Pharmacokinetics and pharmacodynamics of PF‐05231023, a novel long‐acting FGF21 mimetic, in a first‐in‐human study

Abstract

AIMSThe aim of the present study was to evaluate the pharmacokinetics/pharmacodynamics (PK/PD), safety and tolerability of single intravenous (IV) doses of PF-05231023, a long acting fibroblast growth factor 21 (FGF21) analogue being developed for the treatment of type 2 diabetes mellitus (T2DM). METHODST2DM subjects (glycosylated haemoglobin: 7.0-10.5%; on stable metformin therapy and/or diet and exercise) were randomized to receive a single dose of placebo or PF-05231023 (0.5-200 mg). Safety evaluations were performed up to 14 days after dosing. PK and PD endpoints were measured and a PK/PD model was developed for triglyceride -an early marker of drug activity. RESULTSNo antidrug antibody or serious adverse events (AEs) were observed. The most frequent AEs were gastrointestinal but were generally mild. Plasma PF-05231023 levels peaked immediately post-IV dosing, with mean terminal half-lives of 6.5-7.7 h and 66.5-96.6 h for intact C-and N-termini, respectively. Intact C-terminus exposures increased proportionally with increasing dose, whereas N-terminus exposures appeared to trend higher than dose-proportionally. Although no apparent effect on plasma glucose was seen, dose-dependent decreases in triglyceride were observed, with a maximum reduction of 48.5 ± 10.0% (mean ± standard deviation) for the 200 mg dose compared with a reduction of 19.1 ± 26.4% for placebo, demonstrating proof of pharmacology. Moreover, a reduction in total cholesterol and low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol were observed in the high-dose groups.

Modulation of energy balance by fibroblast growth factor 21

“…PEGylated FGF21 [134,135], FGF21-antibody conjugates [136], and antibody-based activation of the FGFR/β-Klotho complex [137] are under study. Also, the FGF21 analogs LY2405319 and PF05231023 were tested in two different pilot studies in humans [138,139]. LY2405319 was administered subcutaneously once daily for 4 weeks in patients with diabetes and obesity.…”

Lipodystrophy HIV-related and FGF21: A new marker to follow the progression of lipodystrophy?

“…Only two FGF21 analog are study in humans [22,23] as been performed and the results of these studies shown a decrease of body weight, decrease of insulin resistance, decrease of triglycerides, and LDL cholesterol with increase of HDL.…”

Fibroblast Activation Protein Cleaves and Inactivates Fibroblast Growth Factor 21

“…The metabolic action of FGF21 appears to be conserved in obese diabetic humans, at least to a certain extent. Small clinical trials have demonstrated that FGF21 analogs are efficacious in inducing weight loss and correcting hyperinsulinemia, dyslipidemia, and hypoadiponectinemia in obese individuals with type 2 diabetes (15,16).…”