Emerging IgE and non-IgE targeted therapies for chronic urticaria

Abstract

Chronic urticaria (CU) affects a significant percent of the global population and carries a higher burden of unmet medical need. Current standard-of-care includes antihistamines and omalizumab, but omalizumab is not effective in all patients and has not been shown to induce long-term disease remission. This review examines the diverse therapeutic pipeline spanning IgE-based and non-IgE based mast cell targeting strategies, including recent clinical data. The therapeutic landscape has expanded rapidly with multiple mechanisms under investigation. IgE-targeted approaches include omalizumab biosimilars, with CT-P39 having received FDA approval. Dupilumab received FDA approval for antihistamine refractory chronic spontaneous urticaria (CSU) supporting the targeting of type-2 cytokines, IL-4 and IL-13, in this disease. Bruton's tyrosine kinase (BTK) inhibitors show promise, with remibrutinib receiving FDA approval and demonstrating significant reductions in UAS7 in Phase 3 trials. c-Kit (c-Kit or KIT) inhibition with barzolvolimab shows robust efficacy with sustained effects post-treatment. Finally, JAK inhibitors, MRGPRX2 antagonists and other novel mechanisms are advancing through clinical trials. Although some programs have been discontinued due to safety concerns or lack of efficacy such as fenebrutinib (BTK inhibitor), THB001 (c-Kit inhibitor), EP262 (MRGPRX2 antagonist), tezepelumab (anti- TSLP), as well as lirentelimab and AK006 (Siglec-targeting agents), these studies have informed many of the other positive studies. In summary, over the last year, we have seen the CU pipeline mature with multiple Phase 3 programs and new approvals representing diverse mechanisms of action. Nevertheless, significant therapeutic gaps persist for omalizumab-refractory disease and chronic inducible urticaria.