DAY 2: Efruxifermin Proves Superior to Placebo in Reversing Metabolic Dysfunction-Associated Steatohepatitis

A meta-analysis presented at the 2025 Annual Scientific Meeting of the American College of Gastroenterology in Phoenix, Arizona suggests that efruxifermin may emerge as a promising targeted therapy with the potential to improve hepatic fibrosis in patients with metabolic dysfunction-associated steatohepatitis (MASH).

MASH is a progressive liver disease characterized by steatosis, inflammation, and fibrosis. Despite two approved therapies designed specifically for MASH with moderate-to-severe fibrosis, the management of this disease continues to pose challenges in clinical practice, due to the many metabolic drivers implicated in its pathophysiology.

Efruxifermin is an investigational drug that mimics the biological activity of the natural hormone fibroblast growth factor 21 (FGF21), which regulates metabolic pathways and liver processes. This therapy is currently being investigated in phase 3 clinical trials to evaluate its safety and efficacy for patients with MASH. In the Phase IIb SYMMETRY clinical trial, treatment with efruxifermin did not result in a significant reduction in fibrosis without worsening of MASH at week 36 as compared with placebo, however, the results suggested potential benefit for fibrosis reduction across a 96-week treatment regimen with the 50-mg dose of efruxifermin. The therapy also appeared to be associated with improvements in MASH-related histologic outcomes, noninvasive markers of liver injury and fibrosis, and markers of glucose and lipid metabolism (Noureddin M et al. N Engl J Med 2025;392:2413-24).

A systematic review and meta-analysis of randomized controlled trials was conducted to evaluate the efficacy of efruxifermin across key histologic outcomes in patients with MASH. The investigators searched PubMed, Scopus, Web of Science, and Cochrane CENTRAL through May 28, 2025 to identify studies that compared efruxifermin with placebo in treating adults with MASH. The analysis included four randomized controlled trials with a total of 419 patients. Of those, 284 patients received efruxifermin and 135 received placebo.

The results showed that efruxifermin was associated with significant improvements in fibrosis and MASH resolution compared to placebo. Efruxifermin led to MASH resolution without worsening of the disease in approximately 45% of treated patients, whereas only 13.5% of the participants assigned to placebo achieved similar outcomes. Significant improvements in moderate-to-advanced fibrosis (≥1-stage fibrosis) were also documented in patients treated with efruxifermin (nearly 40%) compared to those who received placebo (17%), without worsening of the disease. Participants who received efruxifermin were more likely to achieve both resolution of MASH and improvement in fibrosis (28.8% vs 4%) than those assigned to placebo.

“This meta-analysis supports the therapeutic potential of efruxifermin for MASH, showing significant improvements in fibrosis, histologic resolution, liver biomarkers, and metabolic profiles compared with placebo,” lead author Islam Rajab, MD, an internal medicine specialist at St. Joseph's University Medical Center in Paterson, New Jersey, said during a poster presentation. “While safety concerns exist, they appear manageable.”

In the meta-analysis, efruxifermin was associated with a higher risk of drug-related adverse events and higher rates of discontinuation due to adverse events compared with placebo. Rajab noted that, while no significant differences were observed in serious adverse events or mortality rates, the safety of long-term efruxifermin therapy has yet to be tested in randomized controlled trials, as well as in real-world clinical settings.