International Journal of Hematology

, Volume 90, Issue 2, pp 157–165 | Cite as

A phase II, open-label, sequential-cohort, dose-escalation study of romiplostim in Japanese patients with chronic immune thrombocytopenic purpura

  • Yukari Shirasugi
  • Kiyoshi Ando
  • Satoshi Hashino
  • Toshiro Nagasawa
  • Yoshiyuki Kurata
  • Yuji Kishimoto
  • Koji Iwato
  • Tomoko Ohtsu
  • Dietmar P. Berger
Original Article

Abstract

This phase II, multicenter, open-label, sequential-cohort, dose-escalation study was designed to evaluate the safety and efficacy of romiplostim, a novel peptibody that increases platelet production, in Japanese patients with chronic immune thrombocytopenic purpura (ITP). Sequential cohorts of four patients each received romiplostim (1, 3, or 6 μg/kg) subcutaneously on days 1 and 8 of the dose-escalation phase. Patients who achieved platelet responses (doubling of baseline platelet counts to ≥50 × 109/L) continued romiplostim weekly during the treatment-continuation phase. Romiplostim produced dose-dependent increases in mean and peak platelet counts. Five patients received romiplostim during the treatment-continuation phase, with platelet counts ≥50 × 109/L maintained in approximately half of the weekly assessments. Romiplostim was well tolerated. No severe, serious, or life-threatening adverse events were reported. No binding antibodies to romiplostim or thrombopoietin were detected. Romiplostim is safe and well tolerated in Japanese patients with chronic ITP and is effective in producing platelet count increases, consistent with the results from studies in non-Japanese patients. On the basis of these findings, a starting dose of 3 μg/kg was recommended for phase III evaluation of romiplostim in Japanese patients with chronic ITP.

Keywords

Immune thrombocytopenic purpura Romiplostim Thrombopoiesis Platelet production 

References

  1. 1.
    British Committee for Standards in Haematology General Hematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol. 2003;120:574–96. doi:10.1046/j.1365-2141.2003.04131.x.CrossRefGoogle Scholar
  2. 2.
    Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:995–1008. doi:10.1056/NEJMra010501.PubMedCrossRefGoogle Scholar
  3. 3.
    George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood. 1996;88:3–40.PubMedGoogle Scholar
  4. 4.
    McMillan R. The pathogenesis of chronic immune thrombocytopenic purpura. Semin Hematol. 2007;44:S3–11. doi:10.1053/j.seminhematol.2007.11.002.PubMedCrossRefGoogle Scholar
  5. 5.
    Bromberg ME. Immune thrombocytopenic purpura: the changing therapeutic landscape. N Engl J Med. 2006;355:1643–5. doi:10.1056/NEJMp068169.PubMedCrossRefGoogle Scholar
  6. 6.
    Cines DB, McMillan R. Management of adult idiopathic thrombocytopenic purpura. Annu Rev Med. 2005;56:425–42. doi:10.1146/annurev.med.56.082103.104644.PubMedCrossRefGoogle Scholar
  7. 7.
    George JN, Kojouri K, Perdue JJ, Vesely SK. Management of patients with chronic, refractory idiopathic thrombocytopenic purpura. Semin Hematol. 2000;37:290–8. doi:10.1016/S0037-1963(00)90107-0.PubMedCrossRefGoogle Scholar
  8. 8.
    Chang M, Nakagawa PA, Williams SA, Schwartz MR, Imfeld KL, Buzby JS, et al. Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro. Blood. 2003;102:887–95. doi:10.1182/blood-2002-05-1475.PubMedCrossRefGoogle Scholar
  9. 9.
    McMillan R, Wang L, Tomer A, Nichol J, Pistillo J. Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood. 2004;103:1364–9. doi:10.1182/blood-2003-08-2672.PubMedCrossRefGoogle Scholar
  10. 10.
    Kosugi S, Kurata Y, Tomiyama Y, Tahara T, Kato T, Tadokoro S, et al. Circulating thrombopoietin level in chronic immune thrombocytopenic purpura. Br J Haematol. 1996;93:704–6. doi:10.1046/j.1365-2141.1996.d01-1702.x.PubMedCrossRefGoogle Scholar
  11. 11.
    Mukai HY, Kojima H, Todokoro K, Tahara T, Kato T, Hasegawa Y, et al. Serum thrombopoietin (TPO) levels in patients with amegakaryocytic thrombocytopenia are much higher than those with immune thrombocytopenic purpura. Thromb Haemost. 1996;76:675–8.PubMedGoogle Scholar
  12. 12.
    Kuter DJ. New thrombopoietic growth factors. Blood. 2007;109:4607–16. doi:10.1182/blood-2006-10-019315.PubMedCrossRefGoogle Scholar
  13. 13.
    Nomura S, Dan K, Hotta T, Fujimura K, Ikeda Y. Effects of pegylated recombinant human megakaryocyte growth and development factor in patients with idiopathic thrombocytopenic purpura. Blood. 2002;100:728–30. doi:10.1182/blood.V100.2.728.PubMedCrossRefGoogle Scholar
  14. 14.
    Li J, Yang C, Xia Y, Bertino A, Glaspy J, Roberts M, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98:3241–8. doi:10.1182/blood.V98.12.3241.PubMedCrossRefGoogle Scholar
  15. 15.
    Broudy VC, Lin NL. AMG531 stimulates megakaryopoiesis in vitro by binding to Mpl. Cytokine. 2004;25:52–60. doi:10.1016/j.cyto.2003.05.001.PubMedCrossRefGoogle Scholar
  16. 16.
    Nichol JL. AMG 531: an investigational thrombopoiesis-stimulating peptibody. Pediatr Blood Cancer. 2006;47:723–5. doi:10.1002/pbc.20972.PubMedCrossRefGoogle Scholar
  17. 17.
    Bussel JB, Kuter DJ, George JN, McMillan R, Aledort LM, Conklin GT, et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med. 2006;355:1672–81. doi:10.1056/NEJMoa054626.PubMedCrossRefGoogle Scholar
  18. 18.
    Newland A, Caulier MT, Kappers-Klunne M, Schipperus MR, Lefrere F, Zwaginga JJ, et al. An open-label, unit dose-finding study of AMG 531, a novel thrombopoiesis-stimulating peptibody, in patients with immune thrombocytopenic purpura. Br J Haematol. 2006;135:547–53. doi:10.1111/j.1365-2141.2006.06339.x.PubMedCrossRefGoogle Scholar
  19. 19.
    Wang B, Nichol JL, Sullivan JT. Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clin Pharmacol Ther. 2004;76:628–38. doi:10.1016/j.clpt.2004.08.010.PubMedCrossRefGoogle Scholar
  20. 20.
    Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008;371:395–403. doi:10.1016/S0140-6736(08)60203-2.PubMedCrossRefGoogle Scholar
  21. 21.
    Kumagai Y, Fujita T, Ozaki M, Sahashi K, Ohkura M, Ohtsu T, et al. Pharmacodynamics and pharmacokinetics of AMG 531, a thrombopoiesis-stimulating peptibody, in healthy japanese subjects: a randomized, placebo-controlled study. J Clin Pharmacol. 2007;47:1489–97. doi:10.1177/0091270007306563.PubMedCrossRefGoogle Scholar
  22. 22.
    Nakagawa M. Idiopathic thrombocytopenic purpura: a practice guideline for diagnosis and treatment of intractable diseases. ed Rev. ed. Tokyo: Roppo shuppansha; 2001.Google Scholar
  23. 23.
    Bussel JB, Kuter DJ, Pullarkat V, Lyons RM, Guo M, Nichol JL. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic itp. Blood. 2009;113:2161–71. doi:10.1182/blood-2008-04-150078.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2009

Authors and Affiliations

  • Yukari Shirasugi
    • 1
  • Kiyoshi Ando
    • 1
  • Satoshi Hashino
    • 2
  • Toshiro Nagasawa
    • 3
  • Yoshiyuki Kurata
    • 4
  • Yuji Kishimoto
    • 5
  • Koji Iwato
    • 6
  • Tomoko Ohtsu
    • 7
  • Dietmar P. Berger
    • 8
  1. 1.Tokai University HospitalIseharaJapan
  2. 2.Hokkaido University HospitalSapporoJapan
  3. 3.Tsukuba University HospitalTsukubaJapan
  4. 4.Osaka University HospitalSuitaJapan
  5. 5.Kansai Medical University Takii HospitalMoriguchiJapan
  6. 6.Hiroshima Red Cross Hospital and Atomic-Bomb Survivors HospitalHiroshimaJapan
  7. 7.Amgen KKTokyoJapan
  8. 8.Amgen Inc., One Amgen Center DriveThousand OaksUSA

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