Expanding Treatment Options for Chronic Spontaneous Urticaria

Chronic spontaneous urticaria (CSU) continues to pose a significant therapeutic challenge for patients inadequately controlled with second-generation antihistamines. A recent review published in Allergy reviewed phase 3 trial data for omalizumab, dupilumab, and the Bruton tyrosine kinase (BTK) inhibitor remibrutinib, providing insights into efficacy, placebo effects, and implications for clinical practice.1

Omalizumab, a humanized anti-IgE monoclonal antibody, has the most extensive clinical trial data in CSU management. Across the pivotal phase 3 ASTERIA I, ASTERIA II, and GLACIAL studies, omalizumab consistently demonstrated superior symptom control compared with placebo. At week 12, 34% to 44% of patients receiving omalizumab achieved complete control (UAS7 = 0), while partial control was achieved in 52% to 66% of patients.

While omalizumab remains the most validated biologic option for CSU unresponsive to antihistamines, the emergence of dupilumab and remibrutinib as effective alternatives signifies a shift in the management of refractory CSU. | Image Credit: StockWorld - stock.adobe.com

“While omalizumab has established itself as a second-­line treatment in CSU management, the emergence of dupilumab and remibrutinib as effective alternatives holds promise for patients with refractory disease,” researchers noted.

Dupilumab, approved for CSU in April 2025, is an IL-4Rα antagonist that offers a novel approach by blocking signaling of both IL-4 and IL-13, key drivers of type 2 inflammation often implicated in CSU pathogenesis.2 The phase 3 LIBERTY-CSU CUPID A, B, and C studies trials demonstrated clinical benefit, although response rates were somewhat lower than those seen with omalizumab. Complete response rates for dupilumab in these trials ranged from 13% to 31% at Week 24, with partial response rates between 24% and 46%. Given its broad efficacy across other type 2 inflammatory conditions like atopic dermatitis and asthma, dupilumab may be beneficial for patients with concomitant atopic comorbidities.

Remibrutinib, a highly selective oral BTK inhibitor targeting mast cell and basophil activation, has recently demonstrated efficacy in phase 3 trials REMIX-1 and REMIX-2. Complete response rates were 28% to 31% at week 12, increasing to approximately 36% at week 24, while partial control reached 47% to 50% at week 12 and 52% to 55% at week 24. The authors highlighted that “remibrutinib's oral route could improve adherence and convenience,” offering a valuable alternative to injectable biologics. While not yet approved, regulatory submissions are currently under review with both the FDA and EMA.

Importantly, researchers noted that “relatively high placebo response rates observed in these trials deserve further attention, and several factors are likely to contribute to this phenomenon,” first emphasizing that CSU naturally has a fluctuating course with some patients experiencing spontaneous remission.1 Furthermore, the study authors highlight that participation in clinical trials, coupled with ongoing background antihistamine therapy and the use of rescue medication, may contribute to perceived symptom improvement independently of the investigational drug. Placebo response rates ranged from 4% to 20% for complete symptom control, with as many as 35% achieving partial control across all studies. The "regression to the mean" effect, where patients enrolled during symptomatic peaks naturally tend to improve over time, also plays a role in these observed placebo responses.

Overall, the safety profiles of omalizumab, dupilumab, and remibrutinib were generally favorable across their respective studies, with serious adverse events being rare and comparable between active treatment and placebo groups, noting that “discontinuations due to adverse events were infrequent.”

While omalizumab remains the most validated biologic option for CSU unresponsive to antihistamines, the emergence of dupilumab and remibrutinib as effective alternatives signifies a shift in the management of refractory CSU. These agents, with their distinct mechanisms of action and routes of administration, offer opportunities for more personalized therapeutic strategies.

References

1. Türk M, Yılmaz İ, Ertaş R, Kocatürk E. Efficacy of Omalizumab, Dupilumab, and Remibrutinib in chronic spontaneous urticaria: Phase data and placebo response. Allergy. 2025;80(8):2410-2413. doi:10.1111/all.16670
2. Andrus E, Hebebrand M. FDA approves dupilumab for adolescents and adults with H1 antihistamine-refractory chronic spontaneous urticaria. Dermatology Times. 2025;46(5). Published April 18, 2025. https://www.dermatologytimes.com/view/fda-approves-dupilumab-chronic-spontaneous-urticaria