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Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies

https://doi.org/10.1016/S2213-2600(17)30344-2Get rights and content

Summary

Background

Benralizumab is an anti-eosinophilic, anti-interleukin-5 receptor α monoclonal antibody that has been shown to significantly reduce asthma exacerbations and improve lung function for patients with severe, uncontrolled asthma. We further explored the efficacy of benralizumab for patients with different baseline blood eosinophil thresholds and exacerbation histories.

Methods

This study is a pooled analysis of the results from the randomised, double-blind, placebo-controlled SIROCCO (NCT01928771) and CALIMA (NCT01914757) phase 3 studies. In these studies, patients with severe, uncontrolled asthma were randomly assigned (1:1:1) to receive subcutaneous benralizumab 30 mg, either every 4 weeks or every 8 weeks (with first three doses given every 4 weeks), or placebo every 4 weeks. The primary endpoint was annual exacerbation rate (AER) ratio versus placebo, analysed by baseline eosinophil counts (≥0, ≥150, ≥300, or ≥450 cells per μL) and by number of exacerbations (two vs three or more) during the year before enrolment. The analyses were done in accordance with the intention-to-treat principle.

Findings

Of 2295 patients, 756 received benralizumab every 4 weeks, 762 received benralizumab every 8 weeks, and 777 patients received placebo. AER among patients with baseline blood eosinophil counts of at least 0 cells per μL was 1·16 (95% CI 1·05–1·28) in patients who received placebo versus 0·75 (0·66–0·84) in patients who received benralizumab every 8 weeks (rate ratio 0·64, 0·55–0·75; p<0·0001). In patients who received benralizumab every 4 weeks who had eosinophil counts of 0 or more cells per μL, AER was 0·73 (0·65–0·82); rate ratio versus placebo was 0·63 (0·54–0·74; p<0·0001). The extent to which exacerbation rates were reduced increased with increasing blood eosinophil thresholds and with greater exacerbation history in patients in the 4-weekly and 8-weekly benralizumab groups. Greater improvements in AER were seen with benralizumab compared with placebo for patients with a combination of high blood eosinophil thresholds and a history of more frequent exacerbations.

Interpretation

These results will help to guide clinicians when they are deciding whether to use benralizumab to treat patients with severe, uncontrolled, eosinophilic asthma.

Funding

AstraZeneca.

Introduction

Despite the prescription of high-dosage inhaled corticosteroids in combination with a second controller drug (including oral corticosteroids), severe asthma often remains uncontrolled.1 Historical estimates suggest that up to 10% of the more than 315 million people worldwide with asthma have severe or uncontrolled disease.2, 3 Patients with severe, uncontrolled asthma have a high disease burden, reduced health-related quality of life, and increased health-care resource use and costs, and are at risk of severe asthma exacerbations.4, 5, 6 Thus, there is an unmet need for additional therapeutic options.4

Eosinophilic inflammation is present in about half of patients with asthma and is associated with increased disease severity, exacerbation frequency, and symptom burden, as well as decreased lung function.7, 8, 9 Consequently, therapeutic approaches that target and reduce eosinophilic inflammation selectively with anti-eosinophilic and anti-interleukin-5 monoclonal antibodies have been shown to be efficacious in reducing exacerbations for patients with evidence of eosinophilic inflammation, as measured by baseline blood eosinophil count.10, 11, 12, 13, 14, 15 An understanding of the relationship between blood eosinophil counts (and other baseline disease state characteristics) and response to treatment is necessary to help to identify which patients are most likely to benefit from these novel therapies.

Benralizumab is a humanised, afucosylated, anti-interleukin-5 receptor α monoclonal antibody 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.16, 17 In combination with high-dosage inhaled corticosteroids plus long-acting β2 agonists (LABAs), this anti-eosinophilic monoclonal antibody significantly reduced asthma exacerbations and improved disease control for patients with severe, uncontrolled asthma and blood eosinophil counts of at least 300 cells per μL in two phase 3 trials, SIROCCO (NCT01928771)10 and CALIMA (NCT01914757).11 In these studies, benralizumab was well tolerated and significantly reduced exacerbations by up to 51%, increased lung function, and improved symptom control.10, 11 More recently, add-on benralizumab was reported to allow significant reduction of oral corticosteroid dosage while maintaining asthma control for patients with asthma dependent on oral corticosteroids.18

Research in context

Evidence before this study

We searched PubMed for English-language clinical trial reports on the use of biologicals that target interleukin 5 or the interleukin-5 receptor to treat people with asthma published from Jan 1, 2007, to May 31, 2017. We used the search terms “asthma” AND “interleukin 5” AND “antibody;” as well as the independent terms “benralizumab;” “mepolizumab;” and “reslizumab”. The search yielded 26 results, including four multicentre, randomised, double-blind, placebo-controlled phase 3 trials of benralizumab for patients with asthma published in 2016–17, three of which were for patients with severe, uncontrolled asthma with eosinophilic inflammation. In these three phase 3 studies, benralizumab significantly reduced the annual exacerbation rate, increased lung function, improved asthma symptoms, and reduced the need for oral corticosteroid therapy relative to placebo, while completely depleting blood eosinophil counts. In a pooled analysis of data from two of these studies, benralizumab demonstrated efficacy for patients with severe asthma and blood eosinophil counts greater than or equal to 150 cells per μL.

Added value of this study

Our results expand the potential population of patients with severe, uncontrolled asthma with eosinophilic inflammation who might be responsive to benralizumab treatment. Patients with blood eosinophil counts greater than or equal to 0 cells per μL who were treated with benralizumab every 4 or 8 weeks for 48–56 weeks had reduced annual exacerbation rate, increased forced expiratory volume in 1 s, and improved asthma symptoms compared with placebo recipients. Furthermore, patients with a history of more frequent exacerbations had greater efficacy with benralizumab treatment than did patients with fewer exacerbations.

Implications of all the available evidence

Our findings illustrate the limitations of clinicians' and regulatory agencies' use of only blood eosinophil counts greater than or equal to 300 cells per μL to identify patients with eosinophilic inflammation and, hence, probable responders to benralizumab treatment for severe, uncontrolled asthma. If available, other biomarkers of eosinophilic inflammation, along with additional clinical characteristics, such as exacerbation history, should be taken into account alongside blood eosinophil counts in decisions about whether a patient might respond to benralizumab treatment.

In this study, we analysed the pooled efficacy results from the SIROCCO and CALIMA studies to better understand the relationship between the clinical efficacy of benralizumab and baseline blood eosinophil counts and exacerbation history. The purpose of this analysis was to help clinicians to develop management strategies for the use of benralizumab to treat patients with severe, uncontrolled, eosinophilic asthma.

Section snippets

Study design and participants

SIROCCO and CALIMA were randomised, double-blind, parallel-group, placebo-controlled, phase 3 studies that enrolled patients at 677 (303 in SIROCCO and 374 in CALIMA) clinical research centres in Africa, Asia, Europe, North America, and South America.10, 11 The designs of the two studies were similar, consisting of an enrolment visit (week −4), a 4-week screening and run-in phase, randomisation (week 0), a treatment period from weeks 0 to 48 (SIROCCO) or 0 to 56 (CALIMA), and a final follow-up

Results

We used pooled results from 1204 patients in SIROCCO and 1091 patients in CALIMA for the analyses. Of these 2295 patients, 756 received 4-weekly benralizumab, 762 received 8-weekly benralizumab, and 777 received placebo. Patients from both studies had similar baseline demographic and clinical characteristics (table 1). In an analysis of demographic and clinical characteristics of patients with baseline eosinophil counts greater than or equal to 300 cells per μL, larger AER reductions and FEV1

Discussion

The results of the SIROCCO and CALIMA studies previously demonstrated that benralizumab, in combination with high-dosage inhaled corticosteroids plus LABAs, significantly improved AER, prebronchodilator FEV1, and total asthma symptom scores compared with placebo for patients with severe, uncontrolled asthma with baseline blood eosinophil counts greater than or equal to 300 cells per μL.10, 11 A subsequent pooled analysis of data from the SIROCCO and CALIMA studies supported the efficacy and

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