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Clinical Trial
. 2020 Dec;50(12):1342-1351.
doi: 10.1111/cea.13731. Epub 2020 Oct 4.

A randomized, placebo-controlled trial evaluating effects of lebrikizumab on airway eosinophilic inflammation and remodelling in uncontrolled asthma (CLAVIER)

Cary D Austin  1 , Melissa Gonzalez Edick  1 , Ronald E Ferrando  1 , Margaret Solon  1 , Miriam Baca  1 , Kathryn Mesh  1 , Peter Bradding  2 , Gail M Gauvreau  3 , Kaharu Sumino  4 , J Mark FitzGerald  5 , Elliot Israel  6 , Lief Bjermer  7 , Arnaud Bourdin  8 , Joseph R Arron  1 , David F Choy  1 , Julie K Olsson  1 , Francis Abreu  1 , Monet Howard  1 , Kit Wong  1 , Fang Cai  1 , Kun Peng  1 , Wendy S Putnam  1 , Cécile T J Holweg  1 , John G Matthews  1 , Monica Kraft  9 , Prescott G Woodruff  10 ; CLAVIER Investigators
Affiliations
Clinical Trial

A randomized, placebo-controlled trial evaluating effects of lebrikizumab on airway eosinophilic inflammation and remodelling in uncontrolled asthma (CLAVIER)

Cary D Austin et al. Clin Exp Allergy. 2020 Dec.

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.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
Trial design, with lebrikizumab 125 mg or placebo administered subcutaneously on day 1, day 8, week 4 and week 8 during the 12‐week placebo‐controlled period. SC, subcutaneous
Figure 2
Figure 2
Patient disposition
Figure 3
Figure 3
Mean relative (%) changes from baseline in number of airway subepithelial eosinophils per mm2 of basement membrane at week 12 in the primary analysis population. Estimates were based on a linear model that used relative change from baseline in airway subepithelial eosinophils as the response variable and included terms for treatment, number of asthma exacerbations within 12 mo of study entry and baseline asthma medications. Relative change was defined as the absolute change from baseline to week 12 divided by the value at baseline. Placebo‐corrected adjusted mean change is the difference in adjusted mean changes between the lebrikizumab and placebo groups. Boxplots of the corresponding unadjusted data are provided in Figure S2
Figure 4
Figure 4
Mean adjusted relative (%) changes from baseline in thickness of subepithelial collagen at week 12 in the primary analysis population. Estimates were based on a linear model that used relative change from baseline in thickness of subepithelial collagen as the response variable and included terms for treatment, number of asthma exacerbations within 12 months of study entry and baseline asthma medications. Relative change was defined as the absolute change from baseline to week 12 divided by the value at baseline. Placebo‐corrected adjusted mean change is the difference in adjusted mean changes between the lebrikizumab and placebo groups. Boxplots of the corresponding unadjusted data are provided in Figure S7
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References

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