Why inflammatory phenotyping is necessary for successful drug evaluation in asthma and COPD

Abstract

@ERSpublicationsPathway specific drug trials must account for prevalence of the pathway by subject selection or by adjusting sample size http://ow.ly/nx4k9Identifying and treating the eosinophilic subtype of asthma has now achieved renewed importance for clinicians and scientists involved in clinical trials. This has happened following the near-demise of an antiinterleukin (IL)-5 monoclonal antibody (mepolizumab) as a candidate for asthma treatment [1] and its resurrection in trials based around using induced sputum eosinophils to identify a treatment responsive phenotype [2,3]. The improvement in outcome was spectacular. An effect size close to zero was converted to a massive effect size of a 50% reduction in asthma exacerbations, simply by using assessment of clinical status and eosinophils to identify a treatment responsive phenotype. The spotlight is now firmly on clinical trial design in airway diseases and how to identify disease subtypes for testing new therapies. An article by DASGUPTA et al. [4], in this issue of the European Respiratory Journal, addresses this issue by reporting a systematic review of the use of one biomarker, sputum eosinophils, in randomised controlled trials over the past 10 years, and assesses the implications for study design, analysis and sample size in particular.For a long time, asthma pharmacotherapy has been based around b 2 -agonists and corticosteroids, which are regularly reformulated to tweak their clinical efficacy. The promise of new blockbuster treatments has remained both a hope and a necessity, but elusive. Basic scientists have elucidated pathobiological pathways in asthma and, in collaboration with pharmaceutical chemists and immunobiologists, pathway specific treatments have been developed. Once a drug passes the safety hurdle, the next step has been for clinical trials to demonstrate drug efficacy in people with asthma, a phase 3 trial. While every step in this chain is critical, by the time a drug is ready for phase 3 trials, the intellectual and financial investment has been massive and an error at this stage is particularly costly. It is against this background that we need to view modern drug development in asthma and chronic obstructive pulmonary disease (COPD).What we have learnt from the mepolizumab story is that drugs designed to target a very specific pathway actually target a very specific pathway. If that pathway is not important in the people tested, then the drug has little or no effect. The logical next step is to ask how these pathways and their importance, i.e. clinical relevance, can be identified. Part of the answer lies in the use of biomarkers. The principle of this approach is to use a biomarker to identify the people in whom the pathobiological pathway is active, termed an endotype [5], and then treat them with the pathway specific therapy. We are seeing a technological revolution in biomarker discovery, with the application of 'omics technologies to this area. A recent example is the use of periostin, a serum biomarker identified using tran...

Importance of concomitant local and systemic eosinophilia in uncontrolled asthma

“…In addition it was reassuring that the patients for whom the clinician did not feel the need to prescribe an ICS after their asthma clinic visit, did not report any exacerbation in the following year. This suggests that using the mere cell count to assess inflammation in clinical practice may still carry some value and help phenotype asthma patients [9]. This assumption was indeed further supported by the DREAM study results where the efficacy of mepolizumab was partly dependent on the blood eosinophil count [10].…”

Identification of responders to inhaled corticosteroids in a chronic obstructive pulmonary disease population using cluster analysis

“… 24–26 Earlier work focused on sputum eosinophils, but blood eosinophils are now being accepted as an alternative measurement that is more practical to use in a clinical setting. 27 28 The clinical relevance of the 2.4% cut-off in blood eosinophil levels requires additional exploration; however, it lies between the 3% value commonly used to define sputum eosinophilia 8 22 29 and the 2% value that was identified as a relevant cut-off point in patients with COPD based on an analysis of the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End points (ECLIPSE) cohort. 30 No minimal clinically important difference has yet been defined for eosinophilia in COPD, 29 but clinically meaningful differences have been found in other studies and analyses based on either a 2% or 2.5% cut-off.…”

“… 27 28 The clinical relevance of the 2.4% cut-off in blood eosinophil levels requires additional exploration; however, it lies between the 3% value commonly used to define sputum eosinophilia 8 22 29 and the 2% value that was identified as a relevant cut-off point in patients with COPD based on an analysis of the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End points (ECLIPSE) cohort. 30 No minimal clinically important difference has yet been defined for eosinophilia in COPD, 29 but clinically meaningful differences have been found in other studies and analyses based on either a 2% or 2.5% cut-off. 3 16 20 23 In particular, this work complements the post hoc subgroup analysis of the same clinical trials of FF/VI versus VI that was conducted by Pascoe et al 23 That analysis found that patients with COPD with blood eosinophils ≥2% at baseline experienced a reduction in exacerbation rates of 29% (p<0.001) when treated with FF/VI (all strengths) versus VI alone; the corresponding reduction in patients with eosinophils <2% was 10% (p=0.283).…”

Importance of concomitant local and systemic eosinophilia in uncontrolled asthma

“…Our approach was therefore different from that used in hierarchical unsupervised cluster analysis. We do not deny the great interest of this type of cluster analysis in the emergence of clinical asthma phenotypes, but we believe that classifying asthmatics according to their eosinophilic profile is useful because sputum and blood eosinophils are good biomarkers to target treatment and predict response to corticoids or biologicals directed towards Th2 cytokines [37,38]. Furthermore, it has recently been advocated that sputum eosinophils may be a valuable outcome in asthma drug trials [37].…”