Remibrutinib alleviates symptoms in chronic spontaneous urticaria resistant to H1-antihistamines

1. In this randomized controlled trial, among patients with chronic spontaneous urticaria who continue to have symptoms while on second-generation H1-antihistamines, it was found that remibrutinib more effectively reduced itching and hives compared with placebo.

2. Adverse events among patients who received remibrutinib were generally similar to those in the placebo group, with most adverse events being mild or moderate.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Chronic spontaneous urticaria is characterized by itch, hives, or angioedema that recur unpredictably for over six weeks without any specific triggers. Second-generation H1-antihistamines are currently the first-line treatment, but over 50% of patients receiving H1-antihistamines continue to experience symptoms. International guidelines recommend the addition of an anti-IgE biologic agent as a second-line treatment if chronic spontaneous urticaria remains uncontrolled with H1-antihistamines. Remibrutinib is an oral, highly selective Bruton’s tyrosine kinase (BTK) inhibitor that blocks BTK-mediated degranulation of mast cells and basophils, thus preventing the release of histamine and other pro-inflammatory mediators that lead to the itch, hives, and angioedema seen in chronic spontaneous urticaria. Remibrutinib has been shown in phase 2b studies to be both effective and safe. The present trial assessed the efficacy and safety of remibrutinib as an add-on treatment compared with a placebo among patients with chronic spontaneous urticaria who continue to have symptoms while on second-generation H1-antihistamines. Compared with placebo, remibrutinib was more effective in reducing itching and hives. Additionally, remibrutinib was found to be safe, with adverse events being similar between the two groups and most adverse events being mild or moderate. Limitations of the study included its failure to account for the effects of background medication and additional rescue medications, which might have contributed to the decrease in symptoms seen in the placebo group. Nevertheless, these findings serve as a valuable step in demonstrating the clinical value of remibrutinib as a second-line treatment for chronic spontaneous urticaria in patients whose disease remains uncontrolled on H1-antihistamines.

Click to read the study in NEJM

In-Depth [randomized controlled trial]: This phase three, double-blind, randomized trial assessed the efficacy and safety of remibrutinib compared with placebo as an add-on treatment in patients with chronic spontaneous urticaria who continue to have symptoms while on second-generation H1-antihistamines. Patients 18 years of age or older with a diagnosis of chronic spontaneous urticaria who have remained symptomatic during treatment with second-generation H1-antihistamines were included. The primary outcome was the change in urticaria activity score during a 7-day period (UAS7) from baseline to week 12. A total of 918 patients were included in the study, with 606 assigned to the remibrutinib group and 306 assigned to the placebo group. At 12 weeks, improvement in UAS7 was significantly greater in the remibrutinib group compared with placebo. The percentage of patients with well-controlled urticaria was also higher with remibrutinib than with placebo at week two (33.7% vs 3.3%; odds ratio, 15.7; 95% Confidence Interval [CI], 6.2 to 39.8; p<0.001), and the complete absence of itch and hives occurred in more patients in the remibrutinib group than in the placebo group at week 12 (31.1% vs 10.5%; odds ratio, 3.8; 95% CI, 2.2 to 6.8; p<0.001). With regards to safety, the percentage of patients with any adverse effect was similar between the groups (64.9% and 64.7%, respectively), with most adverse events being mild or moderate. Laboratory measures were typically within normal limits, with outliers being similar between the groups. In summary, among patients with chronic spontaneous urticaria who continue to have symptoms despite treatment with second-generation H1-antihistamines, remibrutinib was shown to be safe and more effective compared with placebo, as assessed via a composite weekly measure of itching and hives.

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