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

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.

Eltrombopag: an update on the novel, non-peptide thrombopoietin receptor agonist for the treatment of immune thrombocytopenia

“…The ultimate responses to eltrombopag are similar to those observed with endogenous TPO with stimulation of transcription through STAT-based and megakaryocytespecific promoters [37]. However, studies have reported some differences in activation of downstream targets of the TPO receptor between eltrombopag and human recombinant TPO (hrTPO).…”

“…However, treatment with eltrombopag did not result in a significant change in differentiation nor maturation characteristics of the granulocytic/monocytic or the erythrocytic lineages, indicating that eltrombopag preferentially acts on progenitor and precursor cells harbouring megakaryocytic potential [38]. Thus, eltrombopag is a true agonist of the human TPO receptor that is able to act on megakaryocytes and their progenitors in a manner similar to TPO with the potential to induce differentiation and proliferation of megakaryocytes and ultimately relieve thrombocytopenia [37].…”

“…The assays confirmed the ability of eltrombopag to activate signalling in cells expressing the TPO receptor but showed that it had no effect on cells expressing only interferon-γ, granulocyte macrophage-colony stimulating factor (GM-CSF), G-CSF, erythropoietin or interleukin-3 receptors [36]. The fact that eltrombopag lacks activity against cells expressing growth factor receptors other than TPO, even those acting through the JAK/STAT signalling pathway, suggests that the activation of JAK/STAT by eltrombopag is due to the specific activation of the TPO receptor [37].…”

“…2). Since eltrombopag and TPO do not bind to the same site, competitive binding is avoided, and eltrombopag and TPO confer additive cellsignalling effects [37] (Fig. 2).…”

Eltrombopag and Improved Hematopoiesis in Refractory Aplastic Anemia

“…20 Eltrombopag does not compete with thrombopoietin for binding to c-MPL, since it binds in the membrane-spanning region outside the ligand-binding pocket of c-MPL, and it activates signaling through JAK-STAT (Janus-associated kinase-signal transducers and activators of transcription) and MAPK (mitogen-activated protein kinase) pathways. 22 Eltrombopag may stimulate hematopoiesis by non-competitive activation of c-MPL, despite elevated thrombopoietin levels, and it may activate signaling in a way that is distinct from that of thrombopoietin.…”