Efruxifermin Shows Potential for Fibrosis Reduction in Phase 2b MASH Cirrhosis Trial

Efruxifermin, a bivalent fibroblast growth factor 21 (FGF21) analogue being developed for the treatment of metabolic dysfunction–associated steatohepatitis (MASH), failed to significantly reduce fibrosis without worsening of MASH at 36 weeks in a phase 2b trial.1

Data from the SYMMETRY trial were published in the New England Journal of Medicine and show that although the trial missed its primary endpoint for fibrosis reduction without worsening of MASH, the 50 mg dose of efruxifermin may have possible benefit on fibrosis reduction at 96 weeks. Notably, efruxifermin also appeared to be associated with improvements in MASH-related histologic findings, noninvasive markers of liver injury and fibrosis, and markers of glucose and lipid metabolism.1

“Trials of therapies that target metabolic dysregulation, inflammation, and fibrosis in patients with MASH cirrhosis thus far have not resulted in a reduction in fibrosis,” Mazen Noureddin, MD, MHSc, a professor of medicine and transplant hepatologist at Houston Methodist Hospital, and principal investigator for the SYMMETRY study, and colleagues wrote.1

An FGF21 analogue in development for the treatment of advanced fibrosis and cirrhosis caused by MASH, efruxifermin features a bivalent configuration consisting of 2 modified human FGF21 polypeptides fused to each fragment crystallizable domain of homodimeric human immunoglobulin G1, which extends both pharmacokinetic and pharmacodynamic half-lives.1

SYMMETRY was a phase 2b, randomized, double-blind, placebo-controlled trial conducted at 45 sites in the United States, Puerto Rico, and Mexico. It enrolled patients 18-75 years of age with liver histologic features consistent with MASH and compensated cirrhosis, defined as stage 4 fibrosis with a Child–Pugh score of 5 or 6. Patients also had type 2 diabetes or 2 components of metabolic syndrome.1

Participants were randomly assigned in a 1:1:1 ratio to receive 28 mg or 50 mg of efruxifermin or matching placebo, administered subcutaneously once weekly. Randomization was stratified according to whether they had type 2 diabetes and their MASH diagnosis, biopsy-confirmed MASH or cryptogenic cirrhosis attributed to MASH.1

The primary outcome was a reduction of ≥ 1 stage of fibrosis without worsening of MASH at week 36. Selected secondary endpoints were a reduction in fibrosis without a worsening of MASH at week 96 and MASH resolution at weeks 36 and 96.1

A total of 181 patients underwent randomization and received ≥ 1 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.1

Preliminary topline week 96 results from SYMMETRY announced earlier in 2025 showed 39% of patients with baseline and week 96 biopsies who were treated with efruxifermin 50 mg experienced reversal of cirrhosis with no worsening of MASH, compared to 15% for placebo (P = .009). In the intent-to-treat population with all missing week 96 biopsies treated as failures, 29% of patients in the 50 mg efruxifermin group experienced reversal of cirrhosis with no worsening of MASH, compared to approximately 12% in the placebo group (P = .031).2

In the latest data published in NEJM, at 36 weeks, a reduction in fibrosis without worsening of MASH occurred in 13% of the placebo group and 18% of the 28 mg efruxifermin group (difference from placebo after adjustment for stratification factors, 3 percentage points; 95% confidence interval [CI], –11 to 17; P = .62), and in 19% of the 50 mg efruxifermin group (difference from placebo, 4 percentage points; 95% CI, –10 to 18; P = .52).1

At week 96, a reduction in fibrosis without worsening of MASH occurred in 11% of the placebo group, in 21% of the 28 mg efruxifermin group (difference from placebo, 10 percentage points; 95% CI, –4 to 24), and in 29% of the 50-mg efruxifermin group (difference from placebo, 16 percentage points; 95% CI, 2 to 30).1

In an analysis involving the 134 patients for whom liver-biopsy data were available at week 96 without imputation of missing data, a reduction in fibrosis without MASH worsening was observed in 29% of the 28 mg efruxifermin group, 39% of the 50 mg efruxifermin, and 15% of the placebo group. In an exploratory analysis involving patients who had a primary-outcome response at weeks 36 and 96, investigators noted most of those in the efruxifermin groups who had a response at week 36 sustained their response at week 96. Additionally, some patients without a response at week 36 had a response by week 96, particularly in the 50-mg dose group.1

Comparison of the proportion of patients with a fibrosis reduction at week 36 and week 96 in the pre-specified analysis of patients with baseline and week 96 biopsies, showed more than a doubling of placebo-adjusted treatment effect for the EFX 50mg group, from 10% to 24%, highlighting the importance of longer treatment with efruxifermin for patients with compensated cirrhosis.3

Efruxifermin was also associated with improvements in noninvasive markers of fibrosis, including ELF test scores, liver-stiffness measurements, and Pro-C3 levels, as well as levels of lipids — triglycerides, non–high-density-lipoprotein (HDL) cholesterol, and HDL cholesterol — and markers of insulin sensitivity.1

Adverse events were reported by 99% of the patients who received efruxifermin and 97% of those who received placebo. Adverse events that were more common with efruxifermin than with placebo were primarily gastrointestinal as well as administration-site reactions, and most adverse events were mild or moderate in severity.1

“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,” investigators concluded.1 “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.”

References

1. Noureddin M, Rinella ME, Chalasani NP, et al. Efruxifermin in Compensated Liver Cirrhosis Caused by MASH. N Engl J Med. doi:10.1056/NEJMoa2502242

2. Brooks A. Efruxifermin Reverses MASH Compensated Cirrhosis in Phase 2b SYMMETRY Study. HCPLive. January 27, 2025. Accessed May 9, 2025. https://www.hcplive.com/view/efruxifermin-reverses-mash-compensated-cirrhosis-phase-2b-symmetry-study

3. Akero Therapeutics. Akero Therapeutics Presents Week 96 Results from Phase 2b SYMMETRY Clinical Trial of Efruxifermin in Patients with Compensated Cirrhosis Caused by MASH Showing Fibrosis Improvement without Worsening of MASH at the EASL Congress 2025. May 9, 2025. Accessed May 9, 2025. https://ir.akerotx.com/news-releases/news-release-details/akero-therapeutics-presents-week-96-results-phase-2b-symmetry