Investigational Rezpegaldesleukin Drives Early EASI Improvement and Symptom Relief in Adults with Moderate-to-Severe Atopic Dermatitis
In the phase 2b trial, the IL-2 pathway agonist and Treg proliferator demonstrated a strong dose-dependent biological response across 3 treatment arms vs placebo.
Rezpegaldesleukin, an investigational first-in-class IL-2 pathway agonist and regulatory T-cell (Treg) proliferator, demonstrated statistically significant efficacy across primary and key secondary endpoints in a global phase 2b clinical trial of adults with moderate-to-severe atopic dermatitis (AD), according to an announcement from Nektar Therapeutics.1 The REZOLVE-AD trial met its primary endpoint of mean improvement in Eczema Area and Severity Score (EASI) from baseline at week 16 for all 3 investigational dose arms versus placebo (P <.001), with improvement of 61% for high dose, 58% for the medium dose, and 53% for the low dose vs 31% for placebo, the company reported.
The drug's mechanism targets the interleukin-2 receptor complex to stimulate Treg proliferation, potentially addressing the underlying immune system imbalance in autoimmune and inflammatory conditions. This approach differs from other atopic dermatitis treatments by focusing on broad-based Treg activation rather than targeted inhibition of specific inflammatory pathways, according to Nektar.
The trial enrolled 393 adults with minimum EASI scores of 16.0, minimum Body Surface Area involvement of 10%, and minimum validated Investigator's Global Assessment (IGA) scores of 3. Participants were randomly assigned to receive subcutaneous treatment with rezpegaldesleukin 24 µg/kg every 2 weeks (high dose), 18 µg/kg every 2 weeks (middle dose), 24 µg/kg every 4 weeks (low dose), or placebo every 2 weeks in a 3:3:3:2 randomization scheme.
All 3 dose arms achieved statistical significance for key secondary endpoints including EASI-75 (42%, 46%, and 34% vs 17% placebo), EASI-50 (66%, 66%, and 55% vs 34% placebo), and mean improvement in Body Surface Area score (54%, 48%, and 43% vs 17% placebo). The medium- and high-dose arms administered every 2 weeks also reached significance for validated IGA scores of 0 (clear) or 1 (almost clear) (20% and 26% vs 8% placebo) and Itch Numerical Rating Score improvements in patients with baseline scores of 4 or greater (42% and 35% vs 16% placebo). The high dose also reached statistical significance for EASI-90 responses (25% vs 9% placebo).
"These data from REZOLVE-AD show a fast onset of both EASI response and itch relief within the first few doses of rezpegaldesleukin treatment, which are important metrics for physicians as they assess treatment options in atopic dermatitis," Jonathan Silverberg, MD, PhD, MPH, professor of dermatology at George Washington University School of Medicine and Health Sciences, said in a statement. "This shows the advantage of a broad-based Treg mechanism over other immune-modulation approaches in development to treat the disease." Investigators also reported no increased risk of incidence of conjunctivitis, oral herpes, or oral ulcers with this mechanism of action, as is frequently seen with other mechanisms, Silverberg added.
Translational biomarker data revealed dose-dependent pharmacologic activity with up to 6-fold increases in Treg cells in the high-dose arm. Sustained Treg proliferation at week 16 correlated with reductions in key T helper 2 inflammatory markers including IL-19, TARC/CCL17, periostin, and MDC/CCL22.
The safety profile remained consistent with previous reports. Injection site reactions occurred in 69.7% of rezpegaldesleukin-treated patients, with 99.6% classified as mild or moderate and less than 1% leading to discontinuation. Among all rezpegaldesleukin doses, 55.9% of participants reported no injection site reactions, 30.1% had mild reactions, 13.8% moderate, and only 0.2% of reported reactions were severe. Other treatment-emergent adverse events (TEAE) occurring in more than 5% of study participants vs placebo included eosinophilia (7.8% vs 2.7%), pyrexia (6.3% vs 2.7%), headache (6.3% vs 4.1%) and arthralgia (5.0% vs 1.4%).
"These REZOLVE-AD results present a new therapeutic hypothesis for treatment of dermatological diseases and the investigators are looking forward to rezpegaldesleukin advancing in development in atopic dermatitis," David Rosmarin, MD, chair, department of dermatology, associate professor of dermatology at Indiana University School of Medicine, said in the Nektar statement.
The FDA granted Fast Track designation for rezpegaldesleukin in February 2025 for treating adult and pediatric patients 12 years and older with moderate-to-severe atopic dermatitis inadequately controlled by topical therapies.2 Long-term maintenance data from REZOLVE-AD participants continuing treatment through week 52 will be available in Q1 2026, with Phase 2b results in alopecia areata expected in Q4 2025.
References
REZOLVE-AD phase 2b study of rezpegaldesleukin meets primary and key secondary endpoints in patients with moderate-to-severe atopic dermatitis. News release. Nektar Therapeutics. June 24, 2025. Accessed June 25, 2025. https://ir.nektar.com/news-releases/news-release-details/rezolve-ad-phase-2b-study-rezpegaldesleukin-meets-primary-and
Nektar Therapeutics receives fast track designation for rezpegaldesleukin for the treatment of moderate-to-severe atopic dermatitis. News release. Nektar Therapeutics. February 10, 2025. Accessed June 25, 2025. https://ir.nektar.com/news-releases/news-release-details/nektar-therapeutics-receives-fast-track-designation
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