Efruxifermin FGF21 Analog Reverses Liver Fibrosis in MASH: Phase 3 HARMONY Trial Shows 41% Fibrosis Improvement

How Does Efruxifermin Work to Reverse Liver Fibrosis?

Efruxifermin (EFX) is an Fc-fusion protein analog of fibroblast growth factor 21 (FGF21), a metabolic hormone that regulates lipid metabolism, glucose homeostasis, and energy expenditure. Unlike GLP-1 receptor agonists that address liver fat indirectly through weight loss and insulin sensitization, FGF21 acts directly on hepatocytes via the FGFR1c/β-Klotho receptor complex to upregulate fatty acid oxidation, suppress de novo lipogenesis, and reduce very-low-density lipoprotein secretion. Preclinical research suggests that efruxifermin also directly inhibits hepatic stellate cell activation, thereby targeting fibrogenesis at its cellular source. The drug's Phase 2a results, published in Nature Medicine (2021), demonstrated significant liver fat reduction and improvements in fibrosis biomarkers, laying the groundwork for larger trials.

The Phase 3 HARMONY trial enrolled patients with biopsy-confirmed MASH and compensated cirrhosis (fibrosis stage F4) across multiple countries. Patients were randomized to efruxifermin 50 mg weekly, efruxifermin 28 mg weekly, or placebo, all administered as subcutaneous injections. According to Akero Therapeutics, the primary endpoint of fibrosis improvement by ≥1 stage without worsening MASH was achieved by approximately 41% of the higher-dose group compared to roughly 18% of the placebo group at 96 weeks. The company also reported that over half of patients on the 50 mg dose achieved MASH resolution, and MRI-PDFF imaging showed substantial relative reductions in liver fat content, consistent with the large reductions observed in the Phase 2 program.

What Does This Mean for Patients With Advanced Liver Disease?

MASH-related cirrhosis is the fastest-growing indication for liver transplantation in the Western world, with millions of Americans estimated to be living with MASH-related advanced fibrosis or cirrhosis. Currently, there is no approved pharmacotherapy for this population—resmetirom (Rezdiffra), approved by the FDA in March 2024, is indicated only for non-cirrhotic MASH (F2–F3 fibrosis). Efruxifermin's reported ability to improve F4 fibrosis fills a critical unmet medical need. Akero has stated that a meaningful proportion of patients on the higher dose achieved a two-stage fibrosis improvement (from F4 to F2), suggesting potential reversal of established cirrhosis, though full peer-reviewed data are awaited.

The clinical implications extend beyond histological endpoints. Akero has reported improvements in markers of portal hypertension, which drives complications such as variceal bleeding, ascites, and hepatic encephalopathy. Additionally, the company reported that liver-related clinical events (including decompensation, hepatocellular carcinoma, transplant, or liver-related death) were numerically lower in the efruxifermin group, though the trial was not powered for clinical outcomes. Akero Therapeutics has indicated plans to pursue regulatory filing with the FDA, with an approval decision potentially following within 12 months of submission. The European Medicines Agency (EMA) filing is also expected. Patients with MASH cirrhosis may be able to access the drug through expanded access programs before formal approval.

What Are the Side Effects and Risks of Efruxifermin Treatment?

Efruxifermin has been generally well tolerated across its clinical development program, with an overall adverse event profile considered manageable given the severity of the underlying disease. Gastrointestinal symptoms—primarily diarrhea and nausea—have been the most frequently reported adverse events across Phase 2 and Phase 3 trials, occurring more often than with placebo. Injection site reactions have also been observed. Treatment discontinuation rates due to adverse events were modestly higher in the efruxifermin groups compared to placebo. Importantly, there have been no signals for pancreatitis, thyroid malignancy, or bone fracture—concerns that have limited some metabolic therapies in this population.

A recognized pharmacodynamic finding is a transient increase in LDL cholesterol during the initial weeks of treatment, attributed to FGF21-mediated effects on hepatic lipoprotein metabolism. This phenomenon was observed in Phase 2 trials and has been described as self-limiting, with LDL levels returning to or below baseline over continued treatment as overall hepatic metabolic function improves. Data safety monitoring committees have reviewed this finding and allowed trials to continue without modification. Mean body weight also decreased in the efruxifermin groups—Phase 2 data showed approximately 3–5% weight loss, with potentially greater reductions seen in the longer Phase 3 trial. This is a clinically meaningful but secondary benefit, as the drug's mechanism is hepatocentric rather than appetite-based.