Mechanistic clinical trial of blocking the IL-4/13 axis in asthmatics precision phenotyped in an aeroallergen challenge chamber before, during and after receipt of dupilumab

7. Project Summary/Abstract We propose a high-impact, randomized, double-blind, placebo-controlled, mechanistic clinical trial aimed at elucidating the basis for the wide heterogeneity in severity of and treatment responses in persons with allergic rhinoconjunctivitis (ARC) and allergic asthma (AA). AA and ARC are highly prevalent, environmentally triggered

and often comorbid conditions that share mechanistic correlates. We will study persons with house dust mite (HDM)-associated PARC and AA, termed HDM+PARC+AA+. HDMs are influential in AA/ARC pathogenesis and disease severity. To investigate mechanisms that may contribute to heterogeneity, we capitalized on an

aeroallergen challenge chamber (ACC), a unique and relatively rare resource, which allows for controlled exposures to disease triggers of ARC/AA. Challenge studies with a fixed dose of HDM in persons with HDM- associated PARC without AA evoked (i) maladaptive (persistently higher ARC symptoms), (ii) adaptive

(progressive symptom reduction with repeated challenges), and (ii) resilient (resistance to symptom induction) phenotypes. Symptom severity in the natural environment was an imprecise correlate of the phenotypes. Congruently, challenge studies in HDM+PARC+AA+ persons with HDMs in the ACC also evoked these

phenotypes. Mechanistic studies revealed that these phenotypes may relate to an imbalance between levels of airway epithelial integrity and inflammation. To further test this concept, we will evaluate 88 HDM+PARC+AA+ persons with persistent mild-to-moderate asthma. The ACC will be used identify persons with the maladaptive

and adaptive phenotypes, defined by higher and lower symptom severity evoked in response to HDM exposures in the ACC. Each phenotype strata will be randomized 1:1 and administered a 22-week course of dupilumab (monoclonal antibody targeting IL-4 receptor alpha) or placebo. Exposure to HDMs in an ACC for 1 daily 5-hour

challenge will occur: 1) for phenotyping and baseline assessment of symptoms (pre-randomization), 2) intermittently while on dupilumab/placebo administration for assessment of heterogeneity in responses to drug, and 3) intermittently while off dupilumab/placebo for assessment of heterogeneity in the recrudescence in

symptoms. Mechanistic correlates of the upper airway (nasal) and systemic (peripheral blood) compartments will be determined pre-treatment, on-treatment, and off-treatment. Thus, this clinical trial will test the hypothesis that a 22-week course of dupilumab will attenuate AA/ARC symptoms in persistent mild-to-moderate allergic

asthmatic subjects by mitigating inflammation with or without fully restoring epithelial integrity. However, the rate of symptom attenuation and recrudescence will be less and greater, respectively, in persons with the maladaptive compared with adaptive phenotypes. Affirmation of this hypothesis will provide new insights into the mechanisms

underpinning heterogeneity in disease severity and treatment responses, as well as provide a basis to consider multi-modal therapeutic interventions to achieve durable suppression of AA/ARC symptoms.