The U.S. Food and Drug Administration (FDA) has approved Novo Nordisk's Alhemo (concizumab-mtci) injection as a once-daily prophylactic treatment to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age and older with hemophilia A or B with inhibitors. This approval marks a significant advancement in the treatment of hemophilia, providing a new subcutaneous option for patients who have developed inhibitors against standard clotting factor replacement therapies. Alhemo's approval is based on the Phase 3 explorer7 trial, which demonstrated a substantial reduction in bleeding rates compared to no prophylaxis.
Clinical Significance
Hemophilia A and B are rare genetic bleeding disorders characterized by a deficiency in clotting factors, leading to prolonged bleeding. A significant challenge in hemophilia treatment is the development of inhibitors, which are antibodies that neutralize the effect of replacement clotting factors. Approximately 30% of patients with severe hemophilia A and 5-10% with severe hemophilia B develop these inhibitors, making treatment more complex and necessitating alternative approaches.
Alhemo offers a novel mechanism of action by targeting tissue factor pathway inhibitor (TFPI). By blocking TFPI, Alhemo enhances thrombin production, a critical component in blood clot formation. This mechanism bypasses the need for functional factors VIII or IX, making it effective even in the presence of inhibitors. The drug is administered via subcutaneous injection using a prefilled pen, offering a more convenient alternative to traditional intravenous infusions.
Efficacy and Safety Data
The FDA's approval was primarily based on data from the Phase 3 explorer7 trial (NCT04083781), a multi-center, open-label study that evaluated the efficacy and safety of Alhemo in patients with hemophilia A or B with inhibitors. The trial included 133 male patients aged 12 years and older. Patients were randomized to receive either Alhemo prophylaxis or no prophylaxis. The primary endpoint was the number of treated spontaneous and traumatic bleeding episodes, measured by the annual bleeding rate (ABR).
Results from the explorer7 trial demonstrated an 86% reduction in ABR in patients receiving Alhemo prophylaxis compared to those receiving no prophylaxis (ABR ratio, 0.14; 95% CI, 0.07 - 0.29; P < .001). The estimated mean ABR was 1.7 for patients on Alhemo prophylaxis compared to 11.8 for patients with no prophylaxis. Furthermore, 64% of patients on Alhemo prophylaxis experienced no treated spontaneous and traumatic bleeds in the first 24 weeks, compared to only 11% in the no prophylaxis group.
The most common adverse reactions reported in the trial were injection site reactions (18%) and urticaria (6%). Serious adverse reactions included renal infarct and hypersensitivity reactions. These safety findings are consistent with the drug's mechanism of action and provide a comprehensive understanding of its risk profile.
Expert Commentary
"The development of inhibitors remains the most serious treatment-related complication for people living with hemophilia," said Amy Shapiro, MD, CEO and co-medical director at the Indiana Hemophilia & Thrombosis Center. "The approval of Alhemo provides a much-needed alternative to the current standard of care in hemophilia B with inhibitors, while offering patients with hemophilia A with inhibitors more treatment options, ultimately providing more patients with inhibitors the opportunity to personalize their care and address current treatment gaps."
Dosing and Administration
Alhemo (concizumab-mtci) is available as a prefilled, premixed pen for subcutaneous injection in various concentrations (60 mg/1.5 mL, 150 mg/1.5 mL, or 300 mg/3 mL). The recommended initial loading dose is 1 mg per kilogram of body weight, followed by a daily maintenance dose of 0.2 mg per kilogram. Dosing may be individualized based on concizumab-mtci plasma concentration, as measured at week 4.
Conclusion
The approval of Alhemo represents a significant advancement in the treatment of hemophilia A and B with inhibitors. Its novel mechanism of action, combined with the convenience of subcutaneous administration, offers a valuable new option for patients who have limited treatment alternatives. The robust efficacy and safety data from the Phase 3 explorer7 trial support its use as a prophylactic treatment to reduce bleeding episodes and improve the quality of life for individuals with hemophilia and inhibitors.
