Concizumab prophylaxis significantly reduces bleeding events for people with hemophilia
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Key takeaways:
- The monoclonal antibody significantly reduced both treated spontaneous and traumatic bleeds among individuals with hemophilia.
- No thromboembolic adverse events occurred after the trial’s treatment restart.
Prophylactic concizumab conferred significant reductions in treated spontaneous and traumatic bleeds among patients with hemophilia A or B without inhibitors, a primary analysis of the randomized phase 3 explorer8 study showed.
Concizumab (Novo Nordisk) prophylaxis reduced the number of bleeds by 86% for trial participants with hemophilia A and by 79% for participants with hemophilia B compared with those who did not receive prophylaxis and were treated on demand, according to data presented at International Society on Thrombosis and Haemostasis Congress.
However, the trial failed to establish noninferiority for prophylactic use of the investigational therapy compared with use of previous standard prophylactic treatments, the researchers noted.
“Concizumab has the potential to be one of the first subcutaneous treatment options for hemophilia B,” Anthony K. Chan, MBBS, pediatric hematologist and chair in pediatric thrombosis and hemostasis at McMaster Children's Hospital/Hamilton Health Sciences, said during a press briefing.
“Subcutaneous therapy could help substantially lower treatment obstacles ... or allow patients to find an alternative treatment option that fits into how they live their lives,” he told Healio.
Background
Concizumab is a high-affinity, antitissue factor pathway inhibitor monoclonal antibody. The investigational therapy is for all hemophilia subtypes and acts independent of factor VIII and factor IX. It is designed to enhance the body’s ability to generate adequate amounts of factor Xa, which allows for increased thrombin generation to achieve effective hemostasis and prevent bleeds.
Methodology
The multicenter explorer8 trial prospectively evaluated the efficacy and safety of concizumab as a prophylactic treatment among 148 individuals with hemophilia A or B without inhibitors.
Participants previously treated on demand underwent random assignment in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (arm 1) or concizumab prophylaxis for at least 32 weeks (arm 2), or nonrandom assignment to concizumab prophylaxis (arms 3 and 4).
The trial restarted in September 2020 following a 6-month pause due to treatment-related thromboembolic events. Investigators revised the treatment protocol to provide patients with a 1 mg/kg concizumab loading dose, followed by a subcutaneous once-daily dose of 0.2 mg/kg concizumab.
The comparative number of treated spontaneous and traumatic bleeding episodes, expressed as the estimated mean annualized bleeding rate, between treatment arms 1 (on-demand factor treatment, no prophylaxis) and 2 (concizumab prophylaxis) served as the study’s primary endpoint.
The confirmatory secondary endpoint included a noninferiority analysis of the estimated mean annualized bleeding rate in treatment arm 4 (concizumab prophylaxis) in the explorer8 trial compared with previous standard prophylactic care used in the explorer6 trial.
Key findings
The study met its primary endpoint, with researchers reporting a significantly lower estimated mean annualized bleeding rate (ABR) among patients with hemophilia A treated with prophylactic concizumab compared with no prophylaxis (2.7 [95% CI, 1.6-4.6] vs. 19.3 [95% CI, 11.3-33]; ABR ratio = 0.14; 95% CI, 0.07-0.29). Prophylactic concizumab also conferred significantly lower ABR among patients with hemophilia B compared with no prophylaxis (3.1 [95% CI, 1.9-5] vs. 14.8 [95% CI, 8.1-26.9]; ABR ratio = 0.21; 95% CI, 0.1-0.45).
The trial did not its meet key second confirmatory endpoint, as it failed to establish noninferiority of concizumab compared with previous prophylaxis. Researchers noted comparable median ABR values for those who received concizumab compared with previous prophylaxis (2.3 vs. 2.2 for hemophilia A; 1.4 vs. 2.1 for hemophilia B).
No thromboembolic adverse events occurred after the trial’s treatment restart.
Clinical implications
The results demonstrate that concizumab — following an adjustment to the dosing regimen — is safe and well tolerated and, when used prophylactically, can significantly reduce the number of bleeding events in patients with hemophilia A and B without inhibitors, according to Chan.
“Not all of the needs of patients with hemophilia are fulfilled by currently available factor concentrates,” he said, adding that venous access is often an issue for a large subgroup of patients.
“This subcutaneous option will help provide an additional therapy to help fill that need for patients without inhibitors,” Chan told Healio. “This is especially true for patients with hemophilia B without inhibitors, who have no other good treatment options.”
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Chowdary P, et al. Abstract OC 59.1. Presented at: International Society on Thrombosis and Haemostasis Congress; June 24-28, 2023; Montreal.
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