Evaluation of Afimetoran Efficacy and Safety in Active Systemic Lupus Erythematosus: A Phase 2 Randomized, Double-blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of Afimetoran compared to placebo in participants with active **Systemic Lupus Erythematosus** (SLE) using a composite measure of improvement in lupus activity, primarily driven by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). This is clinically relevant as it aims to determine the potential of Afimetoran to reduce disease activity in SLE, a chronic autoimmune condition characterized by inflammation and tissue damage.

Secondary objectives include:

• Assessing the efficacy of Afimetoran versus placebo using an alternative composite measure of improvement in lupus activity, primarily driven by the British Isles Lupus Assessment Group (BILAG), in participants with active SLE.
• Evaluating the efficacy of Afimetoran versus placebo on measures of global and organ-specific clinical response in participants with active SLE.
• Assessing the steroid-sparing effect of Afimetoran versus placebo in participants with active SLE.
• Characterizing patient-reported health status in participants with active SLE on Afimetoran.
• Assessing the safety and tolerability of Afimetoran versus placebo in participants with active SLE.

The clinical trial involves a total of **464 participants** diagnosed with **Active Systemic Lupus Erythematosus**. The study population includes both male and female subjects, with an age range that spans from young adults to older adults. Participants were selected based on specific criteria, including a diagnosis of Systemic Lupus Erythematosus (SLE) at least 12 weeks prior to the screening visit, and a positive test for lupus-related autoantibodies. The trial population is characterized by a diverse health status, with a focus on individuals who have a total Hybrid Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score of 6 or higher, and a clinical Hybrid SLEDAI score of 4 or higher, indicating joint involvement and/or rash. The study also considers vulnerable populations, ensuring a comprehensive assessment of the treatment's efficacy across different demographic groups. Lifestyle factors such as diet and physical activity were not specified in the available data.

The clinical trial is a **Phase 2**, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of **Afimetoran** in participants with active **Systemic Lupus Erythematosus** (SLE). The trial aims to assess the efficacy of Afimetoran versus placebo using a composite measure of improvement in lupus activity, primarily driven by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). The trial is expected to run from August 23, 2021, to June 16, 2026, with a maximum treatment period of 100 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of SLE at least 12 weeks prior and a positive test for lupus-related autoantibodies. The trial includes follow-up visits at specified intervals to monitor the primary endpoint, which is the proportion of participants achieving an SLE Responder Index 4 (SRI[4]) response at Week 48. Secondary endpoints include assessments at Weeks 24 and 48, such as the British Isles Lupus Assessment Group (BILAG)-based Combined Lupus Assessment (BICLA) and changes in joint counts and disease activity scores.

The expected length of participant involvement is up to 48 weeks, with an optional long-term extension period for those who complete the initial study treatment and may benefit from continued participation. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or failure to meet ongoing eligibility criteria. The trial employs a double-blind design, ensuring that neither participants nor investigators know whether Afimetoran or placebo is administered, thus maintaining the integrity of the study results.

The clinical trial involves the administration of **Afimetoran**, a chemical compound known as afimetoran besilate dihydrate, developed by Bristol-Myers Squibb International Corporation. Afimetoran is provided in a **capsule** form and is intended for **oral** administration. The dosage is measured in milligrams, with a maximum daily dose and total dose amount set at 9999 mg. The treatment period is capped at 100 days. The trial aims to evaluate the efficacy and safety of Afimetoran in participants with active **Systemic Lupus Erythematosus** (SLE). The medication is not a pediatric formulation and is classified as a medicinal product of chemical origin.

In addition to the experimental medication, the study includes the use of an **Afimetoran placebo**. The placebo is designed to mimic the appearance of the Afimetoran capsules but does not contain the active substance. The placebo serves as a comparator treatment to assess the efficacy of Afimetoran in a double-blind, randomized, and placebo-controlled setting. The placebo is administered following the same schedule and route as the active medication to ensure consistency in the trial's methodology.

The efficacy of Afimetoran in the treatment of active **Systemic Lupus Erythematosus** (SLE) will be assessed using a composite measure of improvement in lupus activity, primarily driven by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). The primary endpoint for evaluating efficacy is the proportion of participants who achieve an SLE Responder Index 4 (SRI[4]) response at Week 48. Secondary endpoints include the proportion of participants achieving a British Isles Lupus Assessment Group (BILAG)-based Combined Lupus Assessment (BICLA) at Week 24 and Week 48, and the proportion achieving a Lupus Low Disease Activity State (LLDAS) response at these same timepoints.

Additional secondary endpoints involve the assessment of joint involvement and cutaneous manifestations, such as the proportion of participants with a Cutaneous Lupus Erythematosus Disease Area and Severity Index; Activity (CLASI-A) score ≥ 10 at baseline who achieve a decrease of ≥ 50% from baseline CLASI-A score (CLASI-50) response at Week 24 and Week 48. Joint assessments will include the mean change from baseline in swollen and tender joint counts using the 28-joint count at Week 24 and Week 48. Patient-reported outcomes will be measured using the 36-item Short Form Health Questionnaire (SF-36) to evaluate changes in disease activity from baseline to Week 24 and Week 48.

Data collection will occur at specified intervals, with key timepoints at Week 24 and Week 48, to ensure comprehensive evaluation of the treatment's efficacy. The analysis will be conducted using validated scales and instruments to ensure the reliability and accuracy of the results. The trial is designed to provide robust data on the efficacy of Afimetoran in improving clinical outcomes for participants with active SLE.