Adding the fibroblast growth factor 21 (FGF-21) analogue zalfermin to semaglutide did not significantly improve liver fibrosis without worsening metabolic dysfunction-associated steatohepatitis (MASH) after one year in patients with moderate to advanced fibrosis, according to a phase 2 randomized trial. However, semaglutide alone showed promising improvements in liver histology that the investigators said warrant further study.
The study, published in The Lancet Gastroenterology & Hepatology, enrolled patients with biopsy-confirmed MASH and clinically significant fibrosis, including compensated cirrhosis, to test whether combining two drugs with complementary mechanisms could reduce liver fibrosis more effectively than either drug alone.
The international, double-blind, dose-ranging trial was conducted at 187 sites in 22 countries. Investigators screened 2,420 patients and randomly assigned 698 adults with stage F2 through compensated F4 fibrosis to one of seven weekly treatment groups: three doses of zalfermin plus semaglutide, zalfermin alone, semaglutide alone, cagrilintide plus semaglutide, or placebo. The primary analysis compared the highest-dose combination of zalfermin 30 mg plus semaglutide 2.4 mg with placebo after 52 weeks of treatment.
The primary endpoint was at least a one-stage improvement in liver fibrosis without worsening MASH, based on a central review of liver biopsy samples.
At 52 weeks, 30 (30%) of 100 patients receiving semaglutide alone met the primary endpoint vs. 16 (16%) of 100 receiving placebo — a nominally significant difference (estimated difference in responder proportions, 14.05; 95% CI, 1.88-26.23; P = .024). Because the primary comparison did not reach significance, the investigators described this as a nominal finding requiring confirmation.
Subgroup analyses also found no significant benefit for combination therapy. Among patients with stage F2 or F3 fibrosis, 22% of those receiving the combination met the primary endpoint vs. 17% of those receiving placebo. Among patients with compensated cirrhosis, the rates were 27% vs. 15%, respectively. Semaglutide alone also showed higher response rates than placebo in both subgroups, but those findings were considered exploratory rather than confirmatory.
The investigators also looked at resolution of MASH without worsening fibrosis, a key secondary endpoint. Numerically, all active treatment groups performed better than placebo. The endpoint was achieved by 55% of patients receiving combination therapy, compared with 28% receiving placebo. Response rates were similar with semaglutide alone and zalfermin alone, at 54% each. Among patients with compensated cirrhosis, 59% of those receiving combination therapy and 53% receiving semaglutide alone achieved disease resolution without worsening fibrosis, compared with 25% of those receiving placebo. However, because the primary endpoint was not met, these secondary findings are considered exploratory rather than confirmatory.
The trial also showed consistent improvements in several noninvasive measures of liver disease. Compared with placebo, all active treatment groups had greater reductions in liver enzymes, liver stiffness, fibrosis scores, liver fat, and other markers of liver injury and fibrosis. Triglyceride levels decreased and adiponectin levels increased across active treatment groups. Patients receiving semaglutide-containing regimens also lost about 11% of their body weight, substantially more than those receiving placebo or zalfermin alone.
The safety findings were generally consistent with previous studies of these drugs. Most side effects were mild to moderate, with gastrointestinal symptoms occurring most often. Gastrointestinal side effects were reported by 80% of patients receiving combination therapy, 73% receiving semaglutide alone, 60% receiving zalfermin alone, and 51% receiving placebo. Nausea, vomiting, and diarrhea were the most common, with nausea and vomiting occurring more often in patients receiving the combination. Serious adverse events occurred in 7% of patients receiving combination therapy, 13% receiving zalfermin alone, 10% receiving semaglutide alone, and 5% receiving placebo. Five patients died during the study. One death from heart failure in the zalfermin-alone group was considered possibly related to treatment.
For practicing physicians, the findings suggest that combining zalfermin with semaglutide does not provide additional histologic benefit over semaglutide alone during one year of treatment in patients with MASH and advanced fibrosis. At the same time, the results add to growing evidence that semaglutide may have disease-modifying potential, including in patients with compensated cirrhosis, although the authors emphasized that longer studies will be needed to determine whether early improvements in disease activity ultimately translate into greater fibrosis regression.
The investigators acknowledged several limitations. Most patients were White, and women outnumbered men, which may limit how well the findings apply to other populations. The study evaluated only one dose of zalfermin alone, and zalfermin was started while semaglutide was still being increased to its full dose rather than after patients had reached a stable maintenance dose. The authors also noted that the results may not apply to patients diagnosed without a liver biopsy or to those with less advanced liver fibrosis.
Novo Nordisk funded the study. Several authors reported consulting, research funding, speaker fees, employment, stock ownership, patents, or other relationships with Novo Nordisk and multiple pharmaceutical companies.
Expert Insight
GI & Hepatology News invited corresponding author Rohit Loomba, MD, MHSc, chief of the division of gastroenterology and hepatology at the University of California, San Diego, to elaborate on the findings.
The combination of zalfermin and semaglutide did not improve the primary fibrosis endpoint beyond semaglutide alone, despite encouraging preclinical data. What do you think explains the lack of additive benefit, and does this change your view of combination therapy targeting multiple pathways in MASH?
Dr. Loomba: Zalfermin did not have any significant improvements in addition to semaglutide. It is plausible that there’s no synergy or additive benefit of these two combinations. It is also plausible that zalfermin may be a less potent FGF-21 analogue; perhaps a more potent FGF-21 analogue may have greater additive benefits with semaglutide. It is also plausible that increased appetite due to FGF-21 analogues may counter the decreased appetite seen with semaglutide. These are speculations and cannot be determined based upon this study and future studies are needed to determine the biological plausibility behind these findings.
Your study found a nominally significant antifibrotic signal with semaglutide in patients with compensated cirrhosis (F4c), a population with few effective treatment options. How should clinicians interpret these findings today, and do you believe they are strong enough to influence management while we await additional confirmatory studies?
Dr. Loomba: The findings are encouraging, but it is important to distinguish between the two histologic endpoints. In the F4c subgroup, fibrosis improvement without worsening of MASH occurred in 33% of participants receiving semaglutide compared with 15% receiving placebo. This was directionally favorable, but it did not reach nominal statistical significance, with a P value of 0.063. The nominally significant finding was for MASH resolution without worsening of fibrosis, which occurred in 53% of the semaglutide group compared with 25% of the placebo group.
These results should therefore be considered hypothesis-generating rather than practice-changing. The F4c analyses were subgroup analyses, the statistical hierarchy had already been broken after the primary comparison was not met, and the study was not powered to provide definitive evidence of efficacy specifically in compensated cirrhosis. We cannot conclude from this trial alone that semaglutide is an established disease-modifying treatment for MASH cirrhosis.
Nevertheless, the consistency and magnitude of the signal are clinically meaningful and provide a strong rationale for additional prospective studies in this population. For a patient with compensated MASH cirrhosis who also has obesity or type 2 diabetes and an established metabolic indication for semaglutide, these liver findings may provide additional reassurance regarding its potential broader benefit. However, I would not initiate semaglutide solely as an antifibrotic therapy for cirrhosis on the basis of these data.