Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist

Connie L Erickson-Miller,Kevin J Duffy,Jon Rosen,Shin-Shay Tian,Teresa S Sellers,Juan I Luengo,Evelyne Delorme,Amy J Landis,Elizabeth I Valoret,Christopher B Hopson,Stephen G Miller,Julian M Jenkins

doi:10.1634/stemcells.2008-0366

Abstract

Eltrombopag is a first-in-class, orally bioavailable, small-molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), which is being developed as a treatment for thrombocytopenia of various etiologies. In vitro studies have demonstrated that the activity of eltrombopag is dependent on expression of TpoR, which activates the signaling transducers and activators of transcription (STAT) and mitogen-activated protein kinase signal transduction pathways. The objective of this preclinical study is to determine if eltrombopag interacts selectively with the TpoR to facilitate megakaryocyte differentiation in platelets. Functional thrombopoietic activity was demonstrated by the proliferation and differentiation of primary human CD34+ bone marrow cells into CD41+ megakaryocytes. Measurements in platelets in several species indicated that eltrombopag specifically activates only the human and chimpanzee STAT pathways. The in vivo activity of eltrombopag was demonstrated by an increase of up to 100% in platelet numbers when administered orally (10 mg/kg per day for 5 days) to chimpanzees. In conclusion, eltrombopag interacts selectively with the TpoR without competing with Tpo, leading to the increased proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes and increased platelet production. These results suggest that eltrombopag and Tpo may be able to act additively to increase platelet production.

Highlights

Thrombocytopenia is a condition of an unusually low level of platelets in the blood and results from an imbalance between the production and destruction of platelets
The binding of Tpo to the thrombopoietin receptor (TpoR) on cells in the megakaryocyte pathway triggers the activation of the cytoplasmic tyrosine kinases Janus kinase (JAK)2 and tyrosine kinase 2, which in turn activate signal transducers and activators of transcription five (STAT)5, phosphoinositide-3 kinase, and Rasmitogen-activated protein kinase (MAPK) [8 –10]
We show that eltrombopag interacts with the TpoR without competing with Tpo, thereby activating intracellular signal transduction pathways additively with endogenous Tpo, leading to the increased proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes, and increased platelet production

Summary

Introduction

Thrombocytopenia is a condition of an unusually low level of platelets in the blood and results from an imbalance between the production and destruction of platelets. Thrombocytopenia can be associated with severe chronic liver disease due to the reduced production of the endogenous thrombopoietic growth factor, thrombopoietin (Tpo), and/or the increased sequestration of platelets [4]. In patients infected with the hepatitis C virus (HCV), thrombocytopenia may occur due to the myelosuppressive effects of the virus on the bone marrow [5]. Platelet production initially originates from megakaryocyte precursor cells in the bone marrow. The binding of Tpo to the thrombopoietin receptor (TpoR) on cells in the megakaryocyte pathway triggers the activation of the cytoplasmic tyrosine kinases Janus kinase (JAK) and tyrosine kinase 2, which in turn activate signal transducers and activators of transcription five (STAT), phosphoinositide-3 kinase, and Rasmitogen-activated protein kinase (MAPK) [8 –10].

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