Regeneron Pharmaceuticals is set to advance two novel Factor XI-targeting monoclonal antibodies, REGN7508 and REGN9933, into Phase 3 trials in 2025 following promising Phase 2 results. The trials, which evaluated the drugs for thrombosis control, demonstrated robust antithrombotic effects without clinically relevant bleeding. These findings suggest a potential breakthrough in anticoagulation therapy, addressing the critical need for safer options.
Phase 2 Trial Results
The Phase 2 trials, ROXI-VTE-I and ROXI-VTE-II, were open-label and active-controlled, evaluating REGN7508 and REGN9933 for preventing venous thromboembolism (VTE) after unilateral total knee arthroplasty. Patients were administered a single intravenous dose of either REGN7508 or REGN9933, and compared to daily enoxaparin or twice-daily apixaban. Notably, treatment began 12 to 24 hours post-surgery, aligning with standard administration protocols for active comparators.
A pooled analysis revealed that REGN7508 was superior to enoxaparin and non-inferior to apixaban in reducing VTE rates. Specifically, REGN7508 showed VTE events in 7% of patients (8 out of 113), compared to 21% for enoxaparin (36 out of 175) and 12% for apixaban (14 out of 113). REGN9933 demonstrated non-inferiority to enoxaparin, with a 17% VTE event rate (20 out of 116 patients).
Safety Profile
An encouraging aspect of the study was the safety profile of both antibodies. There were no reports of major bleeding or clinically relevant non-major bleeding in any treatment arm. The only treatment-related adverse event was a single case of minimal bleeding (contusion) in the enoxaparin arm of ROXI-VTE-I. Across both trials, adverse event rates were generally similar among the treatment arms.
Factor XI as a Therapeutic Target
Factor XI has emerged as a promising target for next-generation anticoagulants. Current standard-of-care anticoagulants are often underutilized due to bleeding concerns, and oral agents can suffer from poor patient adherence. By targeting Factor XI, Regeneron aims to provide therapies that can prevent thrombosis without increasing bleeding risk.
George D. Yancopoulos, M.D., Ph.D., Board Co-Chair, President and Chief Scientific Officer at Regeneron, stated, "Our Factor XI antibodies targeting the catalytic and A2 domains were rigorously evaluated alongside current standards of care and showed clear evidence of antithrombotic effect with an encouraging safety profile after a convenient single dose."
Differentiated Mechanisms of Action
REGN7508 and REGN9933 are designed with distinct mechanisms of action. REGN7508 targets the catalytic domain of Factor XI to maximize anticoagulant activity while minimizing bleeding risk. REGN9933, on the other hand, targets the A2 domain and is designed to provide an additional option for patients with the highest bleeding risk who may not be suitable candidates for currently available anticoagulants.
Implications for Thrombosis Management
Thrombosis, responsible for one in four deaths worldwide, presents a significant global health challenge. The potential for single-dose administration of REGN7508 and REGN9933, in contrast to the daily or twice-daily dosing of current treatments, could significantly improve patient convenience and adherence. These advancements may lead to a paradigm shift in thrombosis management, offering tailored therapies for patients with varying bleeding risk profiles.
