Investigational IL-2 Pathway Agonist Rezpegaldesleukin Shows Promise in Phase 2b REZOLVE-AD Trial

The phase 2b REZOLVE-AD trial of rezpegaldesleukin, the investigational IL-2 pathway agonist for the treatment of moderate-to-severe atopic dermatitis, met its primary endpoint, according to data presented in a late-breaking oral session at the European Academy of Dermatology and Venereology Congress in Paris.1

The results, announced by Nektar Therapeutics, showed that at week 16, mean Eczema Area and Severity Index (EASI) score improved by 61% for the high-dose arm (24 µg/kg every 2 weeks), 58% for the middle dose (18 µg/kg every 2 weeks), and 53% for the low dose (24 µg/kg every 4 weeks, compared with 31% for placebo (all P <.001 vs placebo for active arms). Key secondary endpoints also reached significance and included EASI-75 responses of 42%, 46%, and 34% for the high-, middle-, and low-dose arms, respectively, versus 17% for placebo, according to a Nektar press statement.1

Participants Report Significant Improvements

Patient reported outcome scores also saw statistically significant improvement among study participants receiving rezpegaldesleukin. At week 16, 67% of those receiving the high dose achieved an Atopic Dermatitis Control Tool (ADCT) reduction of more than 5 points compared with 35% of those treated with placebo (P <.001). A 4 point or greater reduction in Itch numeric rating scale (iNRS) was reported by 42% of participants in the high-dose arm vs 16% on placebo (P <.01). Daily Life Quality Index (DLQI) responses were 72% with high- dose rezpegaldesleukin and 54% with placebo (P <.05).1

“These data from REZOLVE-AD...show a rapid onset of treatment effect for both clinician-assessed and patient-reported outcomes following the first few doses of rezpegaldesleukin, presenter Jonathan Silverberg, MD, PhD, MPH, said, in a statement. "In addition, for the first time, we observe a deepening of clinical effect for patients with extended dosing of investigational therapy beyond 16 weeks, with a strengthening of absolute EASI reduction, along with higher EASI-75 and vIGA 0/1 response rates following 24 weeks of treatment.” Silverberg is associate professor of dermatology at the George Washington University School of Medicine and Health Sciences in Washington, DC.

Interim data from 42 study participants originally randomized to placebo who crossed over to high-dose rezpegaldesleukin treatment supported these findings. At 24 weeks of active therapy, there was a mean EASI reduction of reached 75%, with 62% achieving EASI-75 and 38% reaching vIGA-AD 0/1.

The Promise of Tregs

“These results from REZOLVE-AD, including the improved responses observed with duration of dosing beyond 16 weeks, demonstrate the potential of this new biology and the promise of Tregs as a therapeutic modality to treat inflammatory skin disorders,” Jonathan Zalevsky, PhD, Nektar’s chief research and development officer, said in the statement.

Tregs, or regulatory T cells, are central to immune homeostasis through their modulation of Th1, Th2, and Th17 effector subsets, but are impaired in atopic dermatitis.2 Through PEGylation, rezpegaldesleukin preferentially stimulates Treg cells rather than effector T cells, enhancing immune regulation in autoimmune and inflammatory conditions without broadly suppressing immunity. This selectivity allows for a more controlled reduction of inflammation by promoting inhibitory Treg responses over conventional T cell activation.2

Nektar reported treatment-emergent adverse events (TEAEs) (excluding injection site reactions) in 60.3% of participants across all 3 active treatment arms compared with 57.5% in the placebo group. Severe AEs occurred in 3.1% of active-treated patients and 1.4% on placebo. Discontinuations due to adverse events were more frequent with rezpegaldesleukin (5.6% pooled) than placebo (0%).

The FDA in February granted Fast Track designation for rezpegaldesleukin for the treatment of adult and pediatric patients 12 years of age and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.3

References

1. Nektar presents new data from REZOLVE-AD phase 2b study for
   rezpegaldesleukin in late-breaker oral presentation at EADV 2025. News release. Nektar. Published September 18, 2025. Accessed September 22, 2025. https://ir.nektar.com/news-releases/news-release-details/nektar-presents-new-data-rezolve-ad-phase-2b-study

2. Silverberg JI, Rosmarin D, Chovatiya R, et al. The regulatory T cell-selective interleukin-2 receptor agonist rezpegaldesleukin in the treatment of inflammatory skin diseases: two randomized, double-blind, placebo-controlled phase 1b trials. Nat Commun. 2024;15(9230). doi:10.1038/s41467-024-53384-1

3. Nektar Therapeutics receives fast track designation for rezpegaldesleukin for the treatment of moderate-to-severe atopic dermatitis. News release. PRNewswire. February 10, 2025. Accessed September 22, 2025. https://www.prnewswire.com/news-releases/nektar-therapeutics-receives-fast-track-designation-for-rezpegaldesleukin-for-the-treatment-of-moderate-to-severe-atopic-dermatitis-302371995.html