First-in-Class IL-2 Pathway Agonist Advances in AD

At the 2025 European Academy of Dermatology and Venereology (EADV) Congress in Paris, France, investigators presented new data from the REZOLVE-AD phase 2b trial evaluating rezpegaldesleukin (REZPEG, NKTR-358; Nektar), an IL-2 pathway agonist designed to selectively expand regulatory T cells (Tregs), in patients with moderate to severe atopic dermatitis (AD).¹

Study Overview

REZOLVE-AD (NCT06136741) is a global, randomized, placebo-controlled Phase 2b study initiated in 2023. The trial enrolled 393 patients across 110 sites, with the majority recruited in Europe. Participants were randomized to one of three dosing regimens:

• 24 µg/kg every 2 weeks (high dose)
• 18 µg/kg every 2 weeks (middle dose)
• 24 µg/kg every 4 weeks (low dose)
• Placebo every 2 weeks

The primary endpoint was mean improvement in Eczema Area and Severity Index (EASI) at week 16. Secondary endpoints included EASI-75, EASI-90, validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD), body surface area (BSA), Itch Numerical Rating Scale (NRS), and patient-reported outcomes such as the Dermatology Life Quality Index (DLQI), Atopic Dermatitis Control Tool (ADCT), and sleep and pain measures.

Week 16 Efficacy Results

All three active treatment arms achieved statistically significant improvements in EASI compared to placebo at week 16.

• EASI reduction: 61% (high dose), 58% (middle dose), 53% (low dose) vs. 31% placebo.
• EASI-75 response rates: 42% (high), 46% (middle), 34% (low) vs. 17% placebo.
• EASI-90: Achieved in 25% (high dose), though not statistically significant in middle and low dose groups.
• vIGA-AD 0/1 (clear/almost clear): 20–26% across active arms vs. 8% placebo.
• BSA reduction: 43–54% across active arms vs. 17% placebo.

Improvements were also seen in pruritus, with up to 42% of high-dose patients achieving ≥4-point reductions in Itch NRS compared with 16% of placebo-treated patients.

Patient-Reported Outcomes

High-dose rezpegaldesleukin demonstrated benefit across several patient-reported outcome measures at week 16:

• DLQI: 72% reported ≥4-point reduction vs. 54% placebo.
• ADCT: 67% vs. 35% placebo.
• Sleep disturbance (ADSS Q1): 57% vs. 30% placebo.
• Pain NRS: 45% vs. 22% placebo.

Extended Dosing and Placebo Escape Data

The trial design included re-randomization for maintenance dosing after week 16 and an escape arm for placebo non-responders. Interim data from 42 patients who crossed over from placebo to high-dose treatment showed further clinical gains:

• EASI-75 improved from 50% at week 16 post-crossover to 62% at week 24.
• vIGA-AD 0/1 increased from 28% to 38% over the same period.
• Mean EASI reduction deepened from 68% at crossover week 16 to 75% at week 24.

Safety Profile

During the 16-week induction phase, treatment-emergent adverse events (TEAEs) excluding injection-site reactions occurred in approximately 60% of patients across active arms, comparable to 57.5% in placebo. Serious adverse events were infrequent (≤3.8%), with drug-related events including hypersensitivity and tonsillitis, both of which resolved. Severe drug-related adverse events occurred in <3% of patients and included pyrexia and injection-site reactions. No deaths were reported.

Clinical Implications

Rezpegaldesleukin’s mechanism, targeting Tregs to restore immune tolerance, represents a distinct therapeutic approach compared with currently approved biologics that primarily inhibit Th2-driven pathways. The phase 2b findings suggest both rapid onset of action and continued deepening of response with extended treatment. The safety profile appears acceptable for further development, with no unexpected signals.

Notably, the US FDA has granted Fast Track designation for rezpegaldesleukin in both atopic dermatitis and severe alopecia areata, reflecting regulatory recognition of its potential clinical value. Results from the alopecia areata phase 2b program are expected later in 2025.^2-3

Conclusion

Data presented at EADV 2025 demonstrate that rezpegaldesleukin significantly improved clinical and patient-reported outcomes in moderate to severe AD over 16 weeks, with extended dosing providing further benefit. Researchers state this trial supports continued evaluation of this first-in-class Treg-stimulating agent as a potential new option for patients with inadequately controlled AD.

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 20, 2025. https://ir.nektar.com/news-releases/news-release-details/nektar-presents-new-data-rezolve-ad-phase-2b-study
2. 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 20, 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
3. Nektar Therapeutics receives Fast Track Designation for rezpegaldesleukin for the treatment of severe-to-very severe alopecia areata. News release. Nektar Therapeutics. July 29, 2025. Accessed September 20, 2025. https://www.prnewswire.com/news-releases/nektar-therapeutics-receives-fast-track-designation-for-rezpegaldesleukin-for-the-treatment-of-severe-to-very-severe-alopecia-areata-302515436.html