Cancer drug navigates new path, shows signals against peanut allergy

A small but promising study showed that acalabrutinib, an oral BTK* inhibitor approved for B-cell malignancies**, may reduce or even prevent clinical reactivity to peanuts in peanut-allergic adults.

“During acalabrutinib therapy, the amount of peanut protein tolerated [by participants] significantly increased from a median baseline of 29 mg to 4,044 mg,” said Dr Ragha Suresh from Johns Hopkins University School of Medicine, Baltimore, Maryland, US, at AAAAI 2023.

Seven participants tolerated this amount without any clinical sign or symptoms. “The other three had a shift in their tolerated dose by 1–2 logs,” she said.

Baseline wheal area size was halved following acalabrutinib use (from a median 126 mm² to 57 mm²; p=0.002). The highest nonreactive peanut dilution increased substantially with acalabrutinib compared with baseline (p=0.0039).

Moreover, acalabrutinib completely suppressed basophil activation in all subjects, who all had a positive basophil activation at baseline.

Four*** adverse events (AEs) may be related to acalabrutinib, but there were no serious treatment-related AEs or study or treatment withdrawals due to an AE.

“In summary, 2 days of acalabrutinib pretreatment prevented clinical reactivity to oral exposure to food allergen in most allergic patients and significantly increased tolerance threshold in others. Acalabrutinib eliminated basophil activation responses, reduced skin test responsiveness, and was well-tolerated by all participants,” said Suresh.

 

Enzyme of interest: BTK

There are no known therapies that can reliably prevent IgE-mediated anaphylaxis and avoiding triggers is not always possible, especially with food. [AAAAI 2023, abstract 679]

“Epinephrine is the only known treatment that can reduce mortality from anaphylaxis. However, even with prompt and comprehensive medical therapy, anaphylaxis can be fatal. Therefore, there is a huge unmet need for therapies to prevent morbidity and mortality from anaphylaxis,” Suresh said.

IgE pathway inhibition is an attractive target to prevent any IgE-mediated allergic reaction, she noted. “When peanut-specific IgE binds to peanut protein, it cross-links high-affinity IgE receptors on the surface of mast cells and basophils. The signalling cascade causes the release of numerous mediators responsible for inducing signs and symptoms of an allergic reaction.”

Signalling through high-affinity IgE receptors proceeds through several kinases deemed essential for the pathway. Inhibiting these enzymes may prevent IgE-mediated reactions caused by any allergen, Suresh explained. “Our enzyme of interest is BTK.”

Preclinical data show that acalabrutinib pretreatment completely prevents moderate anaphylaxis and protects against death during severe anaphylaxis. [J Clin Invest 2020;130:4759-4770] “This suggests that BTK inhibitors may be repurposed for allergic reactions,” noted Suresh. “This brings us to the ultimate question: Can BTK inhibitors prevent anaphylaxis in humans?”

The team designed an open-label, proof-of-concept trial using acalabrutinib to test this hypothesis. “We chose acalabrutinib because it is a more selective second-generation BTK inhibitor with fewer off-target side effects,” said Suresh.

Ten individuals (median age 28 years, 60 percent female) with a positive peanut skin test or peanut IgE and an objective anaphylactic reaction to ≤1,044 mg of peanut protein at baseline were included. Almost all had other atopic comorbidities, six had a history of epinephrine use after peanut exposure, and eight had a prior ER visit following a peanut reaction.

Two oral food challenges were conducted with both placebo and peanut doses to determine the peanut dose that participants can tolerate at baseline. After a 6-week rest period, they received four standard doses of acalabrutinib 100 mg BID.

 

Paradigm shifting for allergy

“If successful in preventing IgE-mediated reactions in humans, BTK inhibitors could be paradigm shifting for the field of allergy,” underlined Suresh. “Our results could have important ramifications for how we approach more risky procedures related to food allergy. Short-term use may enhance the speed and safety of immunotherapy build-up or drug desensitizations.”

Chronic use is also possible given the advanced safety profile of newer inhibitors under development, she added.

Further investigation is warranted to ascertain the drug’s efficacy, including minimum effective dose and onset and duration of protection, as well as factors that may reduce its efficacy.