Phase III Trials Confirm Remibrutinib Effectively Reduces Chronic Spontaneous Urticaria Symptoms

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Findings from the Phase III REMIX-1 (NCT05030311) and REMIX-2 (NCT05032157) clinical trials show that remibrutinib reduces the symptoms of chronic spontaneous urticaria (CSU) in patients who are unresponsive to second-generation H1-antihistamines. The drug was found to have rapid onset with efficacy that was sustained through 24 weeks, as well a favorable safety profile, according to the study, published by The New England Journal of Medicine.^1-3

Remibrutinib is an oral Bruton’s tyrosine kinase (BTK) inhibitor that inhibits the BTK cascade and stops the release of histamine that causes itch, hives/welts, and swelling. Patients with CSU typically develop itchy hives and/or deep tissue swelling on the face, throat, hands, and feet, lasting for more than six weeks.

CSU affects approximately 40 million people worldwide, primarily between 20 and 40 years of age. The condition may lead to emotional distress, sleep deprivation, anxiety, depression, and diminished work productivity.⁴

“In chronic spontaneous urticaria, activation of BTK downstream of the high-affinity IgE receptor (FcεRI) in mast cells and basophils leads to the release of histamine and other proinflammatory mediators that cause the symptoms of this disease,” the study authors wrote. “In addition, activation of BTK is responsible for autoantibody production by B cells in chronic spontaneous urticaria.”¹

Trial Design

Both REMIX-1 and REMIX-2 were multicenter, double-blind, randomized, placebo-controlled trials that evaluated the efficacy, safety, and adverse effect (AE) profile of remibrutinib administered at a dose of 25 mg twice daily as an add-on treatment for patients with CSU who continued to have symptoms while receiving second-generation H1-antihistamines.

The trials were comprised of a screening period lasting no more than four weeks; a double-blind, placebo-controlled treatment period lasting 24 weeks that was followed by an open-label treatment period of 28 weeks; and finally, a treatment-free follow-up period lasting four weeks in patients who did not withdraw or continued in the extension trial. After 24 weeks, patients in the placebo cohort were switched over to remibrutinib.

Investigators randomly assigned 470 patients in REMIX-1 to receive either remibrutinib (n = 313) or placebo (n = 157) and randomly assigned 455 patients in REMIX-2 to receive remibrutinib (n = 300) or placebo (n = 155).

The results show that patients administered remibrutinib achieved a significantly greater decrease in urticaria activity score during a seven-day period (UAS7) after 12 weeks compared to the placebo cohort, with a least-squares mean (±SE) change of −20.0±0.7 compared to −13.8±1.0 (P<0.001<) respectively, in REMIX-1 and −19.4±0.7 compared to −11.7±0.9 (P<0.001), respectively, in REMIX-2. These results appeared to be sustained through 24 weeks, according to the investigators. After 12 weeks, 49.8% of patients in REMIX-1 and 46.8% of patients in REMIX-2 had a UAS7 of 6 or lower compared to 24.8% and 19.6% (P<0.001), respectively, in the placebo cohorts.

In terms of safety, percentages of any AE and serious AEs were similar in both the remibrutinib cohort and the placebo cohort across both trials. However, 3.8% of patients administered remibrutinib had petechiae compared to 0.3% in the placebo cohort.

“In both phase 3 REMIX trials involving patients with chronic spontaneous urticaria who continued to have symptoms despite treatment with second-generation H1-antihistamines, remibrutinib showed efficacy as compared with placebo at week 12 as assessed by means of a composite weekly measure of itching and hives, an effect that appeared sustained through week 24,” the study authors wrote. “Remibrutinib had a fast onset of action, with a decrease in symptoms (itch and hives) that appeared to occur as early as week 1. At week 24, half the patients in the remibrutinib group had well-controlled chronic spontaneous urticaria and one third had a complete absence of itch and hives, with more patients in the remibrutinib group than in the placebo group having well-controlled or completely controlled chronic spontaneous urticaria.”¹

References

1. Metz, M., et al. Remibrutinib in Chronic Spontaneous Urticaria. Published March 5, 2025. N Engl J Med 2025;392:984-994. DOI: 10.1056/NEJMoa2408792. Vol. 392 No. 10.

2. A Phase 3 Study of Efficacy and Safety of Remibrutinib in the Treatment of CSU in Adults Inadequately Controlled by H1 Antihistamines (REMIX-1). ClinicalTrials.gov. Updated December 2, 2024. Accessed March 6, 2025. https://clinicaltrials.gov/study/NCT05030311

3. A Phase 3 Study of Efficacy and Safety of Remibrutinib in the Treatment of CSU in Adults Inadequately Controlled by H1-antihistamines (REMIX-2). ClinicalTrials.gov. Updated January 7, 2025. Accessed March 6, 2025. https://clinicaltrials.gov/study/NCT05032157

4. Novartis data show potential of remibrutinib as an oral treatment for chronic spontaneous urticaria providing significant symptom improvement as early as Week 2. Novartis. News release. November 9, 2023. Accessed November 28, 2023. Accessed March 6, 2025. https://www.novartis.com/news/media-releases/novartis-data-show-potential-remibrutinib-oral-treatment-chronic-spontaneous-urticaria-providing-significant-symptom-improvement-early-week-2.