A Randomized, Blinded, Placebo Controlled, Phase 2a Proof-of-Concept Study to Evaluate Efficacy, Safety, and Tolerability of GS-5718 in Participants with Cutaneous Lupus Erythematosus (CLE)

The primary objective of this study is to evaluate the **efficacy** of GS-5718 compared to PTM in reducing skin disease activity in participants with **Cutaneous Lupus Erythematosus (CLE)**, with or without Systemic Lupus Erythematosus (SLE). This is clinically relevant as it aims to determine the potential of GS-5718 as a therapeutic option for managing skin manifestations in CLE, which can significantly impact patients' quality of life.

Secondary objectives include:

• Evaluating the efficacy of GS-5718 versus PTM in reducing skin disease activity for participants with CLE with or without SLE.
• Assessing the **safety** and tolerability of GS-5718 in participants with CLE with or without SLE.
• Characterizing the **pharmacokinetics (PK)** of GS-5718 in participants with CLE with or without SLE.

The clinical trial involves a total of **13 participants** diagnosed with **Cutaneous Lupus Erythematosus (CLE)**, with or without Systemic Lupus Erythematosus (SLE). The study population includes both male and female subjects, encompassing an **age range** of adolescents to adults. Participants were selected based on specific criteria, including the presence of active CLE at screening and Day 1, and a documented prior intolerance or inadequate response to certain treatments. The trial population includes individuals who are part of a vulnerable group, indicating a need for careful ethical considerations. Participants are required to have a lifestyle that allows compliance with all study visits and assessments. The selection process ensures that individuals have a representative lupus skin lesion amenable to biopsy, and they must be willing to undergo skin punch biopsy at two time points. The trial aims to evaluate the efficacy of GS-5718 versus PTM in reducing skin disease activity in this specific population.

The clinical trial is designed as a **randomized**, **blinded**, placebo-controlled, Phase 2a proof-of-concept study to evaluate the efficacy, safety, and tolerability of GS-5718 in participants with **Cutaneous Lupus Erythematosus (CLE)**. The primary objective is to assess the efficacy of GS-5718 versus PTM in reducing skin disease activity in participants with CLE, with or without systemic lupus erythematosus (SLE). The trial is expected to last until December 20, 2024, with recruitment starting on September 23, 2023. Participants will be involved in the study for a maximum treatment period of 12 weeks.

The trial includes several key study visits. The initial visit is the inclusion (screening) visit, where participants are assessed for eligibility based on criteria such as active CLE at screening and Day 1, a CLASI-A score of ≥ 8, and a willingness to undergo skin punch biopsy. Follow-up visits will occur throughout the study to monitor the participants' response to the treatment and to collect data on primary and secondary endpoints, including the percent change from baseline in CLASI-A score at Week 12 and the incidence of treatment-emergent adverse events. The end-of-study visit will conclude the trial, where final assessments will be conducted.

Participants are expected to comply with all study visits and assessments. Conditions that may lead to early termination from the study include non-compliance with study procedures or the occurrence of significant adverse events. The study aims to provide valuable insights into the treatment of CLE, contributing to the understanding of GS-5718's potential benefits and risks.

The clinical trial involves the administration of **GS-5718**, a film-coated tablet, as the experimental medication. The active substance in this formulation is **GS-5718-03**, a chemical compound developed by Gilead Sciences Inc. The pharmaceutical form of the medication is a film-coated tablet, with each tablet containing 15 mg of the active substance. The medication is administered orally, with a maximum daily dose of 30 mg, equating to two tablets per day. The total maximum dose over the treatment period is 2520 mg. The treatment duration is set for a maximum of 12 weeks. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

The study also includes a **placebo** group to serve as a comparator. The placebo is designed to match the experimental medication in appearance and administration route but does not contain the active substance. This allows for a blinded assessment of the efficacy, safety, and tolerability of GS-5718 in participants with Cutaneous Lupus Erythematosus (CLE), with or without Systemic Lupus Erythematosus (SLE). The placebo is administered under the same conditions as the experimental medication, ensuring consistency in the trial's methodology.

The efficacy of GS-5718 in the treatment of **Cutaneous Lupus Erythematosus (CLE)** will be assessed through a randomized, blinded, placebo-controlled, Phase 2a proof-of-concept study. The primary endpoint for evaluating efficacy is the percent change from baseline in the Cutaneous Lupus Erythematosus Disease Area and Severity Index activity (CLASI-A) score at Week 12. Secondary endpoints include the proportion of participants achieving a Cutaneous Lupus Activity Investigator Global Assessment (CLA-IGA) score of 0 or 1 at Week 12, as well as the incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), and treatment-emergent laboratory abnormalities. Pharmacokinetic (PK) characteristics of GS-5718 will also be evaluated.