IL-33 receptor inhibition in subjects with uncontrolled asthma: A randomized, placebo-controlled trial

Courtney Crim; Sally Stone; Valerie Millar; Sally Lettis; Elisabeth H Bel; Andrew Menzies-Gow; Pascal Chanez; Sally Wenzel; Njira Lugogo; Eugene R Bleecker

doi:10.1016/j.jacig.2022.07.002

IL-33 receptor inhibition in subjects with uncontrolled asthma: A randomized, placebo-controlled trial

J Allergy Clin Immunol Glob. 2022 Aug 17;1(4):198-208. doi: 10.1016/j.jacig.2022.07.002. eCollection 2022 Nov.

Authors

Affiliations

¹ Research and Development, GSK, Research Triangle Park, NC.
² Biostatistics, GSK, Stockley Park, London, United Kingdom.
³ Department of Respiratory Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
⁴ Department of Respiratory Medicine, Royal Brompton Hospital, London, United Kingdom.
⁵ Department of Respiratory Diseases, C2VN Inserm University of Aix-Marseille, Marseille, France.
⁶ Asthma Institute at University of Pittsburgh Medical Center, Pulmonary Allergy and Critical Care Medicine Division and Department of Environmental and Occupational Health, Pittsburgh, Pa.
⁷ Internal Medicine, Division of Pulmonary, Critical Care Medicine, University of Michigan, Ann Arbor, Mich.
⁸ Department of Medicine, University of Arizona, Tucson, Ariz.

Abstract

Background: Most biologics for severe asthma target only type 2 immunity. Inhibition of IL-33 signaling has the potential to target type 2 and non-type 2 pathways.

Objective: This multicenter phase IIA study evaluated the safety and efficacy of GSK3772847, a human mAb directed against the IL-33 receptor (IL-33R) in subjects with moderate-to-severe uncontrolled asthma.

Methods: Adults with uncontrolled asthma despite inhaled corticosteroid/long-acting β₂-agonist therapy received equivalent replacement medication (open-label fluticasone propionate/salmeterol [500/50 μg, twice daily]) for 2 weeks before randomization at week 0. At weeks 0, 4, 8, and 12, participants were administered blinded placebo or 10 mg/kg of intravenous GSK3772847. At week 2, salmeterol was discontinued; thereafter, fluticasone propionate was titrated by approximately 50% on weeks 4, 6, 8, and 10. Asthma control was assessed until week 16. Participants with loss of asthma control discontinued treatment. The primary end point was loss of asthma control; secondary end points were the efficacy, safety, tolerability, pharmacodynamics, and pharmacokinetics of GSK3772847.

Results: At week 16, 56 participants (81%) and 45 (66%) receiving placebo and GSK3772847, respectively, had loss of asthma control (an 18% reduction [95% credible interval = 2%-35%]). Early loss of asthma control prevented full analysis of the secondary efficacy end points after week 4. The most frequent classes of treatment-related adverse events were cardiac disorders (n = 3 [4%] in both groups) and musculoskeletal/connective tissue disorders (with GSK3772847, n = 3 [4%]; with placebo n = 0). Target engagement of IL-33R by GSK3772847 was demonstrated.

Conclusion: Treatment with GSK3772847 may be beneficial for patients with uncontrolled asthma. Further studies are warranted.

Keywords: Asthma; GSK37772847; IL-1 receptor-like 1 protein; IL-33; mAb; placebo-controlled trial; randomized trial.