INTRODUCTION
Chronic rhinosinusitis (CRS) has a prevalence of more than 10% in the
United States and Europe and is associated with several co-morbidities
including asthma, acute infection, and obstructive sleep apnoea.(1-3)
Total health care expenditure for CRS is more than $60 billion annually
in the United States accounting for as much as 5% of the total US
health care budget.(3-5) CRS with nasal polyps (CRSwNP) in particular,
can be a severe and debilitating disease associated with significant
morbidity, complete anosmia, sinus pressure, and acute asthma
exacerbations. Not uncommonly, patients with CRSwNP often require
multiple courses of oral corticosteroids and repeated surgical
polypectomies to manage their disease.
CRSwNP is not exclusively related to immunoglobulin E (IgE) and
interleukin-4 (IL-4) processes. As such, allergen immunotherapy is of
limited value although, evidence suggests that immunotherapy improves
innate immune function in addition to affecting the IL-4/IgE mediated
immune axis.(6) Anti-IgE therapy such as omalizumab has also been shown
to have some benefit in this population.(7-10) Dupilumab, an anti IL-4Rα
antibody, has been shown to be efficacious in the CRSwNP patient
population; however, it is worth noting that treatment resulted in a
decrease in eosinophil-associated plasma eotaxin-3, indicating that
other non-IL-4/IgE pathways are also impacted by this drug.(11)
Similarly, the efficacy of dupilumab in eosinophilic asthmatics resulted
in a reduction in eotaxin-3 and Fractional exhaled Nitric Oxide (FeNO)
and an increase in blood eosinophils, suggesting re-compartmentalization
and other effects on this inflammatory cell cascade.(12)
In up to 90% of Caucasian patients with chronic nasal polyps, the
disease exhibits pathology associated with eosinophils and interleukin-5
(IL-5).(13) CRSwNP patients with elevations in serum and mucosal
eosinophils tend to have more severe NP disease and higher recurrence
rates.(14) Eosinophilia is often so pronounced that patients with CRSwNP
are sometimes evaluated for clonal hypereosinophilic processes,
parasitic infections and autoimmune disorders.(15, 16) Despite chronic
corticosteroid use, eosinophils may remain elevated. Indeed, high blood
and tissue eosinophil counts are associated with increased disease
severity and recurrence rates post surgery.(14) In addition, a number of
proinflammatory genes that upregulate eosinophil recruitment and
survival have been shown to be activated in nasal polyp tissue.(17)
A proof-of-concept study in Europe previously showed a reduction in
polyp burden using mepolizumab, a monoclonal antibody that binds free
IL-5 protein in circulation.(15) Benralizumab on the other hand, is an
afucosylated monoclonal antibody that directly targets the α chain of
the IL-5 receptor and has been shown to have powerful apoptotic effects
on eosinophils. Benralizumab is efficacious treating severe asthmatics
with eosinophilia(18, 19); however the potential for this drug to be
used to treat patients with CRSwNP has not been previously evaluated.
The unique mechanism of action of benralizumab targeting the IL-5
receptor on the surface of eosinophils leads to degradation of
signalling, antibody-dependent cell-mediated cytotoxicity (ADCC), and
apoptosis.(18) This direct effect on eosinophils leads to reduction of
proinflammatory processes in the asthmatic airways but the effect on
nasal polyp burden still needs to be determined.
We hypothesized that benralizumab 30mg SC given subcutaneously for
twenty weeks would reduce endoscopic and radiographic nasal polyp size,
as well as symptoms of nasal blockage and poor sense of smell in a
double-blind randomized placebo-controlled study.