Efficacy and Safety of Concizumab Prophylaxis in Patients with Hemophilia A or B Without Inhibitors: 56-Week Cut-Off Results of the Phase 3 Explorer8 Study

Introduction Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in development as a once-daily subcutaneous prophylactic treatment for hemophilia of all subtypes. Results from the 56-week cut-off of the prospective, multicenter, open-label explorer8 study (NCT04082429; phase 3) in patients with hemophilia A or B without inhibitors (HA/HB) are presented, further to the 32-week confirmatory analysis cut-off (CACO) results previously reported (Chowdary P et al. ISTH 2023, OC 59.1). Aim To assess the longer-term efficacy and safety of daily concizumab prophylaxis in patients with HA/HB. Methods Male patients (aged ≥12 years) with HA/HB were randomized 1:2 to no prophylaxis (arm 1; 24 weeks) or concizumab prophylaxis (arm 2; ≥32 weeks) or assigned to non-randomized concizumab prophylaxis (arms 3 and 4; ≥32 weeks). After the main part of the trial (24 weeks for arm 1), patients in arm 1 could switch to concizumab prophylaxis. After treatment restart following the treatment pause due to thromboembolic events, patients received a 1.0 mg/kg concizumab loading dose on Day 1, followed by an initial 0.20 mg/kg daily dose starting on Day 2, with potential adjustment to 0.15 or 0.25 mg/kg based on measured plasma concizumab concentration after week 4. Assessments at the 56-week cut-off included efficacy, safety, pharmacokinetic and pharmacodynamic measurements. Informed consent/ethics committee approval were obtained. Results The study included 148 patients (HA, n=82; HB, n=66), of which 21 patients were randomized to no prophylaxis (arm 1: HA, n=9; HB, n=12), 42 patients to concizumab prophylaxis (arm 2: HA, n=18; HB, n=24) and the remaining 85 patients were assigned to concizumab prophylaxis (non-randomized arms 3 and 4). After the main part of the trial, 17 patients from arm 1 switched to concizumab prophylaxis, receiving the same dosing regimen as patients in arms 2‒4 when first starting on concizumab. A total of 132 patients (HA, n=73; HB, n=59) completed the 56-week cut-off. The overall median (interquartile range) annualized bleeding rate (ABR) on concizumab prophylaxis in arms 1‒4 was 1.7 (0.0‒4.5) for HA and 2.8 (0.0‒6.4) for HB (Table 1); these results were also supported by the supportive secondary efficacy assessments. After treatment restart, no thromboembolic events were reported (Table 2). A total of 30 serious adverse events (AEs) were reported in 20 patients at the 56-week cut-off. As previously reported at CACO, one patient experienced a serious AE with fatal outcome (intra-abdominal hemorrhage) and 6 patients experienced AEs leading to withdrawal of concizumab treatment. The rate of injection site reactions was comparable to CACO. No hypersensitivity type reactions were reported in the study and low-titer anti-concizumab antibodies were detected in a total of 21 patients at the 56-week cut-off, with no apparent impact on bleeds or AEs. Concizumab plasma concentration remained stable over time. Free TFPI and thrombin peak levels continued to be stable over time. Conclusions Concizumab prophylaxis showed longer-term (≥1 year) efficacy in adult and adolescent patients with HA/HB at the 56-week cut-off, which was consistent with the results observed at CACO. Concizumab prophylaxis was considered safe and well tolerated in patients with HA/HB.