Abstract
BACKGROUND: Efruxifermin (EFX), a fibroblast growth factor 21 analogue, has demonstrated the potential to improve liver fat and markers of liver injury, fibrosis, and key metabolic biomarkers in individuals with metabolic dysfunction-associated steatohepatitis (MASH) in phase 2 clinical trials. AIM: To summarize the safety and effectiveness of EFX in managing MASH. METHODS: Electronic databases and registries were systematically searched from their inception to May 15, 2025, for randomized-controlled trials (RCTs) that included EFX in the intervention arm and placebo in the control arm in individuals with MASH. The primary outcome was the safety of EFX, while additional outcomes included its efficacy in altering hepatic and metabolic parameters. Meta-analyses were conducted using the RevMan web computer program with the random-effects model. RESULTS: Four phase 2 RCTs (five reports), mostly with low risk of bias, involving 450 subjects, were analyzed. Compared to the placebo, EFX 50 mg was associated with higher risks of treatment-emergent adverse events (TEAEs) [risk ratio (RR) = 1.05], TEAEs leading to discontinuation (RR = 3.05), nausea (RR = 1.78), and diarrhea (RR = 1.9). EFX 28 mg increased risks of vomiting (RR = 2.17) and frequent bowel movements (RR = 8.98). Both doses of EFX were associated with higher risks of drug-related TEAEs (28 mg: RR = 1.45; 50 mg: RR = 1.67) and increased appetite (28 mg: RR = 3.16; 50 mg: RR = 5.66). EFX (28 and 50 mg) and placebo exhibited identical risks for severe TEAEs, serious AEs, abdominal pain, fatigue, headache, injection site erythema, and injection site reactions. EFX (28 and 50 mg) was associated with improvements in hepatic safety outcomes, including liver enzymes and urate levels. EFX outperformed the placebo in both relative and absolute reductions in hepatic fat fraction. Reductions in enhanced liver fibrosis score, Pro-C3, and liver stiffness were also more robust with EFX. EFX was superior in terms of MASH resolution and improvement in fibrosis stage, MASH resolution and no worsening of the fibrosis stage, and fibrosis regression by ≥ 1 stage and no worsening in steatohepatitis. Furthermore, EFX also improved metabolic parameters, including reductions in HbA1c and insulin resistance, as well as improvements in adiponectin and lipid parameters. CONCLUSION: EFX demonstrates promising dual efficacy on liver histology and metabolic markers in MASH. However, gastrointestinal side effects and the need for parenteral administration require caution. Long-term data are still necessary to fully evaluate safety and long-term effectiveness.