This was a study in people, not animals or cells. Researchers ran a phase 2, double-blind, randomised controlled trial across 187 clinical sites in more than 20 countries, published in The Lancet Gastroenterology & Hepatology and funded by Novo Nordisk.
The disease in question is metabolic dysfunction-associated steatohepatitis, often shortened to MASH. It involves fat, inflammation, and scarring in the liver. Everyone enrolled had biopsy-confirmed steatohepatitis and clinically significant fibrosis, staged F2 through F4c, meaning some participants had compensated cirrhosis without signs of liver failure.
What the study tested
Between August 2021 and March 2025, investigators screened 2,420 people and enrolled 698. Participants were randomly assigned to one of seven once-weekly groups for 52 weeks: three combinations of zalfermin with semaglutide, zalfermin alone, semaglutide alone, a combination of cagrilintide with semaglutide, or placebo. All products were given by subcutaneous injection.
The main question was whether treatment improved liver scarring. Specifically, the primary endpoint was improvement of at least one fibrosis stage on the NASH CRN scale, with no worsening of steatohepatitis, measured at week 52.
What the researchers reported
The headline comparison, zalfermin 30 mg plus semaglutide versus placebo, did not reach statistical significance. In that combination group, 24 of 99 participants (24%) met the endpoint, compared with 16 of 100 (16%) on placebo. The estimated difference was about 8 percentage points, but the confidence interval crossed zero and the p value was 0.19.
The lower-dose zalfermin combinations and the cagrilintide-plus-semaglutide group also did not differ substantially from placebo. Zalfermin alone did not reach significance either, with 22 of 101 participants (22%) responding.
Semaglutide alone stood out. In that group, 30 of 100 participants (30%) met the endpoint, a nominally significant difference over placebo. The authors write that semaglutide might be considered for further clinical assessment as a potential disease-modifying therapy in the compensated cirrhosis population.
Safety as reported
Adverse events were mostly non-serious and mild to moderate. Gastrointestinal complaints were most common, reported by 80% in the zalfermin-plus-semaglutide 30 mg group, 60% with zalfermin alone, 73% with semaglutide alone, and 51% on placebo. Serious adverse events occurred in 7% of the combination 30 mg group, 13% with zalfermin alone, 10% with semaglutide alone, and 5% on placebo.
Five deaths were reported during the trial. One, a case of heart failure in the zalfermin 30 mg group, was assessed as possibly related to study drug.
What this does and does not mean
For someone weighing options, the practical takeaway is narrow. This trial did not show that adding zalfermin to semaglutide improved liver fibrosis more than placebo over one year. The semaglutide-alone result was described as nominally significant, which is a signal worth further study rather than proof of benefit. The authors framed semaglutide as a candidate for additional clinical assessment, not a settled treatment.
One honest limitation
This was a proof-of-concept phase 2 trial with a few hundred people per group, powered to explore signals rather than deliver a final verdict. The endpoint depended on liver biopsy, which is one snapshot of a complex organ, and the study population was predominantly White and Asian and mostly female. Findings from this single 52-week trial would need confirmation in larger studies before firm conclusions could be drawn.