@article{9e56ade953a64fbd9a63a5adb8588534,
title = "A randomized, placebo-controlled trial evaluating effects of lebrikizumab on airway eosinophilic inflammation and remodelling in uncontrolled asthma (CLAVIER)",
abstract = "Background: The anti-interleukin 13 (IL-13) monoclonal antibody lebrikizumab improves lung function in patients with moderate-to-severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling. Objective: To report safety and efficacy results from enrolled participants with available data from CLAVIER. Methods: We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomized double-blinded treatment with lebrikizumab (n = 31) or placebo (n = 33). The pre-specified primary end-point 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 remodelling. Results: There 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%), and fractional exhaled nitric oxide, CCL26 and SERPINB2 mRNA expression in bronchial tissues also reduced. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies. Conclusions & Clinical Relevance: We did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre-specified exploratory analyses, lebrikizumab treatment was associated with reduced degree of subepithelial fibrosis, a feature of airway remodelling, 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 remodelling. Clinical Trial Registration: NCT02099656.",
author = "{the CLAVIER Investigators} and Austin, {Cary D.} and {Gonzalez Edick}, Melissa and Ferrando, {Ronald E.} and Margaret Solon and Miriam Baca and Kathryn Mesh and Peter Bradding and Gauvreau, {Gail M.} and Kaharu Sumino and FitzGerald, {J. Mark} and Elliot Israel and Lief Bjermer and Arnaud Bourdin and Arron, {Joseph R.} and Choy, {David F.} and Olsson, {Julie K.} and Francis Abreu and Monet Howard and Kit Wong and Fang Cai and Kun Peng and Putnam, {Wendy S.} and Holweg, {C{\'e}cile T.J.} and Matthews, {John G.} and Monica Kraft and Woodruff, {Prescott G.}",
note = "Funding Information: All authors report support of the parent study and funding of editorial support from F. Hoffmann‐La Roche. CDA, MGE, RF, MS, MB, KM, JA, DC, JO, FA, KP, MH, KW, FC, WSP and CTJH are employees of Genentech, Inc. JGM was an employee at Genentech, Inc, at the time of the study but is now an employee of 23andMe. PB has received grant funding from Genentech, Inc. GMG has received research funding from Genentech, Inc, paid directly to McMaster University. MF has received research funding from Genentech, Inc, paid directly to UBC. EI has received grants and nonfinancial support from Genentech during the conduct of the study. MK receives research funding for asthma (paid to the University of Arizona) from the National Institutes of Health, American Lung Association, AstraZeneca and Sanofi. MK engages in consulting activities with AstraZeneca and Sanofi and receives royalties from Elsevier. AB has received personal fees and nonfinancial support from Roche outside the submitted work. PW reports fees to his institution for assistance with analysis of samples in this clinical study and personal fees from Amgen, NGM biopharmaceuticals, Theravance, Clarus Ventures, AstraZeneca, 23andMe, Sanofi, Regeneron and GSK outside the submitted work. Funding Information: The study was sponsored by F. Hoffmann-La Roche Ltd. The sponsor was responsible for the clinical operations oversight, data management, medical monitoring, drug supply, statistical analysis, drug safety process, medical writing and journal article processing charges. All authors had full access to all the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. We thank the participants of the study. We thank Wendy Lam, Jian Jiang and Carmina Espiritu for help with the histological processing; Linda Rangell for help with the immunohistochemistry; Kathryn Mesh, Maya Stark, Jeffrey Eastham-Anderson and Johnnie Bremholm Andersen for help with the stereological analysis; James J. Lee for generously providing mAb MM25-82.2 (Mayo Clinic Arizona); and Olga Li and Amelia AU-Yeung for help with the analyses of the sample quality and mRNA extraction. Support for third-party writing assistance for this manuscript, furnished by writer Christine Gould, PhD, CMPP, of Health Interactions, Inc, was provided by F. Hoffmann-La Roche Ltd. and Genentech, Inc Funding Information: The study was sponsored by F. Hoffmann‐La Roche Ltd. The sponsor was responsible for the clinical operations oversight, data management, medical monitoring, drug supply, statistical analysis, drug safety process, medical writing and journal article processing charges. All authors had full access to all the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. Publisher Copyright: {\textcopyright} 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd",
year = "2020",
month = dec,
doi = "10.1111/cea.13731",
language = "English (US)",
volume = "50",
pages = "1342--1351",
journal = "Clinical Allergy",
issn = "0954-7894",
publisher = "Wiley-Blackwell",
number = "12",
}