Stratified approaches to the treatment of asthma

Abstract

While asthma is a chronic inflammatory disorder that is managed with inhaled controller and reliever drugs, there remains a large unmet need at the severe end of the disease spectrum. Here, a novel stratified approach to its treatment is reviewed, based upon identification of causal pathways, with a focus on biologics. A systematic search of the literature was made using Medline, and publications were selected on the basis of their relevance to the topic. Despite strong preclinical data for many of the more recently identified asthma targets, especially those relating to the T-helper 2 allergic pathway, clinical trials with specific biologics in moderate to severe asthma as a group have been disappointing. However, subgroup analyses based upon pathway-specific biomarkers suggest specific endotypes that are responsive. Application of hypothesis-free analytical approaches (the 'omics') to well-defined phenotypes is leading to the stratification of asthma along causal pathways. Refinement of this approach is likely to be the future for diagnosing and treating this group of diseases, as well as helping to define new causal pathways. The identification of responders and nonresponders to targeted asthma treatments provides a new way of looking at asthma diagnosis and management, especially with biologics that are costly. The identification of novel biomarkers linked to well-phenotyped patients provides a stratified approach to disease management beyond simple disease severity and involving causal pathways. In order to achieve this effectively, a closer interaction will be required between industry (therapeutic and diagnostic), academia and health workers.

Keywords: asthma; biologics; biomarkers; stratification; treatment.

Figure 1

The evolution of inhaled β-adrenoceptor bronchodilators for the treatment of asthma. The discovery of adrenaline in 1901 and its powerful bronchodilator effect, initially when administered by injection but later as a nebulized aqueous aerosol, was to stimulate a relentless search for improved specificity, potency and duration of action. Application of medicinal chemistry and classical structure–activity pharmacology led to the sequential separation of α- (noradrenaline) from β-receptor activity (isoprenaline), followed by the selection of β₂ activity, mediating airway smooth muscle relaxation and anti-bronchoconstriction, from cardiovascular β₁ effects (e.g. salbutamol, turbutaline). The next discovery was to incorporate structural properties that extended the duration of action to 12 h (salmeterol, formoterol) and finally to 24 h (indacaterol) following a single inhalation

Figure 2

Top panel shows results from a randomized controlled trial of oral montelukast (10 μg twice daily) and inhaled beclomethasone (200 μg twice daily) against the asthma outcome measure of morning peak expiratory flow (am-PEF), over 21 days of treatment of moderate asthma. Improvement in am-PEF was more rapid and initially greater with montelukast compared with beclomethasone, but after day 8, the beclomethasone treatment effect surpassed that of montelukast. Bottom panel shows results from the same clinical trial, but displayed as the percentage of individuals achieving changes in peak expiratory flow at week 12, showing the large range of responders and nonresponders for both drugs (Adapted from 53). , beclomethasone (n = 246); , montelukast (n = 375)

Figure 3

Schematic diagram of the interleukin (IL)-4/IL-13 signal transducer and activator of transcription factor (STAT)-6 signalling pathways linked to T-helper 2 (Th2)-type inflammation. Interleukin-4 and IL-13 are recognized by IL-4Rα, a component of the IL-4 type I (IL-4Rα and γC) and type II receptors (IL-4Rα and IL-13Rα₁). Interleukin-4 signals through both type I and type II receptor pathways, whereas IL-13 signals only through the type II IL-4R. Interleukin-13 also binds to the IL-13Rα₂ chain with greater affinity, lacking a transmembrane-signalling domain, but functions to interfere with janus kinase (JAK) 2 activation in the IL-4Rα/ IL-13Rα₁ complex as well as functioning as a decoy receptor to down-regulate IL-13 signalling. γC activates JAK3, while IL-13Rα₁ activates tyrosine kinase 2 (TYK2) and JAK2. Activated JAKs phosphorylate STAT-6 which, upon dimerization, translocates to the nucleus, where it binds to the promoters of the IL-4- and IL-13-responsive genes associated with Th2 cell differentiation, airway inflammation, airway hyperresponsiveness, fibrosis and epithelial mucous metaplasia (Adapted from reference ; reproduced with permission of Trends in Immunology)