Regeneron’s Factor XI Antibodies Prevent Thromboembolism After Knee Replacement

A pair of novel, mechanically distinct, investigational factor XI antibodies in development by Regeneron, REGN7508 and REGN9933, have both displayed robust and distinct efficacy in preventing deep venous thromboembolism (VTE) in patients undergoing knee replacement surgery, according to new phase 2 trial data.1

These phase 2 data were presented at the American Heart Association’s Scientific Sessions 2025 in New Orleans, Louisiana, by Jeffrey Weitz, MD, Distinguished University Professor at McMaster University.1

REGN7508, which binds to the factor XI catalytic domain to block both activity and activation by factor XIIa and thrombin, aimed to maximize anticoagulant activity while diminishing bleeding risk. REGN9933, binding to the factor XI apple 2 domain and inhibiting its activation by factor XIIa, was designed as an additional possible option for patients at high risk of bleeding who would otherwise not be candidates for currently available anticoagulants.1,2

“The risk of bleeding with current anticoagulants prevents many patients from starting or staying on treatment, leaving them vulnerable to potentially life-threatening blood clots,” Weitz said in a statement. “These positive phase 2 results confirm the role of factor XI in postoperative venous thromboembolism and suggest that these 2 distinct antibodies may enable flexibility for physicians to tailor anticoagulant therapy for patients with different risk profiles.”1

Both trials, ROXI-VTE-I and ROXI-VTE-II, were randomized, open-label, phase 2 studies conducted in patients undergoing knee arthroplasty. ROXI-VTE-I saw 373 patients randomly assigned to receive either 300 mg REGN9933 in a single intravitreal dose, 40 mg enoxaparin subcutaneously once daily, or 2.5 mg apixaban orally twice daily. ROXI-VTE-II included 179 patients, who were randomly assigned to either 250 mg REGN7508 in a single intravitreal dose or 40 mg enoxaparin subcutaneously once daily post-surgery.2

REGN9933 and REGN7508 were considered superior to enoxaparin if the posterior probability of log odds ratio <() was >95%. For ROXI-VTE-II, the odds ratio was estimated for REGN7508 versus the combined enoxaparin arms of ROXI-VTE-I discounted by half and ROXI-VTE-II. Investigators noted a principal safety outcome of bleeding.2

In ROXI-VTE-I, investigators found VTE rates were 17.2% (20/116), 22.2% (26/117), and 12.4% (14/113) with REGN9933, enoxaparin, and apixaban, respectively. REGN9933 versus enoxaparin exhibited a mean adjusted odds ratio (90% credible interval) of 0.78 (0.47-1.32), with a posterior probability of 79%. The ROX-VTE-II trial saw VTE rates of 7.1% (8/113) and 17.2% (10.58) with REGN7508 and enoxaparin, respectively. Mean adjusted OR (90% credible interval) was 0.37 (0.20-0.68), with a posterior probability of >99%.2

The team recorded no major bleeding or clinically relevant non-major bleeding in any arm. The only major treatment-related adverse event was a single case of minimal bleeding reported in the enoxaparin arm of ROXI-VTE-I. The most common treatment-related adverse event was postoperative anemia, which appeared in 10% of patients in all treatment arms of ROXI-VTE-I and in 3% of all patients in ROXI-VTE-II.2

Another 2 phase 3 trials are currently underway to further evaluate REGN7508 for preventing VTE after total knee replacement surgery. A phase 2 trial has also been instigated to evaluate the safety of REGN7508 and REGN9933 versus apixaban in patients with atrial fibrillation. According to a press release, Regeneron plans to initiate phase 3 trials for stroke prevention in atrial fibrillation, as well as other indications such as cancer-associated thrombosis.1

References

1. Regeneron. Phase 2 Trials Demonstrating Antithrombotic Effect of Two Novel Regeneron Factor XI Antibodies Presented at American Heart Association Scientific Sessions and Published in The Lancet. GlobeNewswire. November 8, 2025. Accessed November 9, 2025. https://www.globenewswire.com/news-release/2025/11/08/3184069/0/en/Phase-2-Trials-Demonstrating-Antithrombotic-Effect-of-Two-Novel-Regeneron-Factor-XI-Antibodies-Presented-at-American-Heart-Association-Scientific-Sessions-and-Published-in-The-Lanc.html

2. Weitz J, Kithcart A, O’Brien M, et al. Two Mechanistically Distinct Factor XI Antibodies, REGN9933A2 and REGN7508Cat, for the Prevention of Venous Thromboembolism After Knee Arthroplasty: the ROXI-VTE-I and ROXI-VTE-II Trials. Presented at the American Heart Association’s Scientific Sessions 2025. New Orleans, Louisiana. November 8-10, 2025.