A randomized, placebo‐controlled trial evaluating effects of lebrikizumab on airway eosinophilic inflammation and remodelling in uncontrolled asthma (CLAVIER)
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 in...
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| Published in | Clinical and experimental allergy Vol. 50; no. 12; pp. 1342 - 1351 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Wiley Subscription Services, Inc
01.12.2020
Wiley John Wiley and Sons Inc |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0954-7894 1365-2222 1365-2222 |
| DOI | 10.1111/cea.13731 |
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| 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. |
|---|---|
| AbstractList | 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. BackgroundThe 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.ObjectiveTo report safety and efficacy results from enrolled participants with available data from CLAVIER.MethodsWe 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.ResultsThere 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 RelevanceWe 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. 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.BACKGROUNDThe 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.To report safety and efficacy results from enrolled participants with available data from CLAVIER.OBJECTIVETo report safety and efficacy results from enrolled participants with available data from CLAVIER.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.METHODSWe 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.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.RESULTSThere 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.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.CONCLUSIONS & CLINICAL RELEVANCEWe 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.NCT02099656.CLINICAL TRIAL REGISTRATIONNCT02099656. 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. To report safety and efficacy results from enrolled participants with available data from CLAVIER. 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 mm of basement membrane (cells/mm ). Pre-specified secondary and exploratory outcomes included change in IL-13-associated biomarkers and measures of airway remodelling. 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 in response to lebrikizumab (95% CI, -82.5%, 97.5%). As previously observed, FEV 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. 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. NCT02099656. 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. |
| Author | Holweg, Cécile T.J. Peng, Kun Matthews, John G. Kraft, Monica Cai, Fang Woodruff, Prescott G. FitzGerald, J. Mark Bjermer, Lief Bradding, Peter Gauvreau, Gail M. Wong, Kit Choy, David F. Israel, Elliot Solon, Margaret Olsson, Julie K. Putnam, Wendy S. Austin, Cary D. Gonzalez Edick, Melissa Bourdin, Arnaud Abreu, Francis Sumino, Kaharu Ferrando, Ronald E. Howard, Monet Baca, Miriam Arron, Joseph R. Mesh, Kathryn |
| AuthorAffiliation | 3 McMaster University Hamilton ON Canada 5 University of British Columbia Vancouver BC Canada 11 Present address: Stemcentrx/AbbVie, Inc. South San Francisco CA USA 4 Washington University School of Medicine in St. Louis St Louis MO USA 8 CHU de Montpellier Montpellier France 12 Present address: 23andMe Mountain View CA USA 6 Brigham and Women’s Hospital Boston MA USA 9 University of Arizona College of Medicine Tucson AZ USA 1 Genentech, Inc. South San Francisco CA USA 2 University of Leicester and Glenfield Hospital Leicester UK 7 Skåne University Hospital Lund Sweden 10 San Francisco Medical Center University of California San Francisco CA USA |
| AuthorAffiliation_xml | – name: 9 University of Arizona College of Medicine Tucson AZ USA – name: 12 Present address: 23andMe Mountain View CA USA – name: 2 University of Leicester and Glenfield Hospital Leicester UK – name: 1 Genentech, Inc. South San Francisco CA USA – name: 6 Brigham and Women’s Hospital Boston MA USA – name: 7 Skåne University Hospital Lund Sweden – name: 8 CHU de Montpellier Montpellier France – name: 3 McMaster University Hamilton ON Canada – name: 4 Washington University School of Medicine in St. Louis St Louis MO USA – name: 5 University of British Columbia Vancouver BC Canada – name: 10 San Francisco Medical Center University of California San Francisco CA USA – name: 11 Present address: Stemcentrx/AbbVie, Inc. South San Francisco CA USA |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32909660$$D View this record in MEDLINE/PubMed https://hal.science/hal-02936982$$DView record in HAL |
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| Copyright | 2020 The Authors. published by John Wiley & Sons Ltd 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd. 2020. This article is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. Distributed under a Creative Commons Attribution 4.0 International License |
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| License | Attribution 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd. Distributed under a Creative Commons Attribution 4.0 International License: http://creativecommons.org/licenses/by/4.0 This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
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| Notes | 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. SourceType-Scholarly Journals-1 content type line 14 ObjectType-Editorial-2 ObjectType-Commentary-1 ObjectType-Article-2 ObjectType-Feature-1 content type line 23 ObjectType-Undefined-3 |
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The anti‐interleukin 13 (IL‐13) monoclonal antibody lebrikizumab improves lung function in patients with moderate‐to‐severe uncontrolled asthma, but... The anti-interleukin 13 (IL-13) monoclonal antibody lebrikizumab improves lung function in patients with moderate-to-severe uncontrolled asthma, but its... BackgroundThe anti‐interleukin 13 (IL‐13) monoclonal antibody lebrikizumab improves lung function in patients with moderate‐to‐severe uncontrolled asthma, but... Background: The anti‐interleukin 13 (IL‐13) monoclonal antibody lebrikizumab improves lung function in patients with moderate‐to‐severe uncontrolled asthma,... |
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| SubjectTerms | Adolescent Adult Aged Airway Remodeling - drug effects Allergology Anti-Asthmatic Agents - adverse effects Anti-Asthmatic Agents - pharmacokinetics Anti-Asthmatic Agents - therapeutic use Antibodies, Monoclonal - adverse effects Antibodies, Monoclonal - pharmacokinetics Antibodies, Monoclonal - therapeutic use Asthma Asthma - drug therapy Asthma - immunology Asthma - physiopathology Biomarkers Bronchoscopy Clinical trials Collagen (type I) Double-Blind Method Eosinophils - drug effects Eosinophils - immunology Eosinophils - metabolism Female Fibrosis Gene expression Human health and pathology Humans Immunology Immunotherapy Inflammation Interleukin 13 Interleukin-13 - antagonists & inhibitors Leukocytes (eosinophilic) Life Sciences Lung - drug effects Lung - immunology Lung - physiopathology Male Middle Aged Monoclonal antibodies Nitric oxide Original ORIGINAL ARTICLES Patients Pharmacodynamics Pulmonology and respiratory tract Respiratory function Respiratory tract Respiratory tract diseases Signal Transduction Time Factors Treatment Outcome Young Adult |
| Title | A randomized, placebo‐controlled trial evaluating effects of lebrikizumab on airway eosinophilic inflammation and remodelling in uncontrolled asthma (CLAVIER) |
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