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.

BACKGROUND: This phase 2 study evaluated once-weekly zalfermin and semaglutide for efficacy and safety in patients with metabolic dysfunction-associated steatohepatitis and clinically significant fibrosis, including patients with compensated cirrhosis (F4c). METHODS: This proof-of-concept, phase 2, dose-ranging, double-blind, randomised controlled trial was done in 187 clinical trial sites in Australia, Belgium, Bulgaria, Canada, Czech Republic, Denmark, France, Germany, Greece, India, Italy, Japan, Malaysia, Poland, Portugal, Russia, Singapore, South Korea, Spain, Taiwan, Türkiye, and the USA. Eligible participants were aged 18 years or older with histological confirmation of steatohepatitis on liver biopsy (baseline or historical within 180 days). Eligible participants had clinically significant fibrosis (stage F2-F4c) in the absence of decompensation. Eligible participants were randomly assigned to receive subcutaneous zalfermin 7·5 mg plus subcutaneous 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, or placebo only once a week for 52 weeks. The primary endpoint was improvement in liver fibrosis on the NASH CRN fibrosis scale of at least one stage and no worsening of metabolic dysfunction-associated steatohepatitis at week 52. Efficacy was assessed in the full analysis set (all randomly assigned participants) and safety was analysed in all participants who were randomly assigned and received at least one dose of trial product or placebo. The trial is registered with ClinicalTrials.gov, NCT05016882, and is completed. FINDINGS: Between Aug 31, 2021, and March 14, 2025, 2420 people were screened for inclusion. 178 withdrew before random assignment and 1544 were disqualified. 698 participants were enrolled and randomly assigned to zalfermin 7·5 mg plus semaglutide 2·4 mg (n=99), zalfermin 15 mg plus semaglutide 2·4 mg (n=100), zalfermin 30 mg plus semaglutide 2·4 mg (n=99), zalfermin 30 mg (n=101), semaglutide 2·4 mg (n=100), cagrilintide 2·4 mg plus semaglutide 2·4 mg (n=99), or placebo (n=100). 441 (63%) of 698 participants were female and 257 (37%) were male. 484 (69%) of 698 participants were White and 172 (25%) were Asian. At week 52, the proportion of participants who had an improvement in liver fibrosis and no worsening of metabolic dysfunction-associated steatohepatitis with zalfermin 30 mg plus semaglutide 2·4 mg was not significantly greater than with placebo (24 [24%] of 99 participants in the combination group vs 16 [16%] of 100 participants in the placebo group; estimated difference in responder proportions [EDP] 7·98, 95% CI -3·82 to 19·79; p=0·19). A nominally significantly greater proportion of participants in the semaglutide 2·4 mg group achieved this endpoint than in the placebo group (30 [30%] of 100 participants in the semaglutide group; EDP 14·05, 95% CI 1·88 to 26·23; p=0·024), but not in the zalfermin 30 mg group versus placebo (22 [22%] of 101 participants in the zalfermin group; 4·99, -6·51 to 16·49; p=0·39). Similarly, the proportions of participants achieving this endpoint in the two groups that combined lower doses of zalfermin with semaglutide 2·4 mg and in the exploratory group combining cagrilintide 2·4 mg with semaglutide 2·4 mg were not substantially different than with placebo. Adverse events were mostly non-serious and mild to moderate in severity. The most frequent adverse events were gastrointestinal, reported in 79 (80%) of 99 participants in the zalfermin 30 mg plus semaglutide 2·4 mg group, 61 (60%) of 101 participants in the zalfermin 30 mg group, 73 (73%) of 100 participants in the semaglutide 2·4 mg group, and 51 (51%) of 100 participants in the placebo group. Serious adverse events were reported in seven (7%) participants in the zalfermin 30 mg plus semaglutide 2·4 mg group, 13 (13%) participants in the zalfermin 30 mg group, ten (10%) participants in the semaglutide 2·4 mg group, and five (5%) participants in the placebo group. Five deaths were reported in the trial, one of which was assessed as possibly related to study drug (heart failure, zalfermin 30 mg group). INTERPRETATION: In participants with metabolic dysfunction-associated steatohepatitis and clinically significant fibrosis, the combination of zalfermin 30 mg plus semaglutide 2·4 mg did not significantly increase the proportion of participants who had an improvement in liver fibrosis and no worsening of metabolic dysfunction-associated steatohepatitis compared with placebo by week 52. However, a nominally significant treatment effect was observed for semaglutide 2·4 mg versus placebo. Semaglutide might be considered for further clinical assessment as a potential disease-modifying therapy in the F4c population. FUNDING: Novo Nordisk.