Clinical trial: Effects of pegozafermin on the liver and on metabolic comorbidities in subjects with biopsy-confirmed nonalcoholic steatohepatitis

Background: An approved therapy for nonalcoholic steatohepatitis (NASH) and fibrosis remains a major unmet medical need. Aim: To investigate the histological and metabolic benefits of pegozafermin, a glycoPEGylated FGF21 analogue, in subjects with biopsy-confirmed NASH. Methods: This proof-of- concept, open-label, single-cohort study, part 2 of a phase 1b/2a clinical trial, was conducted at 16 centres in the United States. Adults (age 21-75 years) with NASH (stage 2 or 3 fibrosis, NAS=4) and magnetic resonance imaging proton density fat fraction (MRI-PDFF) =8% received subcutaneous pegozafermin 27 mg once weekly for 20 weeks. Primary outcomes were improvements in liver histology, and safety and tolerability. Results: Of 20 enrolled subjects, 19 completed the study. Twelve subjects (63%) met the primary endpoint of =2-point improvement in NAFLD activity score with =1-point improvement in ballooning or lobular inflammation and no worsening of fibrosis. Improvement of fibrosis without worsening of NASH was observed in 26% of subjects, and NASH resolution without worsening of fibrosis in 32%. Least-squares mean relative change from baseline in MRI-PDFF was -64.7% (95% CI: -71.7, -57.7; p < 0.0001). Significant improvements from baseline were also seen in serum aminotransferases, noninvasive fibrosis tests, serum lipids, glycaemic control and body weight. Adverse events (AEs) were reported in 18 subjects (90%). The most frequently reported AEs were mild/moderate nausea and diarrhoea. There were no serious AEs, discontinuations due to AEs, or deaths. Conclusions: Pegozafermin treatment for 20 weeks had beneficial effects on hepatic and metabolic parameters and was well tolerated in subjects with NASH.