Efficacy and Safety Evaluation of Rezpegaldesleukin in Biologic-Naive Adults with Moderate-to-Severe Atopic Dermatitis: A Phase 2b Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of each dose regimen of **rezpegaldesleukin** compared to placebo, as measured by the percent change from baseline in the Eczema Area and Severity Index (EASI) in biologic-naive patients with moderate-to-severe **Atopic Dermatitis** (AD). This is clinically relevant as it aims to determine the potential of rezpegaldesleukin to improve the condition of patients who have not previously been treated with biological therapies, potentially offering a new therapeutic option for this patient population.

Secondary objectives include: - Comparing the efficacy of rezpegaldesleukin versus placebo by assessing improvement in signs and/or symptoms in the treatment of biologic-naive patients with moderate-to-severe AD. - Characterizing the pharmacokinetics (PK) of rezpegaldesleukin in patients with moderate-to-severe AD. - Describing the observed safety of rezpegaldesleukin in patients with moderate-to-severe AD.

The clinical trial involves a total of **189 participants** diagnosed with **Atopic Dermatitis**. The study population includes both male and female subjects who are at least 18 years of age. Participants are biologic-naive patients with moderate-to-severe atopic dermatitis, as defined by specific severity criteria, including an EASI score of 16 or higher and a vIGA-AD score of 3 or higher. The trial population was selected based on their candidacy for systemic therapy and a documented history of inadequate response or intolerance to existing topical medications. Participants are required to provide informed consent and adhere to contraception requirements. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, indicating that additional ethical considerations are in place to protect these participants.

The clinical trial is a **Phase 2b**, randomized, double-blind, parallel-group, placebo-controlled study designed to evaluate the efficacy and safety of **rezpegaldesleukin** in the treatment of adult patients with moderate-to-severe **atopic dermatitis**. The trial aims to compare the efficacy of different dose regimens of rezpegaldesleukin versus placebo, with the primary endpoint being the mean percent change in the Eczema Area and Severity Index (EASI) from baseline at Week 16. Secondary endpoints include various measures of improvement in disease severity and patient-reported outcomes over a period extending to Week 104.

The trial is expected to commence recruitment on April 30, 2024, and is estimated to conclude by December 31, 2026. Participants will be involved in the study for a maximum treatment period of 10 weeks, with the total duration of involvement potentially extending to 104 weeks, depending on follow-up assessments. The study will include several key visits: an initial screening visit to confirm eligibility, a randomization visit, multiple follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes.

Inclusion criteria require participants to be adults diagnosed with atopic dermatitis for at least 12 months prior to screening, with specific severity criteria met at both screening and randomization. Participants must also be candidates for systemic therapy and have a documented history of inadequate response to topical treatments. Conditions for early termination from the study include non-compliance with study procedures, withdrawal of consent, or the occurrence of adverse events that, in the investigator's opinion, warrant discontinuation of treatment.

The clinical trial involves the administration of **NKTR-358**, a **solution for injection** containing the active substance **rezpegaldesleukin**. This investigational drug is developed by Nektar Therapeutics and is classified as a biological product. The pharmaceutical form is a solution intended for **subcutaneous injection**. The trial aims to evaluate the efficacy and safety of rezpegaldesleukin in adult patients with moderate-to-severe **atopic dermatitis**. The dosing regimen and frequency of administration are determined by the study protocol, with a maximum treatment period of 10 days. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, the study includes a **placebo** group for comparison. The placebo used in this trial is a **Sodium Chloride 0.9% solution**, which serves as a control to evaluate the efficacy of the investigational drug. The placebo is administered in the same manner as the experimental treatment, ensuring that the study remains double-blind. This means neither the participants nor the investigators know which treatment the participants are receiving, thereby reducing bias in the assessment of the treatment's efficacy and safety.

The efficacy of rezpegaldesleukin in the treatment of moderate-to-severe **Atopic Dermatitis** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the mean percent change in the Eczema Area and Severity Index (EASI) from baseline at Week 16. Secondary endpoints include the proportion of patients achieving a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 or 1 with at least a 2-point reduction from baseline at Week 16, as well as achieving EASI-75, EASI-90, and EASI-50. Additional secondary endpoints involve a ≥4-point improvement from baseline in the Itch Numeric Rating Scale (NRS) for patients with a baseline score of ≥4, and SCORing Atopic Dermatitis (SCORAD)-75 and SCORAD-50.

Further efficacy assessments will be conducted over the period between Week 0 and Week 104, measuring mean change and mean percent change from baseline in EASI, SCORAD, and Body Surface Area (BSA) involvement. These assessments will be evaluated at various time points during induction therapy, maintenance therapy, and follow-up. Rezpegaldesleukin plasma concentrations will also be measured at various time points throughout the study. The incidence of serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs) will be monitored as part of the safety evaluation.