Atrial fibrillation is one of the most common persistent arrhythmias, affecting approximately 50 million people worldwide, and its associated stroke risk is five times higher than that of the population without this disease. Therefore, anticoagulant therapy for preventing cardioembolic stroke has become a key focus of atrial fibrillation treatment. Clinical guidelines prioritize the use of DOAC for the treatment of such patients. However, bleeding, especially gastrointestinal bleeding, remains the main complication of DOACs treatment. This side effect leads to inadequate treatment for many patients. Therefore, there is an urgent need to develop safer anticoagulants.
Coagulation factor XI has been considered a potential target for safer anticoagulants. Research has shown that coagulation factor XI is crucial in thrombus formation, but in most cases it is not necessary for normal hemostasis. In populations with hereditary coagulation factor XI deficiency, the incidence of thrombotic events is significantly reduced, while the risk of spontaneous bleeding is not significantly increased. Therefore, inhibitors of coagulation factor XI are expected to achieve the separation of thrombus formation and hemostatic function, providing a safer option for anticoagulant therapy.
AZALEA-TIMI 71 is a randomized, active controlled, blinded endpoint, parallel group Phase 2 clinical study with a total of 1287 patients enrolled. The primary endpoint is to evaluate the efficacy of two blinded doses of abelacimab compared to the standard therapy of oral anticoagulant rivaroxaban in atrial fibrillation patients with moderate to high risk of stroke. The primary endpoint of the study is the composite endpoint of the incidence of major bleeding or clinically relevant non major bleeding events. The secondary endpoint is severe bleeding itself. Patients were randomly divided into 1:1:1 groups and subcutaneously administered 90 mg, 150 mg abelacimab once a month, or 20 mg of active control drug once a day.
Analysis shows that the median level of free coagulation factor XI decreased by 99% (interquartile range: 98-99) in patients treated with 150 mg abelacimab, while the 90 mg abelacimab group decreased by 97% (interquartile range: 51-99). Due to the significantly unexpected reduction in bleeding events by abelacimab, the trial was terminated prematurely in September 2023 (median follow-up of 2.1 years) based on the recommendation of the Independent Data Monitoring Committee (IDMC).
Dr. Dan Bloomfield, Chief Medical Officer of Anthos Therapeutics, stated, "Based on a large amount of positive data from the AZALEA study, the safety of abelacimab in surgical patients and those receiving antiplatelet therapy further validates the principle of inhibiting coagulation factor XI, which may prevent thrombotic events without affecting normal hemostasis. Even in situations with the highest risk of bleeding, such as surgery, invasive procedures, or antiplatelet therapy, patients receiving abelacimab treatment still have extremely low bleeding rates, attributed to its almost complete inhibition of factor XI. The safety data of Abelacimab is increasing. If approved, it will become an ideal choice for patients seeking safer and more convenient anticoagulant therapy
Abelacimab is a novel and highly selective all human monoclonal antibody that can target coagulation factor XI and lock it in an inactive state, thereby simultaneously inhibiting coagulation factor XI and its activated form, coagulation factor XIa. A proof of concept study published in the New England Journal of Medicine in 2021 showed that compared to standard control drugs, abelacimab reduced venous thromboembolism (VTE) in patients by approximately 80%. In July 2022, abelacimab was granted fast track status by the FDA for the treatment of cancer-related thrombosis. In September of the same year, the drug once again obtained fast track qualification for the prevention of stroke and systemic embolism in patients with atrial fibrillation.
<Reprinted from WuXi AppTec>
