Long-Term Dosing of AMG 531 Is Effective and Well Tolerated in Thrombocytopenic Patients with Immune Thrombocytopenic Purpura.

AMG 531 is a novel platelet-stimulating peptibody that targets the TPO receptor, resulting in increased production of platelets. This ongoing, open-label study assessed the safety and efficacy of long-term AMG 531 dosing in ITP patients. Eligible patients have completed a previous AMG 531 study in ITP, are ≥18 years of age, have a baseline platelet count ≤50 x 10⁹/L, with no recent significant change in medical history. The AMG 531 starting dose is 1μg/kg by SC injection with dose adjustment to an original maximum of 30μg/kg, since reduced to 15μg/kg. Patients are treated weekly unless the platelet count is >400x10⁹/L. Concurrent corticosteroids can be tapered when the platelet count is ≥50x10⁹/L. Preliminary data are available for 26 patients treated for up to 24 weeks: 17 women and 9 men; mean age, 48.4±11.6 (SD) years; mean baseline platelet count, 18.5±12.3 (SD) x10⁹/L. Twenty-one patients (80.8%) had undergone a splenectomy before study entry; 6 (23.1%) were receiving concurrent corticosteroids for ITP. Twenty-one of 26 patients (80.8%) had a protocol-defined platelet response to AMG 531 (doubling of the baseline platelet count and ≥50x10⁹/L). The mean AMG 531 dose at the first response was 3.7±2.7 (SD) μg/kg (at median 5 weeks); the mean dose at week 24 was 7.2±4.2 (SD) μg/kg. Twelve of 26 patients (46.2%) had a durable platelet response (doubling of the baseline count and ≥50x10⁹/L at 6 or more of weeks 17–24). Twenty patients (76.9%) had a platelet count ≥100x10⁹/L at least once; 7 (26.9%) had a platelet count ≥400x10⁹/L. Of 6 patients on concurrent corticosteroids, 3 discontinued treatment and 2 had a ≥25% dose reduction. At least 1 serious adverse event was reported in 4 patients: anal fistula (unrelated to treatment), adverse drug reaction (unrelated), multiple sclerosis relapse (unrelated), bone pain (related), and diffuse reticulin formation in the bone marrow reported as myelofibrosis (related). Reticulin formation is hypothesized as due to excessive accumulation of megakaryocytes in the bone marrow. AMG 531 was discontinued, and a bone marrow 3 months later showed improvement. One patient experienced adverse events (musculoskeletal pain and headache) resulting in withdrawal from the study. No neutralizing antibodies have been detected to date. In summary, repeated exposure to AMG 531 has been generally well tolerated in this ongoing study. A total 80.8% of patients achieved a platelet response, defined as doubling of the baseline count and ≥50x10⁹/L. Individualized weekly doses of AMG 531 may provide a therapeutic option in ITP, potentially enabling patients to taper off long-term corticosteroid therapy.