New Findings on Rezpegaldesleukin Show Improvement at Week 16 in Atopic Dermatitis

An announcement by Nektar Therapeutics has revealed significant findings from the 16-week induction phase of the company's ongoing phase 2b REZOLVE-AD trial regarding the investigational agent rezpegaldesleukin for atopic dermatitis.1

Rezpegaldesleukin, a selective interleukin (IL)-pathway agonist designed to expand regulatory T cells (Tregs), was shown to be effective at 16 weeks among patients with moderate-to-severe atopic dermatitis. The skin disease is the most common form of eczema and impacts approximately 30 million people within the US.

"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 of the Department of Dermatology and associate professor of dermatology at Indiana University School of Medicine, said in a statement.1 "With the establishment of this efficacy profile in the dermatological setting of atopic dermatitis, we are also eager to see the upcoming results from the ongoing REZOLVE-AA study in patients with severe to very-severe alopecia areata."

The global analysis assessing rezpegaldesleukin included 393 individuals as participants, all of whom were randomized in a 3:3:3:2 ratio to receive a single dose of 3 rezpegaldesleukin regimens or placebo. The dosing cohorts in the REZOLVE-AA analysis included: 24 µg/kg every 2 weeks (Q2W), 18 µg/kg Q2W, 24 µg/kg on an every-4-weeks basis (Q4W), and placebo Q2W.

Both primary and secondary efficacy outcomes were evaluated by the investigative team by the conclusion of the 16-week induction period. Those who were shown to have attained >50% improvement in their Eczema Area and Severity Index (EASI-50) scores were re-randomized (1:1) to carry on with the same dose either every 4 weeks or every 12 through Week 52 in a double-blind maintenance phase. Placebo responders would continue on placebo Q4W.

Overall, the team found that REZOLVE-AD successfully met its primary endpoint, with all 3 rezpegaldesleukin arms showing a statistically significant mean improvement from the point of baseline in their EASI scores compared to placebo at the 16-week mark (P < .001).1

Key secondary endpoints were also met at the 16-week mark across all dosing arms, including statistically significant improvements observed in:

• EASI-75 (≥75% reduction in EASI from the point of baseline);
• EASI-50 (≥50% reduction), and;
• Body Surface Area (BSA) involvement.

Additionally, the investigators found that both Q2W dosing regimens (24 µg/kg and 18 µg/kg) attained significance for:

• vIGA-AD 0/1, which was defined as an Investigator’s Global Assessment score of 0 (clear) or 1 (almost clear) with at least a 2-point drop from baseline;
• Itch Numeric Rating Scale (NRS), in which patients with a baseline score ≥4 attained a ≥4-point reduction.

In 1 notable finding, the REZOLVE-AD team found that those in the high-dose Q2W cohort (24 µg/kg) also achieved statistical significance for EASI-90 by Week 16. Their subgroup analyses, stratified by baseline disease severity, demonstrated consistent EASI-75 and EASI-90 response rates in subjects with severe disease (vIGA-AD 4) and moderate disease (vIGA-AD 3).

The investigators' pharmacodynamic data indicated a strong dose-dependent biological response among those involved.1 Specifically, the participants in the high-dose arm had up to a 6-fold increase in circulating Treg cells at the 16-week mark relative to baseline. This Treg expansion was correlated with declines in key Th2-associated inflammatory biomarkers, which the investigative team noted includes TARC/CCL17, IL-19, periostin, and MDC/CCL22.

The safety profile of rezpegaldesleukin in the induction period remained in line with earlier findings. The most frequently reported treatment-emergent adverse events (TEAEs) were shown to be injection site reactions (ISRs). ISRs took place in 69.7% of individuals given the study drug.

The REZOLVE-AD team highlighted that all ISRs (99.6%) had been shown to be mild or moderate in their severity, as well as self-limiting and resulting in treatment discontinuation in fewer than 1% of cases. ISR severity breakdown across all dosing regimens indicated that 55.9% of subjects had no ISR, 30.1% had mild ISR, 13.8% reported moderate ISR, and only 0.2% were shown to have a severe ISR.

Other TEAEs observed by the investigative team more often in the active treatment arms compared to placebo included:

• Eosinophilia (7.8% versus 2.7%),
• Fever (pyrexia) (6.3% versus 2.7%),
• Headache (6.3% versus 4.1%), and
• Joint pain (arthralgia) (5.0% versus 1.4%).

When they excluded ISRs, the team found that overall TEAE incidence was comparable between the pooled rezpegaldesleukin arms (60.3%) and those in the placebo arm (57.5%). No elevated risk of oral ulcers, conjunctivitis, or infections was noted by the REZOLVE-AD investigators in any of the rezpegaldesleukin treatment cohorts.

"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.1 "This shows the advantage of a broad-based Treg mechanism over other immune-modulation approaches in development to treat the disease. Additionally, we don't see any increased risk of incidence of conjunctivitis, oral herpes, or oral ulcers with this mechanism of action as we do with other mechanisms."

The company is slated to present these 16-week induction data at a scientific meeting scheduled for later in 2025, according to their announcement.1

References

1. REZOLVE-AD Phase 2b Study of Rezpegaldesleukin Meets Primary and Key Secondary Endpoints in Patients with Moderate-to-Severe Atopic Dermatitis. 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.