New drugs for familiar therapeutic targets: thrombopoietin receptor agonists and immune thrombocytopenic purpura

Abstract

Various agents to treat immune thrombocytopenic purpura (ITP) have been developed on the principle that stimulating the thrombopoietin (TPO) receptor would increase platelet production. First-generation agents--recombinant human thrombopoietin (rHuTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG rHuMGDF)--showed promise, but observations of antibody formation to PEG rHuMGDF led to the discontinuation of development of both agents. Second-generation agents--the TPO peptide mimetics, TPO non-peptide mimetics, and TPO agonist antibodies--have been developed to reduce or eliminate the problem of antigenicity. Clinical studies for some of these agents, such as AMG 531 (romiplosim, Nplate) and eltrombopag (Promacta), are demonstrating their relative safety and efficacy in increasing platelet counts in patients with ITP; AMG 531 and eltrombopag are in late-stage clinical development and are able to stimulate platelet production in patients with ITP. Some differences in safety profiles have been described and are undergoing further study. There are currently seven second-generation TPO receptor agonists that have been reported in the literature, representing the potential advantages--and continuing challenges--with this novel class of platelet-stimulating therapies for ITP and possibly thrombocytopenia in other disease states as well.

Platelet factor 4 regulates megakaryopoiesis through low-density lipoprotein receptor–related protein 1 (LRP1) on megakaryocytes

“…42 We have already demonstrated this for CIT,7 and in unpublished data (M.P.L., March 2009) found the same for radiation-induced thrombocytopenia. We propose that the 25% of patients showing less than acceptable responses to TPO mimetic therapy [43][44][45][46][47] may have release an excess of intramedullary PF4.In summary, the studies reported here extend our understanding of the underlying receptor and target cell in PF4's negative paracrine effect on megakaryopoiesis and extend the potential therapeutic targets to limit thrombocytopenia secondary to intramedullary PF4 release. These studies also highlight the transient presence of LRP1 on developing megakaryocytes and extend the range of activities in which this receptor participates during megakaryopoiesis.…”

“…42 We have already demonstrated this for CIT, 7 and in unpublished data (M.P.L., March 2009) found the same for radiation-induced thrombocytopenia. We propose that the 25% of patients showing less than acceptable responses to TPO mimetic therapy [43][44][45][46][47] may have release an excess of intramedullary PF4.…”

The biology of thrombopoietin and thrombopoietin receptor agonists

“…Out of these efforts have come two TPO receptor agonists, romiplostim and eltrombopag [11,12,[62][63][64].…”

Comparative analysis of human ex vivo–generated platelets vs megakaryocyte-generated platelets in mice: a cautionary tale

“…Thrombopoietin mimetics increase platelet counts in some thrombocytopenias. 12 In others, donor platelet transfusions remain the mainstay of care. 13 The need for platelet transfusions has been increasing so understanding thrombopoiesis and developing platelets from ex vivo-derived (EV) human megakaryocytes, especially from self-renewing cells such as embryonic stem cells and induced pluripotent stem cells (iPSCs), [14][15][16][17][18] have been investigated.…”