Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of ESK-001 and Apremilast in Moderate to Severe Plaque Psoriasis Patients

The primary objective of this study is to evaluate whether the **efficacy** of ESK-001 is superior to placebo at Week 16 in patients with moderate to severe plaque psoriasis. This is clinically relevant as it aims to establish the potential of ESK-001 as a more effective treatment option compared to placebo, thereby addressing the therapeutic needs of patients with this chronic skin condition.

Secondary objectives include:

• Determining whether the efficacy of ESK-001 is superior to apremilast at Weeks 16 and 24, which could provide insights into its comparative effectiveness against an existing treatment.
• Assessing the safety and tolerability of ESK-001 over a 24-week treatment period, which is crucial for understanding the risk-benefit profile of the drug.
• Characterizing the pharmacokinetics of ESK-001, which will help in understanding the drug's absorption, distribution, metabolism, and excretion, thereby informing dosing regimens.

The clinical trial for evaluating the efficacy of ESK-001 in treating **Moderate to Severe Plaque Psoriasis** involves a total of 327 participants. The study population comprises both male and female subjects aged 18 years and older. Participants were selected based on specific criteria, including a diagnosis of plaque psoriasis for at least six months prior to the screening visit, with plaques covering at least 10% of the body surface area at screening and on Day 1. Additionally, participants were required to have a Psoriasis Area and Severity Index (PASI) score of 12 or higher and a static Physician's Global Assessment (sPGA) score of 3 or higher at both screening and Day 1. The trial does not include a vulnerable population, and all participants are expected to adhere to highly effective methods of contraception throughout the study. The selection process ensures a representative sample of individuals with the condition, without specific lifestyle considerations such as diet or physical activity being highlighted as part of the selection criteria.

The clinical trial is designed as a **randomized, double-blind, placebo and active comparator controlled Phase 3 study** to evaluate the efficacy and safety of ESK-001 in patients with moderate to severe plaque psoriasis. The primary objective is to determine whether the efficacy of ESK-001 is superior to placebo at Week 16. The trial will involve multiple study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, diagnosis duration, and severity of psoriasis. Participants must be 18 years or older, have a diagnosis of plaque psoriasis for at least six months, and meet specific severity criteria at screening and Day 1.

The trial will span an estimated duration until June 2026, with recruitment starting in February 2025. Participants will be involved for a maximum treatment period of 24 weeks. The study will include follow-up visits to monitor progress and assess primary and secondary endpoints, such as the achievement of PASI-75 and sPGA-0/1 at Week 16 compared to placebo. Secondary endpoints will be evaluated at Weeks 16 and 24, including additional PASI scores and patient-reported outcomes.

Participants will receive either ESK-001, **apremilast**, or a placebo, administered orally in the form of film-coated tablets or capsules. The maximum daily dose for ESK-001 is 80 mg, while for apremilast, it is 60 mg. The trial will conclude with an end-of-study visit to evaluate the overall outcomes and any adverse events. Conditions that may lead to early termination from the study include non-compliance with the protocol, withdrawal of consent, or adverse reactions that necessitate discontinuation. The trial is not categorized as low intervention and is conducted under strict regulatory guidelines to ensure participant safety and data integrity.

The clinical trial involves the administration of **Otezla** (apremilast) in the form of film-coated tablets. Otezla is provided in dosages of 10 mg, 20 mg, and 30 mg, with a maximum daily dose of 60 mg. The tablets are administered orally, and the treatment period can extend up to 24 weeks. The pharmaceutical form of Otezla is film-coated tablets, and it is manufactured by Amgen Europe B.V. The active substance, apremilast, is of chemical origin and is classified under the ATC code L04AA32. The product has undergone changes related to over-encapsulation, packaging, and labeling to ensure compliance with trial requirements.

Another experimental medication used in the trial is **ESK-001**, which contains the active substance envudeucitinib. ESK-001 is also administered in tablet form, with a maximum daily dose of 80 mg. The route of administration is oral, and the treatment duration is up to 24 weeks. Envudeucitinib is a chemical compound, and the product is developed by Alumis Inc. The trial aims to evaluate the efficacy and safety of ESK-001 in comparison to placebo and active comparator treatments.

The trial includes the use of a placebo, specifically the **ESK-001 placebo**, which is a film-coated tablet administered orally. The maximum duration of treatment with the ESK-001 placebo is 16 weeks. Additionally, an **apremilast placebo** is utilized, which consists of an over-encapsulating capsule shell containing backfill, without an actual tablet. This placebo is also administered orally, with a treatment duration of up to 16 weeks. These placebo treatments are used to maintain the double-blind nature of the study and to serve as controls for evaluating the efficacy of the experimental medications.

The efficacy of ESK-001 in the treatment of moderate to severe plaque psoriasis will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is the achievement of co-primary endpoint **PASI-75** (Psoriasis Area and Severity Index 75) and **sPGA-0/1** (static Physician's Global Assessment of 0 or 1) at Week 16 compared with placebo. Secondary endpoints include the achievement of PASI-90, PASI-100, sPGA-0, and ss-PGA-0/1 at Week 16, as well as patient-reported outcomes (PROs) such as PSSD-0 (Psoriasis Symptom Scale Diary) and DLQI-0/1 (Dermatology Life Quality Index). Additionally, changes from baseline in percentage of Body Surface Area (%BSA) affected and Pruritis Numeric Rating Scale (NRS) score will be evaluated.

These efficacy parameters will be measured at specific timepoints, including Week 16 and Week 24, with comparisons made to both placebo and apremilast. The assessments will utilize validated scales and instruments to ensure accuracy and reliability of the data collected. The trial is designed to determine whether the efficacy of ESK-001 is superior to placebo at Week 16, with further comparisons to apremilast at Week 24. The data collected will be analyzed to evaluate the treatment's impact on the severity and extent of psoriasis, as well as its effect on patients' quality of life and symptom relief.