Zalfermin co-administered with semaglutide evaluated for MASH fibrosis and cirrhosis in large Phase 2 trial

Metabolic dysfunction-associated steatohepatitis (MASH), a severe form of MASLD, is characterized by liver inflammation and progressive fibrosis, potentially leading to cirrhosis and liver failure. Current treatments are limited, with a significant unmet need for therapies that can reverse fibrosis. Semaglutide, a GLP-1 receptor agonist, has shown promise in MASH by improving metabolic parameters, but its direct impact on fibrosis reversal is inconsistent. This study investigates the combination of zalfermin (a novel agent) with semaglutide to target multiple pathways involved in MASH progression and fibrosis.

This was a multi-center, double-blind, randomized, placebo-controlled Phase 2 trial across 187 sites, enrolling 698 participants with histologically confirmed MASH and clinically significant fibrosis (F2-F4c), including compensated cirrhosis. Participants were randomized to receive once-weekly subcutaneous injections for 52 weeks: zalfermin 7.5 mg + semaglutide 2.4 mg, zalfermin 15 mg + semaglutide 2.4 mg, zalfermin 30 mg + semaglutide 2.4 mg, zalfermin 30 mg alone, semaglutide 2.4 mg alone, cagrilintide 2.4 mg + semaglutide 2.4 mg, or placebo. The primary endpoint was improvement in liver fibrosis by at least one stage on the NASH CRN fibrosis scale without worsening of MASH at week 52.

Between August 31, 2021, and March 14, 2025, a total of 2420 individuals were screened for inclusion in the study. Of these, 178 participants withdrew before randomization, and 1544 were disqualified based on eligibility criteria. Ultimately, 698 participants were successfully enrolled and randomized into the various treatment arms. Specific group allocations were: zalfermin 7.5 mg + semaglutide 2.4 mg (n=99), zalfermin 15 mg + semaglutide 2.4 mg (n=100), zalfermin 30 mg + semaglutide 2.4 mg (n=100), zalfermin 30 mg alone (n=100), semaglutide 2.4 mg alone (n=100), cagrilintide 2.4 mg + semaglutide 2.4 mg (n=100), and placebo (n=99). The abstract provided does not include the efficacy or safety outcomes for the primary or secondary endpoints, as the 'FINDINGS' section was truncated before these results were detailed. Therefore, specific data on fibrosis improvement or MASH resolution from this trial are not available in the provided text.