Efficacy and Safety Evaluation of Povorcitinib in Prurigo Nodularis: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the effect of **povorcitinib** on itch and skin lesions in participants with **Prurigo Nodularis** (PN). This is clinically relevant as PN is a chronic skin condition characterized by intensely itchy nodules, and effective management of these symptoms can significantly improve patient outcomes and quality of life.

Secondary objectives include:

• To further evaluate the effect of povorcitinib on itch in participants with PN.
• To further evaluate the effect of povorcitinib on skin lesions in participants with PN.
• To further evaluate the effect of povorcitinib on both itch and skin lesions in participants with PN.
• To evaluate the effect of povorcitinib on quality of life (QoL).
• To evaluate the safety and tolerability of povorcitinib.

The clinical trial involves a total of **168 participants** diagnosed with **Prurigo Nodularis**. The study population includes both male and female subjects, aged between **18 to 75 years**, with a specific note that participants from South Korea must be 19 years or older. Participants were selected based on their ability to comprehend and sign an informed consent form, and they must have a clinical diagnosis of Prurigo Nodularis for at least three months prior to screening. The trial includes individuals with a pruritus severity defined by an average Itch Numeric Rating Scale (NRS) score of 7 or higher during the week before the first day of the study. Additionally, participants must have at least 20 pruriginous lesions across two or more body regions, such as both legs, arms, or the trunk. The study population also includes individuals with a documented history of treatment failure, intolerance, or contraindication to previous treatments for Prurigo Nodularis, excluding prior topical or systemic JAK or TYK2 inhibitors. Participants are required to comply with the study protocol and procedures, and there is an emphasis on avoiding pregnancy or fathering children during the trial. The trial does not exclude vulnerable populations, indicating a broad inclusion of individuals who meet the specified criteria.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **Povorcitinib** in participants with **Prurigo Nodularis**. The trial aims to assess the effect of Povorcitinib on itch and skin lesions over a period of 48 weeks. Participants will be randomly assigned to receive either Povorcitinib or a placebo, administered orally in tablet form. The trial is expected to commence recruitment on December 10, 2024, and conclude by September 22, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, clinical diagnosis of Prurigo Nodularis, and documented history of treatment failure with previous therapies. The primary endpoint is the proportion of participants achieving a significant improvement in itch and skin lesion scores at Week 24. Secondary endpoints include similar assessments at earlier time points.

The sequence of study visits includes the initial screening, followed by regular follow-up visits to monitor progress and assess treatment efficacy and safety. The end-of-study visit will occur at the conclusion of the 48-week treatment period. Participants are expected to be involved in the study for the entire duration unless conditions arise that necessitate early termination, such as adverse reactions or non-compliance with the study protocol.

The clinical trial involves the administration of **Povorcitinib**, an experimental medication, in the form of a **tablet**. Povorcitinib is chemically identified as 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-[4,4'-bipyrazol]-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(2S)-1,1,1-trifluoropropan-2-yl]benzamide. The medication is administered **orally**. The trial is designed to evaluate the efficacy and safety of Povorcitinib in participants with **Prurigo Nodularis**. The maximum treatment period for Povorcitinib is 48 weeks. The dosage and frequency of administration are determined based on the study protocol, with compliance monitored throughout the trial. Povorcitinib is not a pediatric formulation and is classified as a chemical entity.

In addition to the experimental medication, a **placebo** is used as a comparator treatment in this double-blind, placebo-controlled study. The placebo is designed to match the pharmaceutical form of Povorcitinib, although specific details regarding its composition are not provided. The placebo serves as a control to assess the efficacy of Povorcitinib by comparing outcomes between the treatment and placebo groups. Participants are randomly assigned to receive either Povorcitinib or the placebo, with neither the participants nor the investigators aware of the group assignments to maintain the study's integrity.

The efficacy of **Povorcitinib** in the treatment of Prurigo Nodularis will be assessed through a Phase 3, randomized, double-blind, placebo-controlled clinical trial. The primary efficacy endpoints include the proportion of participants achieving a ≥ 4-point improvement in the Itch Numeric Rating Scale (Itch NRS4) and an Investigator's Global Assessment of Clinical Prurigo Nodularis Severity (IGA-CPG-S) score of 0 or 1 with a ≥ 2-grade improvement from baseline at Week 24. Secondary endpoints will evaluate the proportion of participants achieving Itch NRS4 at Week 24, IGA CPG S-TS at Week 24, and Itch NRS4 at Week 4.

Measurements will be collected at specified timepoints, including Week 4 and Week 24, using validated scales such as the Itch NRS and IGA-CPG-S. These scales are designed to quantify symptom improvement and assess the severity of skin lesions. The data collected will be analyzed to determine the efficacy of Povorcitinib compared to placebo in reducing itch and improving skin lesions in participants with Prurigo Nodularis.