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

Diabetes Obes Metab. 2017 Dec;19(12):1762-1772. doi: 10.1111/dom.13023. Epub 2017 Jul 21.

Abstract

Aims: To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-05231023, a long-acting fibroblast growth factor 21 (FGF21) analogue, in obese people with hypertriglyceridaemia on atorvastatin, with or without type 2 diabetes.

Methods: Participants received PF-05231023 or placebo intravenously once weekly for 4 weeks. Safety (12-lead 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 (BP; mean, systolic and diastolic) and ECGs were monitored.

Results: A total of 107 people were randomized. PF-05231023 significantly decreased mean placebo-adjusted fasting triglycerides (day 25, 33%-43%) and increased HDL cholesterol (day 25, 15.7%-28.6%) and adiponectin (day 25, 1574 to 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 (P1NP) on day 25, although C-telopeptide cross-linking of type 1 collagen (CTX-1) increased minimally. Systolic, diastolic BP, and pulse rate increased in a dose- and time-related manner. There were 5 serious AEs (one treatment-related) and no deaths. Three participants discontinued because of AEs. The majority of AEs were gastrointestinal. PF-05231023 increased BP 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 showing increases in BP and pulse rate in humans and rats after pharmacological administration of a long-acting FGF21 molecule.

Trial registration: ClinicalTrials.gov NCT01673178.

Keywords: IGF-1; blood pressure; bone biomarkers; fibroblast growth factor 21; heart rate; type 2 diabetes.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Obesity Agents / administration & dosage
  • Anti-Obesity Agents / adverse effects
  • Anti-Obesity Agents / pharmacokinetics
  • Anti-Obesity Agents / therapeutic use*
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / pharmacokinetics
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Biomarkers / blood
  • Body Mass Index
  • Bone Remodeling / drug effects*
  • Delayed-Action Preparations / administration & dosage
  • Delayed-Action Preparations / adverse effects
  • Delayed-Action Preparations / pharmacokinetics
  • Delayed-Action Preparations / therapeutic use
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Drug Resistance
  • Female
  • Fibroblast Growth Factors / administration & dosage
  • Fibroblast Growth Factors / adverse effects
  • Fibroblast Growth Factors / pharmacokinetics
  • Fibroblast Growth Factors / therapeutic use*
  • Follow-Up Studies
  • Half-Life
  • Humans
  • Hypertension / chemically induced
  • Hypertension / physiopathology
  • Hypertriglyceridemia / blood
  • Hypertriglyceridemia / complications
  • Hypertriglyceridemia / drug therapy*
  • Hypolipidemic Agents / administration & dosage
  • Hypolipidemic Agents / adverse effects
  • Hypolipidemic Agents / pharmacokinetics
  • Hypolipidemic Agents / therapeutic use*
  • Infusions, Intravenous
  • Male
  • Middle Aged
  • Obesity / blood
  • Obesity / complications
  • Obesity / drug therapy*
  • Severity of Illness Index
  • Species Specificity

Substances

  • Anti-Obesity Agents
  • Antibodies, Monoclonal, Humanized
  • Biomarkers
  • Delayed-Action Preparations
  • Hypolipidemic Agents
  • PF-05231023
  • Fibroblast Growth Factors

Associated data

  • ClinicalTrials.gov/NCT01673178