Pharmacodynamics of Caplacizumab in Healthy Volunteers and Phase 2/3 Trial Patients with Immune-mediated Thrombotic Thrombocytopenic Purpura

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by autoantibody-mediated deficiency of ADAMTS13 activity, leading to formation of platelet-rich microthrombi. The inhibitory effect of caplacizumab on von Willebrand factor (VWF)-platelet interactions and its rapid kinetics were characterized. Post hoc analyses of caplacizumab dosing were performed using data from the phase 1 healthy volunteers (NCT03172208) trial and phase 2 TITAN (NCT01151423)/phase 3 HERCULES (NCT02553317) trials of patients with iTTP. The time course for inhibition of VWF activity was analyzed using the VWF ristocetin cofactor activity (VWF:RCo) assay. Most healthy volunteers with intravenous (IV) dosing (15/16 [94%]) and half of participants (8/16) with subcutaneous dosing achieved VWF:RCo activity suppression < 20% with caplacizumab at 1 hour; all participants achieved VWF:RCo suppression < 20% at 3 hours. A majority of patients with iTTP achieved VWF:RCo activity suppression < 20% postfirst IV caplacizumab dose in TITAN at 5 to 10 minutes (8/11 [72.7%]) and almost all in HERCULES at day 2 (62/64 [96.9%]); suppression was maintained throughout the first 5 weeks, with return to baseline values by the first visit after discontinuation (follow-up period day 3 in TITAN and day 7 in HERCULES). In a combined analysis of TITAN and HERCULES, median (IQR) change in VWF:RCo activity from baseline to day 2 was 90.2% (119.5, 61.5) in the caplacizumab group and 12.6% (20.0, 33.8) in the placebo group. This post hoc analysis demonstrated the pharmacodynamics of the rapid inhibitory effect of caplacizumab on VWF-platelet interaction (i.e., VWF:RCo suppression < 20%) that does not appear to be impacted by TPE in patients with iTTP.