AMG 531 is a novel platelet-stimulating peptibody that targets the thrombopoietin (TPO) receptor, resulting in an increased production of platelets. AMG 531 lacks sequence homology to native TPO. To date, AMG 531 has been administered in two phase 1 studies in a total of 56 healthy volunteers and in three phase 2 studies, with the option to continue in an open-label extension study, in a total of 57 patients with immune thrombocytopenic purpura (ITP). In general, no deaths or detectable neutralizing antibodies have occurred across the AMG 531 development program. In the two phase 1 studies, AMG 531 increased platelet counts in a dose-response manner when administered as a single subcutaneous (SC) or intravenous (IV) dose of ≥ 1.0 μg/kg. The dynamics of the platelet response were as expected based on experience with other Mpl ligands. Single doses of AMG 531 ≤ 10.0 μg/kg were well tolerated. No deaths, serious or severe adverse events, or other events of clinical importance were reported at any dose administered (0.1, 0.3, 1.0, and 2.0 μg/kg SC; 0.3, 1.0, and 10.0 μg/kg IV). Commonly reported adverse events in healthy subjects receiving AMG 531 were mild to moderate headache (13% incidence in both studies), malaise/fatigue (4% and 6%), and various flu-like reactions. In the phase 2 studies in patients with ITP, AMG 531 was administered SC using weight-based dosing in all but one study. The maximum dose administered (in the extension study) was 23 μg/kg; most patients received doses of 3 to 9 μg/kg. AMG 531 has been administered as frequently as weekly for > 24 weeks. To date, three studies have been completed: two studies of two administrations on day 1 and 15, administered as unit (μg) doses in one study (N=16 and N=24, respectively), one placebo-controlled study of 6 weeks’ duration with weekly dosing (AMG 531 N=17; placebo N=4). One open-label extension (N=26) is ongoing. AMG 531 has been generally well tolerated in ITP patients. Most of the reported adverse events have been mild to moderate in severity; no dose-related trends have been observed. Across the four studies, the most commonly reported adverse events in patients receiving AMG 531 were headache (29%–54% incidence), contusion (15%–53%), and epistaxis (13%–41%). In the 6-week, weekly-dosing study, contusion and epistaxis were each reported for 50% and 41% of placebo-treated patients, respectively. Across the phase 2 studies, five patients treated with AMG 531 have experienced serious adverse events deemed as serious, unexpected, and reported as related to study drug. These include worsening of thrombocytopenia in three patients after completing treatment, headache and elevated LDH in one patient, and diffuse reticulin formation in the bone marrow reported as myelofibrosis in one patient. The reticulin formation is hypothesized to be due to an excessive accumulation of megakaryocytes in the bone marrow. AMG 531 was discontinued, and a follow-up bone marrow (after 3 months) showed improvement in reticulin. In summary, AMG 531 has been generally well tolerated and able to stimulate platelet production in a dose-response manner in healthy volunteers and ITP patients. Results suggest that both unit dosing and weight-based dosing provide a predictable platelet response. AMG 531 may represent a new treatment option for thrombocytopenic patients with ITP. Safety surveillance is ongoing to further establish the safety profile of AMG 531.

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