Pegbelfermin, a PEGylated FGF21 analogue, has pharmacology without bone toxicity after 1-year dosing in skeletally-mature monkeys

Highlights: • Fibroblast growth factor 21 (FGF21) regulates glucose and fat metabolism. • Pegbelfermin (PGBF) is a PEGylated recombinant human FGF21 analogue. • PGBF causes metabolic-related pharmacological effects in monkeys. • Clinically relevant PGBF doses did not adversely affect adult monkey bone health. • Further study of PGBF in patients with nonalcoholic steatohepatitis is ongoing. Pegbelfermin (PGBF) is a PEGylated fibroblast growth factor 21 (FGF21) analogue in development for treatment of nonalcoholic steatohepatitis (NASH). Mouse models highlight potential utility of FGF21 in NASH, but also suggest negative effects on bone, though these findings are confounded by profound FGF21-related decreases in body mass/growth. This study aimed to profile PGBF-related bone effects in adult nonhuman primates after long-term, clinically-relevant exposures. Adult male cynomolgus monkeys received weekly subcutaneous PGBF (0.3, 0.75 mg/kg) or control injections for 1 year (n = 5/group). Assessments included body weight, clinical chemistry, adiponectin levels, bone turnover biomarkers, skeletal radiography, pharmacokinetics, immunogenicity, and histopathology. Bone densitometry and body composition were evaluated in vivo and/or ex vivo with dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, and biomechanical strength testing. After 1 year of PGBF administration, there was clear evidence of sustained PGBF pharmacology in monkeys (peak increase in serum adiponectin of 1.7× and 2.35× pretest at 0.3 and 0.75 mg/kg PGBF, respectively) and decreased body weight compared with control at exposures comparable to those tested in humans. At 0.75 mg/kg PGBF, pharmacologically-mediated reductions in lean mass, lean area, and fat area were observed relative to controls. There were no PGBF-related effects on bone biomarkers, radiography, densitometry, or strength. Together, these data demonstrate that PGBF did not adversely alter bone metabolism, density, or strength following 1 year of dosing at clinically relevant (0.7–2.2× human AUC[0-168 h] at 20 mg once weekly), pharmacologically-active exposures in adult monkeys, suggesting a low potential for negative effects on bone quality in adult humans.