A Phase 3, Multicenter, Randomized, Open-Label, Sponsor-Blinded, Study to Evaluate REGN7508, A Factor XI Monoclonal Antibody, Versus Apixaban and Enoxaparin for Prophylaxis of Venous Thromboembolism After Elective Total Knee Arthroplasty (ROXI-APEX).

The primary objective of this study is to evaluate the efficacy of intravenous REGN7508 for the prevention of venous thromboembolism after total knee arthroplasty compared to enoxaparin and apixaban. This comparison is clinically relevant as it assesses whether a factor XI monoclonal antibody can provide effective thromboprophylaxis following elective orthopedic surgery, a setting with established thromboembolic risk.

The secondary objectives are:

• To evaluate the efficacy of intravenous REGN7508 for the prevention of clinical thrombosis compared to enoxaparin and apixaban.

• To evaluate the clinically relevant bleeding risk of intravenous REGN7508 for the prevention of venous thromboembolism after total knee arthroplasty compared to enoxaparin and apixaban.

• To evaluate the efficacy of subcutaneous REGN7508 for the prevention of venous thromboembolism after total knee arthroplasty compared to enoxaparin and apixaban.

• To evaluate the efficacy of subcutaneous REGN7508 for the prevention of clinical thrombosis compared to enoxaparin and apixaban.

• To evaluate the clinically relevant bleeding risk of subcutaneous REGN7508 for the prevention of venous thromboembolism after total knee arthroplasty compared to enoxaparin and apixaban.

• To evaluate the occurrence of minor bleeding following intravenous REGN7508 and subcutaneous REGN7508 compared to enoxaparin and apixaban.

• To evaluate the overall safety and tolerability of intravenous REGN7508 and subcutaneous REGN7508 in participants undergoing total knee arthroplasty.

• To evaluate immunogenicity following treatment with REGN7508.

• To evaluate pharmacokinetics following treatment with REGN7508.

This clinical trial enrolled a total of **933 participants** undergoing primary elective unilateral **total knee arthroplasty (TKA)** for the prevention of **venous thromboembolism (VTE)**. The study population included both **male and female subjects** from adult and elderly age categories. Participants were required to be in good general health based on laboratory safety testing conducted according to the protocol specifications. A key selection criterion included a body weight restriction of less than 130 kg at the screening visit. The trial did not include vulnerable populations. Additional protocol-defined inclusion criteria were applied during the participant selection process to ensure a suitable study cohort for evaluating the efficacy of the investigational treatment compared to standard anticoagulant therapies.

This is a Phase 3, multicenter, randomized, open-label, sponsor-blinded clinical trial designed to evaluate the efficacy and safety of REGN7508, a monoclonal antibody targeting Factor XI and activated Factor XI, compared to apixaban and enoxaparin for the prevention of venous thromboembolism following elective total knee arthroplasty. The trial investigates thromboembolic disease prevention in adult participants undergoing primary elective unilateral total knee arthroplasty. REGN7508 will be administered as a powder for solution for infusion via intravenous injection or as a solution for injection via subcutaneous injection for a maximum treatment period of one day or one week, respectively. The comparator enoxaparin sodium will be administered via subcutaneous injection for a maximum of two weeks, while apixaban will be administered orally as film-coated tablets for a maximum of two weeks. Sodium chloride solution for injection will serve as placebo and will be administered via intravenous injection or infusion for a maximum of one day.

The primary objective of the trial is to evaluate the efficacy of intravenous REGN7508 for the prevention of venous thromboembolism after total knee arthroplasty compared to enoxaparin and apixaban. The primary endpoint is the incidence of the composite endpoint of asymptomatic or symptomatic venous thromboembolism, including venous thromboembolism-related death. Secondary endpoints include the incidence of confirmed symptomatic deep venous thrombosis, confirmed pulmonary embolism, venous thromboembolism-related death, the composite endpoint of major and clinically relevant nonmajor bleeding, the composite endpoint of asymptomatic or symptomatic venous thromboembolism including venous thromboembolism-related death, minor bleeding, treatment-emergent adverse events, incidence and titer of anti-drug antibodies to REGN7508, and concentrations of REGN7508.

Principal inclusion criteria require that participants are undergoing a primary elective unilateral total knee arthroplasty, are in good health based on laboratory safety testing as described in the protocol, and have a body weight of less than 130 kg at the screening visit. Additional protocol-defined inclusion criteria apply. The trial is estimated to commence recruitment on June 30, 2025, and is expected to conclude on May 12, 2027. The expected duration of participant involvement and the sequence of study visits, including screening, follow-up, and end-of-study visits, are determined by the treatment period and follow-up schedule outlined in the protocol. Conditions that may lead to early termination from the study will be defined according to protocol-specified criteria for discontinuation.

The experimental medication **REGN7508** is a human IgG4 S228P **monoclonal antibody** directed against **factor XI** and activated factor XI. This investigational product is administered in two pharmaceutical formulations. The first formulation is presented as a **powder for solution for infusion**, administered via **intravenous injection**, with a maximum treatment period of one day. The second formulation is provided as a **solution for injection**, administered via **subcutaneous injection**, with a maximum treatment period of one week. REGN7508 is classified as a protein-based therapeutic substance and serves as the test product in this clinical trial.

**Enoxaparin sodium** is utilized as a comparator treatment in this study. The product is marketed as CLEXANE 4,000 IU (40 mg)/0.4 ml solution for injection in pre-filled syringe. This **low molecular weight heparin** is presented as a **solution for injection** and is administered via **subcutaneous injection**. The active substance is of polymer origin. The maximum treatment period for enoxaparin sodium is two days. This medicinal product is manufactured by Sanofi Belgium and holds marketing authorization in Belgium.

**Apixaban** serves as an additional comparator treatment in the trial. The product is marketed as Eliquis 2.5 mg **film-coated tablets**. This **direct factor Xa inhibitor** is administered via **oral use**. The active substance is of chemical origin. The maximum treatment period for apixaban is two days. This medicinal product is manufactured by Bristol-Myers Squibb/Pfizer EEIG and holds centralized marketing authorization in the European Union.

**Sodium chloride** solution for injection functions as the **placebo** in this clinical trial. This chemical substance is administered via **intravenous injection** or **intravenous infusion**. The maximum treatment period for sodium chloride is one day. This product is used to maintain blinding in the study design.

The primary efficacy endpoint is the incidence of the composite endpoint of asymptomatic or symptomatic **venous thromboembolism** (VTE), including VTE-related death. Secondary efficacy endpoints include the incidence of confirmed symptomatic **deep venous thrombosis** (DVT), the incidence of confirmed **pulmonary embolism** (PE), the incidence of VTE-related death, and the incidence of the composite endpoint of asymptomatic or symptomatic VTE (including VTE-related death). Additional secondary endpoints encompass the incidence of the composite endpoint of major and clinically relevant nonmajor (CRNM) bleeding, the incidence of minor bleeding, the incidence of treatment emergent adverse events (TEAEs), the incidence of anti-drug antibodies (ADA) to REGN7508, the titer of ADA to REGN7508, and the concentrations of REGN7508.