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.