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Efruxifermin in Compensated Liver Cirrhosis Caused by MASH
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Authors: Mazen Noureddin, M.D., Mary E. Rinella, M.D., Naga P. Chalasani, M.D., Guy W. Neff, M.D., K. Jean Lucas, M.D., Manuel E. Rodriguez, M.D., Madhavi Rudraraju, M.D., +11 , and Kitty Yale, B.S.
Published May 9, 2025
Cirrhosis caused by MASH remains a major unmet medical need for treatment. In this trial, efruxifermin did not have significant benefit regarding a reduction in fibrosis without a worsening of MASH at week 36. However, the trial duration of 96 weeks enabled identification of possible treatment effects that were not apparent at week 36. Longer studies in diverse populations will be necessary to evaluate clinical outcomes, safety, and generalizability of the findings and to assess benefits of longer-term treatment.
A potential reduction in fibrosis is consistent with the results of previous trials of efruxifermin in patients with MASH and stage 2 or 3 fibrosis.25,26 However, fibrosis regression in patients with cirrhosis appeared to occur more slowly than in patients with less advanced (stage 2 or stage 3) fibrosis.8,14-18 This finding is consistent with observations in patients with cirrhosis caused by viral hepatitis, in whom a reduction of fibrosis was observed 5 years after successful antiviral treatment,11,12 and probably reflects the longer duration needed to allow resorption of the extensive fibrotic structures associated with cirrhosis after removal of the underlying cause.10
Cirrhosis caused by MASH remains a major unmet medical need for treatment. In this trial, efruxifermin did not have significant benefit regarding a reduction in fibrosis without a worsening of MASH at week 36. However, the trial duration of 96 weeks enabled identification of possible treatment effects that were not apparent at week 36. Longer studies in diverse populations will be necessary to evaluate clinical outcomes, safety, and generalizability of the findings and to assess benefits of longer-term treatment.
Abstract
Background
In phase 2 trials involving patients with stage 2 or 3 fibrosis caused by metabolic dysfunction-associated steatohepatitis (MASH), efruxifermin, a bivalent fibroblast growth factor 21 (FGF21) analogue, reduced fibrosis and resolved MASH. Data are needed on the efficacy and safety of efruxifermin in patients with compensated cirrhosis (stage 4 fibrosis) caused by MASH.
Methods
In this phase 2b, randomized, placebo-controlled, double-blind trial, we assigned patients with MASH who had biopsy-confirmed compensated cirrhosis (stage 4 fibrosis) to receive subcutaneous efruxifermin (at a dose of 28 mg or 50 mg once daily) or placebo. The primary outcome was a reduction of at least one stage of fibrosis without worsening of MASH at week 36. Secondary outcomes included the same criterion at week 96.
Results
A total of 181 patients underwent randomization and received at least one dose of efruxifermin or placebo. Of these patients, liver biopsy was performed in 154 patients at 36 weeks and in 134 patients at 96 weeks.
At 36 weeks, a reduction in fibrosis without worsening of MASH occurred in 8 of 61 patients (13%) in the placebo group, in 10 of 57 patients (18%) in the 28-mg efruxifermin group (difference from placebo after adjustment for stratification factors, 3 percentage points; 95% confidence interval [CI], -11 to 17; P=0.62), and in 12 of 63 patients (19%) in the 50-mg efruxifermin group (difference from placebo, 4 percentage points; 95% CI, -10 to 18; P=0.52).
At week 96, a reduction in fibrosis without worsening of MASH occurred in 7 of 61 patients (11%) in the placebo group, in 12 of 57 patients (21%) in the 28-mg efruxifermin group (difference from placebo, 10 percentage points; 95% CI, -4 to 24), and in 18 of 63 patients (29%) in the 50-mg efruxifermin group (difference from placebo, 16 percentage points; 95% CI, 2 to 30). Gastrointestinal adverse events were more common with efruxifermin; most events were mild or moderate.
Conclusions
In patients with compensated cirrhosis caused by MASH, efruxifermin did not significantly reduce fibrosis at 36 weeks. (Funded by Akero Therapeutics; SYMMETRY
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