Phase 3 Study to Evaluate the Efficacy and Safety of ESK-001 in Patients with Moderate to Severe Plaque Psoriasis

The primary objective of this study is to determine 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, which could significantly impact therapeutic strategies for this condition.

Secondary objectives include:

• To determine whether the efficacy of ESK-001 is superior to apremilast at Weeks 16 and 24, providing insights into its comparative effectiveness against an active comparator.
• To assess the safety and tolerability of ESK-001 over 24 weeks of treatment, which is crucial for understanding the risk-benefit profile of the drug.
• To characterize the pharmacokinetics of ESK-001, which will help in understanding the drug's absorption, distribution, metabolism, and excretion.

The clinical trial involves a total of **451 participants** diagnosed with **moderate to severe plaque psoriasis**. The study population includes both males and females 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. Participants' general health status is not specified beyond the inclusion criteria related to psoriasis. Lifestyle considerations such as diet, physical activity, or habits are not detailed in the available data. Women of childbearing potential and males who are sexually active with such women must adhere to highly effective methods of contraception throughout the study duration.

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 a screening visit to confirm eligibility based on criteria such as age, diagnosis duration, and severity of psoriasis. Participants must have a diagnosis of plaque psoriasis for at least six months, with plaques covering at least 10% of their body surface area and a Psoriasis Area and Severity Index (PASI) score of 12 or higher.

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, with the primary endpoint assessed at Week 16. The study will include follow-up visits to monitor safety and efficacy, with secondary endpoints evaluated at both Week 16 and Week 24. These endpoints include the achievement of PASI-75, PASI-90, PASI-100, and static Physician's Global Assessment (sPGA) scores, as well as patient-reported outcomes such as the Psoriasis Symptom Scale and Dermatology Life Quality Index.

Participants will be randomly assigned to receive either ESK-001, **apremilast**, or a placebo, with all treatments administered orally. The study is double-blind, meaning neither the participants nor the investigators will know which treatment is being administered. The trial may be terminated early for individual participants if they experience significant adverse effects or if they do not adhere to the study protocol. The end-of-study visit will involve a final assessment of the participant's condition and any remaining safety evaluations. The trial is not categorized as low intervention, reflecting its comprehensive design to assess both safety and efficacy in a controlled environment.

The clinical trial involves the administration of **Otezla**, which contains the active substance **apremilast**. Otezla is available in film-coated tablet form with dosages of 10 mg, 20 mg, and 30 mg. The medication is administered orally, with a maximum daily dose of 60 mg. The treatment period can extend up to 24 weeks. The tablets are manufactured by Amgen Europe B.V. and are subject to over-encapsulation, packaging, and labeling modifications for the trial. Participant compliance with the dosing schedule will be monitored throughout the study.

Another experimental medication used in the trial is **ESK-001**, which contains the active substance **envudeucitinib**. ESK-001 is provided in tablet form and is also administered orally. The maximum daily dose for ESK-001 is 80 mg, with a treatment duration of up to 24 weeks. This investigational product is developed by Alumis Inc. and is chemically synthesized. Compliance with the dosing regimen will be closely monitored to ensure adherence to the study protocol.

The trial includes a placebo control for ESK-001, which is provided as a film-coated tablet. The placebo is administered orally, with a maximum treatment duration of 16 weeks. This placebo is designed to match the appearance of the active ESK-001 tablets to maintain the double-blind nature of the study.

Additionally, a placebo for apremilast is utilized in the study. This placebo is presented as an over-encapsulating capsule shell containing backfill, without an active tablet. It is administered orally, with a treatment duration of up to 16 weeks. The placebo is intended to mimic the administration of the active apremilast tablets, ensuring blinding is maintained throughout the trial.

The efficacy of ESK-001 in patients with moderate to severe plaque psoriasis will be assessed through a multicenter, randomized, double-blind, placebo, and active comparator-controlled Phase 3 study. The primary efficacy endpoint is the achievement of co-primary endpoints, specifically the **Psoriasis Area and Severity Index (PASI-75)** and the **static Physician's Global Assessment (sPGA-0/1)** at Week 16 compared with placebo. Secondary endpoints include the achievement of PASI-90, PASI-100, sPGA-0, and sPGA-0/1, as well as patient-reported outcomes (PROs) such as the Psoriasis Symptom Scale Diary (PSSD-0) and the Dermatology Life Quality Index (DLQI-0/1). Changes from baseline in the percentage of Body Surface Area (%BSA) affected and the Pruritus Numeric Rating Scale (NRS) score will also be evaluated.

Efficacy assessments will be conducted at specified time points, including Week 16 and Week 24, with comparisons made to both placebo and the active comparator, **apremilast**. The study will utilize validated scales and instruments to measure these endpoints, ensuring the reliability and accuracy of the data collected. The trial aims to determine whether ESK-001 demonstrates superior efficacy compared to placebo, with additional comparisons to apremilast to further evaluate its therapeutic potential.