Once‐weekly administration of a long‐acting fibroblast growth factor 21 analogue modulates lipids, bone turnover markers, blood pressure and body weight differently in obese people with hypertriglyceridaemia and in non‐human primates

Aims To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-05231023, a long-acting FGF21 analogue, in obese, hypertriglyceridemic subjects on atorvastatin with or without type 2 diabetes. Methods Subjects received PF-05231023 or placebo intravenously once-weekly for 4 weeks. Safety (12-lead electrocardiogram [ECGs], vital signs, adverse events [AEs], laboratory tests) and longitudinal weight assessments were performed. Blood samples were collected for pharmacokinetic and pharmacodynamic analyses. Cardiovascular safety studies were also conducted in telemetered rats and monkeys. Blood pressure (mean, systolic, and diastolic) and ECGs were monitored. Results One hundred and seven (107) subjects were randomised. PF-05231023 significantly decreased mean placebo-adjusted fasting triglycerides (day 25, 33–43%) and increased high-density lipoprotein cholesterol (day 25, 15.7–28.6%) and adiponectin (day 25, 1574–3272 ng/ml) across all doses, without significant changes in body weight (day 25, −0.45 to −1.21%). Modest decreases from baseline were observed for N-terminal propeptides of type 1 collagen at day 25, although C-telopeptide cross-linking of type 1 collagen increased minimally. Systolic, diastolic blood pressure, and pulse rate increased in a dose- and time-related manner. There were five serious AEs (one treatment-related) and no deaths. Three subjects discontinued due to AEs. The majority of AEs were gastrointestinal. PF-05231023 increased blood pressure and heart rate in rats, but not in monkeys. Conclusions Once-weekly PF-05231023 lowered triglycerides markedly in the absence of weight loss, with modest changes in markers of bone homeostasis. This is the first report demonstrating increases in blood pressure and pulse rate in humans and rats upon pharmacological administration of a long-acting FGF21 molecule. Clinicaltrials.gov: NCT01673178