Emerging Therapies Show Potential for Hard-to-Treat Chronic Spontaneous Urticaria

Novel treatments like dupilumab, remibrutinib, and barzolvolimab are showing promise in achieving complete response for individuals with chronic spontaneous urticaria (CSU), according to a new review published in the journal Drugs.

CSU is a mast cell–driven condition marked by recurrent wheals and/or angioedema lasting longer than 6 weeks. Current guidelines recommend second-generation H₁-antihistamines as first-line therapy, but fewer than 10% of patients achieve complete symptom control. Even with the addition of omalizumab, the second-line treatment, up to 70% of patients with antihistamine-refractory CSU continue to experience symptoms, according to researchers.

Recent advancements in treatment options may offer new hope for clinicians and patients alike. “Several emerging treatments can address these unmet needs including Bruton tyrosine kinase inhibitors, e.g., remibrutinib and rilzabrutinib; anti-KIT monoclonal antibodies, e.g., barzolvolimab; and anti-cytokine therapies, e.g., dupilumab,” wrote investigators. They conducted the current review to provide an update on difficult-to-treat patient populations and the development of emerging drugs for the treatment of CSU and other patient populations.

Dupilumab, an anti–IL-4 receptor alpha monoclonal antibody, was tested in the phase 3 CUPID trials. In CUPID A, which enrolled 138 patients with antihistamine-refractory CSU (including those with prior omalizumab exposure), dupilumab 300 mg every two weeks reduced weekly urticaria activity scores (UAS7) by 8.5 points more than placebo at 24 weeks. Treated patients also reported a 4.2-point greater decrease in itch severity. About 31% of those receiving dupilumab achieved complete symptom control (UAS7 = 0), compared to 13% of placebo recipients (odds ratio, 2.9; P = .0199).

In a separate omalizumab-naive cohort (CUPID C, n = 151), complete response rates at week 24 were 30% with dupilumab versus 18% with placebo (P = .02). Injection-site reactions were more frequent with dupilumab (12%) than with placebo (4%), though overall adverse event rates were similar.

Two large, identically designed phase 3 trials—REMIX-1 and REMIX-2—evaluated the Bruton tyrosine kinase inhibitor remibrutinib in patients with CSU unresponsive to second-generation antihistamines. The trials enrolled more than 900 patients in total.

At week 12, between 28% and 31% of patients treated with remibrutinib 25 mg twice daily achieved complete symptom control, compared to 7% to 11% of those on placebo. Approximately 47% to 50% achieved well-controlled disease (UAS7 ≤ 6), versus 20% to 25% in the placebo arms. Improvements were evident as early as week 1 and maintained through 52 weeks, with nearly half of participants maintaining a complete response at one year.

Safety profiles were similar between remibrutinib and placebo, with adverse events reported in approximately 65% of each group. The most frequently reported events with remibrutinib included respiratory tract infections (up to 15.5%), headache (7.8%), urinary tract infections (4.6%), and petechiae (4.0%). Serious adverse events were rare.

Barzolvolimab, an anti-KIT monoclonal antibody targeting mast cell activity, was evaluated in a phase 2 trial involving 208 patients. Participants were randomly assigned to receive 1 of 3 dosing regimens or placebo.

At week 12, UAS7 scores dropped by more than 23 points in the barzolvolimab arms, compared to a 10.5-point reduction with placebo. Between 38% and 51% of patients on active treatment achieved complete symptom control, versus 6% with placebo.

Long-term safety data over 52 weeks showed hair color changes (26%), neutropenia (17%), skin hypopigmentation (13%), and nasopharyngitis (10%) as the most common adverse effects.

The review also highlighted specific subpopulations that may benefit from these novel treatment modalities, including those with autoimmune CSU and late responders to traditional therapies.

Both dupilumab and remibrutinib are expected to be submitted for regulatory approval for CSU within the year, according to the review authors. Barzolvolimab is advancing into phase 3 development. Researchers noted that long-term studies are needed to determine whether these therapies can modify disease course or provide durable remission after discontinuation.

The emergence of new treatment classes may also support efforts to personalize therapy for CSU, particularly as endotyping tools evolve to identify patient subgroups likely to respond to specific mechanisms of action.

Reference: Kolkhir P, Metz M, Marcelino J, et al. Update on the treatment of chronic spontaneous urticaria. Drugs. Published online March 12, 2025. doi:10.1007/s40265-025-02170-4