Zalfermin plus semaglutide 2.4 mg failed to significantly improve liver fibrosis in a phase 2 MASH trial, while semaglutide showed a signal in compensated cirrhosis.
Written By: Saniya Katakdhond, PharmD
Reviewed By: Pharmacally Editorial Team
Novo Nordisk’s phase 2 trial of zalfermin combined with semaglutide 2.4 mg did not show a statistically significant improvement in liver fibrosis without worsening metabolic dysfunction-associated steatohepatitis (MASH) compared with placebo, tempering expectations for dual FGF21 and GLP-1 receptor targeting in advanced liver disease. Published in The Lancet Gastroenterology & Hepatology, the study was a dose-ranging, double-blind, randomised controlled trial conducted across 187 clinical trial sites in 23 countries.
Combination misses primary endpoint
The double-blind, randomised trial (NCT05016882) enrolled 698 adults with biopsy-confirmed MASH and clinically significant F2-F4c fibrosis, including compensated cirrhosis. Participants received once weekly zalfermin at 7.5, 15, or 30 mg with semaglutide 2.4 mg, zalfermin 30 mg alone, semaglutide 2.4 mg alone, cagrilintide plus semaglutide, or placebo for 52 weeks.
The primary endpoint required at least one-stage improvement in fibrosis with no worsening of MASH. In the 30 mg zalfermin plus semaglutide group, 24% of participants met the endpoint versus 16% with placebo. The estimated treatment difference was 7.98 percentage points, but the result was not statistically significant (95% CI, -3.82 to 19.79; p=0.19).
Semaglutide monotherapy produced a nominally significant result, with 30% of participants meeting the endpoint versus 16% with placebo (estimated difference, 14.05 percentage points; p=0.024). However, the trial’s predefined statistical hierarchy was broken after the combination failed its primary comparison, so subsequent findings were not considered confirmatory.
Why the dual approach was tested
Zalfermin is a long-acting FGF21 receptor agonist. FGF21 regulates glucose and lipid metabolism, insulin sensitivity, energy expenditure, and food intake through receptors expressed in the liver, adipose tissue, and central nervous system. Structural modification gives zalfermin an approximately 120-hour plasma half-life, supporting once-weekly administration.
The combination was supported by preclinical evidence suggesting complementary effects of FGF21 and GLP-1 pathways. In this trial, however, the clinical results did not reproduce the expected additive antifibrotic effect. The investigators noted that differences in semaglutide exposure within the combination arm could also have influenced interpretation.
Cirrhosis subgroup provides a signal for semaglutide
A notable finding emerged among the 301 participants with compensated cirrhosis (F4c). MASH resolution without worsening of fibrosis occurred in 53% of participants receiving semaglutide alone and 25% receiving placebo. The estimated treatment difference was 28.46 percentage points (95% CI, 7.42-49.50; p=0.0080).
The investigators cautioned that this was a secondary subgroup analysis performed after the statistical hierarchy had been broken. They therefore considered the finding hypothesis-generating rather than confirmatory, while recommending further assessment of semaglutide as a potential disease-modifying treatment in compensated MASH cirrhosis.
Safety remains a key consideration
Adverse events were predominantly mild to moderate, with gastrointestinal events most common. They occurred in 80% of participants receiving zalfermin 30 mg plus semaglutide, compared with 73% with semaglutide alone and 51% with placebo. Nausea and vomiting showed an additive effect with the combination. Adverse events led to dose reduction in 18% of participants and premature treatment discontinuation in 13% of those receiving zalfermin 30 mg plus semaglutide.
Serious adverse events occurred in 7% of the combination group, 13% of the zalfermin 30 mg group, 10% of the semaglutide group, and 5% of placebo. Five deaths were reported during the trial: two in the zalfermin 15 mg plus semaglutide group, one in the zalfermin 7.5 mg plus semaglutide group, one in the zalfermin 30 mg plus semaglutide group, and one in the zalfermin 30 mg group. The death from heart failure in the zalfermin 30 mg group was considered possibly related to study treatment, while the other four were assessed as unrelated.
Path Forward for MASH drug development
The results do not eliminate the broader potential of FGF21-based therapy. Other FGF21 analogues have produced fibrosis responses in phase 2 studies, suggesting that molecular structure and receptor-binding characteristics may influence clinical activity. The investigators also highlighted the potential value of longer treatment periods and different combination strategies.
For zalfermin specifically, the phase 2 findings provide no evidence that adding it to semaglutide produces an incremental histological benefit after 52 weeks. For semaglutide, the F4c signal provides a rationale for further prospective evaluation, but larger and appropriately powered studies will be needed to establish whether the observed effect translates into durable fibrosis improvement and clinical benefit.
Reference
About the Writer
Saniya Sanjay Katakdhond (Linkedin) is a Doctor of Pharmacy professional with hands-on experience in patient case review, clinical documentation, medical record analysis, and patient care.
Her hospital experience has strengthened her understanding of clinical conditions, treatment approaches, and multidisciplinary healthcare practices.
With ICH-GCP certification and a research-oriented approach, she brings clinical insight and attention to detail to healthcare content development.
As a healthcare writer, Saniya focuses on translating clinical knowledge and patient-care experience into clear, accurate, and evidence-informed medical content.