Monoclonal Antibody Prophylaxis Reduces Bleeding Events for Hemophilia A/B With Inhibitors

Prophylaxis with a novel monoclonal antibody resulted in fewer bleeding events than standard on-demand treatment in certain patients with both hemophilia A and B, according to results of a phase III study published in the New England Journal of Medicine.

Patients with hemophilia A or B with inhibitors who received daily subcutaneous prophylaxis with concizumab (Alhemo) had a significantly lower estimated mean annualized bleeding rate (11.8 episodes/year) than those who received on-demand treatment only (1.7 episodes/year). The mean annualized rate ratio of 0.14 for treated spontaneous and traumatic bleeding episodes confirmed the superiority of concizumab prophylaxis. Researchers observed similar annualized rates for treatment of spontaneous, joint and target joint bleeding episodes.

“Concizumab represents a novel, subcutaneous treatment option in patients with hemophilia A or B with inhibitors that can potentially improve long-term outcomes,” the researchers wrote. Importantly, the trial included patients with hemophilia B with inhibitors, “who represent 14% of the approximately 370 patients of all ages with clinically confirmed factor IX inhibitors in the annual global survey by the World Federation on Hemophilia in 2020.”

Concizumab works by targeting the tissue factor pathway inhibitor, an anticoagulant protein that blocks factor Xa, promoting hemostasis, making it effective for both hemophilia A and B.

Patients were included in the study if they were at least 12 years and had hemophilia A or B (any severity with inhibitors (neutralizing antibodies to factor-replacement products). Group 1 consisted of 19 patients (9 with hemophilia A) randomly assigned to receive on-demand (replacement therapy to stop bleeding) treatment only; Group 2 consisted of 33 patients (18 with hemophilia A) who received daily subcutaneous prophylaxis with concizumab.

Prophylaxis with concizumab lasted 32 weeks. At 24 weeks, patients in the on-demand therapy group were allowed to cross over to concizumab prophylaxis.

Concizumab offers an alternative to factor replacement therapy and bypassing agents (which work independently of factors VIII and IX). Emicizumab, which mimics the effects of factor VIII to promote coagulation, is approved for subcutaneous prophylaxis in hemophilia A only (with or without inhibitors). The results may be particularly promising for patients with hemophilia B with inhibitors, given that there are currently no effective prophylactic treatments for this condition.

Notably, the trial was stopped briefly due to nonfatal thromboembolic events in three patients in two phase III trials receiving concizumab, including one from the explorer7 trial with a renal infarction. Review by the safety committee recommended implementation of risk-mitigation measures; the trial was restarted with updated guidance for the management of breakthrough bleeding episodes and a new dose regimen.

In terms of safety, the most frequently reported adverse events seen with concizumab treatment included arthralgia (in 10%), injection-site erythema (in 7%) and upper respiratory tract infection (in 6%). There were five serious adverse events occurred in three patients (16%) in group 1 and 18 in 14 patients (11%) who received concizumab (in groups 1 and 2, along with patients from the non-randomized and continuation of treatment groups 3 and 4).

The trial was sponsored by Novo Nordisk. The company was responsible for designing the trial, preparing the initial trial protocol and statistical analysis plan and performing the statistical analyses.