A Randomized, Placebo‐Controlled Trial Evaluating Effects of Lebrikizumab on Airway Eosinophilic Inflammation and Remodeling in Uncontrolled Asthma (CLAVIER)
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BackgroundThe anti–interleukin 13 (IL‐13) monoclonal antibody lebrikizumab improves lung function in patients with moderate‐severe uncontrolled asthma, but its effects on airway inflammation and remodeling are unknown. CLAVIER was designed to assess lebrikizumab’s effect on eosinophilic inflammation and remodeling.MethodsWe performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomised double‐masked treatment with lebrikizumab (n=31) or placebo (n=33). The primary endpoint was relative change in airway subepithelial eosinophils per mm2 of basement membrane (cells/mm2). Pre‐specified secondary and exploratory outcomes included change in IL‐13–associated biomarkers and measures of airway remodeling.FindingsThere was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm2 in response to lebrikizumab (95% CI, −82·5%, 97·5%). As previously observed, FEV1 increased after lebrikizumab treatment. Moreover, subepithelial collagen thickness decreased 21·5% after lebrikizumab treatment (95% CI, −32·9%, −10·2%), while fractional exhaled nitric oxide, CCL26, and SERPINB2 mRNA expression in bronchial tissues also diminished. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies.InterpretationWe did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre‐specified secondary analyses, lebrikizumab treatment was associated with diminished degree of subepithelial fibrosis, a feature of airway remodeling, as well as improved lung function and reduced key pharmacodynamic biomarkers in bronchial tissues. These results reinforce the importance of IL‐13 in airway pathobiology and suggest that neutralization of IL‐13 may reduce asthmatic airway remodeling.Clinical trial registrationNCT02099656Support or Funding InformationThe study was sponsored by F. Hoffmann‐La Roche Ltd.
