Effect of IL-4RαR576 Polymorphism on Response to Dupilumab in Adolescents and Adults With Asthma

This is a double-blind, randomized, placebo-controlled parallel-group phase 2 clinical trial.

Patients will be genotyped and categorized as those with: 1) the wild type allele
(Q576/Q576), 2) heterozygous allele (Q576/R576), or 3) homozygous mutant allele (R576/R576);
the genotype associated with more severe disease.

After a run-in period of 2-4 weeks to determine asthma control, subjects who fulfill all
inclusion/exclusion criteria will be randomized to receive either subcutaneous Dupilumab or
placebo (1:1 randomization allocation ratio).

This study addresses fundamental mechanisms by which the IL-4Rα-R576 variant drives the
TH2/TH17 disease endotype and the influence of this variant on response to Dupilumab therapy.
It brings together individuals with deep clinical and scientific expertise in allergic
diseases, including epidemiology, genetics, inflammation, and tolerance mechanisms to
investigate, in a coordinated strategy, the hypothesis that the IL-4Rα-R576 variant drives
TH2/TH17 cell inflammation by subverting allergen-specific iTreg cells into TH17 cells.
Asthmatics bearing this endotype will be particularly likely to favorably respond to
Dupilumab therapy by virtue of its prevention of iTreg cell reprogramming into TH17-like
cells, potentially leading to their long-term stability and potential for sustained immune
tolerance.

Inclusion Criteria:

1. Ages 12-65

2. Ability to provide informed consent

3. Ability to perform pulmonary function tests and other procedures in protocol in order
to define the phenotype assignments as defined in the protocol

4. Child with persistent asthma, defined as those children with asthma requiring:

1. Physician Diagnosis of Asthma and

2. Existing treatment with ICS with a second controller (eg. long-acting beta
agonist, leukotriene receptor antagonist) and/or a third controller for their
asthma with a stable dose ≥1 month prior to screening.

5. History of asthma exacerbation in the past year, defined as a wheezing episode lasting
>24 hours and associated with albuterol and/or levalbuterol use and associated with
any of the following:

1. Systemic corticosteroid (oral, intravenous, or intramuscular) use prescribed by a
licensed medical provider for wheezing episode with or without a clinical visit
and/or a biologic medication for asthma

2. An increase in >50% of baseline corticosteroid dose for ≥3 days

3. An unscheduled visit for acute asthma/wheezing care (licensed medical
practitioner/nurse office, urgent care intervention, emergency department, or
hospitalization)

Exclusion Criteria:

1. Chronic lung disease other than asthma, which may impair lung function.

2. Current smoker or cessation of smoking within 6 months prior to Visit 1.

3. Comorbid disease that might interfere with the evaluation of the Investigational
Product (Dupilumab).

4. Pregnancy

5. Other chronic pulmonary disorders associated with asthma-like symptoms, including (but
not limited to) cystic fibrosis, chronic obstructive pulmonary disease, chronic
bronchitis, vocal cord dysfunction (that is the sole cause of respiratory symptoms and
at the PI's discretion), severe scoliosis or chest wall deformities that affect lung
function, or congenital disorders of the lungs or airways

6. History of premature birth (before 34 weeks gestation)

7. The presence of clinically important co-morbidities. These include uncontrolled
diabetes, uncontrolled coronary artery disease, acute or chronic renal failure, and
uncontrolled hypertension, hepatic or renal insufficiency, gastrointestinal disease,
arrhythmia, malignancy, diverticulitis, immunodeficiency (including HIV),
opportunistic infection, hepatitis, or any other condition or abnormality that in the
opinion of the Principal Investigator would compromise the safety of the patient or
quality of data

8. Evidence that the participant or family may be unreliable or poorly adherent to their
asthma treatment or study procedures

9. Administration of a live vaccine within 6 weeks of screening.

10. Planning to relocate from the clinical center area before study completion

11. Any other criteria that place the subject at unnecessary risk according to the
judgment of the Principal Investigator and/or attending physician(s) of record.

12. Currently participating in an investigational drug trial

13. Being treated with immunosuppressive/immunodulatory or other investigational agents or
biologics within 30 days or 5 half-lives of enrollment, whichever is longer

14. History of recent respiratory illness including asthma exacerbations in the past 4
weeks at screening requiring antibiotics or systemic corticosteroids.

15. History of alcohol or illicit substance abuse within 6 months of screening

16. Neutropenia (<1,000/mm3) or thrombocytopenia (<100,000/mm3) or hemoglobin < 100 g/L
(10 g/dL) at screening

17. Subjects will be excluded if they have any serious medical problems and cannot perform
study procedures.