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

Abstract

BACKGROUNDIgE-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.METHODSAfter 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.RESULTSAt 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.CONCLUSIONAcalabrutinib pretreatment achieved clinically relevant increases in patients' tolerance to their food allergen, thereby supporting the need for larger, placebo-controlled trials.TRIAL REGISTRATIONClinicalTrials.gov NCT05038904FUNDINGAstraZeneca Pharmaceuticals, the Johns Hopkins Institute for Clinical and Translational Research, the Ludwig Family Foundation, and NIH grants AI143965 and AI106043.

Keywords: Allergy; Basophils; Immunology; Mast cells.

Figures

Figure 1. Schematic representing study design and patient disposition.

Flow diagram summarizing the (A) enrollment and (B) study visit schedule for the trial. OFC, oral food challenge; sIgE, specific IgE.

Figure 2. Maximum tolerated peanut dose and symptom scores during OFC.

(A) The maximum tolerated dose of peanut protein at baseline (blue box) and during treatment with acalabrutinib (orange box) is shown for all patients (n = 10). The maximum protocol dose was 4,044 mg, thus, patients’ tolerated doses of at least 4,044 mg on acalabrutinib is plotted at this maximum. Data were tested using a Wilcoxon matched-pairs signed rank test. (B) Total symptom scores are shown during each placebo (benign food) and peanut dose during baseline OFC (blue boxes) and during OFC while on acalabrutinib (orange boxes). The shaded green area represents placebo doses of each OFC. Data were analyzed using 2-way ANOVA. All box plot midlines represent the median, boxes depict 25th and 75th percentiles, and whiskers depict range. *P < 0.05; **P < 0.01; ***P < 0.001. OFC, oral food challenge.

Figure 3. Secondary outcomes.

(A) Skin puncture test wheal area (in mm2) to undiluted peanut extract and positive (histamine) and negative (saline) controls at patients’ baseline (blue boxes) and during treatment with acalabrutinib (orange boxes) are shown for all patients. Data were analyzed using Wilcoxon matched-pairs signed rank tests. (B) The highest concentration of peanut extract (original units, weight per volume) that produced a negative skin test at baseline and during acalabrutinib treatment is shown for all patients. Data were analyzed using Wilcoxon matched-pairs signed rank tests. (C) On the left side of the graph, the percent of basophils activated ex vivo in response to anti-IgE and fMLP are shown for all patients at baseline (blue boxes) and during treatment with acalabrutinib (orange boxes). On the right, basophil response percentages are displayed for each peanut extract dilution at baseline (blue AUC) and after acalabrutinib treatment (orange AUC). Data were analyzed using Wilcoxon matched pairs signed rank tests for each treatment or dilution. (D) Peanut and peanut-component specific IgE levels for all patients at baseline (blue boxes) and during acalabrutinib treatment (orange boxes) are shown. Data were analyzed using 2-way ANOVA. All graphs depict data from all patients who completed treatment (n = 10). All box plot midlines represent the median, boxes depict 25th and 75th percentiles, and whiskers depict range. fMLP, N-formylmethionyl-leucyl-phenylalanine.