Chronic spontaneous urticaria (CSU) continues to pose significant therapeutic challenges for patients inadequately controlled with second-generation antihistamines, but new treatment options are expanding the therapeutic landscape. Recent phase 3 trial data for omalizumab, dupilumab, and the Bruton tyrosine kinase (BTK) inhibitor remibrutinib provide insights into efficacy and clinical implications for managing this challenging condition.
Established and Emerging Biologic Options
Omalizumab, a humanized anti-IgE monoclonal antibody, maintains 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.
Dupilumab, approved for CSU in April 2025, represents a novel therapeutic approach as an IL-4Rα antagonist that blocks signaling of both IL-4 and IL-13, key drivers of type 2 inflammation often implicated in CSU pathogenesis. The phase 3 LIBERTY-CSU CUPID A, B, and C studies demonstrated clinical benefit, although response rates were somewhat lower than those seen with omalizumab. Complete response rates for dupilumab ranged from 13% to 31% at Week 24, with partial response rates between 24% and 46%.
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. Researchers highlighted that "remibrutinib's oral route could improve adherence and convenience," offering a valuable alternative to injectable biologics.
Real-World Experience with Treatment Switching
A prospective pilot study at Nihon University Itabashi Hospital investigated dupilumab in 12 CSU patients with persistent UCT scores <12 despite receiving at least four doses of omalizumab. Patients received an initial 600 mg dose followed by 300 mg biweekly while continuing high-dose second-generation antihistamines.
At dupilumab initiation, the mean UCT score was 6.5 ± 2.2. Following 1 month of dupilumab therapy, the mean UCT score rose to 8.4 ± 3.0 (P = 0.016), and at 4 months, it remained 8.1 ± 3.9 (P = 0.045). Three patients achieved a UCT score ≥12, meeting the threshold for effective disease control. However, 4 patients experienced decreased UCT scores compared with baseline, highlighting the heterogeneity of response.
Notably, 3 patients who did not respond to dupilumab returned to monthly omalizumab, subsequently achieving UCT scores ≥12 within 1 month, with effects persisting beyond 3 months. This observation suggests that while IL-4/13 blockade may temporarily modify IgE-related pathways, the downstream impact on clinical disease control varies and may allow renewed responsiveness to omalizumab in certain patients.
Understanding Placebo Effects in CSU Trials
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." CSU naturally has a fluctuating course with some patients experiencing spontaneous remission. Furthermore, 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.
Safety and Clinical Implications
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. Researchers noted 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. As researchers noted, "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."
These agents, with their distinct mechanisms of action and routes of administration, offer opportunities for more personalized therapeutic strategies. Dupilumab may be particularly beneficial for patients with concomitant atopic comorbidities given its broad efficacy across other type 2 inflammatory conditions like atopic dermatitis and asthma, while remibrutinib's oral formulation could improve patient adherence and convenience compared to injectable biologics.
