A Phase 2 Placebo Controlled Study Evaluating the Platelet Response and Safety of Weekly Dosing with a Novel Thrombopoietic Protein (AMG531) in Thrombocytopenic Adult Patients (pts) with Immune Thrombocytopenic Purpura (ITP).

AMG531(A) is a novel thrombopoietic agent that binds and activates the thrombopoietin receptor. This study was a multicenter, randomized, double blind placebo (P) controlled Phase 2 study. The objective was to determine a weekly dose of A that demonstrates a satisfactory safety profile and elevates platelet (plt) counts (cts) to a range of ≥50x10⁹/L and <450x10⁹/L in pts with ITP. There were 6-weeks of treatment (no dose adjustment) and 6-weeks follow-up. Pts were randomized (8:2, A:P) in 2 cohorts of 1μg/kg and 3μg/kg. Major eligibility criteria were: baseline plt ct of <30x10⁹/L (or <50x10⁹/L if on corticosteroids), ≥18 and <65 yrs of age, diagnosis of ITP for 3 months, having 1 ITP treatment and no history of thrombosis. Pts were consented and were dosed on day 1 and weekly unless the plt ct exceeded 500x10⁹/L.

Twenty-one pts were enrolled with the following demographics: 15/21 (71%) females, median age 49 yrs (range 19–64), 15/21 (71%) post splenectomy, 7/21 (33%) receiving corticosteroids. Median baseline plt cts were 16x10⁹/L (range 4–49x10⁹/L). Pts were balanced for these parameters across groups. Safety was evaluated in all pts and efficacy was evaluated in 20 pts. Study drug was discontinued in 3 pts (A) early due to high plt cts (per protocol) and 1 pt (P) discontinued due to an adverse event (AE) (intracranial hemorrhage[ICH]). Plt ct responses were determined excluding effects of rescue medications. Seven of the 8 (88%) A pts (1μg/kg) achieved the targeted level compared to 3/8 (38%) in the 3μg/kg group; 2 additional pts in the 3 μg/kg group exceeded 450x10⁹/L. Of the responding pts in the 1μg/kg group 57% had had a splenectomy. The median time to response was observed at the second study visit (day 8). The median number of weekly vists with a plt ct within the target plt level was 3 (range 1–7) and 5 (range 1–7) for the 1 and 3μg/kg groups, respectively. One pt on P had a sustained plt increase to the normal range following 6 injections. No safety concerns were identified asside from transient thrombocytopenia in 1 pt. Two P pts reported 3 serious AEs (asthma, DVT and ICH) and 1 pt in the 3μg/kg group reported 3 serious AEs after completing A treatment (contusion (bruising), hemorrhage and transient thrombocytopenia). The most frequently reported AEs (A vs P)were: contusion (53% and 50%) epistaxis (41% and 50%), headache (29% and 0%), and oral mucosal blisters (29% and 0%). Hgb, WBC and blood chemistry and coagulation variables remained stable over the study period with no clinically significant on-study changes. No anti-AMG531 or anti-TPO antibodies were detected.

In summary, AMG531 was well tolerated and both doses were able to increase plt cts within the targeted range. With the 1μg/kg dose maintaining cts within the target. The response variability suggests that individual dose adjustment will be required to achieve the desired outcome.