Lancet (London, England)Aug 16, 2025

Safety and effectiveness of once-weekly efruxifermin compared to placebo in fatty liver disease with metabolic problems: 96-week results from a large clinical trial

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 3, 2026

Abstract

After 96 weeks, 49% of participants receiving 50 mg of efruxifermin showed improvement in liver fibrosis without worsening metabolic dysfunction-associated steatohepatitis (MASH).

19% of participants in the placebo group experienced fibrosis improvement without MASH worsening.
30% of participants in the 28 mg efruxifermin group showed similar improvement compared to placebo.
In the 50 mg efruxifermin group, 49% of participants had a decrease in fibrosis stage without worsening MASH.
Among participants who underwent biopsies at week 96, 75% in the 50 mg group showed fibrosis improvement without MASH worsening.
Mild to moderate gastrointestinal adverse events were more frequently reported in efruxifermin groups compared to placebo, but no serious adverse events occurred.

Simplified

BACKGROUND: Efruxifermin is a bivalent fibroblast growth factor 21 analogue in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). This trial aimed to prospectively assess the safety and efficacy of efruxifermin administration for 96 weeks in individuals with MASH and moderate (stage 2; F2) or severe (stage 3; F3) fibrosis.

METHODS: HARMONY is a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial conducted at 41 academic and community centres in the USA. Adults (aged 18-75 years) with biopsy-confirmed MASH (defined as non-alcoholic fatty liver disease activity score of 4 or higher and a score of 1 or higher for steatosis, ballooning, and lobular inflammation), with histological stage F2 or F3 fibrosis, were randomly assigned (1:1:1), via an interactive response system, to receive subcutaneous efruxifermin (28 mg or 50 mg) once per week or placebo. Participants, investigators, pathologists, site staff, and the sponsor were masked to group assignments. The primary endpoint was an improvement in liver fibrosis (decrease ≥1 stage) without worsening of MASH at week 24, which has been previously reported. End-of-treatment endpoints at week 96 included a final evaluation of the primary endpoint, as well as MASH resolution without fibrosis worsening. The trial is registered with ClinicalTrials.gov, NCT04767529, and is complete.

FINDINGS: Between March 22, 2021, and Feb 7, 2022, 128 participants were randomly assigned and 126 received at least one dose of efruxifermin or placebo and were included in the modified intention-to-treat analysis. 79 (62%) of 128 participants were female and 49 (38%) were male. The proportion of participants in the modified intention-to-treat population with ≥1-stage fibrosis improvement without MASH worsening at week 96 was eight (19%) of 43 in the placebo group, 12 (30%) of 40 in the 28 mg group (difference vs placebo: 12 percentage points [95% CI -6 to 31]; p=0·19), and 21 (49%) of 43 in the 50 mg group (difference: 31 percentage points [12 to 49]; p=0·0030). Of 88 participants with week-96 biopsies, ≥1-stage fibrosis improvement without MASH worsening was observed in eight (24%) of 34 participants in the placebo group, 12 (46%) of 26 in the 28 mg group (difference vs placebo: 22 percentage points [95% CI -1 to 45]; p=0·070), and 21 (75%) of 28 in the 50 mg group (difference: 52 percentage points, [31 to 73]; p<0·0001). 38 (95%) of 40 participants in the 28 mg group, 43 (100%) of 43 in the 50 mg group, and 42 (98%) of 43 in the placebo group reported an adverse event. Mild to moderate gastrointestinal adverse events were more common with efruxifermin than placebo. There were no reports of drug-induced liver injury or deaths across the groups.

INTERPRETATION: Efruxifermin resulted in greater improvements in fibrosis than placebo after 96 weeks, warranting further investigation in phase 3 trials.

FUNDING: Akero Therapeutics.

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Declaration of interests MN reports research support from Allergan, Altimmune, Akero Therapeutics, Boehringer Ingelheim, BMS, Boston Pharma, Conatus, Corcept, Gilead, Galectin, Genfit, GSK, Kowa, Enanta, Madrigal, Eli Lilly, Merck, Novartis, Novo Nordisk, Rivus, Shire, Takeda, Terns, Viking, and Zydus; consulting fees from Akero Therapeutics, Altimmune, Alligos, AstraZeneca, Boehringer Ingelheim, Boston Pharma, Cytodyn, GSK, Eli Lilly, Madrigal, Merck, Novo Nordisk, Sagimet, Terns, and Takeda; speaking fees from Madrigal; and stock in Akero Therapeutics, ChronWell, Cytodyn, and Rivus Pharma. JPF reports research support form 89bio, Akero Therapeutics, Altimmune, Boehringer Ingelheim, Eli Lilly, Intercept, IONIS, Janssen, Madrigal, Merch, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Sanofi, and Shionogi; consulting fees from 89bio, Akero Therapeutics, Altimmune, Biomea Fusion, Boehringer Ingelheim, Carmot Therapeutics, Echosense, Eli Lilly, Gilead, Intercept, Metacrine, Merck, Novo Nordisk, Pfizer, and Sanofi; speaking fees from Eli Lilly; membership on the board of directors at T1D Exchange; and employment at and stock in Biomea Fusion. GWN reports research support from Akero Therapeutics, Aligos, Altimmunie, 89bio, Boehringer Ingelheim, Boston Pharma, Cirius Therapeutics, Eli Lilly, Hightide Therapeutics, Inventiva, Madrigal, Merck, Mirium, NGM Biopharma, NorthSea Therapeutics, Novo Nordisk, Takeda, and Viking; and consulting fees from Aligos, Altimmune, Boehringer Ingelheim, and Boston Pharma. CB reports consulting fees from Akero Therapeutics, Boehringer Ingelheim, ICON, and Pathology Institute; a role as part-time associate physician at the University of California; participation in seminars/preceptorships for Alimentev, Pfizer, and Novo Nordisk; and sponsorship from the College of American Pathologists and the American Association for the Study of Liver Disease, in exchange for invited lectures at the 2024 annual meetings. CB reports being a coinvestigator for NIDDK funded U01DK61734: Clinical Research Network in Nonalcoholic Steatohepatitis through an appointment as a part-time (10%) associate physician at the University of California, San Diego; and institutional research grants for non-exclusive laboratory services and/or consulting fees from Akero Therapeutics, Covance, E study site, Genesis Imaging Service, ICON, Eli Lilly, Viking Therapeutics, Medical Research Group, Southern California Research Center, and Takeda. PB reports consulting fees from Akero, Corcept, Madrigal, Sagimet, Bio89, Boehringer, and Canfite, and being a founder and owner of Liverpat. JD reports being a shareholder in Poxel. DC, MB, EF, BdT, MM, KB, RS, EJT, TR, AC, and KY are current or former employees of Akero Therapeutics and own or have options to purchase stock in the company. KJL declares no competing interests.

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Safety and effectiveness of once-weekly efruxifermin compared to placebo in fatty liver disease with metabolic problems: 96-week results from a large clinical trial

Abstract

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Competing interests

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