Dermatology Times 2025 Year in Review: Chronic Spontaneous Urticaria

Chronic spontaneous urticaria (CSU) is a chronic inflammatory skin condition marked by recurrent hives and/or angioedema lasting more than 6 weeks without identifiable triggers. Historically, treatment relied on antihistamines and off-label immunosuppressants, with omalizumab serving as the primary biologic for refractory disease. In 2025, the CSU landscape experienced significant regulatory progress and late-stage clinical advances, expanding treatment options and enabling more personalized care.

Regulatory Milestones

Dupilumab (IL‑4/IL‑13 Inhibitor) Approval

In April 2025, dupilumab (Dupixent; Sanofi, Regeneron) received FDA approval for adults and adolescents (≥12 years) with CSU who remain symptomatic despite H1 antihistamines. Supported by the phase 3 LIBERTY-CSU CUPID trials, dupilumab demonstrated significant reductions in urticaria activity scores and itch severity, along with improved quality of life measures. The approval represents the first new biologic option outside of omalizumab for CSU in over a decade.

FDA Approves Dupilumab for Adolescents and Adults With H1 Antihistamine-Refractory Chronic Spontaneous Urticaria

Remibrutinib — First Oral BTK Inhibitor

Later in 2025, remibrutinib (Rhapsido; Novartis) became the first oral Bruton’s tyrosine kinase (BTK) inhibitor approved for adults with antihistamine-refractory CSU. Phase 3 REMIX-1 and REMIX-2 trials demonstrated symptom improvement as early as week 2, sustained over the controlled treatment period, with a favorable safety profile and no routine lab monitoring requirement. This approval adds a convenient, oral mechanism of action for patients who prefer non-injectable therapy.

FDA Approves Remibrutinib, First Oral BTK Inhibitor for CSU

Omalizumab (Anti-IgE Biologic)

Omalizumab remains a cornerstone of biologic therapy for CSU, approved for adults and adolescents inadequately controlled on H1 antihistamines, with well-established efficacy and safety profiles.

When Hives Do Not Quit: A Practical Update on Chronic Spontaneous Urticaria

Late-Stage Investigational Therapies (Phase 2/3)

Barzolvolimab (Anti-KIT Monoclonal Antibody)

Barzolvolimab (Celldex Therapeutics), targeting the KIT receptor involved in mast cell activation, is in phase 3 trials. Phase 2/3 data indicate durable reductions in urticaria activity and angioedema, with improvements maintained over 52 weeks. Barzolvolimab could further expand the biologic options for CSU.

Celldex Reports Strong Efficacy of Barzolvolimab in Chronic Spontaneous Urticaria Across IgE Subgroups

EVO756

EVO756, a small molecule immunomodulator, is currently in phase 2b studies for CSU. Early results suggest efficacy in reducing itch and hives with good tolerability, representing a non-biologic oral approach.

Evommune Advances EVO756 Into Global Phase 2b Trial for Chronic Spontaneous Urticaria

Ligelizumab

A next-generation high-affinity anti-IgE antibody, ligelizumab completed phase 3 trials but is not currently approved. It showed promise in achieving higher rates of symptom control compared with omalizumab in earlier studies.

Phase 3b Study Confirms Ligelizumab’s Consistent CSU Control

Evolving Treatment Algorithm

The contemporary CSU treatment algorithm reflects stepwise escalation and mechanistic diversity:

1. Second-generation H1 antihistamines remain first-line therapy.
2. Omalizumab is typically the next step for inadequate response.
3. Dupilumab offers an alternative biologic, particularly for patients with type 2 inflammatory comorbidities.
4. Remibrutinib provides a novel oral therapy option.
5. Emerging agents like barzolvolimab and EVO756 may further diversify therapeutic strategies once approved.

Personalized therapy selection is increasingly guided by patient characteristics, response patterns, and tolerability considerations.

Pipeline and Future Directions

Over 20 compounds are in phase 2 or later development, targeting mast cell activation, IgE pathways, and immune signaling mechanisms. Ongoing trials aim to identify predictive biomarkers for response and provide long-term safety and efficacy data. As the pipeline matures, clinicians can anticipate more tailored and mechanism-driven options, addressing unmet needs for patients with refractory CSU.

Conclusion

2025 marked a transformative year in CSU management, with the approval of dupilumab and remibrutinib expanding both biologic and oral treatment options. Omalizumab remains a mainstay, while investigational agents like barzolvolimab and EVO756 signal continued therapeutic innovation. These advances support a more personalized, stepwise, and mechanism-oriented approach to CSU care, offering new hope for patients who have historically faced limited treatment options.