Mechanisms of allergy and clinical immunology
IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti–IL-4 receptor α antagonist

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Background

This is the first large pharmacogenetic investigation of the inflammatory IL-4/IL-13 pathway in patients with moderate-to-severe asthma. We analyzed genomic DNA from participants in a 12-week placebo-controlled efficacy trial of pitrakinra (1, 3, or 10 mg twice daily), a novel IL-4/IL-13 pathway antagonist (Clinicaltrials.gov NCT00801853).

Objectives

The primary hypothesis for this analysis is that amino acid changes in the 3′ end of the IL-4 receptor α gene (IL4RA) or closely proximal variants would predict reductions in asthma exacerbations for subjects randomized to pitrakinra therapy.

Methods

Nineteen IL4RA single nucleotide polymorphisms (SNPs) were tested in 407 non-Hispanic white subjects for association with the primary clinical end point of asthma exacerbations and changes in secondary end points for asthma symptom scores.

Results

The most consistent pharmacogenetic associations were observed for the correlated tagging SNPs rs8832 and rs1029489 in the IL4RA 3′ untranslated and proximal regions, respectively. Subjects homozygous for the rs8832 common G allele randomized to pitrakinra (placebo group nonsignificant) had decreased asthma exacerbations and decreased nocturnal awakenings and activities limited by asthma. There was also a significant pitrakinra dose-response relationship (placebo/1 mg/3 mg/10 mg) for exacerbations in subjects homozygous for the common allele in rs1029489 (P = .005) and rs8832 (P = .009) and the intronic SNPs rs3024585, rs3024622, and rs4787956 (P = .03).

Conclusion

This study demonstrates a significant pharmacogenetic interaction between anti–IL-4 receptor α therapy and IL4RA gene variation, identifying an asthma subgroup that is more responsive to therapy with this antagonist.

Section snippets

Clinical trial population

A pharmacogenetic analysis was performed in a phase 2b clinical trial of pitrakinra, an IL-4Rα antagonist. In this trial 534 participants with moderate-to-severe asthma from the intent-to-treat population were enrolled in a 12-week randomized, placebo-controlled, multicenter (sites in the United States and Europe), double-blind, dose-ranging study (1, 3, or 10 mg twice daily) to test the safety and efficacy of pitrakinra. Subjects were evaluated for the primary end point of incidence of asthma

Demographics

Demographic and baseline clinical characteristics, including lung function, total serum IgE levels, and fraction of exhaled nitric oxide (Feno) levels, of participants were similar for subjects in the overall intent-to-treat trial population (n = 534) and the genotyped non-Hispanic white subjects (n = 407) analyzed in this study (Table I).

Asthma exacerbations

In this pitrakinra 2b clinical trial the frequency of asthma exacerbations was 19.9% overall, and there were no significant differences in exacerbations in

Discussion

This is the first large pharmacogenetic analysis of the TH2-related IL-4/IL-13 inflammatory receptor in subjects with moderate-to-severe asthma. In this relatively short (12-week) trial, LABAs were tapered 4 weeks after initiation of blinded IL-4Rα antagonist or placebo treatment, and inhaled corticosteroids were tapered and withdrawn subsequently. Although there was no overall significant difference between active IL-4Rα therapy and placebo,15, 16 therapeutic efficacy was observed by IL4RA

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  • Cited by (0)

    Supported by Aerovance, Bayer Healthcare, and the National Institute of Heart, Lung, and Blood grants HL065899, HL101487, and HL089992.

    Disclosure of potential conflict of interest: R. E. Slager has received grants from the National Institutes of Health (NIH) and research support from Aerovance. B. A. Otulana and Y. P. Yen are employees of Aerovance. G. A. Hawkins has received research support from Aerovance. S. P. Peters has received research support from the NIH. S. E. Wenzel has consulted for Genentech, and has received research support from Aerovance, GlaxoSmithKline, and Sanofi-Aventis. D. A. Meyers and E. R. Bleecker have consulted for and received research support from Aerovance.

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