Abstract
Inflammatory skin diseases such as atopic dermatitis (AD), psoriasis, and alopecia areata (AA) are characterized by immune dysregulation involving impaired regulatory T cell (Treg) function and persistent activation of effector inflammatory pathways. Current targeted therapies largely suppress downstream inflammatory signaling rather than correcting upstream regulatory abnormalities. Rezpegaldesleukin (REZPEG; NKTR-358) is a first-in-class, Treg-selective interleukin-2 (IL-2) receptor agonist engineered to preferentially expand cluster of differentiation 4 positive (CD4+) FOXP3+ Tregs while minimizing activation of conventional effector T cells and natural killer (NK) cells. This review summarizes the biological rationale, mechanism of action, and emerging clinical evidence supporting REZPEG across dermatologic indications, particularly AD and AA. In phase 1 and phase 1b studies, REZPEG induced selective and durable Treg expansion, attenuation of inflammatory biomarkers, and clinical improvements in AD and psoriasis, including prolonged off-treatment responses. In the phase 2b REZOLVE-AD trial, all active dosing regimens significantly improved Eczema Area and Severity Index outcomes versus placebo, with responses maintained or further deepened through week 52 with monthly or quarterly maintenance dosing. In severe AA, the phase 2b REZOLVE-AA trial did not meet its primary endpoint: mean Severity of Alopecia Tool (SALT) reductions at week 36 were 28.2% and 30.3% with REZPEG 24 and 18 µg/kg, respectively, versus 11.2% with placebo (p = 0.186 and p = 0.121). A supportive sensitivity analysis excluding four participants with major eligibility violations reached statistical significance, while hypothesis-generating extension data suggested further hair regrowth through week 52. Across completed studies, REZPEG has demonstrated a favorable tolerability profile, predominantly characterized by mild injection-site reactions, without major safety signals. Collectively, these findings support selective Treg expansion as a mechanistically novel therapeutic strategy in immune-mediated skin disease, while further controlled studies are needed to define REZPEG's long-term efficacy and therapeutic positioning.