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Introduction & Objectives Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder. Dysfunction of regulatory T cells (Treg) may play a role in AD immunopathogenesis.1 Rezpegaldesleukin (REZPEG: NKTR-358) is a polyethylene glycol (PEG)-conjugated recombinant human interleukin 2 (rhIL-2) with the ability to selectively promote the activation and up-to 12-fold expansion of Tregs, while having relatively minimal effect on conventional T cells (Tcons).2 It represents a potential novel therapeutic approach for patients with moderate-to- severe AD. A Phase 1b study of REZPEG for patients with moderate-to-severe AD demonstrated a rapid time to response (2-4 weeks) during induction therapy and a prolonged durability of response, i.e. throughout the 36- week follow-up after cessation of therapy.3 These results support further development of REZPEG for patients with AD. Objective Evaluate the efficacy and safety of REZPEG in patients with moderate-to-severe AD. Materials & Methods This Phase 2b, randomized, double-blinded, placebo-controlled, international, multicenter study of REZPEG vs placebo enrolls biologic and JAK-inhibitor (JAKi) naïve adults with moderate-to-severe AD, defined by a baseline Eczema Area and Severity Index (EASI) score of ≥16, an Investigator's Global Assessment (IGA) AD score of ≥3, affected total body surface area (BSA) of ≥10%, and chronic AD history of at least one year. Patients are randomized in a 3:3:3:2 ratio to three different REZPEG dosing regimens or placebo, administered subcutaneously during the induction phase. Responders achieving EASI50 post-induction are re-randomized to maintenance dosing every 4 or 12 weeks. Non-responders or those experiencing acute exacerbations are transferred to an open-label rescue arm receiving REZPEG. The primary outcome is the least squares mean percentage reduction in EASI from baseline at the end of induction. Secondary and exploratory endpoints include proportions achieving IGA 0/1 with a ≥2 point reduction, EASI75, EASI90, EASI50, itch relief (≥4 point improvement on the Numerical Rating Scale), % BSA improvement, safety, tolerability, patient-reported outcomes (PROs), pharmacokinetics, and pharmacodynamics. Results Trial ongoing (NCT06136741). Conclusion REZPEG represents an innovative approach to stimulate regulatory T cells, potentially offering lasting benefits for patients with moderate-to-severe AD. This Phase 2b trial seeks to define the optimal dosing schedule and further establish the efficacy and safety profile of REZPEG in a population new to biologic and JAK inhibitor therapies. [ABSTRACT FROM AUTHOR]