Bruton's tyrosine kinase inhibition for the prevention of anaphylaxis: an open-label, phase 2 trial

Abstract

IgE-mediated anaphylaxis is a potentially fatal systemic allergic reaction for which there are no known 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 (NCT05038904), 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 IgE-mediated peanut allergy. After undergoing a graded oral peanut challenge to establish their baseline level of clinical reactivity, all patients then received four 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. 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 of 10 patients tolerated the maximum protocol amount (4,044 mg) of peanut protein with no objective clinical reaction, and the other 3 patients' peanut tolerance increased between 32- and 217-fold. Three patients experienced a total of 4 adverse events that were considered by the investigators to be possibly related to acalabrutinib; all events were transient and nonserious. These results demonstrate that acalabrutinib pretreatment can achieve clinically-relevant increases in patients' tolerance to their food allergen, thereby supporting the need for larger, placebo-controlled trials.

Figure 1

CONSORT flow diagram and study schema. Flow diagram summarizing the (a) enrollment and (b) study visit schedule for the trial. BAT, basophil activation testing; OFC, oral food challenge; sIgE, specific IgE; SPT, skin puncture testing

Figure 2

Maximum tolerated peanut dose and symptom scores during OFC. a, The maximum tolerated dose of peanut protein at baseline (dark gray box with blue circles) and during treatment with acalabrutinib (light gray box with orange circles) is shown for all patients (n = 10). The maximum protocol dose was 4,044 mg, thus patients’ tolerated doses of ≥4,044mg on acalabrutinib is plotted at this maximum. Boxplot midline represents median, box depicts 25th and 75th percentiles, and whiskers depict range. 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 circles and dark gray boxes) and during OFC while on acalabrutinib (orange circles and light gray boxes). The shaded green area represents placebo doses of each OFC. Box plot midline represents the median, box depicts 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 and during treatment with acalabrutinib are shown for all patients. 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. Boxplot midline represents median, box depicts 25th and 75th percentiles, and whiskers depict range. 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 dilutions are shown for all patients at baseline (blue bars) and after treatment with acalabrutinib (orange bars). On the right, basophil response percentages are displayed for each peanut extract dilution at baseline (blue area under the curve) and after acalabrutinib treatment (orange area under the curve). Data were analyzed using Wilcoxon matched pairs signed rank tests. bars represent standard error. d, Peanut and peanut-component specific IgE levels for all patients at baseline (blue circles) and during acalabrutinib treatment (orange circles) are shown. Box plot midline represents the median, box depicts 25th and 75th percentiles, and whiskers depict range. fMLP, N-formylmethionyl-leucyl-phenylalanine.