Could KIT Inhibition Be Feasible for Asthma Treatment?

MARCH 04, 2018
Matt Hoffman
Katherine N. Cahill, MD
Despite treatment with inhaled glucocorticoid therapy, mast cells persist in the airways of patients with severe asthma and often lead to poorer quality of life and inadequate control of symptoms for these patients.

Imatinib, normally a cancer medication, inhibits vital mast cell tyrosine kinase (KIT) receptors, ideally then preventing the homeostasis of these cells. This raised the question to Katherine N. Cahill, MD, an assistant professor of medicine at Brigham and Women’s Hospital, and colleagues, about whether the therapy could be utilized in a novel method to treat patients with severe asthma.

“We conducted a randomized, double-blind, 24-week clinical trial of imatinib versus placebo in patients with poorly controlled severe asthma who had airway hyperresponsiveness despite receiving maximal medical therapy,” Cahill said while presenting the study’s findings at the 2018 American Academy of Allergy, Asthma, and Immunology (AAAAI)/World Allergy Organization (WAO) Joint Congress in Orlando, Florida.

The trial consisted of 62 patients randomized to either the intervention arm (n = 32), which received an initial dose of 200 mg oral imatinib per day for 2 weeks followed by a 400 mg dose for the remainder of the trial, or the placebo arm (n = 30).

The study found that airway reactivity was reduced, increasing the methacholine forced expiratory volume in 1 second by 20% (PC20) by a mean of 1.73 (SD, ±0.60) doubling doses by the 6-month mark, compared with a 1.07 (SD, ±0.60) doubling doses in the placebo group (P = .048).

Additionally, the KIT inhibitor reduced serum tryptase—a mast-cell activation marker—further than placebo (2.02 ±2.32 ng/mL compared to 0.56 ±1.39 ng/mL; P =.02). Overall, the mast-cell counts in the patients’ airways decreased in both groups.

“It is important to point out that imatinib reduced, but did not completely eliminate mast cells,” Cahill said. “Previous data have shown that long-term use of imatinib increases its mast cell reduction effects, so perhaps longer trials will be required to understand those effects.”

The trial was novel in its theory of concept—pointed out by Stephen J. Galli, MD, in an accompanying editorial at the time of the study data’s publication. “No clinical studies have assessed whether specifically targeting mast-cell survival or development would have therapeutic benefit in the treatment of this disorder,” Galli wrote.

Cahill’s presentation of the data at AAAAI/WAO congress piqued interest from the audience in regard to KIT inhibition’s future as an asthma treatment due to its novelty. “This opens the door for a novel mechanism of action for treating conditions with mast cells. I don’t know of any current concrete plans to study this further, but this opens the door [to do so],” Cahill told MD Magazine.

The treatment, however, she admitted, does carry risks with its safety profile. Of the 12 patients that discontinue treatment, 5 stopped due to adverse events (AEs). While the number of AEs were similar between the 2 groups, imatinib carried a higher likelihood of muscle cramps and metabolic abnormalities.

“If someone were to explore imatinib further, they would need to be willing to take on the potential risks,” Cahill said.

Despite that, “antagonism of KIT and decreases in mast-cell counts were associated with reductions in airway hyperresponsiveness and small increases in [forced expiratory volume in 1 second (FEV1)] in a group of patients with severe asthma who were already taking maximal therapy,” Cahill said.

The study, “KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma,” was published in the New England Journal of Medicine.

Click here to sign up for more MD Magazine content and updates.

Related Coverage >>>
Is Indoor Home Intervention for Asthma Effective?
Bradley Chipps, MD: Key Takeaways from AAAAI/WAO
How Race and Background Differs Asthma, Food Allergy Rates

Copyright© MD Magazine 2006-2018 Intellisphere, LLC. All Rights Reserved.