Beyond Omalizumab: Emerging Biologic and Small Molecule Therapies in Chronic Spontaneous Urticaria

ABSTRACT Chronic spontaneous urticaria (CSU) remains inadequately controlled by H1‐antihistamines and omalizumab in a substantial minority of patients at every age. Recognition that mast cell activation proceeds through IgE‐independent as well as IgE‐dependent routes has exposed several tractable targets—Bruton's tyrosine kinase, the IL‐4/IL‐13 axis, KIT, MRGPRX2 and the JAK–STAT pathway—hence the resulting expansion of the treatment armamentarium is the largest since omalizumab. The oral BTK inhibitor remibrutinib is now licensed for adults in the United States and European Union; Dupilumab, approved from 12 years of age in 2025, was extended to children aged 2–11 years in 2026 on basis of extrapolated efficacy supported by paediatric pharmacokinetic and safety data. Barzolvolimab has completed Phase 3 enrolment of 1939 adults, briquilimab, EVO756, EP262 and rilzabrutinib are advancing in adults and ligelizumab failed to demonstrate superiority over omalizumab. This review appraises these agents by mechanism, efficacy, safety and probable place in therapy and argues that the limiting factor is no longer the number of druggable targets but the distribution and quality of the evidence. Adults dominate the trial populations; adolescents are enrolled as underpowered subgroups; dedicated paediatric evidence is essentially confined to dupilumab; and older adults—in whom comorbidity, polypharmacy and the cardiovascular and malignancy signals of JAK inhibition matter most—are almost never analyzed separately. Head‐to‐head and sequencing trials, endotype‐stratified patient selection, age‐inclusive trial design and long‐term safety data are the immediate priorities if mechanism‐based treatment is to reach patients at every stage of life.