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.

Grant Number: 5U01AI158460-04
NIH Institute/Center: NIH
Principal Investigator: Sunil Ahuja