Clinical and Molecular Effect of the Anti– IL ‐18 Antibody Aletekitug in Adults With Atopic Dermatitis

ABSTRACT Background Interleukin‐18 (IL‐18) is a pleiotropic cytokine implicated in atopic dermatitis (AD), affecting both type (T)1 and T2 immune pathways. An anti–IL‐18 monoclonal antibody, aletekitug, was evaluated for its clinical and molecular effects in patients with moderate to severe AD. Methods This randomised, double‐blind, parallel‐group, placebo‐controlled, 24‐week study assessed adults with moderate‐to‐severe AD who were biologic‐naïve or dupilumab‐inadequate responders/intolerant. Participants received a single intravenous (IV) infusion of aletekitug 2 mg/kg or placebo. The primary endpoint was percentage change from baseline (PCFB) in Eczema Area and Severity Index (EASI) score at Week 12. Other endpoints included safety, patient‐reported outcomes (PROs) and transcriptomics. Results Thirty‐four participants (aletekitug, n = 23; placebo, n = 11) were randomised. A greater reduction in the PCFB in EASI score at Week 12 was demonstrated for patients who received aletekitug versus placebo (posterior median PCFB [95% credible intervals]: aletekitug, −68.3% [−79.68, −56.68]; placebo, −32.9% [−45.74, −21.10]), with effects still apparent at Week 24. Aletekitug improved PRO measures of itch, sleep disturbance, fatigue and quality of life versus placebo up to Week 24. Transcriptome analysis suggested aletekitug modulated lesional skin towards a non‐lesional profile and exerted broad immunomodulatory effects, impacting several AD‐associated signalling pathways, not limited to T2 immunity. Aletekitug was well tolerated, with no serious adverse events reported. Conclusion A single 2 mg/kg IV dose of aletekitug was associated with improved outcomes at Week 12, which were sustained to Week 24, and modulated immune mechanisms beyond T2 inflammation. These results support IL‐18 as a potential therapeutic target in moderate‐to‐severe AD.