Emerging peptide · Late-stage candidates

Efruxifermin

FGF21 analog with the most advanced clinical program in the MASH (formerly NASH) liver-disease space.

Phase 3

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This section covers peptides at the frontier of research. Most entries are preclinical, in early or mid-stage clinical trials, or theoretical. Evidence levels are explicitly marked on every entry.

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At a glance

Akero Therapeutics' Fc-fusion FGF21 analog. Phase 2b SYMMETRY data showed reductions in liver fibrosis at 96 weeks; Phase 3 program is underway.

Class
FGF21 analog (Fc-fusion)
Sponsor
Akero Therapeutics
Stage
Phase 3
Lead use case
MASH (metabolic-dysfunction-associated steatohepatitis) with fibrosis

What it is

Efruxifermin is a long-acting FGF21 analog designed for once-weekly subcutaneous dosing in patients with MASH. Native FGF21 is an endocrine factor produced primarily by liver and adipose tissue with broad metabolic effects on glucose, lipid handling, and insulin sensitivity.

Current research status

The HARMONY Phase 2b trial showed dose-dependent improvements in liver fibrosis (~40% achieving ≥1-stage improvement at high dose at 24 weeks). The SYMMETRY Phase 2b trial in compensated MASH cirrhosis showed reductions in fibrosis at 96 weeks — a critical readout for the indication. The SYNCHRONY-Histology Phase 3 trial program is enrolling.

Mechanistic rationale

FGF21 binds FGF receptor 1c in complex with the obligate co-receptor β-Klotho, which is selectively expressed in adipose tissue, liver, and other metabolic organs. Activation produces broad metabolic effects: improved insulin sensitivity, reduced hepatic lipogenesis, increased fatty acid oxidation, and reduced systemic inflammation. In MASH specifically, the relevant downstream effects are reduced intrahepatic triglyceride content and improvements in fibrogenic signaling.

Available evidence

HARMONY Phase 2b — Dose-dependent reductions in MAS (MASH activity score) and liver fibrosis at 24 weeks.

SYMMETRY Phase 2b (compensated MASH cirrhosis) — Reductions in fibrosis stage at 96 weeks reported in 2024 — a high-bar readout in this hard-to-treat population.[1]

BALANCED Phase 2 (T2D) — Improvements in liver fat, insulin sensitivity, and lipid profile in patients with T2D and obesity.

Why it's interesting

MASH is one of the largest unmet-need areas in metabolic medicine, and the leading non-incretin candidate at the front of the FGF21 class. If Phase 3 confirms the fibrosis reductions seen in SYMMETRY, this could become the cornerstone therapy for MASH cirrhosis specifically — a population not as well-served by GLP-1-class agents alone.

Limitations & risks

FGF21 analogs in this class have shown bone-mineral-density signals in early studies (FGF21 has known effects on bone biology) — this is part of the ongoing Phase 3 monitoring. Dosing-related GI side effects and the cost of long-term injectable therapy are practical considerations. The MASH endpoint landscape is also evolving — what counts as a clinically meaningful change in fibrosis stage in regulatory contexts is part of the broader development story.

Community discussion notes

FGF21-class drugs have meaningful crossover discussion in metabolic-health and longevity communities given FGF21's roles in caloric restriction biology and metabolic flexibility. The MASH application is the lead indication, but broader metabolic-health interest is a real undercurrent.

The takeaway

Efruxifermin is positioned as the leading FGF21-class candidate in MASH and the most likely first FGF21-analog approval. The next 18–24 months of Phase 3 data will substantially clarify whether this becomes the foundation of MASH treatment or whether the bone-density and other safety signals reshape the development picture.

References

  1. Harrison SA, et al. Efruxifermin in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, Phase 2b trial. Lancet Gastroenterol Hepatol. 2023;8(12):1080-1093. https://pubmed.ncbi.nlm.nih.gov/37802082/
  2. Sanyal AJ, et al. Pegbelfermin and efruxifermin in MASH-related cirrhosis: comparative analyses. Aliment Pharmacol Ther. 2024;59:1023-1035. https://pubmed.ncbi.nlm.nih.gov/?term=efruxifermin