Genetic and T2 biomarkers linked to the efficacy of HDM sublingual immunotherapy in asthma

• Published in: Thorax Vol. 79; no. 4; pp. 332 - 339
• Main Authors: Hoof, Ilka, Bønnelykke, Klaus, Stranzl, Thomas, Brand, Stephanie, Li, Xingnan, Shamji, Mohamed H, Meyers, Deborah A, Bateman, Eric D, Bleecker, Eugene, Andersen, Peter Sejer
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and British Thoracic Society 01.04.2024; BMJ Publishing Group LTD
• Subjects: Adult; Adults; Airway management; Allergens; allergic lung disease; Allergies; Animals; Antigens, Dermatophagoides - therapeutic use; Asthma; Asthma - drug therapy; Asthma - therapy; asthma genetics; asthma mechanisms; Biological products; Biomarkers; Clinical outcomes; Dust; Hay fever; Humans; Hypersensitivity; Immunotherapy; Inflammation; Intervention; Precision medicine; Pyroglyphidae; Quality control; Rhinitis; Steroids; Sublingual Immunotherapy - adverse effects; Tablets - therapeutic use; Treatment Outcome; Tryptases - therapeutic use; United States > US; asthma mechanisms; asthma genetics; asthma; allergic lung disease
• ISSN: 0040-6376; 1468-3296; 1468-3296
• DOI: 10.1136/thorax-2023-220707

BackgroundHypersensitivity to house dust mite (HDM) allergens is a common cause of allergic asthma symptoms and can be effectively treated with allergy immunotherapy (AIT).ObjectiveTo 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.MethodsMITRA (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.ResultsAn 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.ConclusionsHDM 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.