This study is an open-label phase 1 study of a novel thrombopoietic agent, AMG531. AMG531 acts through activation of the receptor Mpl to stimulate the growth and maturation of megakaryocytes ultimately resulting in blood platelets (plts). Thrombocytopenic adult pts with ITP were enrolled into sequential cohorts of AMG531 at the assigned unit doses of 30, 100, 300, or 500 μg. There were to be 4 pts per cohort with additional pts in a confirmatory cohort at the selected dose (300 μg). Major eligibility criteria were: diagnosis of ITP as defined by the ASH Guidelines 3 months prior to study entry, baseline platelet (plt) count (ct) <30x109/L (<50x109/L if on corticosteroids), age >18 years and no history of thrombosis. Patients were to receive 2 administrations of AMG531 on study day 1 and 15 (or day 22 if plt cts were >50x109/L on day 15). Follow-up continued for 8 weeks after the last dose for safety. The primary objective was safety and the secondary objectives were related to plt response defined as doubling of baseline plt ct and ≥50x109/L and <450x109/L.

Sixteen pts were enrolled into 5 cohorts with the following demographics: 10/16 (63%) females, median age 50 years (range 20–84), 13/16 having had splenectomy (splx). Fourteen of the 16 pts received both administrations of AMG531, and 4 pts received the second dose on day 22. No safety issues or concerns were identified. Headache was the most frequently reported adverse event (AE) in 6/16 (38%) of pts. There were 3 serious AEs reported to be related to AMG531, headache and a transient LDH increase in one pt and thrombocytopenia reported after completing AMG531 in another. Hemoglobin, WBC, blood chemistry and coagulation variables remained stable over the study period and no clinically significant on-study changes were identified. No anti-AMG531 or anti-TPO antibodies were detected. Platelet responses were observed in some pts either the first or second administration in all dose groups. Evaluation of the responses after conversion of the unit (μg) dose to μg/kg demonstrated that in pts that received dose-equivalents of >1 μg/kg, 8/12 (67%) pts achieved the plt response criterion with either the first or the second administration of AMG531. Of these pts with plt responses 6/8 (75%) had previously had a splx. Plt responses were not related to splx status or baseline plt cts. These data suggest that by-weight dosing is appropriate in this pt population and support the need for more frequent dosing.

In summary, AMG531 was well tolerated at all doses tested and was capable of increasing plt cts in 67% of pts with ITP when doses equivalent to >1 μg/kg were administered. Future studies will explore the effects of long-term, weekly by-weight dosing with AMG531 to evaluate the durability of this response. These data suggest that stimulation of platelet production with AMG531 in pts with ITP may provide a new treatment option for ITP regardless of splx status.

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