Pharmacology and Safety of SB-497115-GR, an Orally Active Small Molecular Weight TPO Receptor Agonist, in Chimpanzees, Rats and Dogs.

Abstract

SB 497115-GR is a small molecular weight Tpo receptor (TpoR) agonist that has properties similar to thrombopoietin (TPO), primarily inducing proliferation and differentiation of megakaryocytes from bone marrow progenitor cells. SB-497115-GR is being developed for the treatment of thrombocytopenias, such as immune thrombocytopenic purpura. In vitro and in vivo studies have demonstrated that SB-497115-GR has very distinct species specificity. SB-497115 or other molecules in this class induced dose dependent STAT activation in platelets from humans and chimpanzees but not in platelets from laboratory animal species commonly used in drug safety studies. In order to demonstrate in vivo activity of SB-497115-GR, a single dose and 5 daily dose pharmacology and safety study in chimpanzees was conducted. To support initiation of clinical trials, a comprehensive package of toxicology studies was conducted including studies up to 14 days duration in rats and dogs. All procedures involving the care and use of animals in these studies were reviewed and approved by the appropriate Institutional Animal Care and Use Committees. Female chimpanzees (1–3/group) were administered vehicle or SB-497115-GR at doses of 0.1 to 10 mg/kg/day by oral gavage. For toxicology studies, SB-497115-GR was administered orally to rats (10/sex/group) by gavage at doses of 3 to 40 mg/kg/day and to dogs (3/sex/group) by capsule at doses of 3 to 30 mg/kg/day for 14 days. SB-497115-GR was well tolerated in chimpanzees, rats and dogs at all doses tested. In chimpanzees, no treatment related increases in platelet counts were observed after administration of single doses of up to 10 mg/kg or 5 daily doses of up to 3 mg/kg/day. However, following 5 daily doses of 10 mg/kg/day SB-497115-GR, there was a 1.3- to 2.4-fold increase in circulating platelet counts in 3 chimpanzees. A similar change in reticulated platelet counts was observed preceding this increase. In contrast, there was no effect of treatment for up to 14 days on platelet counts in rats or dogs. In conclusion, SB-497115-GR, an orally bioavailable small molecular weight agonist of the TpoR, has been shown to increase platelet counts in chimpanzees. These in vivo data confirm the in vitro data demonstrating the unique species-specific effects of this novel Tpo receptor agonist on platelets and were predictive of a pharmacodynamic effect currently being observed in human clinical trials.

Comparative Efficacy and Safety of Thrombopoietin Receptor Agonists in Adults With Thrombocytopenia: A Systematic Review and Network Meta-analysis of Randomized Controlled Trial

“…Eltrombopag is an oral, small molecule, non-peptide TPO-RA. By interacting with the transmembrane domain of the receptor, this drug initiates thrombopoietin-receptor signaling, thereby inducing cell proliferation, differentiation and maturation in the megakaryocytic lineage ( Sellers et al, 2004 ). Romiplostim is a novel peptide molecule that stimulates the megakaryocytopoiesis and increases the platelet count in the same manner as TPO ( Wang et al, 2004 ).…”

Eltrombopag: the emerging evidence of its therapeutic value in thrombocytopenia

“…Data from sequencing studies suggested that thrombopoietin receptor agonists interact with the histine 499 and threonine 496 residues to either change the conformation of the receptor or induce dimerization, resulting in activation of the signal transduction pathways of the thrombopoietin receptor (Erickson-Miller et al 2004b). The species specificity was confirmed in vivo by the lack of effect of eltrombopag on platelet count in rats and dogs, in contrast to chimpanzees (Sellers et al 2004).…”

“…In-vivo eltrombopag was well tolerated in chimpanzees, rats, and dogs at all doses tested (Sellers et al 2004). Phase I data in healthy volunteers have shown that eltrombopag was well tolerated over a 16-day period with no serious adverse events reported.…”

“…The in-vivo activity of eltrombopag was initially demonstrated in chimpanzees (Sellers et al 2004). There was a 1.3-to 2.4-fold increase in platelet count in three chimpanzees following five daily doses of eltrombopag (10 mg/kg per day).…”

Use of Hematopoietic Growth Factor in the Management of Hematological Side Effects Associated to Antiviral Treatment for HCV Hepatitis

“…Recently, an oral thrombopoietin-receptor agonist, eltrombopag (SB-497115) has been shown to stimulate megakaryocyte proliferation and differentiation and to cause dose-dependent increases in platelet counts in chimpanzees and humans. 84 – 86 It appears that eltrombopag binds the TPO receptor at a distance from the binding site for TPO and appears to initiate signal transduction by a mechanism different from thrombocytopenic growth factors of first generation. 87 Thus, eltrombopag has an additive, and not competitive, effect on platelet production.…”