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Abstract
Background Hypersensitivity to house dust mite (HDM) allergens is a common cause of allergic asthma symptoms and can be effectively treated with allergy immunotherapy (AIT).
Objective To investigate whether genetic and type 2 (T2) inflammatory biomarkers correlate with disease severity in subjects with allergic asthma, and whether this can be modified by AIT.
Methods MITRA (NCT01433523) was a phase III, randomised, double-blind, placebo-controlled trial of HDM sublingual immunotherapy (SLIT)-tablets in adults with HDM allergic asthma. Post hoc analyses of the study population (N=742) evaluated associations between T2 inflammatory (blood eosinophils, eosinophil cationic protein (ECP), total IgE and tryptase) and genetic (single-nucleotide polymorphisms, SNP) biomarkers (n=582) for the primary study endpoint (time to first moderate/severe asthma exacerbation). SNP associations were verified in HDM-positive subgroup from an independent 3-year Severe Asthma Research Programme (SARP3) subject cohort.
Results An increased asthma exacerbation risk in subjects homozygous for SNP rs7216389 (chromosomal locus 17q12-21) was reduced (p=0.037) by treatment with HDM SLIT (HR=0.37 (95% CI 0.22 to 0.64), p<0.001). The associations between exacerbation risk and 17q12-21 SNPs were replicated in the SARP3 HDM-positive subgroup. High levels of T2 biomarkers were associated with increased risk of asthma exacerbations in the placebo group. HDM SLIT-tablet treatment reduced this risk (blood eosinophils: HR=0.50 (95% CI 0.30 to 0.85); ECP: HR=0.45 (95% CI 0.29 to 0.87); tryptase: HR=0.45 (95% CI 0.25 to 0.80)). The treatment effect was higher (p=0.006) for subjects with a higher number of elevated T2 biomarkers.
Conclusions HDM SLIT-tablet AIT is efficacious in HDM-sensitised asthma subjects with a genetic asthma predisposition and/or an underlying T2 endotype.
Trial registration number NCT01433523.
- allergic lung disease
- asthma
- asthma genetics
- asthma mechanisms
Data availability statement
Data are available on reasonable request.
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Data availability statement
Data are available on reasonable request.
Footnotes
Contributors PSA is the guarantor of the study and accepts full responsibility for the finished work. Study conception and design: PSA, KB, IH and TS. Statistical analysis: IH, TS and XL, Sample preparation and biomarker measurements: SB. Cohort data collection: PSA, EDB and DAM. Analysing and interpreting study results: PSA, KB, IH, SB, TS, XL, EDB, DAM, EB and MHS. Contributed to the manuscript from the outset and read and approved the final draft: PSA, KB, IH, SB, TS, XL, EDB, DAM, EB and MHS. Responsibility for the work’s integrity as a whole from inception to published article: PSA, KB, IH, SB, TS, XL, EDB, DAM, EB and MHS.
Funding This work was supported by ALK-Abelló A/S. No award/grant number.
Competing interests IH is an employee of ALK-Abelló A/S. KB has acted as a paid consultant for ALK-Abelló A/S, AstraZeneca, Boehringer Ingelheim and Sanofi. TS is an employee of ALK-Abelló A/S. SB was an employee of ALK-Abelló A/S when data analysis took place. MHS receives grant support via Imperial College London from the Immune Tolerance Network, National Institute of Allergy and Infectious Diseases, Medical Research council, ALK-Abelló A/S, Regeneron, and serves as a consultant for Allergy Therapeutics, Angany, and UCB. EDB is a member of the Science Committee and Board of GINA. He reports personal fees from ALK-Abelló A/S in relation to the current submission, and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Menarini, Novartis, Orion, Regeneron and Sanofi Genzyme, outside the submitted work. EB has undertaken clinical trials through his employer, Wake Forest School of Medicine and University of Arizona, for AstraZeneca, MedImmune, Boehringer Ingelheim, Genentech, Novartis, Regeneron, and Sanofi Genzyme, and has served as a paid consultant for ALK-Abelló A/S, AstraZeneca, MedImmune, GlaxoSmithKline, Novartis, Regeneron, Sanofi Genzyme and TEVA, outside the submitted work. PSA is an employee of ALK-Abelló A/S.
Provenance and peer review Not commissioned; externally peer reviewed.
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