Long-term Safety, Efficacy, and Response Durability of Envudeucitinib in Moderate to Severe Plaque Psoriasis: An Extension Study

The primary objective of this study is to assess the long-term **safety** and tolerability of ESK-001 in patients with moderate to severe plaque psoriasis. This is clinically relevant as it aims to ensure that ESK-001 can be safely administered over an extended period, which is crucial for chronic conditions like plaque psoriasis that require ongoing management.

Secondary objectives include:

• To assess the long-term efficacy of ESK-001 in patients with plaque psoriasis.
• To characterize the loss of clinical response following withdrawal of ESK-001, applicable only to patients randomized to the treatment withdrawal phase of the study.
• To determine the maintenance of ESK-001 clinical response.
• To determine the proportion of clinical nonresponders who achieve a response with long-term exposure to ESK-001.
• To assess the change in quality of life (QoL) with long-term ESK-001 administration.

These secondary objectives aim to provide a comprehensive understanding of the therapeutic potential and impact of ESK-001 on patient outcomes, including sustained efficacy, response durability, and quality of life improvements.

The clinical trial involves a total of **778 participants** diagnosed with **moderate to severe plaque psoriasis**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their completion of one of the two previous studies of ESK-001, with acceptable safety and tolerability outcomes. The trial does not include a vulnerable population. Participants are required to adhere to highly effective methods of contraception if they are of childbearing potential or are sexually active with someone who is. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial aims to assess the long-term safety and tolerability of ESK-001 in this patient population.

The clinical trial is designed to evaluate the long-term safety, efficacy, and durability of response to **ESK-001** in patients with moderate to severe plaque psoriasis. This is a Phase 3, randomized, double-blind, controlled study involving the administration of ESK-001 and a placebo, both in the form of film-coated tablets, taken orally. The maximum duration of treatment is 24 weeks, with the overall trial expected to conclude by November 2028. Participants are required to have completed one of the two previous studies of ESK-001 and must meet specific inclusion criteria, such as being 18 years or older and agreeing to use highly effective contraception methods if applicable.

The trial will commence with a screening visit to confirm eligibility, followed by randomization into treatment groups. Participants will undergo regular follow-up visits to monitor safety and efficacy endpoints, including the incidence and severity of treatment-emergent adverse events. Secondary endpoints will assess long-term efficacy, clinical response, and quality of life improvements. These visits will occur at specified intervals, such as 24, 48, 72, and 96 weeks, to evaluate the achievement of significant reductions in PASI scores and other clinical measures.

The expected length of participant involvement is up to 48 weeks, with conditions for early termination including unacceptable safety and tolerability outcomes or withdrawal of consent. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any remaining safety assessments are completed. The trial's design ensures rigorous monitoring and data collection to achieve its primary objective of assessing the long-term safety and tolerability of ESK-001 in the target patient population.

The clinical trial involves the administration of **ESK-001**, an experimental medication designed to evaluate its long-term safety, efficacy, and durability of response in patients with moderate to severe plaque psoriasis. **ESK-001** is formulated as a tablet and contains the active substance **envudeucitinib**, a chemical compound. The medication is administered orally, with a maximum daily dose of 80 mg. The treatment period for **ESK-001** extends up to 48 weeks. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

In addition to the experimental treatment, the study includes the use of a placebo, referred to as **ESK-001 placebo**. This placebo is also provided in the form of a film-coated tablet and is administered orally. The placebo is used to maintain the study's double-blind design, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The maximum duration of treatment with the placebo is 24 weeks. The use of the placebo allows for a comparison of the effects of **ESK-001** against a non-active control, providing a baseline for evaluating the experimental medication's efficacy and safety.

Efficacy in this clinical trial will be assessed through a series of predefined endpoints. The primary efficacy endpoints include the incidence and severity of treatment-emergent adverse events and serious adverse events. Secondary efficacy endpoints focus on long-term outcomes and include the achievement of ≥75%, ≥90%, and ≥100% reductions in the **Psoriasis Area and Severity Index (PASI)** after 24, 48, 72, and 96 weeks of treatment with ESK-001. Additionally, the achievement of static Physician's Global Assessment (sPGA) scores of 0 and 0/1 at the same time points will be evaluated.

Clinical response endpoints will also be assessed, such as the loss of response following ESK-001 withdrawal, specifically in terms of PASI-75 and sPGA-0/1, and the median time to loss of response. The maintenance of response at Weeks 24 and 48 in the long-term extension (LTE) study will be evaluated for PASI-75, PASI-90, PASI-100, and sPGA-0/1. Quality of life endpoints will be measured using the Dermatology Life Quality Index (DLQI), with a focus on achieving DLQI-0/1 and changes from baseline in DLQI, Psoriasis Symptom Diary (PSSD), and Numerical Rating Scale (NRS) for pruritus, joint pain, and joint disease activity, as well as the SF-36 health survey.