AI-Based Digital Pathology Confirms Histological Fibrosis Improvements with Eruxifermin

Findings from a post hoc analysis of the phase 2b SYMMETRY trial of efruxifermin in patients with metabolic dysfunction-associated steatohepatitis (MASH) and compensated cirrhosis are shedding light on the treatment’s impact on overall fibrosis burden and septa area.1

The data were presented during a late-breaking poster session at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025 by Mary Rinella, MD, a professor of medicine and director of Clinical Trials and the Metabolic and Fatty Liver Program at the University of Chicago, and leverage AI-based digital pathology assessment to confirm previously demonstrated histological fibrosis improvements with efruxifermin at week 96.1

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.2

In May 2025, data from the phase 2b, randomized, placebo-controlled, double-blind SYMMETRY trial were published in the New England Journal of Medicine and showed that although the trial missed its primary endpoint for fibrosis reduction without worsening of MASH, the 50 mg dose of efruxifermin was hypothesized to 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.2

Unstained liver biopsies were available at baseline, week 36, and week 96 for 130 SYMMETRY participants (placebo, n = 44; efruxifermin 28 mg, n = 40; efruxifermin 50 mg, n = 46). Biopsies were imaged using second harmonic generation/two-photon excitation fluorescence microscopy and analyzed by qFibrosis for continuous and categorical fibrosis changes and qSepta for changes in septa morphology, specifically septa area.1

Results presented at AASLD showed a significantly greater proportion of participants in the efruxifermin 50 mg group had ≥1-stage fibrosis improvement by qFibrosis vs placebo (46% for efruxifermin 50 mg vs 25% for placebo; P <.05), consistent with NASH CRN fibrosis stage. Investigators noted increased septa area at baseline was associated with higher CSPH risk category based on Baveno VII criteria.1

Efruxifermin resulted in a greater reduction from baseline to week 96 in median septa area vs placebo (-35% and -36% for efruxifermin 28 mg and 50 mg vs -10% for placebo; both P <.05). Additionally, investigators noted a greater proportion of participants in the efruxifermin groups than in placebo had decreased septa area, while more participants in the placebo group than the efruxifermin groups had increased septa area at week 96.1

In NASH CRN responders, septa area decreased to a similar extent in all treatment groups (median change -34% to -42%). Investigators pointed out septa area was also reduced in NASH CRN non-responders treated with efruxifermin (-24% to -25%), but not with placebo (14%).1

“Efruxifermin reduced septa area, which was associated with disease severity, independent of categorical histological fibrosis response,” investigators concluded.1 “Digital analysis of septa area, which may detect more subtle changes in fibrosis, demonstrated a broad antifibrotic effect of efruxifermin in participants with MASH and F4c that may yield clinically meaningful improvements in liver outcomes.”

References

1. Rinella M, Choudhury Y, Gan G, et al. Efruxifermin reduced fibrosis and septa area by quantitative digital pathology in participants with compensated cirrhosis due to MASH: Results from the 96-week, placebo-controlled, phase 2b SYMMETRY trial. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

2. Brooks A. Efruxifermin Shows Potential for Fibrosis Reduction in Phase 2b MASH Cirrhosis Trial. HCPLive. May 9, 2025. Accessed November 8, 2025. https://www.hcplive.com/view/exfruxifermin-misses-primary-endpoint-phase-2b-compensated-mash-cirrhosis-trial