Stimulation of Platelet Production in Healthy Volunteers by a Novel Pegylated Peptide-Based Thrombopoietin (TPO) Receptor Agonist.

A novel, pegylated, peptide-based thrombopoietin receptor agonist (peg-TPOmp) was shown to possess in vitro and in vivo thrombopoietic activity. In cell-based assays, peg-TPOmp was active at picomolar concentrations. In vivo, peg-TPOmp increased platelet production dose-dependently in rats (ED50 single i.v. dose ~ 100 μg/kg), dogs and mice. A phase I study was conducted in healthy male volunteers to investigate the tolerability, PD and PK of peg-TPOmp. Forty volunteers were randomized to receive peg-TPOmp or placebo as a single i.v. bolus injection in a ratio of 6:2. The peg-TPOmp dose range explored was 0.375, 0.75, 1.5, 2.25 or 3 μg/kg. PK analysis indicated dose-related kinetics of peg-TPOmp, although at doses of 0.75 μg/kg or lower, plasma concentrations were generally below the LOQ of 6.25 ng/mL. Mean Cmax values ranged from 11 ng/mL for 0.75 μg/kg to 62 ng/mL at 3.0 μg/kg. The mean terminal half-life ranged from approx. 18 to 36 hours. Platelet counts increased dose-dependently reaching peak levels at Day 10–12, and counts returned to baseline within 3–4 weeks. Mean peak platelet levels ranged from 315 x10⁹/L at 0.375 μg/kg to 685 x 10⁹/L at 3 μg/kg. Mean increase of peak platelet counts from baseline ranged from 1.4-fold at 0.375 μg/kg to 3.2-fold at 3.0 μg/kg. Endogenous TPO levels dose-dependently increased, reaching peak levels at 3 days post-dose, possibly due to a reduced rate of clearance. No significant changes were observed in blood levels of IL-6, IL-11 and EPO levels. Platelet function, assessed as collagen-induced platelet aggregation in whole blood, was not different between the treatments. None of the subjects experienced serious adverse events or dose-limiting toxicities. The most frequently observed adverse events included mild headache and fatigue and occurred both after active treatment and placebo. No antibodies against peg-TPOmp were detected. Based on the safety, PK and PD data, peg-TPOmp shows promise as an agent to treat thrombocytopenic disorders.