NOVEL THERAPIES FOR URTICARIA

Chronic urticaria (CU), a condition characterized by recurrent wheals, angioedema, or both, signifi-cantly impacts patients’ quality of life and remains challenging to manage in a subset of individuals. It encompasses chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU), both driven primarily by mast cell activation. Despite the availability of guideline-based therapies—such as second-generation H1-antihistamines and omalizumab—30-40% of patients remain symptomat-ic, especially those with autoimmune endotypes. The need for safer, faster-acting, and more targeted therapeutic options has led to significant advances in our understanding of CSU pathogenesis and the development of novel therapeutics. Recent insights reveal that CSU is a multifactorial immune disorder involving Type I and Type IIb autoimmunity, multiple cytokines including interleukins (e.g., IL-4, IL-5, IL-13), and a wide array of effector cells beyond mast cells, including eosinophils, B cells, and T cells. These discoveries have paved the way for targeted biologics and small molecules that address specific pathways. Anti-IgE agents such as ligelizumab and UB-221, Bruton’s tyrosine kinase (BTK) inhibitors like remibrutinib and rilzabrutinib, and IL-4Rα inhibitors such as dupilumab have shown promise in clinical trials. Other approaches include anti-Siglec therapies (lirentelimab, AK006), anti-KIT antibodies (barzolvolimab, briquilimab), Janus kinase inhibitors (JAKi) (tofacitinib, abrocitinib), and cytokine-targeted treatments (e.g., benralizumab, mepolizumab, secukinumab, til-drakizumab). Notably, complement activation has emerged as a novel target, with C5a-C5aR1 signal-ing implicated in mast cell and basophil activation. INF904, an oral C5aR1 antagonist, is under Phase 2a investigation and represents a promising option for antihistamine-refractory CSU. Similarly, the MAS-related GPR family member X2 (MRGPRX2) antagonist EP262 and wild-type KIT inhibitors (e.g., BLU-808) exemplify additional innovative directions. However, some candidates, including fen-ebrutinib and AK006, have shown limited efficacy, highlighting the complexity of CSU pathogenesis and the necessity for precise patient stratification. In conclusion, evolving insights into CSU immuno-pathology have driven the development of a new generation of targeted therapies. These novel agents hold the potential to address unmet clinical needs, particularly in refractory cases, and to shift the treatment paradigm toward personalized and mechanistically informed care.