Chronic spontaneous urticaria (CSU), a common and distressing skin condition driven by mast cells, is typically managed with a stepwise approach using second-generation H1-antihistamines, omalizumab and cyclosporine, as recommended by international guidelines. However, many patients with CSU do not respond optimally to this standardized treatment, likely due to the diverse underlying mechanisms involved. As a result, a personalized approach based on specific phenotype or endotype is gaining traction, aiming to identify various drivers of CSU pathogenesis.1
Since the last update of the urticaria guideline in 2020, several molecules have shown promising results in clinical trials, such as mast cell silencing and depleting treatments as well as anti-cytokine treatments like anti-interleukin(IL) 5/5Rα, anti-IL-4/-13 and Bruton tyrosine kinase (BTK) inhibitors.2 Among those, BTK inhibitors seem to be the options that will be available sooner than others since a highly selective, oral BTK inhibitor remibrutinib was reported to meet primary endpoints and showed rapid symptom control in CSU in phase III trials.
BTK is a kinase that is activated in downstream signalling cascades triggered by surface receptors such as the BCR in B cells and the high‐affinity immunoglobulin E receptor FcεRI in mast cells and basophils.2 BTK inhibitors are first designed to treat B-cell malignancies; however, they received increased attention as a promising target for treatment of various disorders beyond malignancy including autoimmunity and mast cell-driven diseases such as CSU. The rationale for using BTK inhibitors in CSU depends on the major mechanism of action: the inhibition of FcεRI signalling via BTK inhibition in mast cells and basophils and decrease autoantibody production by B cells. First-generation BTK inhibitors showed severe adverse events (AEs) such as thrombocytopenia, diarrhoea, neutropenia, anaemia, bruising and increased risk of infection; however, next-generation selective, reversible, oral BTK inhibitors like fenebrutinib, remibrutinib, rilzabrutinib and tirabrutinib show better safety profile. Fenebrutinib is a highly selective, reversible, non‐covalent, oral BTK inhibitor, while remibrutinib, rilzabrutinib and tirabrutinib are all oral agents, which bind covalently to their BTK target but with high levels of selectivity. In the case of remibrutinib, improved selectivity and tolerability are likely attributable to its ability to bind to an inactive conformation of BTK. Among these BTK inhibitors, fenebrutinib, remibrutinib and rilzabrutinib are involved in CSU clinical trials.3
Fenebrutinib was evaluated in a phase II study in 93 adult patients with CSU. Results of this study revealed dose-dependent improvements in the weekly Urticaria Activity Score (UAS7) at week 8, supporting the potential use of BTK inhibitors in antihistamine-refractory CSU. Symptom improvement was rapid with the change from baseline in UAS7 at week 4 similar to that at week 8. Fenebrutinib at 200 mg twice daily was effective in patients with and without markers of autoimmune CSU.4 Furthermore, fenebrutinib markedly reduced levels of IgG-anti-FcεRI autoantibodies at week 8 at all doses compared with placebo. Reduction of IgG-anti-FcεRI correlated with improvement in disease activity, likely reflecting decreased autoantibody-mediated activation of mast cells and basophils in patients with autoimmune CSU. The most common AEs were urticaria, nasopharyngitis and headache. Four patients (fenebrutinib 150 mg daily and 200 mg twice daily, 2 patients each) demonstrated drug-related asymptomatic, reversible grade 2 and 3 liver transaminase increase.4 A follow-up study was terminated after an interim analysis of the parent study. And fenebrutinib in CSU programme was stopped. A phase II study of rilzabrutinib in CSU is currently ongoing.5
In phase II trials, remibrutinib significantly improved UAS7 scores from baseline at week 4 in a dose–response manner. Remibrutinib 25 mg twice daily demonstrated the greatest overall efficacy. Similar to fenebrutinib, remibrutinib showed a rapid onset of action as early as week 1 and sustained until the end of the treatment period. Most AEs were mild or moderate; most common AEs were headache, nasopharyngitis, nausea, upper respiratory tract infection, diarrhoea and pyrexia. Patients with or without past treatment with omalizumab did not show any differences in terms of remibrutinib efficacy. An in vitro study showed that remibrutinib inhibited activation of human basophils and mast cells induced in vitro by exposure to the serum of patients with CSU and chronic inducible urticaria regardless of their response to omalizumab. This suggests that remibrutinib works in both antibody-dependent and antibody-independent chronic urticaria mechanisms that is in line with fenebrutinib efficacy in both autoimmune and non-autoimmune CSU endotypes.6,7
Phase III trials Remix-I and Remix-II are two identically designed global, multicentre, randomized, double-blind, parallel-group, placebo-controlled studies, to evaluate the efficacy, safety and tolerability of remibrutinib versus placebo in 470 and 455 patients with CSU who are inadequately controlled by second-generation H1-antihistamines compared with placebo, respectively. Patients are being randomized in a 2:1 ratio to receive remibrutinib (n=300) or placebo (n=150). The studies have a total duration of up to 60 weeks consisting of a 4-week screening period, a 24-week double-blind treatment period with remibrutinib or placebo, a 28-week open-label treatment period with remibrutinib and a 4-week follow-up period or extension study. Primary efficacy endpoints were change from baseline in UAS7, ISS7 and HSS7 at week 12 while secondary endpoints were proportion of participants achieving disease control (UAS7≤6) and complete absence of hives and itch (UAS7=0) at week 12 and early onset of disease control (UAS7≤6 at Week 2) as well as occurrence of treatment-emergent AEs and SAEs during the study. On 9 August 2023, Novartis shared an ad hoc analysis reporting that remibrutinib met all primary and secondary endpoints, showing rapid, clinically meaningful improvements across urticaria disease activity scores. The patients also showed rapid improvement as early as 2 weeks after treatment initiation. The medication was well tolerated and demonstrated a favourable safety profile, including balanced liver function tests in active and placebo arms across both studies. Final (52 weeks) results and full data will be presented at upcoming medical meetings.
As a conclusion, remibrutinib, being an oral medication showing efficacy in both type 1 and type IIb CSU endotypes and showing a favourable AE profile stands out as a practical medication for patients with antihistamine refractory CSU.8,9