Asthma has been estimated to affect more than 315 million people worldwide, with approximately 10% having severe or uncontrolled asthma.1, 2 The worldwide prevalence of asthma continues to increase, and is projected to reach more than 400 million by 2020,3 representing a growing unmet need for the treatment of patients with uncontrolled disease.
Research in context
Evidence before this study
Benralizumab is a humanised, anti-eosinophil monoclonal antibody against interleukin-5 receptor α that is intended for patients with severe, uncontrolled asthma with eosinophilic inflammation. We searched PubMed on June 7, 2016, for articles with the terms “asthma”, “anti-interleukin-5”, and “eosinophil” in the title or abstract. This search yielded 29 results, including one study describing a randomised, controlled, double-blind, dose-ranging phase 2b trial of benralizumab for patients with uncontrolled eosinophilic asthma. Based on this systematic review, benralizumab is the only monoclonal antibody against interleukin-5 receptor α used to treat asthma. Benralizumab induces direct, rapid, and nearly complete depletion of eosinophils in the bone marrow, blood, and target tissue via enhanced antibody-dependent cell-mediated cytotoxicity. Given the promising results obtained in the phase 2b trial, we undertook the phase 3 SIROCCO study to confirm the efficacy and safety of benralizumab 30-mg dosage for patients with severe, uncontrolled, eosinophilic asthma, and to seek regulatory approval in the USA, Europe, and Japan.
Added value of this study
This study is, to our knowledge, the first phase 3 trial of benralizumab in patients with severe, uncontrolled asthma with eosinophilic inflammation. Benralizumab given once every 4 or 8 weeks decreased exacerbations and improved lung function, with improvement in asthma symptoms noted with the once every 8 weeks dosage.
Implications of all the available evidence
Severe asthma affects the health and wellbeing of millions of people worldwide. Exacerbations are life threatening for these patients, and their health-related quality of life is substantially diminished. These findings show the potential for benralizumab to improve outcomes for patients with severe asthma.
Patients with severe asthma need high-dosage inhaled corticosteroids in combination with long-acting β2-agonists to control their disease.4 Despite the proven effectiveness of this approach for most asthmatics, many patients continue to have uncontrolled disease and are at risk for severe asthma exacerbations. Patients with severe, uncontrolled asthma experience a high disease burden, including recurrent exacerbations and hospital admissions (defined as admission to an inpatient facility and/or assessment and treatment in a health-care facility for ≥24 h).5, 6 As a result, most health-care resources used for asthma care are attributable to those patients with severe disease.5, 6 Furthermore, the cost of asthma increases proportionally with disease severity.7
Eosinophilic inflammation is present in approximately 50% of patients with asthma8 and is associated with asthma severity, greater frequency of exacerbations, and decreased lung function.9, 10 Additionally, poor asthma control is associated with progressive increases in sputum and blood eosinophil counts.11
Interleukin 5 is one of several cytokine mediators involved in eosinophil development, activation, proliferation, and survival, and concentrations of this cytokine in the lungs are increased in patients with asthma.12, 13 Findings from clinical trials have shown efficacy and safety of treatment with monoclonal antibodies against interleukin 5 in patients with asthma and have led to the approval of mepolizumab and reslizumab in the USA and mepolizumab in Europe as add-on maintenance treatment for patients with severe asthma aged 18 years (reslizumab) or 12 years (mepolizumab) and older with an eosinophilic phenotype.14, 15, 16, 17
Benralizumab is a humanised, afucosylated, monoclonal antibody against interleukin-5 receptor α that induces direct, rapid, and nearly complete depletion of eosinophils through enhanced antibody-dependent cell-mediated cytotoxicity, an apoptotic process of eosinophil elimination involving natural killer cells.18, 19 This mechanism is in contrast to current treatments, which target interleukin 5 directly and act through a passive (ie, indirect) mechanism that ultimately results in eosinophil reduction but not depletion.12 Benralizumab has a broad efficacy profile for patients with severe, uncontrolled asthma with eosinophilic inflammation.20, 21, 22 In a phase 2b study,22 benralizumab 100 mg Q8W for 1 year seemed to reduce exacerbation rates compared with placebo (0·34 vs 0·57; 41% reduction, 80% CI 11–60; p=0·096) for patients with uncontrolled asthma treated with medium-dosage or high-dosage inhaled corticosteroids and long-acting β2-agonists (ICS plus LABA). A lower 20 mg dosage was efficacious in reducing exacerbation rates (0·30 vs 0·68 in placebo, 57% reduction, 80% CI 33–72; p=0·015) in patients with blood eosinophil counts at least 300 cells per μL.22 Results from this study prompted the decision to investigate a 30 mg dosage in phase 3 trials.22, 23
We report the results from SIROCCO, one of two phase 3 trials that investigated the efficacy and safety of benralizumab in patients with severe asthma with eosinophilia inadequately controlled with high-dosage ICS plus LABA.