The FGF21 analog pegozafermin in severe hypertriglyceridemia: a randomized phase 2 trial.

Pegozafermin, a long-acting glycopegylated analog of human fibroblast growth factor 21, is in development for the treatment of severe hypertriglyceridemia (SHTG) and nonalcoholic steatohepatitis. Here we report the results of a phase 2, double-blind, randomized, five-arm trial testing pegozafermin at four different doses (n = 67; 52 male) versus placebo (n = 18; 12 male) for 8 weeks in patients with SHTG (triglycerides (TGs), ≥500 mg dl -1 and ≤2,000 mg dl -1 ). Treated patients showed a significant reduction in median TGs for the pooled pegozafermin group versus placebo (57.3% versus 11.9%, difference versus placebo -43.7%, 95% confidence interval (CI): -57.1%, -30.3%; P < 0.001), meeting the primary endpoint of the trial. Reductions in median TGs ranged from 36.4% to 63.4% across all treatment arms and were consistent regardless of background lipid-lowering therapy. Results for secondary endpoints included significant decreases in mean apolipoprotein B and non-high-density lipoprotein cholesterol concentrations (-10.5% and -18.3% for pooled doses compared to 1.1% and -0.6% for placebo (95% CI: -21.5%, -2.0%; P = 0.019 and 95% CI: -30.7%, -5.1%; P = 0.007, respectively), as well as a significant decrease in liver fat fraction for pooled treatment (n = 17) versus placebo (n = 6; -42.2% pooled pegozafermin, -8.3% placebo; 95% CI: -60.9%, -8.7%; P = 0.012), as assessed in a magnetic resonance imaging sub-study. No serious adverse events were observed to be related to the study drug. If these results are confirmed in a phase 3 trial, pegozafermin could be a promising treatment for SHTG (ClinicalTrials.gov registration: NCT0441186).