THROMBOPOIETIC AGENTS

Last update: 01/10/2009

 

Preclinical Activity of Eltrombopag (SB-497115), an Oral, Non-peptide Thrombopoietin Receptor Agonist. Stem Cells. 2008 Nov 26. [Epub ahead of print]The in vivo activity of eltrombopag was demonstrated by an increase of up to 100% in platelet numbers when administered orally (10 mg/kg/d for 5 d) 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.

Improved quality of life for romiplostim-treated patients with chronic immune thrombocytopenic purpura: results from two randomized, placebo-controlled trials. Br J Haematol. 2008 Nov 11. [Epub ahead of print]. Data pooled from the two trials, adjusted for splenectomy status, showed significant improvement for romiplostim-treated patients in six scales

Romiplostim.

Nat Rev Drug Discov. 2008 Nov;7(11):887-8. In August 2008, romiplostim (Nplate; Amgen), a thrombopoietin receptor agonist, was approved by the US FDA for the treatment of thrombocytopaenia in patients with chronic immune thrombocytopaenic purpura who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy.

Thrombopoietin and Thrombopoietin Mimetics in the Treatment of Thrombocytopenia.

Annu Rev Public Health. 2008 Oct 31. [Epub ahead of print] In 2008 two new drugs that mimic the effect of TPO became available to treat thrombocytopenia. Romiplostim is a TPO peptide mimetic given by subcutaneous injection that activates the TPO receptor by binding to the distal hematopoietic receptor domain just like TPO. Eltrombopag is a TPO nonpeptide mimetic administered orally that activates the TPO receptor by binding to the transmembrane domain. Both increase the platelet count in healthy humans as well as in >80% of patients with immune thrombocytopenic purpura (ITP). Ongoing studies should establish the incidence of these complications and determine the efficacy of these new agents in a variety of other thrombocytopenic conditions. Expected final online publication date for the Annual Review of Medicine Volume 60 is January 07, 2009. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates

The use of second-generation thrombopoietic agents for chemotherapy-induced thrombocytopenia.

Curr Opin Oncol. 2008 Nov;20(6):690-6. The second generation of thrombopoietic agents has been shown to correct thrombocytopenia in selected diseases with a minimum of side effects. Looking forward, there is great potential for their use in other forms of thrombocytopenia, including chemotherapy-induced thrombocytopenia, but there are also many questions remaining regarding their best and safest use.

The effect of a novel, small non-peptidyl molecule butyzamide on human thrombopoietin receptor and megakaryopoiesis.

Haematologica. 2008 Aug 25. [Epub ahead of print] Butyzamide is an orally bioavailable human Mpl activator, and appears to have potential for clinical development as a therapeutic agent for patients with thrombocytopenia

Emerging treatments for thrombocytopenia: Increasing platelet production.

Drug Discov Today. 2008 Jul 15. [Epub ahead of print] This article reviews second generation thrombopoietic factors and those recently discovered regulators of megakaryopoiesis

The effect of interleukiciated with tyrosine kinase inhibitor therapy n 11 on thrombocytopenia assoin patients with chronic myeloid leukemia.

Cancer. 2008 Jul 15. [Epub ahead of print]  The current results indicated that IL-11 may correct thrombocytopenia associated with TKI therapy for patients with CML and that it has a favorable toxicity profile.

Thrombocytopenia in liver disease.

Curr Opin Hematol. 2008 Sep;15(5):473-80. New insights into the pathophysiological mechanisms of thrombocytopenia in patients with liver disease have provided interesting clinical reflex. In these patients, novel therapies for treating thrombocytopenia seem promising, although it remains to be established whether treating thrombocytopenia may help improve liver disease-associated coagulopathy.

Pharmacodynamics and Pharmacokinetics of the Novel Thrombopoietin Mimetic Peptide RWJ-800088 in Humans.

Clin Pharmacol Ther. 2008 May 21. [Epub ahead of print] RWJ-800088 is a novel thrombopoietin mimetic peptide for the treatment of thrombocytopenia.

Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial.

Lancet. 2008 Feb 2;371(9610):395-403. Romiplostim was well tolerated, and increased and maintained platelet counts in splenectomised and non-splenectomised patients with ITP. Many patients were able to reduce or discontinue other ITP medications. Stimulation of platelet production by romiplostim may provide a new therapeutic option for patients with ITP.

Thrombopoietin mimetic agents in the management of immune thrombocytopenic purpura.

Semin Hematol. 2007 Oct;44(4 Suppl 5):S35-45. Review

Review article: pharmacological approaches for the treatment of thrombocytopenia in patients with chronic liver disease and hepatitis C infection.

Aliment Pharmacol Ther. 2007 Nov;26 Suppl 1:29-39. Results from clinical trials with these agents in healthy subjects confirm that activation of thrombopoiesis via the TPO pathway is an effective method of stimulating platelet production. This approach may provide safer, more effective treatment for thrombocytopenia in patients with chronic liver disease. Several of these agents are currently being tested in large scale trials.

Novel thrombopoietic agents.

Hematology Am Soc Hematol Educ Program. 2007;2007:106-13. A "second-generation" thrombopoietic agents without homology to thrombopoietin were developed. In the past 5 years, these second-generation thrombopoeitic growth factors have undergone substantial clinical development and have demonstrated safety, tolerability and efficacy in subjects with ITP and hepatitis C-related thrombocytopenia. These completed studies, many of which are available only in abstract form, and other ongoing studies suggest that thrombopoietic agents will enhance the hematologist's ability to manage these and other causes of thrombocytopenia.

Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C.

N Engl J Med. 2007 Nov 29;357(22):2227-36. Eltrombopag therapy increases platelet counts in patients with thrombocytopenia due to HCV-related cirrhosis, thereby permitting the initiation of antiviral therapy.

Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura.

N Engl J Med. 2007 Nov 29;357(22):2237-47.Eltrombopag increased platelet counts in a dose-dependent manner in patients with relapsed or refractory ITP.

Biologic aspects of thrombopoietin and the development of novel thrombopoietic agents for clinical use.
Curr Drug Discov Technol. 2007 Oct;4(3):162-73. Although clinical trials with first generation thrombopoietic agents were abruptly discontinued after the development of TPO autoantibodies had been observed, non-antigenic second generation thrombopoietic growth factors with unique pharmacological properties have been developed. These include TPO peptide mimetics (AMG 531 and Fab59), TPO non-peptide mimetics (eltrombopag, NIP-004, and AKR-501) and TPO agonist antibodies. Review

New therapeutic options for adult chronic immune thrombocytopenic purpura: a brief review.
Vox Sang. 2007 Oct 31; [Epub ahead of print] There are no controlled trials with rituximab, but clinical experience has shown a success rate of 40% to 60%. Encouraging phase 1 and 2 data have been published for both thrombopoietin mimetics; preliminary data from an open-label extension trial with AMG 531 and from phase 3 studies with eltrombopag further confirm their efficacy

Maintaining the dose intensity of ICE chemotherapy with a thrombopoietic agent, PEG-rHuMGDF, may confer a survival advantage in relapsed and refractory aggressive non-Hodgkin lymphoma.
Ann Oncol. 2007 Sep 14; [Epub ahead of print] Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) ameliorated thrombocytopenia, improved platelet recovery, and maintained ICE dose intensity. Potential survival advantages conferred by maintaining dose intensity require validation with newer thrombopoietic agents.

Cytokines for the treatment of thrombocytopenia.
Semin Hematol. 2007 Jul;44(3):166-82. Review

[Effect of recombinant human interleukin 11 on the platelet after hematopoietic stem cell transplantation in patients with leukemia.]
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2007 Jun;32(3):433-6. Chinese. rhIL-11 has definite recuperative effect on the recovery of the platelet after PBSCT. There is little side effect, and it can be accepted.

Chemotherapy-induced thrombocytopenia derives from the selective death of megakaryocyte progenitors and can be rescued by stem cell factor.
Cancer Res. 2007 May 15;67(10):4767-73. Apoptosis of megakaryocyte progenitors is a major cause of chemotherapy-induced thrombocytopenia. Stem cell factor may be used to prevent platelet loss in cancer patients with c-kit-negative tumors.

Phase I clinical study of eltrombopag, an oral, non- peptide thrombopoietin receptor agonist.
Blood. 2007 Feb 27; [Epub ahead of print] Eltrombopag increased platelet counts in a dose dependent manner.  Eltrombopag is a once daily, oral TpoR agonist with demonstrated thrombopoietic activity in human subjects, encouraging further studies in patients with thrombocytopenia.

The role of interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with solid tumors, lymphoma, acute myeloid leukemia and bone marrow failure syndromes.
Leuk Lymphoma. 2007 Jan;48(1):9-15. With the use of recombinant human IL-11 in both malignant and non-malignant conditions, adverse reactions often seen with platelet transfusions, such as transfusion reactions, viral and bacterial infections and platelet refractoriness, can now be decreased or avoided.

New thrombopoietic growth factors.
Blood. 2007 Feb 8; [Epub ahead of print] All second generation thrombopoietic growth factors stimulate growth of TPO-dependent cell lines via JAK2/STAT signaling pathways and increase platelet counts in animals. When tested in healthy humans, TPO peptide and non-peptide mimetics produced a dose-dependent rise in platelet count. AMG 531 and eltrombopag markedly increase platelet counts in patients with immune thrombocytopenic purpura, without significant adverse effects. One or more second generation thrombopoietic growth factors should soon be clinically available for treating thrombocytopenic disorders.