Risk Factors and Manageability of the Mucocutaneous Bleeding Profile Observed in aTTP Patients Treated with Caplacizumab during the Phase III HERCULES Study

Scientific Research Question: In acquired thrombotic thrombocytopenic purpura (aTTP) ultra large von Willebrand factor multimers cause systemic microvascular thrombosis. Caplacizumab blocks the adhesion of platelets to vWF and prevents formation of microthrombi. Results of the Phase 3 HERCULES study demonstrated the efficacy of caplacizumab in aTTP patients (Scully et al., Blood 2017;130:LBA-1). Consistent with its mode of action, an increase in mainly mild mucocutaneous bleeding events was observed in patients treated with caplacizumab. Here we report on the risk factors and manageability of these bleeding events.

Methods: Analyses were performed on the study's safety population. Bleeding-related treatment-emergent adverse events (TEAEs) were identified using the Standardized MedDRA (Medical Dictionary for Regulatory Activities) Query (SMQ) for ‘Hemorrhage’, excluding laboratory terms and the Preferred Term TTP. Bleeding-related TEAEs during the double-blind treatment period were analyzed in relation to the use of concomitant antithrombotic therapy, severity, and therapeutic interventions.

Results: The safety population consisted of 71 caplacizumab- and 73 placebo-treated patients. During the treatment period, at least one bleeding event was reported in 44 patients (62.0%; in total 108 events) in the caplacizumab group and 34 patients (46.6%; in total 61 events) in the placebo group. Twelve patients (16.9%) had a bleeding event while on concomitant antithrombotics in the caplacizumab group vs. 9 patients (12.3%) in the placebo group. In patients not receiving antithrombotics, or in patients in which the bleeding event occurred prior to onset of antithrombotic therapy, bleeding events occurred in 32 patients (45.1%) in the caplacizumab group vs. 26 patients in the placebo group (35.6%). The majority of bleeding TEAEs were of mild or moderate severity. The most common bleeding events in the caplacizumab group were epistaxis (23.9% of patients with mild events, 7.0% with moderate events), gingival bleeding (15.5% mild) and contusion (7.0% mild, 1.4% moderate). In the placebo group, contusion was the most frequently reported bleeding event (12.3% mild, 1.4% moderate). Severe bleeding TEAEs were epistaxis (treated with Wilate), gingival bleeding (treated with tranexamic acid), and upper gastrointestinal hemorrhage (requiring transfusion of red blood cells) each in 1 patient (1.4%) in the caplacizumab group. In the placebo group there was 1 severe (fatal) bleeding of hemorrhagic transformation stroke. Therapeutic intervention for bleeding events was reported in 14 patients (19.7%) in the caplacizumab group, compared to 2 patients (2.7%) in the placebo group.

Conclusions: The safety profile of caplacizumab was favorable. In line with its pharmacology, treatment with caplacizumab was associated with an increased risk of mucocutaneous bleeding. These events were generally mild to moderate, and the majority did not require therapeutic intervention.