A phase II study of Bruton’s tyrosine kinase inhibition for the prevention of anaphylaxis

Abstract

BACKGROUND IgE-mediated anaphylaxis is a potentially fatal systemic allergic reaction for which there are no currently FDA-approved preventative therapies. Bruton’s tyrosine kinase (BTK) is an essential enzyme for IgE-mediated signaling pathways and is an ideal pharmacologic target to prevent allergic reactions. In this open-label trial, we evaluated the safety and efficacy of acalabrutinib, a BTK inhibitor that is FDA approved to treat some B cell malignancies, in preventing clinical reactivity to peanut in adults with peanut allergy. METHODS After undergoing graded oral peanut challenge to establish their baseline level of clinical reactivity, 10 patients had a 6-week rest period, then received 4 standard doses of 100 mg acalabrutinib twice daily and underwent repeat food challenge. The primary endpoint was the change in patients’ threshold dose of peanut protein to elicit an objective clinical reaction. RESULTS At baseline, patients tolerated a median of 29 mg of peanut protein before objective clinical reaction. During subsequent food challenge on acalabrutinib, patients’ median tolerated dose significantly increased to 4,044 mg (range 444–4,044 mg). 7 patients tolerated the maximum protocol amount (4,044 mg) of peanut protein with no clinical reaction, and the other 3 patients’ peanut tolerance increased between 32- and 217-fold. 3 patients experienced a total of 4 adverse events that were considered to be possibly related to acalabrutinib; all events were transient and nonserious. CONCLUSION Acalabrutinib pretreatment achieved clinically relevant increases in patients’ tolerance to their food allergen, thereby supporting the need for larger, placebo-controlled trials. TRIAL REGISTRATION ClinicalTrials.gov NCT05038904 FUNDING AstraZeneca Pharmaceuticals, the Johns Hopkins Institute for Clinical and Translational Research, the Ludwig Family Foundation, and NIH grants AI143965 and AI106043.

New evidence in food allergies treatment

“…All four BTK blockers were found to inhibit anti-IgE-induced histamine release from basophils in allergic and non allergica patients [45]. In a phase II study of BTK inhibition, Acalabrutinib pretreatment achieved clinically relevant increases in patients' tolerance to their food allergen [46].…”

Functional human skin explants as tools for assessing mast cell activation and inhibition

“…The function of BTK in mast cells was further delineated in a study by Kawakami et al ( 8 ). The BTK inhibitor acalabrutinib was shown to prevent anaphylaxis completely in a humanized mouse model and in most peanut allergic individuals during an oral food challenge ( 3 , 9 ).…”