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Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials

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Summary

Background

Elevated numbers of blood eosinophils are a risk factor for asthma exacerbations. Reslizumab is a humanised anti-interleukin 5 monoclonal antibody that disrupts eosinophil maturation and promotes programmed cell death. We aimed to assess the efficacy and safety of reslizumab in patients with inadequately controlled, moderate-to-severe asthma.

Methods

We did two duplicate, multicentre, double-blind, parallel-group, randomised, placebo-controlled phase 3 trials. Both trials enrolled patients with asthma aged 12–75 years (from 128 clinical research centres in study 1 and 104 centres in study 2) from Asia, Australia, North America, South America, South Africa, and Europe, whose asthma was inadequately controlled by medium-to-high doses of inhaled corticosteroid based therapy and who had blood eosinophils of 400 cells per μL or higher and one or more exacerbations in the previous year. Patients were randomly assigned (1:1) to receive either intravenous reslizumab (3·0 mg/kg) or placebo every 4 weeks for 1 year by computerised central randomisation. Patients and investigators were masked to treatment assignment during the study. Each patient received a specific volume of study drug (reslizumab or matching placebo) on the basis of the patient's body weight and randomly assigned treatment group. Additionally, the sponsor's clinical personnel involved in the study were masked to the study drug identity until the database was locked for analysis and the treatment assignment revealed. The primary outcome was the annual frequency of clinical asthma exacerbations and was analysed by intention to treat. We assessed safety outcomes in the patients who had received one or more dose of the drug. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT01287039 (study 1) and NCT01285323 (study 2).

Findings

Study 1 was done between April 12, 2011, and March 3, 2014 and study 2 between March 22, 2011, and April 9, 2014. Of 2597 patients screened, 953 were randomly assigned to receive either reslizumab (n=477 [245 in study 1 and 232 in study 2]) or placebo (n=476 [244 and 232]). In both studies, patients receiving reslizumab had a significant reduction in the frequency of asthma exacerbations (study 1: rate ratio [RR] 0·50 [95% CI 0·37–0·67]; study 2: 0·41 [0·28–0·59]; both p<0·0001) compared with those receiving placebo. Common adverse events on reslizumab were similar to placebo. The most common adverse events were worsening asthma symptoms (127 [52%] for placebo and 97 [40%] for reslizumab in study 1; 119 [51%] for placebo and 67 [29%] for reslizumab for study 2), upper respiratory tract infections (32 [13%] and 39 [16%]; 16 [7%] and eight [3%]), and nasopharyngitis (33 [14%] and 28 [11%]; 56 [24%] and 45 [19%]). Two patients in the reslizumab group had anaphylactic reactions; both responded to standard treatment at the study centre and resolved, and the patients were withdrawn from the study.

Interpretation

These results support the use of reslizumab in patients with asthma and elevated blood eosinophil counts who are inadequately controlled on inhaled corticosteroid-based therapy.

Funding

Teva Branded Pharmaceutical Products R&D.

Introduction

Despite the benefits of standard inhaled corticosteroid-based treatment, patients with inadequately controlled asthma remain at risk of asthma exacerbations.1, 2 Eosinophils play a key part in the promotion and maintenance of airway inflammation, airway wall thickening, fibrosis, and angiogenesis (ie, remodelling).3 Increased blood and sputum eosinophil counts are recognised markers of disease severity and have emerged as independent risk factors for future asthma exacerbations.4, 5, 6, 7, 8, 9

Maintenance and activation of eosinophils is dependent on the presence of interleukin 5, the prototypical eosinophil viability-enhancing factor.10 Reduction of interleukin-5-mediated signalling could therefore disrupt the maturation and survival of eosinophils and might thereby contribute to asthma symptom control and reduced airway inflammation, and could potentially help to prevent remodelling. Two different anti-interleukin-5 treatments (one antibody against interleukin 5 and another against the interleukin-5 receptor) reduced exacerbations in patients with clinical features of severe, refractory eosinophilic asthma.11, 12, 13, 14

Reslizumab is an investigational, IgG4k humanised, monoclonal antibody against interleukin 5.15, 16, 17, 18, 19, 20 Preclinical properties of reslizumab, including high interleukin-5-binding affinity, potent inhibition of interleukin-5 activity and associated lung eosinophilia were suggestive of potential clinical activity and underpinned the subsequent clinical trial programme for an intravenous formulation.15, 16, 17, 18, 19, 20 Short-term clinical efficacy of reslizumab was subsequently shown in patients with demonstrable sputum eosinophilia (≥3%) in a phase 2 trial.13

Here, we report two identically designed, 52-week, phase 3 trials (referred to as studies 1 and 2), which were done to assess the efficacy and safety of intravenous reslizumab in patients with inadequately controlled, moderate-to-severe asthma and elevated blood eosinophil counts.

Section snippets

Study design and participants

We did two duplicate, international, double-blind, parallel-group, randomised, placebo-controlled trials. Both trials enrolled patients aged 12–75 years (128 clinical research centres in study 1 and 104 centres in study 2) from Asia, Australia, North America, South America, South Africa, and Europe, with at least one blood eosinophil count of 400 cells per μL or higher during a 2–4 week screening period and inadequately controlled asthma (Asthma Control Questionnaire-7 [ACQ-7] score ≥1·5)21 who

Results

Study 1 was done between April 12, 2011, and March 3, 2014, and study 2 between March 22, 2011, and April 9, 2014. Across both studies, we screened 2597 patients, of whom 489 were randomly assigned to receive either reslizumab (n=245) or placebo (n=244) in study 1, and 464 were randomly assigned to receive either reslizumab (n=232) or placebo (n=232) in study 2 (intention-to-treat populations; figure 1). Of the 1644 patients not included in the trial after screening, 1472 did not meet the

Discussion

The results of these identical, parallel studies show that reslizumab significantly improved outcomes in patients with inadequately controlled asthma and a blood eosinophil concentration of 400 cells per μL or more. These results were achieved despite the continued use of previous asthma treatments throughout the studies. In the primary analysis, reslizumab significantly reduced the annual rate of clinical asthma exacerbations by 50–59% compared with placebo (more than 80% of overall clinical

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