Abstract

Pegozafermin (also known as BIO89-100) is a glycoPEGylated analog of fibroblast growth factor 21 (FGF21) under development to treat nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia (SHTG). In cell-based assays, pegozafermin had a similar receptor engagement profile as native FGF21, with approximately 8-fold higher potency at FGF receptor 1 (FGFR1). In diabetic monkeys, once-weekly and once-every-two-week regimens of subcutaneous pegozafermin provided rapid and robust benefits on an array of metabolic biomarkers, including triglycerides, cholesterol, fasting glucose, HbA1c, adiponectin, ALT, food intake, and body weight. In a single ascending dose study in healthy volunteers, subcutaneously administered pegozafermin was associated with statistically significant improvements in triglycerides, LDL and HDL cholesterol, and adiponectin, an insulin-sensitizing and anti-inflammatory adipokine. Pharmacokinetic half-lives ranged from 55 to 100 hours over the clinically relevant dose range, consistent with the expected half-life extension by glycoPEGylation. These findings provide evidence that pegozafermin is a promising candidate molecule for the treatment of patients with NASH or SHTG.

Significance Statement Fibroblast growth factor 21 (FGF21) is a stress-inducible hormone that has important roles in regulating energy balance and glucose and lipid homeostasis. Studies presented here demonstrate that a novel long-acting FGF21 analog, pegozafermin, has similar pharmacologic properties as FGF21 and that repeated, subcutaneous-dosing of pegozafermin in diabetic monkeys and healthy humans improves lipid metabolism, glucose metabolism, weight and liver transaminases. These results support future development of pegozafermin for the treatment of metabolic diseases, including nonalcoholic steatohepatitis and severe hypertriglyderidemia.