Efruxifermin

Akero Therapeutics' Fc-FGF21 fusion protein (AKR-001), a long-acting FGF21 analog in phase 3 development for metabolic dysfunction-associated steatohepatitis after the HARMONY phase 2b trial showed fibrosis improvement and the SYMMETRY cirrhosis trial missed its primary endpoint.

Also referenced as: EFX, AKR-001, AMG 876

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What is Efruxifermin?

Efruxifermin is not a peptide. It is a recombinant fusion protein in which an engineered version of human fibroblast growth factor 21 (FGF21), a metabolic hormone, is joined to the Fc domain of human immunoglobulin G1. Because the Fc domain dimerizes, each molecule carries two FGF21 moieties, so trial reports call it a bivalent Fc-FGF21 analog. The FGF21 portion carries three amino acid substitutions. L98R suppresses aggregation at high concentration and P171G removes a site-specific proteolytic cleavage found in mice and monkeys; together they define the earlier Fc-FGF21(RG) construct (Hecht et al., PLoS One, 2012;7(11):e49345). A180E near the C-terminus was added to resist the extreme C-terminal clipping that inactivates native FGF21 and to strengthen binding to the co-receptor beta-Klotho (Stanislaus et al., Endocrinology, 2017;158(5):1314–1327). The molecule was engineered at Amgen as Fc-FGF21(RGE), coded AMG 876, and later developed by Akero Therapeutics, which renamed it AKR-001 and then efruxifermin (EFX) (Kaufman et al., Cell Reports Medicine, 2020;1(4):100057). Akero has been a wholly owned subsidiary of Novo Nordisk since December 2025.

Efruxifermin is in phase 3 development for metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) in both its pre-cirrhotic and compensated cirrhotic stages and holds an FDA Breakthrough Therapy designation. As a large recombinant protein it has no presence in the research-peptide market. Pegozafermin is an FGF21 analog from a different sponsor that shares the target but is not an alias.

How it works

• FGF21 is an endocrine regulator of glucose and lipid metabolism. The hormone was identified as a stimulator of glucose uptake in adipocytes, and administered FGF21 reduced plasma glucose and triglycerides to near-normal levels in ob/ob and db/db mice without mitogenicity, hypoglycemia or weight gain (Kharitonenkov et al., Journal of Clinical Investigation, 2005;115(6):1627–1635). FGF21 cannot signal through FGF receptors alone; beta-Klotho is required for its metabolic activity, and the tissue distribution of beta-Klotho and the FGF receptor isoforms determines where the hormone acts (Ogawa et al., Proceedings of the National Academy of Sciences of the United States of America, 2007;104(18):7432–7437; Kurosu et al., Journal of Biological Chemistry, 2007;282(37):26687–26695).
• Engineering for a long half-life. Native FGF21 is cleared within about one to two hours and loses activity when its C-terminus is clipped (Hecht et al., PLoS One, 2012;7(11):e49345). Adding the A180E substitution to the Fc-FGF21(RG) construct reduced C-terminal degradation, doubled the half-life of the intact molecule in mice and cynomolgus monkeys and raised affinity for beta-Klotho three- to fivefold without added immunogenicity (Stanislaus et al., Endocrinology, 2017;158(5):1314–1327). In people with type 2 diabetes the fusion protein had a half-life of 3 to 3.5 days and a steady-state peak-to-trough ratio of about 2 (Kaufman et al., Cell Reports Medicine, 2020;1(4):100057).
• Agonism at FGFR1c, 2c and 3c. The bivalent construct replicates FGF21 signaling through the c-isoforms of FGF receptors 1, 2 and 3 in complex with beta-Klotho (Harrison et al., Lancet Gastroenterology & Hepatology, 2023;8(12):1080–1093). In phase 1 this produced sustained effects on serum markers of insulin sensitivity and the lipoprotein pattern shared by FGF21 analogs: lower triglycerides, non-HDL cholesterol and apolipoproteins B and C3, and higher HDL cholesterol (Kaufman et al., Cell Reports Medicine, 2020;1(4):100057).
• Hepatic fat clearance and antifibrotic effect. Sixteen weeks of treatment removed about 12 to 14 percentage points of absolute liver fat in F1 to F3 MASH, and 24 weeks roughly doubled the proportion of patients with a one-stage histologic fibrosis improvement, consistent with preclinical evidence that FGF21 is antifibrotic as well as metabolically active (Harrison et al., Nature Medicine, 2021;27(7):1262–1271; Harrison et al., Lancet Gastroenterology & Hepatology, 2023;8(12):1080–1093).

Research status

Phase 1 in type 2 diabetes. A phase 1 multiple ascending dose study of AKR-001 in people with type 2 diabetes found acceptable tolerability up to and including 70 mg once weekly; the authors suggested that earlier FGF21 analogs had shown little effect on insulin sensitivity potentially because their systemic exposure was insufficient (Kaufman et al., Cell Reports Medicine, 2020;1(4):100057).

BALANCED phase 2a (NCT03976401). At 27 US centers, 80 patients with biopsy-confirmed NASH and F1 to F3 fibrosis were randomized 1:1:1:1 to placebo or efruxifermin 28, 50 or 70 mg once weekly for 16 weeks. The primary endpoint, absolute change in MRI-measured hepatic fat fraction at week 12, was met: least squares mean changes were −12.3, −13.4 and −14.1 percentage points in the 28, 50 and 70 mg groups against +0.3 with placebo (p<0.0001 for each). Of 79 treated patients, 89% had a treatment-emergent adverse event, mostly grade 1 to 2, and mild gastrointestinal events were the most common drug-related events (46%) (Harrison et al., Nature Medicine, 2021;27(7):1262–1271).

HARMONY phase 2b (NCT04767529). Between March 22, 2021 and February 7, 2022, 41 US clinics randomized 128 adults with biopsy-confirmed NASH and F2 or F3 fibrosis to placebo, efruxifermin 28 mg or 50 mg once weekly. In the week 24 liver biopsy analysis set, fibrosis improved by at least one stage without worsening of NASH in 20% of placebo patients versus 39% on 28 mg (risk ratio 2.3, 95% CI 1.1–4.8; p=0.025) and 41% on 50 mg (risk ratio 2.2, 95% CI 1.0–5.0; p=0.036). Diarrhea occurred in 40% of each efruxifermin group versus 19% on placebo and nausea in 28% and 42% versus 23%, almost all grade 1 to 2; five patients discontinued for adverse events, and the one drug-related serious adverse event was ulcerative esophagitis in a patient with reflux disease (Harrison et al., Lancet Gastroenterology & Hepatology, 2023;8(12):1080–1093). On the week 24 data, the FDA granted Breakthrough Therapy designation for NASH, announced by Akero on December 8, 2022. At week 96, among 126 dosed participants, fibrosis improvement without MASH worsening occurred in 19% of the placebo group, 30% of the 28 mg group (difference 12 percentage points, 95% CI −6 to 31; p=0.19) and 49% of the 50 mg group (difference 31 points, 95% CI 12 to 49; p=0.0030). Mild to moderate gastrointestinal events were more frequent with efruxifermin, and there were no cases of drug-induced liver injury and no deaths (Noureddin et al., Lancet, 2025;406(10504):719–730).

SYMMETRY phase 2b (NCT05039450). Patients with biopsy-confirmed compensated cirrhosis (F4) caused by MASH were randomized to placebo or efruxifermin 28 or 50 mg once weekly; 181 were dosed, 154 had a week 36 biopsy and 134 a week 96 biopsy. The primary endpoint, fibrosis improvement of at least one stage without worsening of MASH at week 36, was not met: 13% on placebo versus 18% on 28 mg (adjusted difference 3 percentage points, 95% CI −11 to 17; p=0.62) and 19% on 50 mg (difference 4 points, 95% CI −10 to 18; p=0.52). At week 96 the rates were 11%, 21% (difference 10 points, 95% CI −4 to 24) and 29% (difference 16 points, 95% CI 2 to 30), a secondary endpoint without a formal hypothesis test. Gastrointestinal adverse events were again more common with efruxifermin and mostly mild or moderate (Noureddin et al., New England Journal of Medicine, 2025;392(24):2413–2424). The registry lists 213 participants in all and a completion date of August 28, 2025. Cohort D, under the same registration, randomized 31 adults with type 2 diabetes and F1 to F3 MASH on a stable GLP-1 receptor agonist 2:1 to efruxifermin 50 mg or placebo for 12 weeks; hepatic fat fell 65% versus 10% (p<0.0001), background weight loss was maintained and there were no treatment-related serious adverse events (Harrison et al., Clinical Gastroenterology and Hepatology, 2025;23(1):103–113).

SYNCHRONY phase 3 program. Three placebo-controlled, quadruple-masked phase 3 trials are registered. SYNCHRONY Histology (NCT06215716) began on December 1, 2023 and plans 1,650 participants with non-cirrhotic MASH and F2 or F3 fibrosis in two cohorts, randomized to efruxifermin 28 mg, 50 mg or placebo; the first cohort’s primary endpoint is MASH resolution with at least one stage of fibrosis improvement at 52 weeks, and the second is event-free survival over 240 weeks. It was recruiting at its October 15, 2026 registry update, with primary completion estimated for February 2033. SYNCHRONY Real-World (NCT06161571) is a safety and tolerability trial in about 700 participants with non-invasively diagnosed MASH or MASLD, randomized to efruxifermin 50 mg or placebo with an open-label rollover arm; it started on November 10, 2023, reached primary completion on March 3, 2026 and study completion on June 19, 2026, and as of November 2026 had no results posted or published. SYNCHRONY Outcomes (NCT06528314) began on October 4, 2024 and plans 2,150 participants with compensated MASH cirrhosis randomized to efruxifermin 50 mg or placebo; its primary endpoint is time to the first clinical event over five years, with a first-cohort histologic endpoint at 96 weeks, and it was recruiting at its October 13, 2026 update with primary completion estimated for February 2030. Drugs@FDA lists no efruxifermin application and DailyMed carries no label as of November 2026.

Common dosage forms

• Investigational subcutaneous injection. Efruxifermin is supplied only to clinical-trial sites as a solution for subcutaneous injection.
• No marketed presentation. No approved product, pen, vial or compounded version exists anywhere, and the molecule is a recombinant protein that cannot be made by peptide synthesis.

Key considerations

• Regulatory status. The Investigational status reflects the three registered phase 3 SYNCHRONY trials (NCT06215716, NCT06161571 and NCT06528314) and the absence of any approved product or marketing application in the US or abroad. The FDA granted Breakthrough Therapy designation for NASH in December 2022, and no application had been filed as of November 2026.
• Strong pre-cirrhotic signal, missed cirrhosis endpoint. The pre-cirrhotic fibrosis benefit in HARMONY grew rather than faded between week 24 and week 96, but SYMMETRY failed its week 36 primary endpoint in compensated cirrhosis, and the week 96 separation there is a secondary observation that only SYNCHRONY Outcomes can confirm.
• Gastrointestinal tolerability is the main adverse-event burden. Diarrhea and nausea affected roughly 30 to 40% of treated patients in HARMONY against about 20% on placebo, and gastrointestinal events were again more common in SYMMETRY; events were mostly mild to moderate, with no drug-induced liver injury or deaths over 96 weeks.
• A protein, not a peptide, with no research-market form. Efruxifermin is a dimeric IgG1 Fc fusion of mutated FGF21 made by recombinant expression, and it has no presence outside sponsored trials.
• Naming. Fc-FGF21(RGE), AMG 876, AKR-001, EFX and efruxifermin denote the same molecule; pegozafermin is a different FGF21 analog, and native FGF21 is a distinct, short-lived hormone.