Efruxifermin Shows Durable Antifibrotic Benefit at 96 Weeks in MASH

A once-weekly investigational fibroblast growth factor 21 (FGF21) analogue, efruxifermin, produced sustained histologic improvements over 96 weeks in adults with metabolic dysfunction–associated steatohepatitis (MASH) and stage F2 or F3 fibrosis, according to final phase 2b HARMONY results.¹

Published in The Lancet, the study was funded by Akero Therapeutics, which manufactures efruxifermin. The 50-mg dose met the study’s end-of-treatment objective on the primary endpoint, with consistent benefits across noninvasive fibrosis measures and metabolic biomarkers, while maintaining an acceptable safety profile.

HARMONY (NCT04767529) enrolled 128 adults with biopsy-confirmed MASH (NAS ≥ 4) and F2 or F3 fibrosis across 41 US centers. Participants were randomized 1:1:1 to efruxifermin 28 mg, efruxifermin 50 mg, or placebo administered subcutaneously once weekly for 96 weeks, with centrally read liver biopsies at baseline and weeks 24 and 96. Most participants were White (92%) and women (62%), and the mean age was in the mid-50s across groups.

Many had type 2 diabetes or other metabolic syndrome features at baseline, and two-thirds had F3 fibrosis. The modified intention-to-treat (mITT) analysis imputed missing biopsies as nonresponse, and a liver biopsy analysis set (LBAS) included participants with paired week 96 biopsies.

More Benefit Seen With Higher Dose

In the mITT population, ≥ 1-stage fibrosis improvement without MASH worsening at week 96 occurred in 49% of the efruxifermin 50-mg group vs 19% of the placebo group (difference, 31 percentage points; P = .0030), and in 30% of the 28-mg group (difference, 12 percentage points; P = .19). In the LBAS, the effect sizes were larger, with 75% on 50 mg, 46% on 28 mg, and 24% on placebo, with the 50-mg dose highly significant (difference, 52 percentage points; P < .0001).

Resolution of MASH without fibrosis worsening reached 57% and 62% in the 28-mg and 50-mg groups, respectively, vs 24% with placebo; ≥2-stage fibrosis improvement was much more common with efruxifermin (20% and 23%) than placebo (2%). A clinically meaningful composite of fibrosis improvement plus MASH resolution was seen in 28% of patients with 28 mg and 35% with 50 mg, vs 7% with placebo. Additionally, 30% of patients on efruxifermin 50 mg achieved a “near-complete reversal” of disease—defined as fibrosis ≤ F1, histologic MASH resolution, and liver fat ≤ 5%—while no patients achieved this with placebo.

“Encouragingly, the fibrosis improvements observed with efruxifermin were similar across subgroups of participants at higher risk of progression to cirrhosis,” the study authors said. “Since fibrosis is considered the strongest predictor of major adverse liver outcomes, efruxifermin has the potential to improve outcomes in patients with pre-cirrhotic MASH.”

Sustained Improvements in Liver Injury and Fibrosis Markers

Beyond histologic improvements, efruxifermin produced rapid and durable reductions in biochemical and noninvasive markers of liver injury. Levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) dropped quickly after treatment initiation and remained lower through 96 weeks. A clinically meaningful ALT reduction of at least 17 U/L at week 96 was achieved in 59% of participants on efruxifermin 50 mg and 63% on 28 mg, compared with only 26% in the placebo arm.

These biochemical gains corresponded with improvements in fibrosis assessments. At week 96, 71% of participants in the 50 mg group and 48% in the 28 mg group achieved a ≥ 30% reduction in liver stiffness, compared with 18% of placebo recipients. Among those with higher baseline stiffness (≥ 10 kPa), three-quarters of participants treated with efruxifermin improved to < 10 kPa, compared with just over a quarter of those on placebo.

Notably, 42% of patients in the 50 mg arm and 19% in the 28 mg arm demonstrated concordant responses across all 3 domains—histologic fibrosis stage, Enhanced Liver Fibrosis (ELF) score, and liver stiffness—while no such overlap was seen in the placebo group. According to the authors, patients who saw greater improvements in ELF score and liver stiffness were more likely to have improved histological fibrosis.

Investigators observed additional metabolic benefits, including improvements in triglycerides, HDL cholesterol, insulin sensitivity (HOMA-IR), C-peptide, and adiponectin. By 96 weeks, progression to cirrhosis was documented in 8 participants, distributed evenly across treatment groups, underscoring the importance of earlier intervention to halt disease progression.

“There was a high degree of concordance between fibrosis improvement as determined by histology and non-invasive tests,” the authors noted.

Acceptable Safety, but More Research Needed

Safety was deemed acceptable over nearly 2 years. Adverse events were common across all groups (as expected in long trials) and were predominantly mild to moderate gastrointestinal events such as diarrhea, nausea, increased appetite—all frequently seen with efruxifermin. Discontinuations for adverse events were higher with active therapy than placebo, and small decreases in bone mineral density were observed by week 96; no drug-induced liver injury, deaths, or adjudicated cardiovascular events occurred. The authors reported that anti-drug antibodies (about 90% incidence) did not appear to affect exposure, safety, efficacy, or pharmacodynamics.

With fewer than 50 participants in each arm, the study was limited by its moderate sample size, as well as its predominantly White US cohort and absence of hard clinical outcomes. However, the authors of the manufacturer-funded study said their long trial duration and serial assessment of liver histopathology helped validate the findings. Phase 3 trials are underway to confirm efficacy and clarify long-term safety and outcome effects.

Potential in Combination Therapy

Other studies suggest efruxifermin’s benefits may be amplified when combined with glucagon-like peptide-1 (GLP-1) receptor agonists. In a 12-week trial of 31 patients with MASH and type 2 diabetes, 88% of participants who received efruxifermin alongside a GLP-1 reached liver fat levels ≤ 5% compared with just 10% of those on placebo.² Hepatic fat fraction fell by 65% from baseline in the combination arm, and nearly 9 in 10 participants achieved at least a 50% reduction. Improvements in fibrosis markers and metabolic parameters were also observed without new safety concerns.

“There are preliminary indications that combining these 2 mechanistic classes could accelerate resolution of MASH and regression of fibrosis,” the authors concluded.

References

1. Noureddin M, Frias JP, Neff GW, et al. Safety and efficacy of once-weekly efruxifermin versus placebo in metabolic dysfunction-associated steatohepatitis (HARMONY): 96-week results from a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet. 2025;406(10504):719-730. doi:10.1016/S0140-6736(25)01073-6
2. Munz K. Amplifying impact: efruxifermin plus GLP-1RA elevates MASH outcomes. AJMC^®. January 27, 2025. Accessed September 5, 2025. https://www.ajmc.com/view/amplifying-impact-efruxifermin-plus-glp-1ra-elevates-mash-outcomes