Efficacy and Safety Evaluation of Litifilimab in Adults with Active Systemic Lupus Erythematosus on Standard Nonbiologic Lupus Care: A Phase 3 Randomized Controlled Trial

The primary objective of this study is to demonstrate the **efficacy** of BIIB059 (litifilimab) compared with placebo in participants with active **systemic lupus erythematosus** (SLE), who are receiving background lupus standard of care (SOC) therapy in reducing disease activity. This is clinically relevant as it aims to provide evidence for a potential new treatment option that could improve disease management and outcomes for patients with SLE.

Secondary objectives include:

• To demonstrate early onset of efficacy of BIIB059 compared with placebo in reducing disease activity.
• To demonstrate organ-specific efficacy in reducing joint and skin disease activity.
• To demonstrate the effect of BIIB059 in reducing oral corticosteroid use.
• To evaluate the efficacy in reducing the occurrence of flare-ups up to Week 52.
• To evaluate additional efficacy with further disease activity measures.
• To assess the difference in participant-reported health-related quality of life, symptoms, and impacts of SLE.
• To evaluate the safety and tolerability of BIIB059 in participants with active SLE.
• To evaluate the immunogenicity of BIIB059 in participants with active SLE.

The clinical trial involves a total of **437 participants** diagnosed with **systemic lupus erythematosus** (SLE). 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 diagnosis of SLE at least 24 weeks prior to screening, and they must meet the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for SLE. The trial includes individuals who are receiving background lupus standard of care therapy, which may consist of antimalarials, oral corticosteroids, and/or a single immunosuppressant. The trial population is characterized by a modified Systemic Lupus Erythematosus Disease Activity Index200 (SLEDAI-2K) score of 6 or higher, excluding certain conditions, and a BILAG-2004 grade A in at least one organ system or grade B in at least two organ systems. The study also considers vulnerable populations, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographic groups.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled, Phase 3 study** to evaluate the efficacy and safety of **litifilimab** (BIIB059) in adult participants with active **systemic lupus erythematosus** (SLE) who are receiving background nonbiologic lupus standard of care therapy. The primary objective is to demonstrate the efficacy of BIIB059 compared with placebo in reducing disease activity. The trial is expected to last until March 2026, with participant recruitment having commenced in August 2021. The study involves a series of visits, beginning with an inclusion (screening) visit where participants must meet specific criteria, such as a diagnosis of SLE at least 24 weeks prior and a modified Systemic Lupus Erythematosus Disease Activity Index 200 (SLEDAI-2K) score of ≥6. Participants will be randomly assigned to receive either BIIB059 or a placebo, administered via subcutaneous injection.

Participants will attend follow-up visits at regular intervals to monitor their response to treatment and assess any adverse events. The primary endpoint is the percentage of participants achieving a Systemic Lupus Erythematosus Responder Index of 4 (SRI-4) response at Week 52. Secondary endpoints include various measures of disease activity and quality of life, such as the percentage of participants achieving an SRI-4 response at Week 24, and changes in the Physician's Global Assessment (PGA) score. The expected length of participant involvement is up to 52 weeks, with conditions for early termination including significant adverse events or failure to adhere to the study protocol. The end-of-study visit will involve a comprehensive assessment of the participant's health status and the collection of final data for analysis. Participants are required to maintain stable doses of their background lupus therapies throughout the study to ensure consistent evaluation of the investigational product's effects.

The clinical trial involves the administration of **BIIB059**, a recombinant monoclonal antibody, to evaluate its efficacy and safety in adult participants with active **systemic lupus erythematosus** (SLE). **BIIB059** is formulated as a sterile liquid for injection and is administered via the subcutaneous route. The active substance in **BIIB059** is **litifilimab**, a protein of other origin. The dosing schedule for **BIIB059** is determined based on the study protocol, with a maximum treatment period of 52 weeks. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

The study also includes a placebo control, which is a sterile liquid for injection. The placebo formulation is identical to that of the **BIIB059** drug product, minus the active ingredient, **litifilimab**. The placebo is administered via the same subcutaneous route as **BIIB059**. The use of a placebo control allows for a double-blind study design, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby reducing bias in the assessment of the drug's efficacy and safety.

Participants in the trial continue to receive background nonbiologic lupus standard-of-care therapy, which is not experimental and is administered according to standard medical practice. This standard-of-care therapy is maintained throughout the study to provide a consistent treatment background against which the effects of **BIIB059** and the placebo can be evaluated. The combination of **BIIB059** or placebo with standard-of-care therapy aims to assess the potential additive or synergistic effects of the investigational drug in reducing disease activity in participants with active SLE.

The efficacy of BIIB059 (litifilimab) in the treatment of **Systemic Lupus Erythematosus (SLE)** will be assessed through a series of predefined endpoints. The primary endpoint is the percentage of participants who achieve a Systemic Lupus Erythematosus Responder Index of 4 (SRI-4) response at Week 52. Secondary endpoints include the percentage of participants achieving an SRI-4 response at Week 24, a Joint-50 response at Week 52 for those with at least 4 swollen and tender joints at baseline, and a reduction in oral corticosteroid (OCS) dosage to ≤7.5 mg/day at Week 40, sustained through Week 52 without disease worsening. Additional secondary endpoints involve improvements in the Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity Score (CLASI-50) at Week 16, annualized flare rate through Week 52, and changes in various health-related quality of life and disease activity scores.

Efficacy assessments will be conducted at multiple timepoints, including Weeks 16, 24, 40, and 52, using validated scales and indices such as the SRI-4, CLASI, and Physician's Global Assessment (PGA) - Visual Analog Scale (VAS). The trial will also evaluate the time to onset of SRI-4 response sustained through Week 52, the percentage of participants achieving various levels of response by visit, and the time to first severe flare as defined by established indices. Data collection will involve both clinical evaluations and patient-reported outcomes to ensure a comprehensive assessment of treatment efficacy.