Interleukin-33 antibody failed to demonstrate benefit in a phase II, double-blind, randomized, placebo-controlled study in adult patients with moderate-to-severe atopic dermatitis

Dear Editor, therapeutic intervention for atopic dermatitis (AD) focuses on neutralizing effector cytokines such as interleukin (IL)‐4 and IL‐13·1,2 IL‐33 is a driver of T helper (Th)2‐mediated inflammation and is upstream of IL‐4 and IL‐13. AD lesional skin includes more IL‐33‐expressing cells than nonlesional skin,3 while serum levels of IL‐33 are reported to be sevenfold higher in patients with AD than in healthy control participants and correlated with disease severity·4 This and proof of concept data led to the hypothesis that an anti‐IL‐33 antibody could be efficacious for the treatment of AD·5 This phase II, randomized, double‐blind, placebo‐controlled study (NCT03831191) aimed to evaluate the safety and efficacy of LY3375880, a human IgG4‐variant monoclonal antibody that binds and neutralizes soluble human IL‐33, in patients with moderate‐to‐severe AD. Investigators evaluated patients in 58 centres in nine countries in Asia, Europe, South America, and North America. Patients [Validated Investigator's Global Assessment ‐ Atopic Dermatitis (vIGA‐AD) score of ≥ 3 and an inadequate response to topical medications] were stratified according to disease severity (vIGA‐AD 3 vs. 4) and geographic region (Japan vs. non‐Japan) and randomized to receive subcutaneous injections of placebo or LY3375880 (50, 150 or 600 mg) (1: 1: 1: 1 ratio using an interactive web‐response system) every 4 weeks for 16 weeks. The primary outcome sought was the proportion of patients achieving vIGA‐AD of 0 or 1 with a ≥ 2‐point improvement at week 16. An internal assessment committee conducted an unblinded interim analysis of efficacy and safety data when one‐third of patients had completed 16 weeks of treatment or discontinued.