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Concizumab Prophylaxis of Hemophilia with Inhibitors

In the company-funded explorer7 phase 3 trial, patients with hemophilia A or B with inhibitors had a lower annualized bleeding rate with concizumab prophylaxis than with no prophylaxis, researchers report. These results “confirm the superiority of concizumab over on-demand treatment in significantly reducing the annualized bleeding rate in a large population of patients with hemophilia A or B with inhibitors,” the investigators conclude. “Overall, adverse events from concizumab were mainly of low grade, and serious events were rare.”

Concizumab is an anti–tissue factor pathway inhibitor monoclonal antibody designed to achieve hemostasis in all hemophilia types. Participants with hemophilia A or B with inhibitors were randomly assigned to no treatment (group 1) or prophylaxis for at least 24 weeks with subcutaneous concizumab (group 2), or nonrandomly assigned to concizumab prophylaxis for at least 24 weeks (groups 3 and 4). During the trial, a treatment pause followed the deaths of 1 participant in this trial and 2 others in other explorer trials. The concizumab dose used after the treatment pause was a loading dose of 1.0 mg/kg followed by 0.2 mg/kg daily, with potential adjustments at week 4 based on plasma concizumab levels. In addition to safety, patient-reported outcomes, and pharmacokinetic and pharmacodynamic outcomes, the primary endpoint was the difference between treated spontaneous and traumatic bleeding episodes in the 2 groups.

“Of 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2; the remaining 81 were assigned to groups 3 and 4,” the authors write. “The estimated mean annualized bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to 19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio, 0.14 [95% CI, 0.07 to 0.29]; P <0.001). The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma concentrations of concizumab remained stable over time.”

Science Behind the Study Editorial: “Although [these] findings … represent an advance in the management of hemophilia, the ramifications of rebalancing hemostasis, particularly during stress or inflammatory conditions, are not well understood and warrant further investigation,” editorialists write. “Furthermore, data on the safety and efficacy of concizumab in early childhood are required. In situations in which additional factor VIII or IX replacement may be needed to enhance hemostasis, even though factor VIII or IX assays can be performed, the clinical implication of their combined effect with concizumab is unclear. The subcutaneous delivery of concizumab provided by pen is certainly more convenient than intravenous infusions but involves daily administration. Protocols for restarting concizumab after dose interruptions also need clarification. The clinical effect of anti-[tissue factor pathway inhibitor] and the recently reported similar clinical efficacy through reduction of antithrombin by small interfering RNA technology provide evidence that effective and sustained hemostasis can also be achieved by restoring a balance between procoagulant and anticoagulant factors in hemophilia.”

Source: New England Journal of Medicine