Evaluation of Frexalimab (SAR441344) Efficacy and Safety in Active Systemic Lupus Erythematosus: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study

The primary objective of this study is to evaluate the **efficacy** of SAR441344, also known as Frexalimab, in comparison with placebo and in addition to standard of care (SOC), over a 24-week period, on disease activity in participants with active **Systemic Lupus Erythematosus** (SLE). This is clinically relevant as it aims to determine the potential of SAR441344 to improve disease management in SLE, a chronic autoimmune condition characterized by widespread inflammation and tissue damage.

Secondary objectives include:

• Evaluating the efficacy of SAR441344 on disease activity in all participants and biomarker subgroups, focusing on oral corticosteroid reduction, skin manifestations, and joint manifestations.
• Assessing the safety profile of SAR441344 compared to placebo and SOC over the same period.
• Investigating the potential for immunogenicity of SAR441344 in participants with active SLE.
• Evaluating the pharmacokinetic exposure of one dose level of SAR441344 over 24 weeks in adult participants with SLE.

The clinical trial involves a total of **166 participants** diagnosed with **systemic lupus erythematosus** (SLE). The study population includes both male and female subjects, with an age range that encompasses adults and adolescents. Participants were selected based on specific criteria, including a confirmed diagnosis of SLE for at least six months prior to screening, and a positive antinuclear antibody (ANA) titer of ≥1:80. The trial includes individuals with a body weight between 45 kg and 120 kg. Participants are required to be on at least one standard of care (SOC) treatment for SLE, with the possibility of combination therapy. The trial population is characterized by a diverse health status, with a focus on those with active disease manifestations. Contraceptive use is mandated in accordance with local regulations for clinical study participants. The study also includes vulnerable populations, ensuring a comprehensive evaluation of the investigational treatment's efficacy and safety across a broad demographic.

The clinical trial is designed to evaluate the **efficacy** and safety of **Frexalimab** in the treatment of **Systemic Lupus Erythematosus** (SLE). This study is a randomized, double-blind, placebo-controlled, Phase 2 trial, conducted over a 24-week period. Participants will be randomly assigned to receive either Frexalimab or a matched placebo, administered as a **solution for injection** via intravenous (IV) or subcutaneous (SC) routes. The trial aims to assess the impact of Frexalimab on disease activity in participants with active SLE, in addition to standard of care (SOC) treatments.

The trial will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as a diagnosis of SLE for at least six months, a positive antinuclear antibody (ANA) titer, and a minimum hSELENA-SLEDAI score. Following successful screening, participants will be enrolled and randomized. The primary endpoint is the percentage of participants achieving a Systemic Lupus Erythematosus Responder Index (SRI-4) response at Week 24. Secondary endpoints include various measures of disease activity and safety, such as the BILAG-based Composite Lupus Assessment (BICLA) response and changes in corticosteroid use.

Study visits will occur at regular intervals throughout the trial, including baseline assessments, periodic evaluations of disease activity, and safety monitoring. The end-of-study visit at Week 36 will include a comprehensive assessment of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and other safety parameters. Participants will be involved in the study for approximately 36 weeks, including the follow-up period. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or withdrawal of consent by the participant.

The clinical trial involves the administration of **Frexalimab**, an experimental medication, to evaluate its efficacy and safety in the treatment of **Systemic Lupus Erythematosus** (SLE). Frexalimab is provided as a **solution for injection** and is administered either **intravenously (IV)** or **subcutaneously (SC)**. The maximum daily dose of Frexalimab is 1200 mg, with a total maximum dose of 7800 mg over the course of the study. The treatment period is set for 24 weeks. Frexalimab is a protein-based therapeutic agent developed by Sanofi Aventis Recherche et Développement (SAR) and is identified by the sponsor product code SAR441344. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

In addition to Frexalimab, a **matched placebo** is utilized in this study to maintain the double-blind design. The placebo is designed to mimic the experimental treatment in appearance and administration route, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo does not contain any active pharmaceutical ingredients and serves as a control to evaluate the true efficacy of Frexalimab. The administration of the placebo follows the same schedule and route as the experimental medication, either intravenously or subcutaneously, over the 24-week study period.

The efficacy of SAR441344 in the treatment of **Systemic Lupus Erythematosus** (SLE) will be assessed through a randomized, double-blind, placebo-controlled, Phase 2 study. The primary endpoint for evaluating efficacy is the percentage of participants who achieve a Systemic Lupus Erythematosus Responder Index (SRI-4) response at Week 24. Secondary endpoints include the percentage of participants achieving an SRI-4 response in prespecified biomarker subgroups at Week 24, a BILAG-based Composite Lupus Assessment (BICLA) response, and a reduction in prednisone dose to ≤7.5 mg at Week 16 maintained through Week 24 in participants with a baseline prednisone dose of ≥10 mg/day.

Additional secondary endpoints involve the total cumulative corticosteroid dose over 24 weeks, percentage of participants achieving an SRI-4 response with sustained reduction of oral corticosteroids, and percent change from baseline in the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI)-A at Week 24 in participants with a baseline CLASI-A score of ≥8. The study will also assess the percentage of participants with ≥50% improvement in CLASI-A and the number of tender and swollen joints at Week 24. Safety and pharmacokinetic parameters, including treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), anti-drug antibodies (ADA), and SAR441344 concentrations, will be monitored from Baseline to Week 36.