The effects of lebrikizumab in patients with mild asthma following whole lung allergen challenge

Abstract

Background: Interleukin 13 (IL13) is a T-helper type 2 (Th2) cytokine associated with inflammation and pathology in allergic diseases such as bronchial asthma. We have shown that treatment with lebrikizumab, an anti-IL13 monoclonal antibody, significantly improves prebronchodilator forced expiratory volume in 1 s (FEV(1)) in a subset of subjects with uncontrolled asthma.

Objective: To evaluate efficacy and safety of lebrikizumab in subjects with mild asthma who underwent bronchial allergen challenge.

Methods: Twenty-nine subjects were randomized 1 : 1-5 mg/kg lebrikizumab (n = 13) or placebo (n = 16) administered subcutaneously every 4 weeks over 12 weeks, a total of four doses. Primary efficacy outcome was late asthmatic response (LAR) at Week 13, defined as area under the curve of FEV1 measured 2-8 h following inhaled allergen challenge. Serum biomarkers were measured to verify IL13 pathway inhibition and identify patients with an increased response to lebrikizumab.

Results: At Week 13, the LAR in lebrikizumab subjects was reduced by 48% compared with placebo subjects, although this was not statistically significant (95% confidence interval, -19%, 90%). Exploratory analysis indicated that lebrikizumab-treated subjects with elevated baseline levels of peripheral blood eosinophils, serum IgE, or periostin exhibited a greater reduction in LAR compared with subjects with lower baseline levels of these biomarkers. Lebrikizumab exerted systemic effects on markers of Th2 inflammation, reducing serum immunoglobulin E (IgE), chemokine ligands 13 and 17 by approximately 25% (P < 0.01). Lebrikizumab was well tolerated.

Conclusion and clinical relevance: Lebrikizumab reduced the LAR in subjects with mild asthma. Clinical trial number NCT00781443.

Keywords: IL13; Th2 inflammation; allergen challenge; asthma; biomarkers; lebrikizumab.

© 2013 John Wiley & Sons Ltd.

Figures

Figure 1

Study design. The study included a 21-day screening period, a 12-week treatment period, and a 16-week follow-up period. At screening and at Week 13, subjects underwent an allergen challenge followed within 18–24 h by a methacholine challenge to determine PC20, defined as the provocative concentration of methacholine that resulted in a > 20% reduction in FEV1. Subjects were randomized 1: 1 to lebrikizumab (5 mg/kg) or placebo, administered subcutaneously once every 4 weeks.

Figure 2

Allergen-induced changes in FEV1 following challenges at screening and Week 13. The allergen-induced percentage change in FEV1 during screening (a) and at Week 13 (b) in placebo- and lebrikizumab-treated subjects. FEV1 was collected every 10 min for the first 90 min and then every hour from 2 to 8 h following allergen challenge. Data points are means. Vertical bars are standard error of the mean.

Figure 3

Lebrikizumab appeared to have a greater but not statistically significant effect on allergen-induced late asthmatic response (LAR) in subjects with increased baseline levels of periostin, IgE, and/or peripheral blood eosinophils based on exploratory analysis. Black bars represent subjects with baseline levels of IgE, peripheral blood eosinophils, and periostin levels below the median of all subjects. Grey bars represent subjects with baseline levels of those biomarkers above the median of all subjects. Data are expressed as placebo-corrected mean LAR reduction at Week 13. The total number of subjects in active subgroups was low (5–8 active subjects/group), and statistical analyses were not performed on these exploratory endpoints.