A Phase 2, Multicenter, Randomized, Open-Label, Active-Control Study of REGN9933, a Factor XI Monoclonal Antibody, for Prevention of Venous Thromboembolism after Elective, Unilateral, Total Knee Arthroplasty

The primary objective of this study is to evaluate the **efficacy** of REGN9933, a Factor XI monoclonal antibody, in the prevention of venous thromboembolism (VTE) following unilateral total knee arthroplasty (TKA), compared to enoxaparin. This is clinically relevant as VTE is a significant postoperative complication that can lead to serious morbidity and mortality. Effective prevention strategies are crucial in improving patient outcomes after TKA.

Secondary objectives include:

• Evaluating the bleeding risk, including major and clinically relevant non-major bleeding, of REGN9933 compared to enoxaparin.
• Assessing the overall safety and tolerability of REGN9933 in participants undergoing TKA.
• Evaluating the efficacy of REGN9933 in the prevention of clinically relevant VTE and deep venous thrombosis (DVT) detected by venography, compared to enoxaparin.
• Evaluating the pharmacokinetics of REGN9933 after single intravenous administration.
• Assessing the pharmacodynamic effects of REGN9933 on intrinsic and extrinsic coagulation pathways.
• Assessing immunogenicity following a single dose of REGN9933 over time.
• Comparing the efficacy of enoxaparin and apixaban in the prevention of VTE after unilateral TKA.

The clinical trial involves a total of **24 participants** who are being evaluated for the efficacy of REGN9933 in preventing venous thromboembolism (VTE) following unilateral total knee arthroplasty (TKA). The study population includes both **male and female** subjects, with an age range that encompasses adults and older adults. Participants were selected based on their ability to undergo elective unilateral TKA and a body weight of 130 kg or less at the screening visit. They are required to be in good health, as determined by medical history, physical examination, vital sign measurements, and laboratory safety testing. The trial does not include a vulnerable population, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The study aims to compare the efficacy of REGN9933 against enoxaparin in this context.

The clinical trial is designed as a **randomized**, open-label, active-control study to evaluate the efficacy of REGN9933, a Factor XI monoclonal antibody, in preventing venous thromboembolism (VTE) following elective unilateral total knee arthroplasty (TKA). The trial will compare REGN9933 to **enoxaparin sodium**, a commonly used anticoagulant. The study is expected to last approximately 75 days for each participant, with the primary endpoint being the incidence of confirmed, adjudicated VTE through day 12. Secondary endpoints include the incidence of major bleeding, clinically relevant non-major bleeding, and treatment-emergent adverse events, among others.

Participants will undergo a series of study visits, beginning with a screening visit to assess eligibility based on criteria such as undergoing elective unilateral TKA, having a body weight of 130 kg or less, and being in good health as determined by medical history, physical examination, and laboratory tests. Following the screening, participants will be randomized to receive either REGN9933 or enoxaparin. The study includes follow-up visits to monitor safety and efficacy outcomes, with the final visit occurring around day 75 to assess long-term safety and the presence of anti-drug antibodies.

The trial will involve a maximum treatment period of 12 days for the primary endpoint assessment, with additional follow-up extending to approximately 75 days. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any other protocol-defined criteria. The study aims to provide valuable data on the effectiveness and safety of REGN9933 in preventing thromboembolic events in patients undergoing knee replacement surgery.

The clinical trial involves the administration of several treatments, including both experimental and comparator medications. The **experimental medication** in this study is REGN9933, a lyophilisate and solvent for solution for injection, developed by Regeneron Pharmaceuticals, Inc. REGN9933 is a monoclonal antibody targeting Factor XI, intended for the prevention of venous thromboembolism (VTE) following unilateral total knee arthroplasty. The medication is administered intravenously, with a maximum daily and total dose of 300 mg. The treatment period for REGN9933 is limited to a single day.

Among the comparator treatments, **Eliquis** (apixaban) is utilized. Eliquis is provided in the form of 2.5 mg film-coated tablets, manufactured by Bristol-Myers Squibb/Pfizer EEIG. The route of administration is oral, with a maximum daily dose of 2.5 mg and a total dose of 5 mg. The treatment period for Eliquis extends up to 12 months.

Another comparator treatment is **Inhixa**, a solution for injection in a pre-filled syringe, containing enoxaparin sodium. This medication is produced by Techdow Pharma Netherlands B.V. and is administered subcutaneously. The maximum daily and total dose for Inhixa is 40 mg, with a treatment period of up to 12 months.

Additionally, **Clexane**, another formulation of enoxaparin sodium, is used as a comparator. Clexane is provided as a solution for injection in a pre-filled syringe, manufactured by Sanofi Belgium. Similar to Inhixa, Clexane is administered subcutaneously, with a maximum daily and total dose of 40 mg, and a treatment period of up to 12 months.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy of REGN9933 in comparison to the standard-of-care therapies, Eliquis, Inhixa, and Clexane, in preventing VTE after knee arthroplasty.

The efficacy of the investigational product, REGN9933, in the clinical trial will be assessed primarily through the incidence of confirmed, adjudicated **venous thromboembolism (VTE)** up to day 12, comparing REGN9933 with enoxaparin. Secondary endpoints include the incidence of major bleeding and clinically relevant non-major bleeding up to approximately day 12, as well as the incidence of treatment-emergent adverse events (TEAEs) through the end of the study, approximately day 75. Additional secondary endpoints involve the incidence of major VTE through day 12, incidence of deep vein thrombosis (DVT) as measured by venography of the operated leg around day 12, and various laboratory parameters such as concentrations of REGN9933 in serum, changes in activated partial thromboplastin time (aPTT) and prothrombin time (PT) from baseline, and the incidence and titer of anti-drug antibodies (ADA) to REGN9933, all assessed through the end of the study.

Measurements will be collected at specified time points, including day 12 for primary and some secondary endpoints, and approximately day 75 for others. The study will utilize validated laboratory tests and imaging techniques, such as venography, to evaluate these parameters. The analysis will involve comparing the outcomes between the treatment groups, REGN9933 and enoxaparin, to determine the relative efficacy of REGN9933 in preventing VTE following unilateral total knee arthroplasty.