Rezpegaldesleukin treatment of moderate-to-severe atopic dermatitis (REZOLVE-AD): final results from the 16-week induction period of an international, double-blind, placebo-controlled, randomised phas

Rezpegaldesleukin is an interleukin-2 receptor agonist that selectively expands and enhances the function of regulatory T cells (Tregs), offering a novel therapeutic approach for autoimmune and inflammatory diseases such as atopic dermatitis. We aimed to compare the efficacy and safety analyses of rezpegaldesleukin with placebo in adults with moderate-to-severe atopic dermatitis naive to biological treatments. REZOLVE-AD was a phase 2b, randomised, double-blind, placebo-controlled study conducted in 107 community research centres or hospitals in ten countries (Australia, Bulgaria, Canada, Croatia, Czechia, Germany, Hungary, Poland, Spain, and the USA). Eligible patients were adults (aged 18 years or older) with confirmed atopic dermatitis (American Academy of Dermatology Consensus Criteria) diagnosed at least 12 months before enrolment, with moderate-to-severe disease activity defined by an Eczema Area and Severity Index (EASI) score of at least 16·0, validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of at least 3 (moderate), and at least 10% affected body surface area. Patients were randomly allocated (3:3:3:2) to receive subcutaneous rezpegaldesleukin 24 μg/kg or rezpegaldesleukin 18 μg/kg every 2 weeks, rezpegaldesleukin 24 μg/kg every 4 weeks, or placebo for 16 weeks during the induction period. Randomisation was done by an independent vendor using Randomisation and Trial Supply Management methodology via an interactive response system and was stratified by baseline disease severity (vIGA-AD 3 [moderate] vs 4 [severe]) and geographical region (North America vs rest of world). All patients, investigators, and those assessing outcomes were masked to treatment assignment. Outcomes for the induction period were assessed through week 16 and are included in this report. The primary endpoint was percentage change from baseline in EASI score at week 16. Efficacy and safety analyses were conducted in all randomly assigned patients exposed to study treatment, excluding those enrolled at two sites closed due to Good Clinical Practice non-compliance, both of which received notification of closure approximately 300 days before database lock. All missing data were imputed with multiple imputation. The trial was registered with ClinicalTrials.gov (NCT06136741). 398 patients were enrolled between Nov 15, 2023, and Jan 9, 2025. A total of 393 patients were analysed (104 in the rezpegaldesleukin 24 μg/kg every 2 weeks group, 106 in the rezpegaldesleukin 18 μg/kg every 2 weeks group, 110 in the rezpegaldesleukin 24 μg/kg every 4 weeks group, and 73 in the placebo group); 203 (52%) patients were female and 190 (48%) were male. All three rezpegaldesleukin groups met the primary endpoint. Rezpegaldesleukin showed dose-dependent improvements compared with placebo in mean percentage change in EASI from baseline at week 16: -61% (SE 3·8) for rezpegaldesleukin 24 μg/kg every 2 weeks, -58% (3·8) for rezpegaldesleukin 18 μg/kg every 2 weeks, and -53% (3·7) for rezpegaldesleukin 24 μg/kg every 4 weeks versus -31% (4·5) for placebo. Treatment differences versus placebo were -30 percentage points (95% CI -41·3 to -18·0; p<0·0001) for rezpegaldesleukin 24 μg/kg every 2 weeks, -27 percentage points (-38·5 to -15·7; p<0·0001) for rezpegaldesleukin 18 μg/kg every 2 weeks, and -22 percentage points (-33·3 to -10·3; p=0·0002) for rezpegaldesleukin 24 μg/kg every 4 weeks. Treatment-emergent adverse events observed in at least 5% of rezpegaldesleukin-treated patients (n=320) and greater than placebo (n=73) included injection-site reaction (223 [70%] vs three [4%]), eosinophilia (25 [8%] vs two [3%]), pyrexia (20 [6%] vs two [3%]), headache (20 [6%] vs three [4%]), upper respiratory tract infections (19 [6%] vs four [5%]), and arthralgia (16 [5%] vs one [1%]). Nearly all (>99%) injection-site reactions were mild to moderate in severity and resolved. There was no evidence of an increased risk of serious or severe adverse events, and no deaths were reported during the induction period. Over the 16-week induction period, rezpegaldesleukin treatment resulted in significant and clinically meaningful improvements across multiple clinical endpoints, including the primary endpoint of EASI percentage change from baseline, in comparison with placebo. Rezpegaldesleukin had a clinically favourable adverse event profile in adult patients with moderate-to-severe atopic dermatitis, supporting its further development as a novel Treg-enhancing biological treatment. Nektar Therapeutics.