Asthma affects an estimated 315 million people worldwide, approximately 10% of whom have severe or uncontrolled asthma.1, 2 Patients with severe asthma require treatment with high-dosage inhaled corticosteroids plus long-acting β2-agonists (LABA) to control their disease.2 Despite currently available treatments, asthma remains uncontrolled for many patients. Because this difficult-to-treat group is at high risk of exacerbations and admissions to hospital, often has diminished health-related quality of life, and represents a major health-care burden,3 additional therapeutic options to control severe asthma are needed.
Research in context
Evidence before this study
We searched PubMed for all clinical trial reports published in English before June 12, 2016, on the use of anti-interleukin-5 biologic drugs for the treatment of asthma in humans. Our search terms included “eosinophils”, “interleukin-5”, “monoclonal antibody”, “asthma”, “benralizumab”, “mepolizumab”, and “reslizumab”. Our search identified 29 results, including two phase 1 studies of benralizumab that reported reduced blood eosinophil counts in patients with mild atopic and eosinophilic asthma, as well as a phase 2b benralizumab dose-ranging study that reported decreased exacerbation rates for patients with severe eosinophilic asthma. In the phase 2b study, benralizumab efficacy seemed to be enhanced for patients with blood eosinophil counts exceeding 300 cells per μL. In addition, we identified two phase 3 studies and a subsequent secondary analysis of phase 3 trial data for mepolizumab, as well as a report of two duplicate phase 3 studies of reslizumab treatment for patients with severe, uncontrolled asthma. Together, these studies reinforced the clinical benefit of therapies targeting the interleukin-5 pathway for patients with severe asthma and provided evidence that clinical efficacy of anti-interleukin-5 biologic therapy is linked to baseline eosinophil counts and exacerbation history.
Added value of this study
The results of the CALIMA trial validate the approach of targeting the interleukin-5 receptor α to deplete eosinophil counts, reduce asthma exacerbations, improve lung function, and substantially alleviate asthma symptoms of patients with severe, uncontrolled asthma.
Implications of all the available evidence
New and existing data support the current Global Initiative for Asthma management strategy, which recommends the addition of anti-interleukin-5 biologic therapy to inhaled corticosteroids and LABA treatment to reduce exacerbations for patients with severe, uncontrolled asthma and eosinophilia. Our data further refine the patient population likely to receive the greatest benefit from benralizumab treatment.
For many patients, eosinophilia is a hallmark of severe, uncontrolled asthma.4 Increased numbers of airway and circulating eosinophils are associated with an increased frequency of asthma exacerbations, a high symptom burden, and impaired lung function.5, 6, 7 Conversely, maintaining lowered eosinophils has been linked with fewer asthma exacerbations and hospital admissions.8 The cytokine interleukin 5 is a main driver of eosinophil proliferation, maturation, activation, and survival.9 Thus, the interleukin-5 pathway is an attractive therapeutic target to decrease eosinophils, with the goal of eliminating lung and airway inflammation.
Current treatment guidelines for patients with severe, uncontrolled asthma with eosinophilia recommend add-on anti-interleukin-5 biologic therapy.10 Mepolizumab and reslizumab are humanised monoclonal antibodies, directed against the interleukin-5 molecule, that disrupt eosinophil maturation.11, 12 Both medications have shown clinical efficacy for patients with severe asthma with an eosinophilic phenotype.13, 14, 15, 16 However, targeting the interleukin-5 molecule could result in suboptimal depletion of eosinophils.17, 18, 19, 20
Benralizumab is a humanised, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and nearly complete depletion of eosinophils via enhanced antibody-dependent cell-mediated cytotoxicity, the process by which natural killer cells cause eosinophil apoptosis.18 In phase 1 studies, benralizumab rapidly depleted eosinophils for patients with mild atopic or eosinophilic asthma.21, 22 In a subsequent phase 2B, dose-ranging study, benralizumab significantly reduced the rate of asthma exacerbations for patients with eosinophilic asthma uncontrolled by inhaled corticosteroids plus LABA therapy.23 Moreover, patients with baseline blood eosinophils 300 cells per μL or greater achieved the greatest therapeutic benefit.23
In the 56-week, phase 3 CALIMA trial, we aimed to investigate the efficacy and safety of benralizumab for patients with severe asthma uncontrolled by high-dosage inhaled corticosteroids plus LABA with baseline blood eosinophils 300 cells per μL or greater.