were randomly assigned to one of seven weekly injection regimens for 52 weeks: zalfermin 7.5 mg, 15 mg, or 30 mg each combined with semaglutide 2.4 mg; zalfermin 30 mg alone; semaglutide 2.4 mg alone; an exploratory arm combining cagrilintide 2.4 mg with semaglutide 2.4 mg; or placebo.

According to a ClinicalTrials.gov description of the study, zalfermin (developmental code NNC0194-0499) is described by the sponsor as a new medicine that works in the liver, intended to act through a different pathway than semaglutide, a GLP-1 receptor agonist that also affects the liver indirectly through weight loss and metabolic effects.

The primary endpoint was improvement in liver fibrosis of at least one stage on the NASH CRN scale, with no worsening of steatohepatitis, at week 52. Zalfermin 30 mg plus semaglutide reached this endpoint in 24% of participants versus 16% on placebo, a difference the study authors described as not statistically significant (estimated difference in responder proportions 7.98 percentage points, 95% CI -3.82 to 19.79; p=0.19). Zalfermin 30 mg alone also did not differ significantly from placebo (22% vs 16%; p=0.39), and the lower-dose combination arms and the exploratory cagrilintide-plus-semaglutide arm were not substantially different from placebo either.

Semaglutide 2.4 mg alone was the one arm to reach a nominally significant difference from placebo on the primary endpoint, at 30% versus 16% (estimated difference 14.05 percentage points, 95% CI 1.88 to 26.23; p=0.024). The study authors wrote that semaglutide might be considered for further clinical assessment as a potential disease-modifying therapy in the F4c, or compensated cirrhosis, population specifically. Semaglutide's only current FDA approval for liver disease, granted in August 2025, covers noncirrhotic MASH with moderate-to-advanced fibrosis (stages F2-F3); it is not approved for MASH with cirrhosis.

Adverse events were reported as mostly non-serious and mild to moderate. Gastrointestinal side effects were the most frequent, occurring in 80% of the zalfermin 30 mg plus semaglutide group, 73% of the semaglutide-alone group, 60% of the zalfermin-alone group, and 51% of the placebo group. Serious adverse events occurred in 7% of the combination group, 10% of the semaglutide-alone group, 13% of the zalfermin-alone group, and 5% of the placebo group. Five deaths were reported across the trial; investigators assessed one, a case of heart failure in a participant taking zalfermin alone, as possibly related to study drug.

The authors described the study as a proof-of-concept, dose-ranging trial rather than a definitive test of any single regimen, and noted the trial was not powered to detect differences between individual dose levels. The trial was funded by Novo Nordisk; several authors reported consulting or research relationships with the company and other pharmaceutical manufacturers, disclosed in the published paper.

The results describe outcomes in this specific trial population and endpoint definition. Zalfermin remains an investigational compound with no approved use in any country. Semaglutide remains approved only for its existing indications, and this trial's findings in patients with compensated cirrhosis do not constitute or imply a label expansion. This report is not medical or dosing guidance.