INTRODUCTION

Chronic spontaneous urticaria (CSU) manifests as wheals ± angioedema for >6 weeks of unknown cause.1-3 It affects about 1% of US adults and is associated with significant morbidity and health burden.4,5 The pathogenic mechanism of CSU is not completely understood. Thus, the first-line treatment of this condition has mostly been palliative that includes second generation H1-antihistamines (SGAH) up to 2-4 times the FDA’s recommended dose.6 However, only 40% of CSU patients respond to this treatment.4 Recently, omalizumab has emerged as the preferred add-on biologic treatment for CSU patients unresponsive to SGAH.7,8 Although, omalizumab has advanced the management of CSU, there are still patients with incomplete to no response to this biologic. Moreover, for most patients who require prolonged treatment with omalizumab, its therapeutic benefit does not persist after discontinuation. These limitations emphasize the need for additional investigation of novel CSU therapies.4,7-9
Several autoimmune mechanisms have been proposed including the production of IgG antibody to FcER1α subunit and anti-IgE antibodies.10-12 The roles of mast cells and eosinophils as key factors in CSU pathogenesis have also been previously investigated,13,14 which may extend beyond stimulation of the FcER1 alpha subunit on mast cells.15 Exact triggers for mast cell activation and degranulation are unknown but both receptor- and non-receptor mediated events have been suggested.16 Evidence supporting a role for the IL5 in the pathomechanism(s) of CSU is suggested by perivascular lymphocytes with eosinophilic infiltrates and an abundant IL5 in lesional vs. non-lesional skin of CSU patients.17 Benralizumab, a humanized anti-IL5-receptor-α monoclonal antibody, has been demonstrated to be clinically effective by decreasing eosinophil counts in blood, induced sputum, and lung tissue in persistent eosinophilic asthma.18-20 However, the efficacy of benralizumab at controlling CSU has never been studied. It was thus hypothesized, that benralizumab would be efficacious in SGAH refractory CSU as measured by Urticaria Activity Score over 7 days (UAS7) as a primary objective supported by the major transcriptomic changes as a secondary objective, and the Chronic Urticaria Quality of Life Questionnaire total score (CU-QoL TS) as an exploratory objective.21-23 We have recently reported the intent-to-treat primary endpoint data analysis.24 Here we now report the primary, secondary and exploratory endpoints of subjects completing all study visits.