An Oral, Non-Petide, Small Molecule Thrombopoietin Receptor Agonist Increases Platelet Counts in Healthy Subjects.

SB497115, is an orally bioavailable, small molecule thrombopoietin receptor agonist that induces differentiation and proliferation of megakaryocytes. In a randomized, single blind, placebo-controlled, parallel group, phase I study conducted in the UK in 72 healthy male subjects, SB497115 was administered as oral capsules once daily for 1 day and, after a 1 week washout, for 10 days at doses of 5 to 75 mg. Subjects were randomized into six groups of 12 subjects to receive either active or placebo medication in a ratio of 9:3. The study was conducted according to Good Clinical Practice and all subjects gave their written informed consent to participate in the study.

SB497115 was well tolerated in the study, there were no serious adverse events, no significant changes in laboratory or cardiovascular safety parameters and there was no observed relationship between the incidence or severity of adverse events and dose. Most adverse events were mild in intensity and self-limiting. SB497115 was shown to be orally bioavailable in humans with a linear pharmacokinetic profile suitable for a once daily oral medication. When administered at oral doses of 30mg and above for 10 days a dose dependent increase in the platelet count was observed, maximum platelet count was observed on days 14 to 16 following initiation of dosing. The dose dependent increase in platelet count is shown in the table below. On the basis of these safety, pharmacokinetic and pharmacodynamic data the oral thrombopoietin receptor agonist, SB497115, will be studied in phase II trials involving thrombocytopenic patients.

Preliminary Data: Mean Platelet Count (platelets/uL)