Efruxifermin

Summary

Efruxifermin is an investigational, long‑acting Fc‑FGF21 fusion protein being developed for metabolic dysfunction‑associated steatohepatitis (MASH/NASH) and related liver fibrosis. Early‑phase clinical trials have evaluated weekly subcutaneous dosing in patients with steatohepatitis ranging from moderate fibrosis (F2) to compensated cirrhosis (F4). The drug aims to lower liver fat, improve metabolic parameters, and promote fibrosis regression.

Mechanism of Action

Efruxifermin is a bivalent analogue of fibroblast growth factor 21 that binds and activates fibroblast growth factor receptors 1c, 2c, and 3c via its Fc‑linked format, prolonging circulation. Activation of these receptors enhances hepatic fatty‑acid oxidation, reduces lipogenesis, improves insulin sensitivity, and exerts anti‑fibrotic signaling that together lower hepatic steatosis and may reverse fibrotic remodeling.

What the Research Shows

In the phase 2a BALANCED trial (80 participants), weekly efruxifermin (28‑70 mg) for 16 weeks produced dose‑dependent reductions in magnetic‑resonance‑measured hepatic fat fraction (≈‑12 % to ‑14 %) versus a 0.3 % rise with placebo, with mostly grade 1‑2 gastrointestinal adverse events. The phase 2b HARMONY study (128 participants, 96 weeks) showed that 50 mg weekly achieved a 49 % fibrosis‑improvement rate versus 19 % with placebo, and a 75 % improvement among biopsied subjects, while gastrointestinal events were more frequent but mild. A separate phase 2b trial in compensated cirrhosis (181 participants) found no statistically significant fibrosis reduction at 36 weeks, though a trend toward benefit emerged at 96 weeks. A network meta‑analysis placed efruxifermin among agents showing significant MASH‑resolution benefit. Across studies, adverse events were common but serious liver injury or death were not reported.

Reported Benefits

Clinical data indicate that efruxifermin can markedly lower liver fat content and, in longer‑duration trials, increase the proportion of patients achieving ≥1‑stage fibrosis regression without worsening steatohepatitis. The drug also improves metabolic markers such as insulin sensitivity and may reduce hepatic inflammation, offering a multi‑targeted approach to MASH management.

Limitations of the Evidence

Evidence is limited to phase 2 trials with modest sample sizes; the cirrhosis study did not achieve statistical significance at the primary 36‑week endpoint. Differences versus placebo, while promising, did not always reach conventional significance thresholds. Long‑term safety, durability of response, and efficacy in broader populations remain unproven pending phase 3 data.

Safety Considerations

Most participants experienced at least one adverse event, predominantly mild‑to‑moderate gastrointestinal symptoms (nausea, diarrhea, abdominal discomfort). Grade 3 events were infrequent, and a single grade 4 event was reported in the BALANCED trial. No drug‑induced liver injury or deaths occurred in the reported studies. Overall, the safety profile appears acceptable but requires confirmation in larger trials.

How It Is Administered

Efruxifermin is administered by subcutaneous injection once weekly. Clinical studies have evaluated fixed doses of 28 mg, 50 mg, and 70 mg, with the 28 mg and 50 mg regimens most frequently used in phase 2 trials.

Routes of Administration

Goals & Uses

• MASH/NASH fibrosis improvementHepatologyModerate
• Treatment of compensated cirrhosis due to MASHHepatologyLow
• Reduction of hepatic steatosisMetabolicModerate
• Type‑2 diabetes mellitusIndicationModerate
• Non‑alcoholic steatohepatitis (NASH)IndicationModerate
• Improvement of metabolic parametersMetabolicModerate
• Body weight reductionMetabolicLow
• MASH resolutionHepatologyModerate

Contraindications

• Known hypersensitivity to efruxifermin or any excipientAllergyHigh
• PregnancyPopulationHighPotential fetal risk or insufficient safety data
• Decompensated cirrhosisHepatic ImpairmentModerate
• Hypersensitivity to efruxifermin or excipientsAllergy/immunologyHigh

Adverse Effects

• Hair loss (alopecia)DermatologicalUncommon
• Injection site reactionsLocalCommon
• HypotensionCardiovascularUncommonLow blood pressure
• NauseaGastrointestinalCommonFeeling of sickness or urge to vomit
• HypophosphatemiaMetabolic/electrolyteUncommon
• VomitingGastrointestinalUncommonForceful expulsion of stomach contents
• Elevated LDL‑cholesterolLipidCommon
• Injection site reactionLocalCommonRedness, swelling, itching, bruising, or pain at the injection site
• DiarrheaGastrointestinalCommonLoose or frequent stools

Drug Interactions

• Insulin and insulin secretagoguesModerate
• StatinsLow
• Lipid-lowering agents (statins, fibrates)Low

Population Constraints

• PregnancyReproductive SafetyRelative
• Severe renal impairmentOrgan ImpairmentRelative
• Pediatric patientsAgeRelative
• Pediatric (<18 y)AgeRelative
• Pregnant or lactating womenReproductiveRelative
• Decompensated cirrhosis (Child-Pugh C)HepaticRelative

Regulatory Status

• European UnionInvestigationalUnder review in clinical programs.
• United StatesInvestigationalPhase 2/3 trials ongoing for NASH.
• United KingdomInvestigationalUnder clinical investigation; not approved by MHRA.

In Phase 2/3 clinical development for NASH and type‑2 diabetes; not approved in any jurisdiction as of 2024.

Evidence & Sources

• Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial
  Journal ArticleModerateHarrison SA, et al.2021-01-01T00:00:00.000000Z
• Efruxifermin in Compensated Liver Cirrhosis Caused by MASH
  Journal ArticleModerateNoureddin M, et al.2025-01-01T00:00:00.000000Z
• Effect of pemvidutide, a GLP-1/glucagon dual receptor agonist, on MASLD: A randomized, double-blind, placebo-controlled study
  Journal ArticleModerateHarrison SA, et al.2025-01-01T00:00:00.000000Z
• Comparison of pharmacological therapies in metabolic dysfunction-associated steatohepatitis for fibrosis regression and MASH resolution: Systematic review and network meta-analysis
  Journal ArticleHighSouza M, et al.2025-01-01T00:00:00.000000Z
• 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
  Journal ArticleModerateNoureddin M, et al.2025-01-01T00:00:00.000000Z
• Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial
  Journal ArticleModerateHarrison SA, et al.2023-01-01T00:00:00.000000Z

Frequently Asked Questions