Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH

Abstract

Background: Pegozafermin is a long-acting glycopegylated (pegylated with the use of site-specific glycosyltransferases) fibroblast growth factor 21 (FGF21) analogue in development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia. The efficacy and safety of pegozafermin in patients with biopsy-proven noncirrhotic NASH are not well established.

Methods: In this phase 2b, multicenter, double-blind, 24-week, randomized, placebo-controlled trial, we randomly assigned patients with biopsy-confirmed NASH and stage F2 or F3 (moderate or severe) fibrosis to receive subcutaneous pegozafermin at a dose of 15 mg or 30 mg weekly or 44 mg once every 2 weeks or placebo weekly or every 2 weeks. The two primary end points were an improvement in fibrosis (defined as reduction by ≥1 stage, on a scale from 0 to 4, with higher stages indicating greater severity), with no worsening of NASH, at 24 weeks and NASH resolution without worsening of fibrosis at 24 weeks. Safety was also assessed.

Results: Among the 222 patients who underwent randomization, 219 received pegozafermin or placebo. 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.

Conclusions: In this phase 2b trial, treatment with pegozafermin led to improvements in fibrosis. These results support the advancement of pegozafermin into phase 3 development. (Funded by 89bio; ENLIVEN ClinicalTrials.gov number, NCT04929483.).

Figure 1.. Primary End Points at Week 24 (Full Analysis Population).

The two primary end points were an improvement in fibrosis (defined as reduction by ≥1 stage, on a scale from 0 to 4, with higher stages indicating greater severity), with no worsening of nonalcoholic steatohepatitis (NASH) at 24 weeks, and NASH resolution (defined as the total absence of ballooning and absent or mild inflammation) without worsening of fibrosis (increase of ≥1 stage) at 24 weeks. Patients were assigned to receive placebo or pegozafermin at a dose of 15 mg every week, 30 mg every week, or 44 mg every 2 weeks. Data from the placebo groups were pooled; the dashed line indicates the results in the pooled placebo group for comparison across the pegozafermin groups. Data were analyzed with the use of a Cochran–Mantel–Haenszel method with adjustment for baseline stratification factors (type 2 diabetes status and fibrosis stage). Missing end-point data (for 28 patients) were imputed with the use of multiple imputation by means of logistic regression with all collected outcomes. The full analysis population included all the enrolled patients who had undergone randomization and received at least one dose of pegozafermin or placebo and who had confirmed fibrosis stage F2 or F3 (indicating moderate or severe fibrosis) and a nonalcoholic fatty liver disease activity score of at least 4 at baseline, as assessed on independent review by a three-pathologist panel. The widths of the confidence intervals have not been adjusted for multiplicity, so the confidence intervals should not be used to reject or not reject treatment effects.