Elsevier

The Lancet

Volume 388, Issue 10056, 29 October–4 November 2016, Pages 2128-2141
The Lancet

Articles
Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial

https://doi.org/10.1016/S0140-6736(16)31322-8Get rights and content

Summary

Background

Benralizumab is a humanised, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and nearly complete depletion of eosinophils. We aimed to assess the efficacy and safety of benralizumab as add-on therapy for patients with severe, uncontrolled asthma and elevated blood eosinophil counts.

Methods

In this randomised, double-blind, parallel-group, placebo-controlled, phase 3 study (CALIMA) undertaken at 303 sites in 11 countries, we enrolled patients aged 12–75 years with severe asthma uncontrolled by medium-dosage to high-dosage inhaled corticosteroids plus long-acting β₂-agonists (ICS plus LABA) and a history of two or more exacerbations in the previous year. Patients were randomly assigned (1:1:1) to receive 56 weeks of benralizumab 30 mg every 4 weeks (Q4W), benralizumab 30 mg every 8 weeks (Q8W; first three doses 4 weeks apart), or placebo (all subcutaneous injection). Patients were stratified (2:1) by baseline blood eosinophil counts 300 cells per μL or greater and less than 300 cells per μL, respectively. Patients and study centre staff were masked to treatment allocation. The primary endpoint was annual exacerbation rate ratio versus placebo for patients receiving high-dosage ICS plus LABA with baseline blood eosinophils 300 cells per μL or greater (intention-to-treat analysis). Key secondary endpoints were pre-bronchodilator forced expiratory volume in 1 s (FEV1) and total asthma symptom score. This study is registered with ClinicalTrials.gov, number NCT01914757.

Findings

Between Aug 21, 2013, and March 16, 2015, 2505 patients were enrolled, of whom 1306 patients were randomised; 425 patients were randomly assigned to and received benralizumab 30 mg Q4W, 441 to benralizumab 30 mg Q8W, and 440 to placebo. 728 patients were included in the primary analysis population. Benralizumab resulted in significantly lower annual exacerbation rates with the Q4W regimen (rate 0·60 [95% CI 0·48–0·74], rate ratio 0·64 [95% CI 0·49–0·85], p=0·0018, n=241) and Q8W regimen (rate 0·66 [95% CI 0·54–0·82], rate ratio 0·72 [95% CI 0·54–0·95], p=0·0188, n=239) compared with placebo (rate 0·93 [95% CI 0·77–1·12], n=248). Benralizumab also significantly improved pre-bronchodilator FEV1 (Q4W and Q8W) and total asthma symptom score (Q8W only) in these patients. The most common adverse events were nasopharyngitis (90 [21%] in the Q4W group, 79 [18%] in the Q8W group, and 92 [21%] in the placebo group) and worsening asthma (61 [14%] in the Q4W group, 47 [11%] in the Q8W group, and 68 [15%] in the group).

Interpretation

Benralizumab significantly reduced annual exacerbation rates and was generally well tolerated for patients with severe, uncontrolled asthma with blood eosinophils 300 cells per μL or greater. Our data further refine the patient population likely to receive the greatest benefit from benralizumab treatment.

Funding

AstraZeneca and Kyowa Hakko Kirin.

Introduction

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.

Section snippets

Study design and participants

This was a randomised, double-blind, parallel-group, placebo-controlled, phase 3 trial (CALIMA). Patients were enrolled at 303 clinical research centres in the USA, Canada, Germany, Sweden, Poland, Romania, Ukraine, Argentina, Chile, Japan, and the Philippines (appendix pp 2–5). The study design comprised an enrolment visit (week −4), a 4-week screening and run-in phase, randomisation (week 0), the treatment period (weeks 0–56), and a final follow-up visit (week 60).

Male and female patients

Results

Between Aug 21, 2013, and March 16, 2015, we recruited 2505 patients. 2181 entered screening and run-in and 1306 were randomised (figure 1). All randomised patients received study treatment: 425 patients were randomly assigned to and received benralizumab 30 mg Q4W, 441 patients to benralizumab 30 mg Q8W, and 440 patients to placebo. Of these, 1157 (89%) patients completed and 149 (11%) patients discontinued treatment, 116 of whom also discontinued the study. The most common reason for

Discussion

The results of the CALIMA study showed that 56 weeks of add-on therapy with benralizumab 30 mg Q4W and Q8W significantly reduced the annual rate of asthma exacerbations by up to 36% for patients with severe asthma and elevated blood eosinophils that were inadequately controlled on existing standard of care therapy. Both benralizumab dosing regimens also significantly improved lung function and, when administered every 8 weeks, significantly improved patient-reported total asthma symptom scores

References (30)

  • ID Pavord et al.

    Mepolizumab in refractory eosinophilic asthma

    Thorax

    (2010)
  • K Parameswaran et al.

    Predictors of loss of asthma control induced by corticosteroid withdrawal

    Can Respir J

    (2006)
  • R Louis et al.

    The relationship between airways inflammation and asthma severity

    Am J Respir Crit Care Med

    (2000)
  • D Talini et al.

    Sputum eosinophilia is a determinant of FEV1 decline in occupational asthma: results of an observational study

    BMJ Open

    (2015)
  • LD Tan et al.

    Benralizumab: a unique IL-5 inhibitor for severe asthma

    J Asthma Allergy

    (2016)
  • Cited by (1031)

    • Lebrikizumab in Uncontrolled Asthma: Reanalysis in a Well-Defined Type 2 Population

      2024, Journal of Allergy and Clinical Immunology: In Practice
    View all citing articles on Scopus

    For the full list of investigators see the appendix pp 2–5

    View full text