Concizumab, a novel prophylactic treatment, has demonstrated a significant reduction in bleeding episodes for adults and adolescents with hemophilia A or B without inhibitors. Data from the Phase 3 explorer8 trial revealed an 86% reduction in mean annualized bleeding rates for hemophilia A patients and a 79% reduction for hemophilia B patients receiving daily subcutaneous injections of concizumab. These findings, published in The Lancet Haematology, highlight the potential of concizumab to address unmet needs in hemophilia management.
The explorer8 study (NCT04082429), a prospective, multicenter, open-label, randomized, phase 3a trial, enrolled males and females ages 12 and older with hemophilia A or B who were on replacement treatment within 24 weeks before screening. Patients were randomized to either daily prophylaxis with concizumab (1 mg/kg loading dose followed by 0.2 mg/kg daily) or no prophylaxis for at least 32 weeks. The primary endpoint was the comparison of annualized bleeding rates between the two groups.
Marked Reduction in Bleeding Episodes
The results showed a substantial decrease in annualized bleeding rates with concizumab prophylaxis. For patients with hemophilia A, the mean reduction in annualized bleeding rate for spontaneous and traumatic bleeding episodes was 86%. Similarly, patients with hemophilia B experienced a 79% reduction. These results align with findings from the explorer7 trial (NCT04083781), where concizumab reduced bleeding rates by 86% in hemophilia A or B patients with inhibitors.
Mechanism of Action and Clinical Implications
Hemophilia, a genetic disorder characterized by impaired blood clotting, affects a significant population worldwide. In hemophilia A, the clotting factor VIII (FVIII) is deficient or faulty, while in hemophilia B, it is factor IX (FIX). Standard treatments involve replacing the missing clotting factor; however, some patients develop inhibitors against the replacement factor, necessitating non-factor treatment options.
Concizumab is a humanized monoclonal antibody that inhibits tissue factor pathway inhibitor (TFPI), a natural anticoagulant. By blocking TFPI, concizumab promotes thrombin generation and enhances blood clotting. This mechanism of action offers a novel approach to hemophilia management, particularly for patients who develop inhibitors or those seeking alternative treatment options.
Safety and Tolerability
The most common adverse events reported in the explorer8 trial were COVID-19 infection (13%), increased D-dimers (8%), and upper respiratory tract infection (7%). One patient with hemophilia A experienced a fatal abdominal bleed, potentially treatment-related but complicated by hypertension. Notably, no new thromboembolic events were reported after the study resumed following a prior pause due to such events.
Expert Commentary
According to the researchers, "Daily, subcutaneous concizumab prophylaxis was efficacious in reducing the bleeding rate and was considered safe in patients with haemophilia A or B." They further emphasized the potential of concizumab as one of the first subcutaneous treatment options for patients with hemophilia B, who currently have fewer treatment choices available.
Regulatory Landscape
Concizumab has already been approved in Canada under the brand name Alhemo for prophylactic use in hemophilia A and B patients aged 12 and older with inhibitors. A European advisory committee has also issued a positive opinion on its use for the same indication. The positive results from the explorer8 trial may further support regulatory submissions for broader use in hemophilia patients without inhibitors.
