Effects of cKit Inhibition by Imatinib in Patients With Severe Refractory Asthma (KIA)

Severe asthmatics remain poorly controlled despite high doses of standard asthma therapy or
even daily doses of systemic corticosteroids or their equivalent. They account for a large
proportion of the morbidity and mortality associated with asthma. Features that seem to
characterize many patients with this disorder include persistent inflammation, symptoms, and
airway hyperresponsiveness in the face of corticosteroid therapy. Mast cells are powerful,
long-lived tissue dwelling effector cells that are resistant to corticosteroid effects and
have been implicated in the pathobiology of asthma. Mast cells in the airway smooth muscle
have been found to be the major distinguishing difference between asthmatic and
non-asthmatic eosinophil airway disease; and putative circulating mast cell progenitors are
increased 5 fold in asthma. Stem cell factor (SCF) is critical to mast cell homeostasis and
upregulation and has pleiotropic effects on mast cells and eosinophils . SCF levels are
elevated in relation to asthma severity and SCF antibodies block hyperresponsiveness and
inflammation and remodeling in murine asthma models. Imatinib, a specific tyrosine kinase
inhibitor, inhibits cKit (Kit), the receptor for SCF on mast cells. Imatinib at doses
equivalent to, or below, doses safely used in humans, also mimics or exceeds anti-SCF
effects in the murine asthma model. Therefore we would like to know Does imatinib, an
inhibitor of Kit, ameliorate severe asthma, in association with effects on lung mast cell
phenotype and/or function?

Specific Aims of the study are:

Specific Aim 1: To investigate whether, in patients with persistent airway responsiveness
and poor asthma control despite intensive asthma therapy, 24 weeks of imatinib therapy
results in a reduction in airway responsiveness and in secondary indicators of asthma
control, airway inflammation, and structural changes in the airways.

Patients will be treated with imatinib in a randomized, double-blind, placebo controlled
trial. Assessments will include methacholine and AMP reactivity, airway function, symptoms,
airway wall thickness by CT scan, analysis of induced sputum, non-invasive markers of airway
inflammation, and bronchoscopy including endobronchial biopsy and bronchoalveolar lavage -
all before and at the end of therapy.

Specific Aim 2: To investigate whether, in patients with persistent airway responsiveness
and poor asthma control despite intensive asthma therapy, 24 weeks of imatinib therapy
results in changes in airway mast cell population and/or phenotype.

Inclusion Criteria:

1. Patients 18-65 years of age, diagnosed with asthma for at least 1 year;

2. Refractory asthma, defined as reporting that their asthma has not been completely
controlled in the past 3 months despite continuous treatment with high-dose inhaled
corticosteroids (ICS) and an additional controller medication, with or without
continuous oral corticosteroids (OCS)

Exclusion Criteria:

1. Current smoking or smoking history of greater than 10 pack-years

2. Any other significant respiratory or cardiac disease, or the presence of clinically
important comorbidities, including uncontrolled diabetes, uncontrolled coronary
artery disease

3. If subject cannot undergo bronchoscopy procedure due to safety reasons

4. Previous treatment with Imatinib

5. A history of acute heart failure or chronic left sided heart failure

6. Uncontrolled systemic arterial hypertension

7. History of major bleeding or intracranial hemorrhage

8. History of immunodeficiency diseases, including HIV

9. Use of other investigational drugs at the time of enrollment, or within 30 days or 5
half-lives of enrollment, whichever is longer

10. History of malignancy of any organ system (other than localized basal cell carcinoma
of the skin), treated or untreated, within the past 5 years, regardless of whether
there is evidence of local recurrence or metastases.

11. Diagnosis of Hepatitis B or C.

12. History of alcohol abuse within 6 months of screening.

13. History of illicit drug abuse within 6 months of screening.

14. Regular use of anticoagulants (eg: Warfarin Sodium, Coumadin), amiodarone,
carbamazepine, Cyclosporine, Rifampicin, or reverse transcriptase inhibitors