Articles
Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study

https://doi.org/10.1016/S2213-2600(14)70201-2Get rights and content

Summary

Background

Persistent eosinophilic airway inflammation in asthma increases the risk of exacerbations. In a phase 2b dose-ranging study, we aimed to assess the efficacy and safety of benralizumab, an anti-interleukin 5 receptor α monoclonal antibody that depletes blood and airway eosinophils, in adults with uncontrolled eosinophilic asthma.

Methods

We did a randomised, controlled, double-blind, dose-ranging phase 2b study. Eligible participants were adults aged 18–75 years with uncontrolled asthma using medium-dose or high-dose inhaled corticosteroids and longacting β agonists, with two to six exacerbations in the past year. Current or former smokers were excluded. We used the ELEN index (an algorithm to predict elevated sputum eosinophils) or baseline fraction of exhaled nitric oxide to stratify patients by eosinophilic status, and with an interactive web–voice response system randomly assigned eosinophilic individuals in a 1:1:1:1 ratio to receive placebo, 2 mg benralizumab, 20 mg benralizumab, or 100 mg benralizumab, and non-eosinophilic individuals in a 1:1 ratio to receive placebo or 100 mg benralizumab. Study drugs were given as two subcutaneous injections every 4 weeks for the first three doses, then every 8 weeks, for 1 year. Patients, treating physicians, and study investigators were masked to treatment allocation. The primary endpoint was annual exacerbation rate in eosinophilic individuals after 1 year of follow-up. Analysis was by modified intention to treat. This study was designed with a two-sided α of 0·2 and powered at 78% for the primary outcome in the eosinophilic population. This study is registered with ClinicalTrials.gov, number NCT01238861.

Findings

Between Jan 3, 2011, and March 6, 2012, we randomly assigned 324 eosinophilic individuals to placebo (n=80) or benralizumab 2 mg dose (n=81), 20 mg dose, (n=81), or 100 mg dose (n=82), and 285 non-eosinophilic individuals to 100 mg benralizumab (n=142, 140 included in analysis) or placebo (n=143, 142 included in analysis). In eosinophilic individuals, benralizumab reduced exacerbation rates compared with placebo in the 100 mg group (0·34 vs 0·57, reduction 41%, 80% CI 11 to 60, p=0·096) but not in the 2 mg group (0·65 vs 0·57, difference −9%, 80% CI −59 to 26, p=0·781) or the 20 mg group (0·37 vs 0·57, reduction 36%, 80% CI 3 to 58, p=0·173). In patients with a baseline blood eosinophil cutoff of at least 300 cells per μL, exacerbation rates in the benralizumab 20 mg group (n=70) and 100 mg group (n=97) were lower than in the placebo group (n=83; 0·30 vs 0·68, reduction 57%, 80% CI 33 to 72, p=0·015 for 20 mg dose; 0·38 vs 0·68, difference 43%, 80% CI 18 to 60, p=0·049 for 100 mg dose). Our findings suggested that benralizumab 20 mg and 100 mg resided at the dose–response plateau. Treatment-emergent adverse events occurred in 277 (72%) of 385 participants receiving any benralizumab dose compared with 143 (65%) of 221 receiving placebo. Nasopharyngitis (44 [11%] patients receiving benralizumab vs 13 [6%] patients receiving placebo) and injection site reactions (60 [16%] vs eight [4%]) occurred more frequently with benralizumab than with placebo.

Interpretation

Benralizumab at 20 mg and 100 mg doses seemed to reduce asthma exacerbations in adults with uncontrolled eosinophilic asthma and baseline blood eosinophils of at least 300 cells per μL, possibly due to targeting of the interleukin 5 receptor rather than interleukin 5 ligand. Further investigation of benralizumab treatment in phase 3 studies is warranted.

Funding

MedImmune.

Introduction

Persistent eosinophilic airway inflammation in asthma increases the risk of subsequent exacerbations.1, 2, 3 Monoclonal antibodies against interleukin 5 (eg, mepolizumab and reslizumab) reduce blood and sputum eosinophils in patients with asthma.4, 5 However, findings from an early study of mepolizumab in an unselected population of patients with asthma did not show clinical benefit,5 suggesting that anti-interleukin 5 therapy might be effective only in a targeted subgroup with an eosinophilic phenotype.6 In three randomised, placebo-controlled studies, mepolizumab significantly reduced exacerbations in participants with asthma and evidence of eosinophilic inflammation.7, 8, 9 Thus, selection of patients with asthma and an eosinophilic phenotype might be a more useful approach to investigate the efficacy of anti-interleukin 5 therapies. Benralizumab (MedImmune, Gaithersburg, MD, USA) is a humanised, afucosylated IgG-1κ monoclonal antibody that targets human interleukin 5 receptor α (IL5Rα)10 expressed on eosinophils and basophils.11, 12, 13 In vitro, benralizumab exhibits enhanced antibody-dependent cell-mediated cytotoxicity and induces apoptosis of target cells.10 Findings from two studies in participants with atopic or eosinophilic asthma have shown that benralizumab depletes eosinophils in blood,14, 15 airway mucosa, and sputum.15

In a phase 2b randomised dose-ranging study, we aimed to assess the efficacy and safety of repeated doses of subcutaneous benralizumab in adults with uncontrolled asthma to determine whether this biological product should undergo further phase 3 development.

Section snippets

Study design and participants

We did a phase 2b, randomised, double-blind, placebo-controlled, dose-ranging study at 33 sites in the USA, Canada, Bulgaria, Brazil, Peru, Mexico, Poland, Russia, Argentina, and Colombia.

We enrolled adults aged 18–75 years who had asthma and were treated with medium-dose to high-dose inhaled corticosteroids in combination with longacting β agonist therapy16 for at least 1 year; criteria for medium and high daily doses of inhaled corticosteroids are provided in the appendix (p 5). Eligible

Results

We screened 964 patients and randomly assigned 609 between Jan 3, 2011 and March 6, 2012. The trial started screening in December 2010 (first participant enrolled Jan 3, 2011) and the first participant was dosed on Jan 3, 2011. The study was completed in August 2013 after the last protocol-specified visit or assessment was done (including telephone contact) for the last participant in the study.

We randomly assigned 324 patients in the eosinophilic cohort (81 in the 2 mg benralizumab group, 81

Discussion

In this phase 2 dose-ranging study in participants with uncontrolled eosinophilic asthma, benralizumab 100 mg seemed to reduce exacerbations and improve lung function and quality of life in participants with a protocol-defined eosinophilic phenotype (and also in a prespecified subgroup analysis in participants with baseline blood eosinophils ≥300 cells per μL), with a predetermined α of 0·169. These potentially promising results are important in the early development of a drug but are not

References (38)

  • A Di Franco et al.

    Analysis of sputum cell counts during spontaneous moderate exacerbations of asthma in comparison to the stable phase

    J Asthma

    (2003)
  • KA Scott et al.

    Eosinophilic airway disorders

    Semin Respir Crit Care Med

    (2006)
  • M Castro et al.

    Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study

    Am J Respir Crit Care Med

    (2011)
  • P Flood-Page et al.

    A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma

    Am J Respir Crit Care Med

    (2007)
  • P Haldar et al.

    Mepolizumab and exacerbations of refractory eosinophilic asthma

    N Engl J Med

    (2009)
  • P Nair et al.

    Mepolizumab for prednisone-dependent asthma with sputum eosinophilia

    N Engl J Med

    (2009)
  • R Kolbeck et al.

    MEDI-563, a humanized anti-IL-5 receptor α mAb with enhanced antibody-dependent cell-mediated cytotoxicity function

    J Allergy Clin Immunol

    (2010)
  • NA Molfino et al.

    Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor

    Clin Exp Allergy

    (2012)
  • K Toba et al.

    Novel technique for the direct flow cytofluorometric analysis of human basophils in unseparated blood and bone marrow, and the characterization of phenotype and peroxidase of human basophils

    Cytometry

    (1999)
  • Cited by (420)

    • Toward a Predict and Prevent Approach in Obstructive Airway Diseases

      2023, Journal of Allergy and Clinical Immunology: In Practice
    • Factors to Consider in Prescribing Asthma Biologic Therapies to Children

      2023, Journal of Allergy and Clinical Immunology: In Practice
    View all citing articles on Scopus
    View full text