Remibrutinib inhibits hives effector cells stimulated by serum from chronic urticaria patients independently of FcεR1 expression level and omalizumab clinical response

Abstract

Background Despite advances in the treatment of chronic urticaria, in a significant percentage of the patients symptoms are not fully controlled with conventional approaches. New strategies under development include blocking intracellular mediators of mast cell and basophil activation. Objective We aim to investigate the effects of the Bruton's tyrosine kinase (BTK) inhibitor remibrutinib on human blood basophils and CD34 + ‐derived mast cells activation induced by serum obtained from chronic urticaria patients. Methods Twenty‐two patients with chronic spontaneous urticaria (mean age 52 years, 27% women) and 22 patients with chronic inducible urticaria (46 years, 27% women) were included in the study together with a sex‐matched control group. Patients were classified as responders or non‐responders to anti‐IgE therapy on the basis of their clinical data, FcεR1a expression on blood basophils and total IgE levels. Changes on CD63 expression—as an activation marker‐, were used to evaluate in vitro the response of basophils and mast cells to serum exposure and the inhibitory effects of remibrutinib. Results Remibrutinib inhibits degranulation induced by IgE cross‐linking in mast cells and basophils and also the activation triggered by factors present in the sera of spontaneous and inducible chronic urticaria patients. Patient's serum induces a greater degranulation of effector cells than controls. Activation of mast cells and basophils by patient sera and remibrutinib effects were not related to omalizumab responsiveness. Conclusion Remibrutinib inhibits activation of human basophils and mast cells induced in vitro by exposure to the serum of chronic urticaria patients independently of their response to omalizumab.

Rapid response of omalizumab-resistant chronic urticaria to acalabrutinib

“…These activated basophils release significantly more leukotriene C4 and are associated with IgE-independent CIU (decreased likelihood of responding to omalizumab). 6 , 7 We hypothesize that our patient has IgE-independent CIU given her high percentage of active CD203c basophils and nonresponse to omalizumab. Of all of her treatments, only prednisone and acalabrutinib at all impacted her UAS7 score of 42, with acalabrutinib quickly reducing it to 0.…”

“… 8 Furthermore, remibrutinib inhibits the degranulation of basophils and mast cells independently of FcεRI expression and omalizumab response in CIU patients. 3 , 6 Similarly, acalabrutinib works via the FcεRI-BTK pathway to inhibit mast cell IgE-induced degranulation, release of histamine, leukotriene C4, and interluekin-4; and to downregulate CD63, CD164, or CD203c in basophils. 9 …”

Metabolite profiling of remibrutinib in rat and human liver microsomes using liquid chromatography combined with benchtop orbitrap high‐resolution mass spectrometry

“…Based on the singular pharmacokinetic/pharmacodynamic profile of a covalent inhibitor, remibrutinib showed potent Bruton's tyrosine kinase occupancy with an EC90 of 1.6 mg/kg after a single oral dose with transient low exposure (Angst et al, 2020). In addition, remibrutinib can inhibit activation of human basophils and mast cells induced in vitro by exposure to the serum of chronic urticaria patients independently of their response to omalizumab (Gimeno et al, 2023). Remibrutinib showed a favorable safety profile and tolerance in patients with chronic spontaneous urticaria (Maurer et al, 2022).…”

The origins and longevity of IgE responses as indicated by serological and cellular studies in mice and humans

“…The response can range from mild tissue oedema, through gastrointestinal symptoms to potentially fatal anaphylaxis which most commonly occurs against ingested foods or administered drugs. 8 , 9 , 10 , 11 , 12 , 13 , 14 Drugs such as BTK inhibitors limit IgE‐bound cell activation and can reduce severity of disease, 15 , 16 but despite six decades since the discovery of IgE, 17 sensitization once established remains difficult to reverse. Current immunotherapy approaches seek to interrupt the production of IgE or to overwhelm IgE with high‐titer IgG to inhibit effector cell activation, 18 with affinity and antibody amount influencing inhibition.…”