S2503 FGF19/FGF21 Analogues in NASH: Systematic Review

Introduction: Nonalcoholic steatohepatitis (NASH) occurs when excess fat accumulates in the liver, causing inflammation and damage, which may lead to liver scarring, cirrhosis, and eventually liver failure. Fibroblast growth factor 19 (FGF19) and 21 (FGF21) analogues are drugs being developed to treat NASH due to their metabolic and anti‐fibrotic effects. This systematic review aims to summarize clinical studies of FGF19/21 analogues in adults with NASH. Methods: A literature search across PubMed, Embase, and Cochrane identified clinical trials of FGF19/21 analogues in adults with NASH. Data on efficacy outcomes (e.g., histologic NASH resolution or fibrosis improvement) and safety (adverse events) were extracted from eligible studies. Results: We found 8 trials of FGF21 analogues (Efruxifermin, Pegozafermin and Pegbelfermin) and 2 of the FGF19 analogue Aldafermin. Efruxifermin produced significant benefits: in the 24-week HARMONY trial (n = 128, F2–F3 fibrosis), 39% of efruxifermin treated patients had ≥1 stage fibrosis improvement (no NASH worsening) vs 20% on placebo. In the 16-week BALANCED trial (F1–F3), efruxifermin decreased hepatic fat fraction on average by 13.26% vs 0.3% with placebo. Pegozafermin 24-week trial by Loomba et. al. showed an average of 25% vs 7% placebo achieving ≥1-stage fibrosis improvement; NASH resolution occurred in an average of 28.6% of treated patients vs 2% on placebo. Pegbelfermin did not meet histological endpoints in the FALCON-1/2 trials, although some improvements in liver fat and inflammation markers were seen. Aldafermin 24-week RCT ALPINE-2/3 did not show a significant fibrosis response. However, in the 48-week cirrhosis trial by Rinella et al., aldafermin 3 mg significantly Enhanced Liver Fibrosis from baseline to week 48 compared to placebo. All agents were generally well tolerated: the most common adverse events were mild to moderate gastrointestinal (diarrhea, nausea), with few treatment-related serious events. Conclusion: FGF21 and FGF19 analogues showed promising effects on NASH. Efruxifermin and pegozafermin significantly improved hepatic steatosis and fibrosis markers and achieved NASH resolution compared to placebo. Aldafermin lowered fibrosis biomarkers in patients with cirrhosis. Common adverse events were GI-related. These results support the further need for FGF19/21 analogues trials for NASH.