AMG 531 Promotes Thrombopoiesis in ITP

Abstract & Commentary

By Andrew S. Artz, MD, Section of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationship to this field of study.

Synopsis: ITP is usually a chronic condition in adults resulting from both platelet destruction and impaired production. This study summarizes the early phase experience in two trials for chronic refractory ITP of AMG 531, a novel thrombopoiesis stimulating protein. Among the 41 patients in total treated at a variety of doses given every 1-2 weeks, 68% showed a good response. No serious side effects occurred. AMG 531 appears promising as a thrombopoiesis stimulating agent in chronic ITP.

Source: Bussel JB, et al. AMG 531, a Thrombopoiesis-Stimulating Protein, for Chronic ITP. N Engl J Med. 2006;355:1672-1681.

Immune Thrombocytopenic Purpura (A/K/A/ Idiopathic Thrombocytopenic Purpura or ITP) is an acquired platelet disorder diagnosed by exclusion.1 The biology of ITP is heterogeneous. Interestingly, not only is there accelerated platelet destruction but also impaired megakaryopoiesis. Clinically, ITP is a characterized by mucocutaneous bleeding and a chronic course. A variety of treatments may be used as initial therapy, including glucocorticoids, IGIV and Anti-D (WinRho). Treatment for relapsed disease may incorporate any treatment employed as initial therapy as well as splenectomy, rituximab, other immunosuppressive agents, and even autologous stem cell transplantation.

The low incidence of serious bleeding from ITP 2 and considerable complications arising from therapy requires clinicians to exercise extreme caution in treatment. For example, chronic steroids can have devastating long-term toxicities. Authorities generally recommend avoiding treatment for chronic asymptomatic ITP with a platelet count above 30,000/uL. More effective and/or less toxic treatment alternatives are sorely needed, particularly for severe chronic ITP. Bussel and colleagues report promising results from an early phase clinical trial of a novel thrombopoiesis stimulating agent in patients with chronic ITP.

The report summarizes data of two studies across nine US institutions employing AMG 531, a novel thrombopoiesis stimulating protein. Eligibility criteria included age 18-65 years, ITP for at least 3 months, at least one line of prior therapy, and a platelet count of < 30,000/uL or < 50,000/uL for those on corticosteroids. The first study was an open-label, dose-escalation trial where AMG 531 was administered once subcutaneously and patients followed for 14 days and then a second dose could be considered. The second study was a double-blind, placebo-controlled study (4:1 assignment favoring AMG 531) where the study drug was administered once weekly for six weeks.

In the first phase, 24 patients were enrolled in six dose cohorts with a median platelet count of 11,000/uL. Twenty-one patients were enrolled in phase 2, of which 17 were assigned to AMG 531. The majority had previously undergone a splenectomy (79% in phase 1 and 67% in phase 2). No serious adverse events appeared related to AMG 531 although in some patients the platelet count fell lower than baseline transiently after discontinuing therapy. No antibodies to AMG 531 or thrombopoietin were detected. The overall response rate was 68% of achieving a platelet count > 50,000/uL and usually occurred within a week of therapy. In those receiving the 1 ug and 3 ug doses in the phase 2 portion, the mean platelet counts were 135,000/uL and 241,000/uL compared to 81,000/uL for placebo.


Bussel and colleagues report intriguing data employing AMG 531, a novel thrombopoiesis stimulating molecule exhibiting a protein structure unique from thrombopoietin. In the combined results of the phase 1 and 2 portions, ultimately 41 patients with chronic refractory ITP were treated at a variety of doses. A platelet count above 50,000/uL occurred in 68% of patients including those on the dose escalation portion.

While this trial evaluated only a small number of patients, the results are noteworthy in several respects. The study documents clinical activity employing a thrombopoiesis stimulating protein in ITP. Therapy aimed at increasing production is a dramatic departure from present therapies focused primarily at reducing platelet destruction. The study builds upon prior results using PEG-MGDF, a recombinant form of thrombopoietin. In early studies, PEG-MGDF improved platelet counts but also caused antibodies against thrombopoietin, leading to severe thromobocytopenia and cessation of drug development. In this study, no antibodies to AMG 531 or thrombopoietin were detected. Longer follow-up with repeated drug administration of AMG-531 will be needed to ensure antibodies do not develop. The fall in platelet count after drug discontinuation, presumably from reduced thrombopoietin levels as the megakaryocyte mass was expanded, necessitates further study as well.

ITP remains a challenging condition. While some patients may not require therapy, a subset either don't respond to therapy or more often have serious consequences from long-term treatment that may pose a more serious risk than bleeding from ITP. An agent working via a different mechanism, such as enhanced production, if safe, could play an important role in chronic refractory ITP as either a treatment alternative, or as a treatment adjunct.

The data derived from early phase studies hold promise but clearly requires much more clinical testing to determine an appropriate dose, ensure safety, and validate efficacy. We must also be cognizant that as a novel recombinant protein with a short duration of action, it would likely have considerable costs and require frequent drug administration. Whether AMG 531 will have a role in other conditions, such as chemotherapy induced thrombocytopenia, remains unknown. In conclusion, AMG 531 has activity in chronic refractory ITP warranting further testing.


1. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:995-1008.

2. Neylon AJ, et al. Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: a prospective study of a population-based cohort of 245 patients. Br J Haematol. 2003;122:966-974.