Risk Factors and Manageability of the Mainly Mild Mucocutaneous Bleeding Profile Observed in Attp Patients Treated with Caplacizumab during the Phase III Hercules Study
Authors: Cataland Spero R , Scully Marie , Peyvandi Flora , Coppo Paul , Knöbl Paul , Kremer Hovinga Johanna A. , Metjian Ara , De La Rubia Javier , Pavenski Katerina , Minkue Jessica , Sousa Rui Passos , Callewaert Filip , De Winter Hilde 
Published: October 2019

Abstract
Introduction : Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening autoimmune blood clotting disorder, manifested by systemic microvascular thrombosis leading to profound thrombocytopenia, hemolytic anemia, and organ ischemia. 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 mechanism 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 (i.e., all patients who received at least 1 administration of study drug). 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 events were analyzed in relation to the use of concomitant antithrombotic therapy and direct oral anticoagulants (DOACs), the severity of the bleeding events, and the requirement and type of therapeutic intervention. Bleeding-related TEAEs were analyzed during the double-blind treatment period.
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 antithrombotic therapy in the caplacizumab group vs. 9 patients (12.3%) in the placebo group. In patients not receiving antithrombotics, or in patients in whom the bleeding event occurred prior to onset of antithrombotic therapy, bleeding event occurred in 32 patients (45.1%) in the caplacizumab group vs. 26 patients in the placebo group (35.6%). Table 1 summarizes the most frequent bleeding events in relation to the use of antithrombotic therapy. Of note, 3 patients (4.2%) in the caplacizumab group vs. none in the placebo group received a DOAC while on study drug treatment (all administered for the treatment of major thromboembolic events). All 3 patients were reported with at least 1 bleeding event. One of these events was a SAE of menorrhagia which was treated with transfusion of red blood cells and resolved. Other events were mild AEs of epistaxis, injection site hemorrhage and gingival bleeding (all resolved without therapy). The majority of bleeding TEAEs were of mild or moderate severity (Table 2). The most common mild or moderate bleeding events in the caplacizumab group were epistaxis (27 mild events in 17 patients [23.9%] and 6 moderate events in 5 patients [7.0%]), gingival bleeding (12 mild events in 11 patients [15.5%]) and contusion (6 mild events in 5 patients [7.0%], and 1 patient [1.4%] with a moderate event). In the placebo group, contusion was the most frequently reported bleeding event (22 mild events in 9 patients [12.3%] and 2 moderate events in 1 patient [1.4%]). 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. Overall, therapeutic intervention for bleeding events was reported in 14 patients (19.7%) in the caplacizumab group for a total of 15 events (15/108 [13.9%]), compared to 2 patients (2.7%) in the placebo group for a total of 2 events (2/61 [3.3%]).
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. While the number of patients receiving DOACs was low, no increased risk for bleeding with antithrombotic therapy was observed.

Disclosures
Cataland: Alexion: Research Funding; Shire: Consultancy; Ablynx: Consultancy, Other: Member of Advisory Board. Scully:Novartis: Honoraria, Other: Member of Advisory Board, Speakers Bureau. Peyvandi:Novo Nordisk: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Kedrion: Consultancy; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Novo Nordisk: Speakers Bureau; Sobi: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Grifols: Speakers Bureau; Kedrion: Consultancy; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Grifols: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Grifols: Speakers Bureau; Kedrion: Consultancy; Sobi: Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Kedrion: Consultancy; Sobi: Speakers Bureau; Octapharma US: Honoraria; Roche: Speakers Bureau; Roche: Speakers Bureau; Octapharma US: Honoraria; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Kedrion: Consultancy; Octapharma US: Honoraria; Octapharma US: Honoraria; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau. Coppo:Ablynx: Consultancy. Knöbl:Ablynx: Consultancy, Other: Member of Advisory Board. Kremer Hovinga:Shire: Other: Member of Advisory Board, Research Funding; Ablynx: Other: Member of Advisory Board. Metjian:Ablynx: Other: Member of Advisory Board. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Minkue:Ablynx: Employment. Sousa:Ablynx: Employment. Callewaert:Ablynx: Employment. De Winter:Ablynx: Employment.