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

Abstract

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.

Hematopoietic growth factors—use in normal blood and stem cell donors: clinical and ethical issues

“…No severe adverse events were reported, and mean PLT counts were 315 × 10 9 per L for the lowest dose and 675 × 10 9 per L for the highest dose. Endogenous TPO levels also increased 91 …”

“…Endogenous TPO levels also increased. 91 AMG 531 (aTPO nonpeptide mimetic) has been studied in a Phase II trial of 48 healthy subjects, who received single doses ranging from 0.3 to 10 mg per kg (intravenous) and 0.1 to 2.0 mg per kg (subcutaneous). A dose-dependent effect on the PLT count was observed and the PLT increase began on Day 5 and peaked on Days 12 to 16.…”

Pharmacokinetic and Pharmacodynamic Modeling of Pegylated Thrombopoietin Mimetic Peptide (PEG‐TPOm) After Single Intravenous Dose Administration in Healthy Subjects

“…It can also stimulate megakaryocyte lineage‐specific growth and differentiation in vivo. After a single dose of 0.3 mg/kg in normal rats, PEG‐TPOm caused a 3‐fold rise in platelet counts and exhibited a significant effect on protection from chemotherapy‐induced thrombocytopenia 11 . At a similar dose, in vivo activity has also been demonstrated in mice, evidenced by a reduction in the severity and duration of thrombocytopenia following carboplatin chemotherapy (data on file).…”

“…10 Pegylated thrombopoietin mimetic peptide (PEG-TPOm) has been shown to be a potent TPO agonist in vitro with promising results for the treatment and the prevention of chemotherapy-induced thrombocytopenia. 11 The synthetic compound is composed of 2 identical 14-mer peptides and is covalently bound to a high molecular weight (approximately 20 kD) methoxy-polyethylene-glycol moiety from each terminal amino acid residue to improve the pharmacokinetic/ pharmacodynamic (PK/PD) and immunological properties. 12 In addition, the peptide sequences bear no homology with TPO, thus further reducing the potential for the generation of anti-TPO antibodies.…”

New drugs for familiar therapeutic targets: thrombopoietin receptor agonists and immune thrombocytopenic purpura

“…TPO mimetic peptides (TPOmp) can also be stabilized and their half‐lives prolonged by pegylation. PEG‐TPOmp, a pegylated peptide, has shown promising activity in preclinical and phase 1 studies (42). In cell‐based assays, PEG‐TPOmp is active at picomolar concentrations.…”