Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: Phase 2 trial results

Results from the main parts (24 weeks) of two concizumab phase 2 trials are presented: explorer4 (NCT03196284) in hemophilia A (HA) or B (HB) with inhibitors (HAwI/HBwI); explorer5 (NCT03196297) in HA without inhibitors. The trials aimed to evaluate the efficacy of daily subcutaneous concizumab prophylaxis (evaluated as annualized bleeding rate [ABR] at last dose level); secondary objectives were safety and immunogenicity (assessed as number of adverse events [AEs] and anti-drug antibodies [ADAs]). Patients received 0.15 mg/kg concizumab, with potential dose escalation to 0.20 and 0.25 mg/kg (if {greater than or equal to}3 spontaneous bleeding episodes within 12 weeks of concizumab treatment). Relevant pharmacokinetic/pharmacodynamic parameters were assessed. 36 HA, 9 HAwI and 8 HBwI patients were exposed to concizumab. Most inhibitor patients (15/17; 88.2%) did not escalate the dose, and all patients chose to continue to the extension phase of the trials. Clinical proof of concept for the prevention of bleeding episodes was demonstrated in both trials. Estimated ABRs in HAwI and HBwI were lower vs. HA: 3.0 (95% confidence interval [CI]: 1.7;5.3) and 5.9 (95% CI: 4.2;8.5) vs. 7.0 (95% CI: 4.6;10.7), respectively. PK/PD results were as expected, with no difference between hemophilia subtypes for concizumab exposure, free tissue factor pathway inhibitor, thrombin generation, prothrombin F1+2 and D-dimers. Concizumab was safe and well tolerated (no severe AEs, AE-related withdrawals, or thromboembolic events). Three patients had (very-low to medium-titer) ADA-positive tests in each trial, with no observed clinical effect. These results support further development of concizumab as a daily prophylactic treatment in all hemophilia patients.