KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma

Abstract

Background: Mast cells are present in the airways of patients who have severe asthma despite glucocorticoid treatment; these cells are associated with disease characteristics including poor quality of life and inadequate asthma control. Stem cell factor and its receptor, KIT, are central to mast-cell homeostasis. We conducted a proof-of-principle trial to evaluate the effect of imatinib, a KIT inhibitor, on airway hyperresponsiveness, a physiological marker of severe asthma, as well as on airway mast-cell numbers and activation in patients with severe asthma.

Methods: We conducted a randomized, double-blind, placebo-controlled, 24-week trial of imatinib in patients with poorly controlled severe asthma who had airway hyperresponsiveness despite receiving maximal medical therapy. The primary end point was the change in airway hyperresponsiveness, measured as the concentration of methacholine required to decrease the forced expiratory volume in 1 second by 20% (PC₂₀). Patients also underwent bronchoscopy.

Results: Among the 62 patients who underwent randomization, imatinib treatment reduced airway hyperresponsiveness to a greater extent than did placebo. At 6 months, the methacholine PC₂₀ increased by a mean (±SD) of 1.73±0.60 doubling doses in the imatinib group, as compared with 1.07±0.60 doubling doses in the placebo group (P=0.048). Imatinib also reduced levels of serum tryptase, a marker of mast-cell activation, to a greater extent than did placebo (decrease of 2.02±2.32 vs. 0.56±1.39 ng per milliliter, P=0.02). Airway mast-cell counts declined in both groups. Muscle cramps and hypophosphatemia were more common in the imatinib group than in the placebo group.

Conclusions: In patients with severe asthma, imatinib decreased airway hyperresponsiveness, mast-cell counts, and tryptase release. These results suggest that KIT-dependent processes and mast cells contribute to the pathobiologic basis of severe asthma. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01097694 .).

Figure 1. Trial Design, Randomization, and Follow-up

Panel A shows an overview of the trial design and procedures. Blue vertical lines denote study visits. The period between screening and initial bronchoscopy, urine testing, and blood testing was a minimum of 2 weeks in duration; during this period, other tests (computed tomography [CT], fraction of exhaled nitric oxide [Fe_NO], maximum bronchodilator response [Max BD], and methacholine challenge [Mch]) were performed at intervals that differed among the patients. Spirometry was performed at each study visit. Blood denotes blood testing (assessments of serum tryptase and peripheral-blood eosinophil counts), Bronch bronchoscopy, R randomization, and SPT skin-prick testing. Panel B summarizes the numbers of patients involved in screening, randomization, and trial completion. In the imatinib group, 24 patients completed the trial procedures through the second bronchoscopy and biopsy. In the placebo group, 26 patients completed the trial procedures through the second bronchoscopy and biopsy. Scores on the six-item Asthma Control Questionnaire (ACQ-6) range from 0 to 6, with lower values denoting better asthma control. The minimally important difference is 0.5. ECG denotes electrocardiographic, FEV₁ forced expiratory volume in 1 second, and PC₂₀ the concentration of methacholine required to decrease the FEV₁ by 20%.

Figure 2. Change in Airway Methacholine Reactivity

Shown is the mean change (±SE) in the concentration of methacholine required to cause a 20% decrease in FEV₁ from baseline (PC₂₀) at month 3 and month 6 relative to the baseline methacholine PC₂₀ obtained before the administration of imatinib or placebo. The P values shown are for the paired t-test evaluating the difference between the indicated time point and baseline. The P value for the between-group difference in the change in values, determined by a mixed-model analysis, is 0.048.

Figure 3. Total Tryptase Levels in Serum

Shown are the mean total tryptase levels (±SE) in serum, as measured by immunoassay (UniCAP, Pharmacia). The P value is for the between-group difference in the change in values from baseline. A 42.7±31.6% decrease in the serum tryptase level was observed in the imatinib group, as compared with an 11.5±31.0% decrease in the placebo group.