Annualized Bleeding Rates in Patients with Hemophilia a or B and Inhibitors with and without Target Joints at Baseline: Results from the Concizumab Phase 3 Explorer7 Study
Authors: Shapiro Amy D. , Apte Shashikant , Boban Ana , Brown Frandsen Renée , Linari Silvia , Mahlangu Johnny , Martins Mazini Tavares Camila , Matsushita Tadashi , Nekkal Salim , Sathar Jameela , Chan Anthony K C 
Published: December 2024

Background
In patients with hemophilia, recurring bleeds into the same joint, known as target joint, cause hemophilic arthropathy and reduce quality of life. Prophylaxis is the current standard of care for severe hemophilia, started early in life to prevent onset and progression of joint damage by reducing recurrent bleeds, allowing patients to participate in physical and social activities, and improve their quality of life. Concizumab is a recombinant anti-tissue factor pathway inhibitor monoclonal antibody under development as a once-daily subcutaneous prophylaxis for hemophilia A/B with and without inhibitors. Here, we present the annualized bleeding rate (ABR) results in patients with hemophilia A/B with inhibitors (HAwI/HBwI), with or without target joints at baseline, from the prospective, multicenter, open-label, phase 3 explorer7 (NCT04083781) study.
Aim
To assess the ABR in patients with HAwI/HBwI, with or without target joints at baseline, during concizumab prophylaxis vs on-demand treatment.
Methods
Target joints were defined as ≥3 spontaneous bleeds into a single joint within a consecutive 6-month period; target joints were deemed resolved when there had been ≤2 bleeds in the joint during the previous 12 months (Blanchette VS et al. J Thromb Haemost. 2014;12(11):1935-39). Treated spontaneous and traumatic bleeding episodes were assessed at the 32- and 56-week cut-offs for patients with and without target joints at baseline. The 32- and 56-week cut-offs were defined as when all patients had completed the visit after 32 or 56 weeks respectively, or permanently discontinued treatment. In the explorer7 study, patients with HAwI/HBwI were randomized 1:2 to on-demand treatment (arm 1; ≥24 weeks) or concizumab prophylaxis (arm 2; ≥32 weeks), or assigned to non-randomized concizumab prophylaxis arms 3 and 4. After ≥24 (arm 1) or ≥32 weeks (arm 2-4), all patients were offered entry into the extension part, and patients in arm 1 switched to concizumab prophylaxis. 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. Results for estimated mean ABRs are presented for arm 2 vs arm 1; descriptive results are presented for all patients (arms 1-4). Informed consent/ethics committee approval were obtained.
Results
Male patients (≥12 years) with HAwI/HBwI were recruited (2.3% American Indian/Alaska Native, 27.8% Asian, 6.8% Black/African American, 58.6% White, 4.5% not reported). Of the 133 patients enrolled (HAwI: 80; HBwI: 53), 19 were randomized to on-demand treatment (arm 1), 33 randomized to concizumab prophylaxis (arm 2), and 81 allocated to concizumab prophylaxis (arms 3/4). After the 32-week cut-off, 13 patients from arm 1 switched to concizumab prophylaxis. A total of 104 patients in arms 1-4 completed treatment at the 56-week cut-off.
At the 32-week cut-off, for patients with target joints at baseline, estimated mean ABR (95% confidence interval [CI]) for treated spontaneous and traumatic bleeding episodes on concizumab prophylaxis (arm 2) was 1.7 (0.55-5.51) vs 10.6 (4.18-26.92) on-demand (arm 1); ABR ratio was 0.16 (0.06-0.48; P=0.001), indicating an 84% reduction in bleeding episodes. For patients with no target joints at baseline, estimated mean ABR (95% CI) for treated spontaneous and traumatic bleeding episodes on concizumab prophylaxis (arm 2) was 0.9 (0.48-1.58) vs 9.0 (5.59-14.53) on-demand (arm 1); ABR ratio was 0.10 (0.05-0.19; P&lt;0.001), indicating a 90% reduction in bleeding episodes.
At the 32-week cut-off, overall median ABR (interquartile range [IQR]) during concizumab prophylaxis (arms 1-4) in patients with and without target joints at baseline, for treated spontaneous and traumatic bleeding episodes was 0.9 (0.0-4.3) and 0.0 (0.0-2.8), for joint bleeding episodes 0.0 (0.0-3.9) and 0.0 (0.0-1.5), and for target joint bleeding episodes 0.0 (0.0-1.1) and 0.0 (0.0-0.0), respectively. By the 56-week cut-off, 92% of target joints had resolved (arms 1-4), and low median ABRs were maintained on concizumab. Overall safety data showed no new findings.
Conclusion
In the explorer7 study, once-daily, subcutaneous concizumab prophylaxis effectively reduced ABR irrespective of the presence of target joints at baseline at the 32-week cut-off, and low ABRs were maintained at the 56-week cut-off.