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A Randomized, Placebo‐Controlled Trial Evaluating Effects of Lebrikizumab on Airway Eosinophilic Inflammation and Remodeling in Uncontrolled Asthma (CLAVIER)
Author(s) -
Austin Cary D.,
Edick Melissa Gonzalez,
Ferrando Ronald E.,
Solon Margaret,
Baca Miriam,
Mesh Kathryn,
Bradding Peter,
Gauvreau Gail M.,
Sumino Kaharu,
Fitzgerald Mark,
Israel Eliott,
Bjermer Leif,
Bourdin Arnaud,
Arron Joseph R.,
Choy David F.,
Olsson Julie K.,
Abreu Francis D.,
Howard Monet D.,
Wong Kit D.,
Cai Fang D.,
Peng Kun D.,
Putman Wendy S.,
Holweg Cécile T. J.,
Matthews John G.,
Kraft Monica,
Woodruff Prescott G.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03747
Subject(s) - medicine , asthma , exhaled nitric oxide , placebo , eosinophil , airway , inflammation , eosinophilic , gastroenterology , fibrosis , pathology , spirometry , surgery , alternative medicine
Background The 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. Methods We 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 mm 2 of basement membrane (cells/mm 2 ). Pre‐specified secondary and exploratory outcomes included change in IL‐13–associated biomarkers and measures of airway remodeling. Findings There was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm 2 in response to lebrikizumab (95% CI, −82·5%, 97·5%). As previously observed, FEV 1 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. Interpretation We 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 registration NCT02099656 Support or Funding Information The study was sponsored by F. Hoffmann‐La Roche Ltd.