Bruton's tyrosine kinase inhibition for the treatment of allergic disorders

Abstract

IgE signaling through its high-affinity receptor FcεRI is central to the pathogenesis of numerous allergic disorders. Oral inhibitors of Bruton's tyrosine kinase (BTKis), which are currently Food and Drug Administration-approved for treating B cell malignancies, broadly inhibit the FcεRI pathway in human mast cells and basophils, and therefore may be effective allergen-independent therapies for a variety of allergic diseases. The application of these drugs to the allergy space was previously limited by the low kinase selectivity and subsequent toxicities of early-generation compounds. Fortunately, next-generation, highly selective BTKis in clinical development appear to have more favorable risk-benefit profiles, and their likelihood of being Food and Drug Administration-approved for an allergy indication is increasing. Recent clinical trials have indicated the remarkable and rapid efficacy of the second-generation BTKi acalabrutinib in preventing clinical reactivity to peanut ingestion in adults with peanut allergy. In addition, next-generation BTKis including remibrutinib effectively reduce disease activity in patients with antihistamine-refractory chronic spontaneous urticaria. Finally, several BTKis are currently under investigation in early clinical trials for atopic dermatitis and asthma. In this review, we summarize recent data supporting the use of these drugs as novel therapies in food allergy, anaphylaxis, urticaria, and other allergic disorders. We also discuss safety data derived from trials using both short-term and chronic dosing of BTKis.

Figure 1:. BTK structure and function.

(A) BTK is a cytoplasmic non-receptor tyrosine kinase expressed primarily in leukocytes. It is an essential enzyme in the IgE-mediated activation of human mast cells and basophils through the high-affinity receptor FcεRI, resulting in cellular activation, degranulation, and production of prostaglandins, leukotrienes, and inflammatory cytokines. Figure created with BioRender. (B) The currently approved BTKis target residue C-481 in the kinase domain (box call-out) to inhibit enzymatic activity. Figure reproduced with permission from Wang et al.

Figure 2:. A two-day course of acalabrutinib prevents clinical reactivity to peanut ingestion during OFC in the majority of peanut-allergic adults.

(A) After taking four 100 mg oral doses (a two-day course) of acalabrutinib, peanut-allergic adult patients experienced a significant increase in the amount of peanut that they could tolerate during oral food challenge from a median of 29 mg of peanut protein at baseline to 4,044 mg (the protocol maximum) during treatment. (B) The dilution of peanut extract that elicited a positive SPT response also significantly increased by several logs from baseline. Figures reproduced with permission from Suresh et al.

Figure 3:. Remibrutinib induces a rapid and sustained improvement in UAS7 scores in CSU patients during long-term therapy up to 52 weeks.

Remibrutinib 100 mg twice daily induced rapid and sustained improvement in UAS7 (A), and more than half of the patients achieved a UAS7 score of 0 at Week 52 of therapy (B). Figures adapted with permission from Jain et al.

Figure 4:. Fenebrutinib reduces pathogenic specific IgG titers over time.

(A) In addition to strong clinical efficacy in CSU, all fenebrutinib doses (red, blue, and green dots) reduced serum levels of IgG-anti-FcεRI autoantibodies compared to placebo (black dots) at 8 weeks after initiation of treatment in its phase 2 trial. Figure reproduced with permission from Metz et al. (B) In its phase 2 trial in SLE patients, fenebrutinib 150 mg daily (blue bars) and 200 mg twice daily (red bars) both demonstrated reduction in serum IgG-anti-dsDNA autoantibodies compared to placebo (black bars). Bars show the median and interquartile range. * P < 0.05 compared to placebo.