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.