Safety Results Normalized to Time of Exposure during the Phase 3 HERCULES Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura

Scientific Research Question: In acquired thrombotic thrombocytopenic purpura (aTTP), accumulation of ultra large von Willebrand factor (ULvWF) multimers leads to formation of microthrombi. Caplacizumab blocks the adhesion of vWF to platelets and prevents microthrombus formation. The key results of the phase 3 HERCULES study of caplacizumab for the treatment of aTTP were reported previously (Scully et al., Blood 2017 130:LBA-1). Here, we present the results of a post-hoc analysis of the safety results normalized to time of exposure to the study drug.

Methods: Patients with an episode of aTTP were randomized 1:1 to placebo or 10 mg caplacizumab, in addition to daily PE and corticosteroids. A single IV dose of study drug was given before the first on-study PE and an SC dose was given daily during the PE period and 30 days thereafter. In case of unresolved disease activity, treatment extension for a maximum of 4 weeks was encouraged. In case of recurrence during the DB treatment period, patients were switched to open-label (OL) caplacizumab, together with re-initiation of daily PE. Analysis of treatment-emergent adverse events (TEAEs) was performed on the study's safety population. To control for differences in exposure time, incidence rates (IR) per 100 patient months were calculated as 100 x number of events/(total number of months observed within analysis period, summed for all patients in the treatment group).

Results: The safety population consisted of 71 caplacizumab-treated and 73 placebo-treated patients. 28 patients were switched to OL treatment with caplacizumab (26 from the DB placebo group). Consequently, the median (min; max) exposure time was 35 (1; 65) days for the DB caplacizumab group and 23 (2; 66) days for the DB placebo group. After normalization for exposure time, the IR of any TEAE was lower in the caplacizumab group (535.6) vs. placebo (821.7). TEAEs with a higher IR (≥5/100 subjects months difference) in the caplacizumab group vs. placebo were epistaxis (39.1 vs 3.3) and gingival bleeding (14.9 vs 1.7); TEAEs with a higher IR in the placebo group vs caplacizumab were TTP (48.3 vs 3.4), hypokalaemia (25.0 vs 5.7), contusion (40.0 vs 8.0). The IR of any SAE was 26.4 in the caplacizumab group and 83.3 in the placebo group. There were no SAEs with a higher IR in the caplacizumab group compared to placebo. SAEs with a higher IR in the placebo group vs. caplacizumab were TTP (48.3 vs 3.4) and anaphylactic transfusion reaction (5.0 vs 0).

Conclusions: After normalization to time of exposure, TEAEs occuring more frequently in the caplacizumab group were epistaxis and gingival bleeding, while TTP, hypokalemia, contusion, rash, imsomnia and hypertension occurred more frequently in the placebo group. This post-hoc analysis confirms the good tolerability of caplacizumab for the treatment of aTTP with mucocutaneous bleeding being the most relevant risk.