Late Breaking Abstract - The biological pathways underlying response to anti-IL-17A (AIN457; secukinumab) therapy differ across severe asthmatic patients

Asthma stratification efforts have predominantly focused on subgroups defined by levels of circulating and sputum eosinophils. In a recent study of AIN457 treated severe asthma patients, post hoc unbiased analysis found that patients who responded to AIN457 had significantly lower levels of IgE than non-responders. This was a multicenter, double-blind, randomized, placebo-controlled study in subjects with severe asthma (GINA 4/5) that were not adequately controlled despite high doses of inhaled and/or oral corticosteroids and long-acting beta agonists. Responders were defined as >5% change from baseline of percent predicted FEV1. Post hoc analysis of the AIN457 responder subgroup was aimed at clinically and molecularly characterizing the responders, utilizing the exploratory profiling data. Analysis of available clinical endpoints showed that total IgE levels in the responder subgroup were significantly (p-value of 0.01) lower than that of the non-responder subgroup. On a molecular level, nasal brushing and PBMC transcriptomics were used to characterize responders and non-responders at baseline. Nasal brushing pathway analysis of the differentially regulated genes identified a number of asthma related pathways. The top enriched upregulated pathway in responders, was “neutrophil chemotaxis in asthma”. In PBMC, “IgE-dependent production of pro-inflammatory mediators by neutrophils in asthma” pathway was downregulated in responders. Unbiased analysis defined responders as those patients with increased nasal epithelial neutrophilic inflammation, and decreased markers of IgE driven systemic inflammation. Clinically these patients had low IgE (