Elsevier

The Lancet

Volume 388, Issue 10056, 29 October–4 November 2016, Pages 2115-2127
The Lancet

Articles
Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial

https://doi.org/10.1016/S0140-6736(16)31324-1Get rights and content

Summary

Background

Eosinophilia is associated with worsening asthma severity and decreased lung function, with increased exacerbation frequency. We assessed the safety and efficacy of benralizumab, a monoclonal antibody against interleukin-5 receptor α that depletes eosinophils by antibody-dependent cell-mediated cytotoxicity, for patients with severe, uncontrolled asthma with eosinophilia.

Methods

We did a randomised, double-blind, parallel-group, placebo-controlled phase 3 study at 374 sites in 17 countries. We recruited patients (aged 12–75 years) with a physician-based diagnosis of asthma for at least 1 year and at least two exacerbations while on high-dosage inhaled corticosteroids and long-acting β2-agonists (ICS plus LABA) in the previous year. Patients were randomly assigned (1:1:1) by an interactive web-based voice response system to benralizumab 30 mg either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses every 4 weeks) or placebo Q4W for 48 weeks as add on to their standard treatment. Patients were stratified 2:1 according to blood eosinophil counts of at least 300 cells per μL and less than 300 cells per μL. All patients and investigators involved in patient treatment or clinical assessment were masked to treatment allocation. The primary endpoint was annual exacerbation rate ratio versus placebo, and key secondary endpoints were prebronchodilator forced expiratory volume in 1 s (FEV1) and total asthma symptom score at week 48, for patients with blood eosinophil counts of at least 300 cells per μL. Efficacy analyses were by intention to treat (based on the full analysis set); safety analyses included patients according to study drug received. This study is registered with ClinicalTrials.gov, number NCT01928771.

Findings

Between Sept 19, 2013, and March 16, 2015, 2681 patients were enrolled, 1205 of whom met the study criteria and were randomly assigned: 407 to placebo, 400 to benralizumab 30 mg Q4W, and 398 to benralizumab 30 mg Q8W. 267 patients in the placebo group, 275 in the benralizumab 30 mg Q4W group, and 267 in the benralizumab 30 mg Q8W group had blood eosinophil counts at least 300 cells per μL and were included in the primary analysis population. Compared with placebo, benralizumab reduced the annual asthma exacerbation rate over 48 weeks when given Q4W (rate ratio 0·55, 95% CI 0·42–0·71; p<0·0001) or Q8W (0·49, 0·37–0·64; p<0·0001). Both benralizumab dosing regimens significantly improved prebronchodilator FEV1 in patients at week 48 compared with placebo (least-squares mean change from baseline: Q4W group 0·106 L, 95% CI 0·016–0·196; Q8W group 0·159 L, 0·068–0·249). Compared with placebo, asthma symptoms were improved by the Q8W regimen (least-squares mean difference −0·25, 95% CI −0·45 to −0·06), but not the Q4W regimen (−0·08, −0·27 to 0·12). The most common adverse events were worsening asthma (105 [13%] of 797 benralizumab-treated patients vs 78 [19%] of 407 placebo-treated patients) and nasopharyngitis (93 [12%] vs 47 [12%]).

Interpretation

These results confirm the efficacy and safety of benralizumab for patients with severe asthma and elevated eosinophils, which are uncontrolled by high-dosage ICS plus LABA, and provide support for benralizumab to be an additional option to treat this disease in this patient population.

Funding

AstraZeneca and Kyowa Hakko Kirin.

Introduction

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.

Section snippets

Study design and participants

SIROCCO was a phase 3, randomised, double-blind, parallel-group, placebo-controlled study done at 374 clinical research centres in Australia, Brazil, Bulgaria, Czech Republic, France, Italy, Mexico, Peru, Poland, Russia, South Africa, South Korea, Spain, Turkey, the UK, the USA, and Vietnam (appendix pp 2–6).

Patients aged 12–75 years who weighed at least 40 kg and who were diagnosed by a physician to have had asthma needing treatment with medium-dosage or high-dosage ICS plus LABA for at least

Results

Between Sept 19, 2013, and March 16, 2015, we enrolled 2681 patients, 2232 of whom were screened for eligibility (figure 1). 1205 patients who met study entry criteria were randomly assigned to treatment: 407 to placebo, 400 to benralizumab 30 mg Q4W, and 398 to benralizumab Q8W. One patient in the benralizumab 30 mg Q4W group was lost to follow-up before treatment; all other patients received their assigned treatments. 267 patients in the placebo group, 275 in the benralizumab 30 mg Q4W group,

Discussion

In the phase 3 SIROCCO study, the anti-eosinophil monoclonal antibody benralizumab significantly reduced the annual rate of exacerbations by up to 51% after 48 weeks of treatment in patients with severe, uncontrolled asthma with eosinophilia (blood eosinophil counts ≥300 cells per μL). Benralizumab also significantly improved pulmonary function, with a 0·106–0·159 L increase in prebronchodilator FEV1 relative to placebo, depending on the dosing regimen. Differences from placebo were generally

References (30)

  • KF Chung et al.

    International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

    Eur Respir J

    (2014)
  • P Chanez et al.

    Asthma: still a promising future?

    Eur Respir Rev

    (2014)
  • Global strategy for asthma management and prevention

  • AG Fernandes et al.

    Risk factors for death in patients with severe asthma

    J Bras Pneumol

    (2014)
  • M Sadatsafavi et al.

    Direct health care costs associated with asthma in British Columbia

    Can Respir J

    (2010)
  • Cited by (1008)

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    Investigators listed in appendix (pp 2–6)

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