Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of LY4100511 in Adults with Moderate-to-Severe Plaque Psoriasis

The primary objective of this study is to compare the **efficacy** of multiple dose regimens of LY4100511 versus placebo in adult participants with moderate-to-severe plaque psoriasis. This is clinically relevant as it aims to determine the potential therapeutic benefit of LY4100511 in managing symptoms of plaque psoriasis, a chronic inflammatory skin condition that significantly impacts patients' quality of life.

Secondary objectives include:

• Comparing the efficacy of multiple dose regimens of LY4100511 versus placebo on additional efficacy endpoints in adult participants with moderate-to-severe plaque psoriasis.
• Comparing the **safety** and **tolerability** of multiple dose regimens of LY4100511 versus placebo in the same patient population.
• Assessing the pharmacokinetics (PK) of LY4100511 in adult participants with moderate-to-severe plaque psoriasis.

The clinical trial involves a total of **86 participants** diagnosed with **plaque psoriasis**, specifically targeting adults aged 18 to 70 years. Both male and female subjects are included, with a focus on individuals with moderate-to-severe plaque psoriasis. Participants are required to have a **Body Mass Index (BMI)** ranging from 18 to 40 kg/m². The study population was selected based on specific criteria, including a clinical diagnosis of plaque psoriasis for at least six months prior to the baseline visit, and a stable condition characterized by significant body surface area involvement and specific scoring thresholds. Participants must be candidates for phototherapy or systemic therapy. Lifestyle considerations include the ability to comply with study procedures, such as scheduled visits and treatment plans, and the willingness to discontinue other psoriasis therapies before the study intervention. Additionally, participants must agree to avoid prolonged sun exposure and refrain from using tanning booths or other ultraviolet light sources during the study. The trial includes individuals assigned male or female at birth, and it is noted that the study population includes a vulnerable group. The sponsor has not provided further details regarding the selection process or additional lifestyle factors.

The clinical trial is a **Phase 2**, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study designed to evaluate the efficacy of LY4100511 (DC-853) in adult participants with moderate-to-severe **plaque psoriasis**. The trial aims to compare multiple dose regimens of LY4100511 against a placebo to determine the proportion of participants achieving a 75% reduction in the Psoriasis Area and Severity Index (PASI 75) at Week 12. Secondary endpoints include achieving a static Physician's Global Assessment (sPGA) score of 0 or 1, various levels of PASI reduction, and safety data, including treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs).

The trial will span approximately 12 months, with an estimated recruitment start date of November 15, 2024, and an estimated end date of November 1, 2025. Participants will be involved in the study for the duration of the treatment period, which is up to 12 weeks, with additional follow-up visits as required. The study will include an initial screening visit to confirm eligibility based on criteria such as age, disease characteristics, and the ability to comply with study procedures. Participants must have a clinical diagnosis of plaque psoriasis for at least six months, with a body surface area (BSA) involvement of 10% or more, an sPGA score of 3 or higher, and a PASI score of 12 or higher at both screening and baseline visits.

Following the screening visit, eligible participants will be randomized to receive either LY4100511 or placebo tablets, which are identical in size, shape, and color. The study drug will be administered orally, with a maximum daily dose of 800 mg and a total dose not exceeding 4000 mg over the treatment period. Participants will attend scheduled visits to monitor efficacy and safety, including assessments of PASI and sPGA scores, as well as laboratory tests to measure plasma concentrations of LY4100511. The end-of-study visit will conclude the participant's involvement, with data collected to evaluate the primary and secondary endpoints.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial is not classified as low intervention, and all participants must provide informed consent, agreeing to comply with the study's requirements and restrictions. The study is conducted under the sponsorship of Eli Lilly and Company Limited, with LY4100511 being the active substance under investigation.

The clinical trial involves the administration of **LY4100511**, a chemical compound developed by Eli Lilly and Company Limited. LY4100511 is formulated as a **tablet** and is designed to inhibit the homo- and heterodimeric forms of the cytokine IL-17 (IL-17AA and IL-17AF). The medication is administered orally, with a maximum daily dose of 800 mg and a total maximum dose of 4000 mg over a treatment period of up to 12 weeks. The trial aims to evaluate the efficacy of multiple dose regimens of LY4100511 in adult participants with moderate-to-severe plaque psoriasis.

In addition to the experimental medication, the study includes the use of **placebo tablets**. These placebo tablets are identical in size, shape, and color to the active LY4100511 tablets and contain the same compendial excipients. The placebo tablets are provided in the same packaging configuration as the active tablets to maintain the double-blind nature of the study. The placebo serves as a comparator treatment to assess the efficacy of LY4100511 against a non-active control.

The efficacy of the investigational product **LY4100511** will be assessed in a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study for the treatment of adult participants with moderate-to-severe plaque psoriasis. The primary endpoint for evaluating efficacy is the proportion of participants achieving a 75% reduction in the Psoriasis Area and Severity Index (PASI 75) at Week 12. Secondary endpoints include the proportion of participants achieving a static Physician's Global Assessment (sPGA) score of 0 or 1 with at least a 2-grade improvement from baseline at Week 12, as well as 50%, 75%, 90%, and 100% reduction in PASI score at all scheduled timepoints. Additional secondary endpoints involve the mean change and percent change from baseline in PASI score and the percentage of Body Surface Area (BSA) affected at all scheduled timepoints.

Measurements will be collected at various timepoints throughout the study, including baseline and Week 12, using validated scales such as PASI and sPGA. The study will also include a summary of safety data, capturing the number and proportion of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and discontinuations due to TEAEs. Furthermore, plasma concentrations of **LY4100511** will be measured at scheduled timepoints to evaluate steady-state maximum concentration (Cmax,ss) and trough concentration (Ctrough,ss), along with associated intra-individual variability. These assessments will provide comprehensive data on the efficacy and safety of **LY4100511** in the target population.