The long-acting glycopegylated fibroblast growth factor 21 (FGF21) analogue pegozafermin improved fibrosis in a phase 2b trial of patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH). “These results support the advancement of pegozafermin into phase 3 development,” the investigators conclude.
Patients with biopsy-confirmed NASH and stage F2 or F3 (moderate or severe) fibrosis were randomized to subcutaneous pegozafermin 15 mg or 30 mg weekly or 44 mg once every 2 weeks or placebo weekly or every 2 weeks. The trial used two primary endpoints: an improvement in fibrosis with no worsening of NASH at 24 weeks and NASH resolution without worsening of fibrosis at 24 weeks.
“Among the 222 patients who underwent randomization, 219 received pegozafermin or placebo,” the authors write. “The percentage of patients who met the criteria for fibrosis improvement was 7% in the pooled placebo group, 22% in the 15-mg pegozafermin group (difference vs. placebo, 14 percentage points; 95% confidence interval [CI], −9 to 38), 26% in the 30-mg pegozafermin group (difference, 19 percentage points; 95% CI, 5 to 32; P = 0.009), and 27% in the 44-mg pegozafermin group (difference, 20 percentage points; 95% CI, 5 to 35; P = 0.008). The percentage of patients who met the criteria for NASH resolution was 2% in the placebo group, 37% in the 15-mg pegozafermin group (difference vs. placebo, 35 percentage points; 95% CI, 10 to 59), 23% in the 30-mg pegozafermin group (difference, 21 percentage points; 95% CI, 9 to 33), and 26% in the 44-mg pegozafermin group (difference, 24 percentage points; 95% CI, 10 to 37). The most common adverse events associated with pegozafermin therapy were nausea and diarrhea.”
Editorial: “NASH is a chronic disease with pathobiologic features that are anchored in energy metabolism, making the temporal horizon of NASH therapeutics likely to be more akin to that of type 2 diabetes (measured in years) than hepatitis C (measured in weeks),” writes an editorialist. “Thus, although the planned 24-week open-label extension in this trial will provide insight into the durability of response to pegozafermin, even a 48-week period may be too short to assess the durability of response for this or any other FGF21-based therapy. The results of [this trial] are an encouraging development in NASH therapeutics. We eagerly await determination of whether the blistering pace of response can be sustained to the end of the marathon.”