Eosinophilia in respiratory disease: can evidence in asthma translate to successful development in COPD?
By Natasha Spiller, Analyst
2 July 2014
I am an Analyst at Datamonitor Healthcare. After joining the company in 2012, I have produced analysis across a number o...
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Eosinophilia can serve as a risk marker for exacerbations in COPD
Dr Marjan Kerkhof from Research in Real Life presented results at the Respiratory Effectiveness Group Summit 2014 that demonstrated an association between blood eosinophilia and an increased exacerbation risk in non-smoking chronic obstructive pulmonary disease (COPD) patients receiving an inhaled corticosteroid (ICS). While eosinophilia airway inflammation can be a characteristic of asthma, the relationship between eosinophilia and COPD symptoms is less clear, and this research attempted to tease out associations between blood eosinophil levels and patient outcomes in COPD.
The research presented by Dr Kerkhof analyzed the outcomes of two patient groups in an observational study of patients with COPD from the Optimum Patient Care Research Database. The first patient group comprised of patients who had no exacerbations four weeks before or after a blood eosinophil measurement. The second patient group comprised of patients who had repeated eosinophil measurements, and who were followed-up for a median time of six years. COPD exacerbations were defined as an acute course of oral steroid or antibiotics prescribed at a lower respiratory consultation or COPD-related hospital admission/accident and emergency attendance.
Blood eosinophilia (defined as ≥450 cells/microliter) was identified in 10% of 13,780 patients. Of these patients, 37% had experienced ≥1 COPD exacerbation following a blood eosinophil measurement. Among non-smoking patients receiving an ICS, blood eosinophilia was associated with a 24% higher exacerbation rate (relative risk: 1.24 (1.10–1.41)). However, this association was not observed in patients who are current smokers or in patients without maintenance inhaler therapy. Importantly, the association with exacerbation rate did not change when patients with any diagnosis of asthma were removed from the analysis, indicating that asthma diagnosis did not impact this outcome. Data from the second patient group indicated that 26% of patients had eosinophilia at some stage during the follow-up period.
The results presented at the summit indicate that eosinophilia may be associated with a risk of exacerbation in COPD within a specific population subset, and add to the body of evidence for an association between eosinophils and COPD exacerbations. A study published by Siva et al. in 2007 also revealed an association. The randomized controlled study of 82 patients with COPD indicated that a treatment strategy aimed at reducing eosinophil airway inflammation can lead to a significant reduction in the frequency of COPD exacerbations. Within this study, patients were either randomized to receive treatment as per British Thoracic Society (BTS) management group protocol or randomized to a protocol designed to minimize eosinophilic airway inflammation (sputum management group). The mean frequency of severe exacerbations per year among patients in the BTS management group was 0.5 (0.3–0.8) compared to 0.2 (0.1–0.4) in the sputum management group. Severe exacerbations were significantly reduced in the sputum management group compared to the BTS management group (p=0.037).
Targeting eosinophilia could provide opportunities to move beyond inhaled treatment for COPD
The pharmaceutical industry has recognized the need to differentiate therapies in COPD in an increasingly saturated and mature market. Developing therapies that treat patients with eosinophilia in COPD is one such measure to differentiate pipeline products. GlaxoSmithKline and AstraZeneca are both developing monoclonal antibodies which will be positioned to treat patients who are exhibiting eosinophilia in COPD. Although studies have yet to provide conclusive evidence regarding the clinical benefit of monoclonal antibodies, this area of research nonetheless represents an opportunity to move beyond inhaled treatments and start addressing underlying physiological mechanisms in COPD.
AstraZeneca is developing benralizumab, a monoclonal anti-interleukin-5 antibody that is currently in Phase II development for COPD. Phase II efficacy results have demonstrated that benralizumab can reduce both peripheral and sputum eosinophils, and improve lung function. However, the study failed to demonstrate that benralizumab can significantly reduce the exacerbation rate in patients with COPD.
Data from a Phase II study of benralizumab in COPD were released at the American Thoracic Society conference, held in San Diego in May 2014. The study involved 101 patients with COPD who had ≥3% sputum eosinophils and who were randomized to receive either placebo or benralizumab. The primary endpoint of the study, which was measured by the rate of moderate to severe acute exacerbations of COPD (AECOPD), was not met. The AECOPD rates of the benralizumab and placebo treatment arms were 0.98 and 0.97 respectively (p=0.913). However, treatment with benralizumab did lead to a statistically significant improvement in pre-bronchodilator forced expiratory volume in one second (FEV1) compared to placebo (p=0.012).
The data were further stratified according to blood eosinophil levels. Patients with blood eosinophil levels of ≥200 cells/microliter or ≥300 cells/microliter demonstrated the greatest improvement in the severe acute exacerbation rate and pre-bronchodilator FEV1. Patients with blood eosinophil levels of Progression to Phase III development is anticipated soon, where the candidate will be evaluated in a Phase III study to assess its efficacy and safety in moderate to very severe patients with COPD (ClinicalTrials.gov identifier: NCT02155660).
GlaxoSmithKline is developing Bosatria (mepolizumab), a monoclonal anti-interleukin-5 antibody, which is currently undergoing evaluation in three Phase III efficacy and safety studies in patients with COPD. Currently, there are no clinical data available regarding the efficacy of Bosatria in COPD.
Phase III clinical development program of Bosatria (mepolizumab; GlaxoSmithKline) in COPD
|Phase (ClinicalTrials.gov identifier)||Sample size||Target patients||Study design||Dosing tested and duration||Primary outcome measure|
|III (NCT01463644)||40||Patients with COPD and eosinophilia bronchitis||Randomized, double-blind, parallel-group study||Mepolizumab (750mg IV) once monthly; placebo
|Percentage decrease of sputum eosinophils from baseline|
|III (NCT02105948)||800||Patients with COPD who have experienced at least two moderate COPD exacerbations or one severe COPD exacerbation in the prior 12 months||Randomized, double-blind, parallel-group study||Mepolizumab (100mg SC) every four weeks in addiction to optimized standard of care; placebo
|Frequency of moderate/severe exacerbations|
|III (NCT02105961)||660||Patients with COPD who have experienced at least two moderate COPD exacerbations or one severe COPD exacerbation in the prior 12 months||Randomized, double-blind, parallel-group study||Mepolizumab (100mg SC) every four weeks; mepolizumab (300mg SC) every four weeks; placebo
|Frequency of moderate/severe exacerbations|
|COPD = chronic obstructive pulmonary disease; IV = intravenous; SC = subcutaneous|
New biologics for respiratory disease will emerge first for severe eosinophilic asthma
The clinical development of Bosatria and benralizumab in asthmatic populations has yielded more promising efficacy data. The clinical program for Bosatria in asthma and a Phase II study of AstraZeneca’s benralizumab signify the clinical potential for these biologics. Asthma is expected to become the first licensed indication for these biologics, since data exhibit more promise for both a symptomatic and physiologic improvement in asthma. However, Datamonitor Healthcare believes that the labelled indication for these therapies will be very narrow, restricting their prescription to patients with severe eosinophilic asthma.
GlaxoSmithKline has reported positive results from the Phase III clinical program for Bosatria, which has shown that the therapy can significantly reduce the frequency of clinically significant exacerbations in patients with severe eosinophilic asthma, as well as reduce the dose of daily oral corticosteroid required for maintenance control in asthma. In the Phase II DREAM study of Bosatria, the therapy was shown to significantly reduce the number of exacerbations per patient per year compared to placebo in patients with a history of recurrent severe asthma exacerbations, who also had signs of eosinophilic inflammation.
Phase II results for benralizumab in asthma have shown that the antibody can significantly reduce the asthma exacerbation rate compared to placebo in patients with severe uncontrolled eosinophilic asthma, alongside reducing blood eosinophil counts. Phase III development of the therapy in patients with uncontrolled asthma is ongoing.
Posted in Analyst Opinion.