Key Takeaways

• Rilzabrutinib 1200 mg/day significantly reduced itch and hives in antihistamine-refractory chronic spontaneous urticaria (CSU) patients.

• Rilzabrutinib had an acceptable safety profile, with mild to moderate adverse events and no safety concerns.

• The study authors think rilzabrutinib could be useful for difficult-to-treat type IIb autoimmune CSU subtypes.

Rilzabrutinib significantly reduced itch and hives in adults with antihistamine-refractory chronic spontaneous urticaria (CSU), according to new phase 2 trial results published in JAMA Dermatology.

"CSU is a skin disease driven mainly by the activation of cutaneous mast cells through various mechanisms," the authors wrote. "Bruton tyrosine kinase (BTK), expressed in B cells and mast cells, plays a critical role in multiple immune-mediated disease processes."

To examine the efficacy and risk profile of rilzabrutinib, study researchers for the RILECSU trial enrolled 160 patients aged 18 to 80 years with a Urticaria Activity Score (UAS7) of at least 16 and Itch Severity Score (ISS7) of at least 8 despite antihistamine therapy. Participants were randomized to rilzabrutinib at doses of 400 mg once daily, 800 mg twice daily, 1200 mg three times daily, or placebo. The primary endpoint was change from baseline at week 12 in ISS7 (for U.S. and U.S. reference countries) or UAS7 (for non-U.S. reference countries).

According to the results, rilzabrutinib, 1200 mg/day, led to a reduction from baseline in ISS7 (least squares [LS] mean difference −3.44; 95% CI, −6.25 to −0.62; P = .02) and UAS7 (LS mean difference −6.75; 95% CI, −12.23 to −1.26; P = .02) vs. placebo. Improvements were observed as early as week 1 across ISS7, UAS7, Hives Severity Score (HSS7), and Angioedema Activity Score (AAS7).

The patient sample included both omalizumab-naive individuals and incomplete responders. In biomarker analyses, the researchers observed reductions in soluble Mas-related G protein-coupled receptor X2, immunoglobulin G anti-thyroid peroxidase, IgG anti-FcεRI, and interleukin-31 levels rilzabrutinib at 1200 mg/day vs. placebo at 12 weeks.

Rilzabrutinib showed a favorable safety profile, with diarrhea, nausea, and headache being the most frequently reported adverse events. No serious drug-related adverse events, deaths, or typical BTK inhibitor-related toxicities were reported during the 12-week double-blind period.

"The results of the RILECSU randomized clinical trial demonstrated efficacy and rapid onset of action of rilzabrutinib, 1200 mg/d, over 12 weeks, in addition to an acceptable adverse event profile," the authors concluded. "Together, these data support the use of rilzabrutinib in treating patients with moderate to severe CSU refractory to H1-antihistamines. Further research is needed to determine long-term efficacy and potential harms."

Source: Giménez-Arnau A, et al. JAMA Dermatology. 2025. doi:10.1001/jamadermatol.2025.0733