SB-497115 is an orally bioavailable, non-peptidyl, small molecule thrombopoietin receptor (TpoR) agonist under development for treatment of thrombocytopenia. SB-497115 requires TpoR to activate the JAK/STAT signalling pathway and stimulates transcription through STAT based and megakaryocyte specific (gpIIb) promoters. SB-497115 did not have activity on cell lines that expressed cytokine receptors other than TpoR (i.e., G-CSF, Epo, IL-3, Interferon -alpha or Interferon-gamma). To characterize the kinetics and specificity of SB-497115 in cells, multiple molecular markers for Tpo activity were measured. Western blot analysis for activation of the JAK2, STAT and MAPK pathways was performed using phospho-specific antibodies on lysates of UT7-Tpo cells treated with SB-497115. The kinetics and level of induction for pathway phosphorylation events were similar to those seen with Tpo. A proliferative response in the human Tpo-dependent cell line, UT7-Tpo, induced by SB-497115 was assayed by thymidine incorporation with an EC50 of 30 nM. SB-497115 was shown to be equivalent to rhTpo in the ability to induce differentiation of normal human bone marrow progenitors (CD34) into CD41+ cells of the megakaryocyte lineage, with an EC50 of 100 nM. SB-497115 specifically induced activity on cells expressing only human or chimpanzee TpoR. In a randomized, single blind, placebo-controlled, parallel group, phase I study conducted in 72 healthy male subjects, SB-497115 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. SB-497115 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. SB-497115 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. In conclusion, SB-497115 is the first non-peptide small molecule TpoR agonist to demonstrate activity in human in vitro bone marrow assays and demonstrate pharmacological activity in humans.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]