We undertook a detailed appraisal of peer-reviewed publications over the past 10 years with the NCBI PubMed website for English language publications with the keywords: “asthma”, in combination with “treatment”, “novel therapy”, “glucocorticoid insensitivity”, “new drugs”, “steroid-sparing”, “severe”, “immunomodulation”, and “unmet need”. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant. We also had source
ReviewNew targets for drug development in asthma
Introduction
Asthma is one of the most common chronic inflammatory diseases, affecting about 300 million people worldwide, a total that is expected to rise by an additional 100 million—mainly in children—over the next 15–20 years.1 Asthma accounts for about one out of every 250 deaths worldwide and has profound health-care costs in terms of emergency room visits and hospitalisations. Asthma also has enormous indirect costs and is one of the leading causes of work and school absenteeism.2 Most patients with asthma respond well to current treatments; however, 5–10% of patients have severe disease that often fails to respond to conventional therapy; these patients account for more than 50% of the total health-care costs associated with asthma.3
By understanding the different types of airway inflammation in various subtypes of asthma, it should be possible to address some of the important questions in asthma research: which triggers or factors underlie airway smooth muscle hyper-responsiveness? What are the processes (genetic or environmental) that underlie different subtypes of asthma? Which aspects of airway remodelling are important in disease subtypes? What are the best biomarkers of disease progression or treatment response? Why are some patients less responsive to conventional therapies than are others? It is now recognised that there are distinct asthma phenotypes4 and that distinct therapeutic approaches may only impinge on some aspects of the disease process, or at least outcome measures, within each subgroup. Thus, treatments might affect exacerbation rates without altering day-to-day symptoms or lung function, reflecting the fact that distinct cells or mediators in the lung could drive airway hyper-responsiveness or specific inflammatory components, and that treatments directed at a single cell or mediator might only affect a single aspect of disease.5 The current reductionist approach to understanding the disease has led to the development of drugs that target specific pathways or mediators. In the future, we may need to target and assess several outcome measures and biomarkers simultaneously, and undertake subgroup analyses of the responses obtained when assessing combinations of new drugs.
Section snippets
Current asthma treatments
Initial approaches to treat asthma emphasised the relief of bronchoconstriction with bronchodilators, particularly β2-adrenergic agonists, but the discovery of airway inflammation as an important pathophysiological component of asthma has led to the use of inhaled corticosteroids as the mainstay of asthma therapy6—these drugs are the most effective anti-inflammatory treatment available for asthma. Asthmatic inflammation is characterised by eosinophilia, mast cell infiltration, and activation of
The need for new therapies
Combinations of inhaled corticosteroids and long-acting β2 agonists are effective in most (about 90%), but not all, asthmatic individuals.14 Indeed, even patients whose asthma is apparently well controlled by existing therapies might benefit from more efficacious therapies that are easier to comply with.11 Surprisingly, telephone surveys of asthmatic patients have reported a high degree of morbidity among patients who report that their asthma was controlled,11 which could reflect either a lack
New longer-acting bronchodilators
The long-acting β2 agonists salmeterol and formoterol have a 12-h bronchodilator effect and, in conjunction with inhaled corticosteroids, improve asthma control and reduce exacerbation rates.25 Several ultra-long-acting β2 agonists that are under development, including indacaterol, carmoterol (Chiesi Farmaceutici, Italy), and GSK159797, act for more than 24 h, are fast acting, and are suitable for once-daily dosing.26 It is also possible to increase the duration of action of inhaled
Infections
Respiratory viral and bacterial infections are a major cause of asthma exacerbations.1 Therefore, antibiotics and antivirals may be beneficial for asthma exacerbations. Telithromycin, a macrolide antibiotic, caused a small but significant reduction in asthma symptoms without changes in lung function compared with placebo when administered to patients with acute exacerbations of asthma.74 Additionally, clarithromycin can reduce levels of interleukin 8 and sputum neutrophilia and can improve
Oxidative stress
Oxidative stress has been implicated as a driving force behind the inflammatory response and lack of corticosteroid sensitivity in severe asthma.123 Moreover, oxidative stress and its byproducts may drive a Th2-dependent immune response.124 Anti-oxidants including N-acetylcysteine, nacystelyn, and the superoxide dismutase mimetic AEOL 10150 (Aeolus Pharmaceuticals, USA) are able to restore corticosteroid functions that were reduced in response to cigarette smoke or other oxidative stresses in
Immunomodulation and anti-allergy treatments
Since asthmatic patients are often atopic, much effort has been directed at modulating the allergic response (figure 1). IgE is the immunoglobulin that mediates the acute allergic response in mast cells and basophils through cross-linking of high-affinity IgE receptors, and may increase allergen uptake by dendritic cells. A humanised monoclonal antibody that binds to IgE (omalizumab) has been introduced for the treatment of severe allergic asthma. Omalizumab is a useful add-on therapy in some
Conclusions
Several new treatments are now under development for mild or moderate asthma but many of them are highly specific, targeting a single receptor, enzyme, or mediator, and are unlikely to have a major clinical impact. New treatments also have a high barrier to overcome in that combination therapy is efficacious and it is likely that once-a-day, fast-onset combinations of long-acting β agonists and steroids will be available soon. Because of the overexpression of interleukin 13 in asthma and its
Search strategy and selection criteria
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