The Novel GlycoPEGylated FGF21 Analog Pegozafermin Activates Human FGF Receptors and Improves Metabolic and Liver Outcomes in Diabetic Monkeys and Healthy Human Volunteers

Pegozafermin (also known as BIO89-100) is a glycoPEGylated an-alog of fibroblast growth factor 21 (FGF21) under development to treat nonalcoholic steatohepatitis (NASH) and severe hypertrigly-ceridemia (SHTG). In cell-based assays, pegozafermin had a simi-lar receptor engagement profile as recombinant FGF21, with approximately eightfold higher potency at fibroblast growth factor receptor 1c (FGFR1c). In diabetic monkeys, once-weekly and once-every-2-weeks regimens of subcutaneous pegozafermin provided rapid and robust benefits for an array of metabolic bio-markers, including triglycerides, cholesterol, fasting glucose, gly-cated hemoglobin, adiponectin, alanine aminotransferase, food intake, and body weight. In a single ascending dose study in healthy volunteers, subcutaneously administered pegozafermin was associated with statistically significant improvements in trigly-cerides, low-and high-density lipoprotein-cholesterol, and adipo-nectin, 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 evi-dence that pegozafermin is a promising candidate molecule for the treatment of patients with NASH or SHTG.SIGNIFICANCE STATEMENTFibroblast growth factor 21 (FGF21) is a stress-inducible hor-mone that has important roles in regulating energy balance and glucose and lipid homeostasis. Studies presented here demon-strate that a novel long-acting FGF21 analog, pegozafermin, has similar pharmacologic properties as FGF21 and that re-peated, subcutaneous dosing of pegozafermin in diabetic mon-keys 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 hypertriglyceridemia.