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.

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

Patient disposition

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

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