Elsevier

The Lancet

Volume 372, Issue 9643, 20–26 September 2008, Pages 1073-1087
The Lancet

Review
New targets for drug development in asthma

https://doi.org/10.1016/S0140-6736(08)61449-XGet rights and content

Summary

Asthma is a chronic inflammatory disease that affects about 300 million people worldwide, a total that is expected to rise to about 400 million over the next 15–20 years. Most asthmatic individuals respond well to the currently available treatments of inhaled corticosteroids and β-adrenergic agonists; however, 5–10% have severe disease that responds poorly. Improved knowledge of asthma mechanisms has led to the recognition of different asthma phenotypes that might reflect distinct types of inflammation, explaining the effectiveness of anti-leucotrienes and the anti-IgE monoclonal antibody omalizumab in some patients. However, more knowledge of the inflammatory mechanisms within the airways is required. Improvements in available therapies—such as the development of fast-onset, once-a-day combination drugs with better safety profiles—will occur. Other drugs, such as inhaled p38 MAPK inhibitors and anti-oxidants, that target specific pathways or mediators could prove useful as monotherapies, but could also, in combination with corticosteroids, reduce the corticosteroid insensitivity often seen in severe asthma. Biological agents directed against the interleukin-13 pathway and new immunoregulatory agents that modulate functions of T-regulatory and T-helper-17 cells are likely to be successful. Patient-specific treatments will depend on the development of discriminatory handprints of distinct asthma subtypes and are probably over the horizon. Although a cure is unlikely to be developed in the near future, a greater understanding of disease mechanisms could bring such a situation nearer to reality.

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

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

References (142)

  • H Schacke et al.

    Selective glucocorticoid receptor agonists (SEGRAs): novel ligands with an improved therapeutic index

    Mol Cell Endocrinol

    (2007)
  • BJ Nevin et al.

    Comparative effects of inhaled budesonide and the NO-donating budesonide derivative, NCX 1020, against leukocyte influx and airway hyperreactivity following lipopolysaccharide challenge

    Pulm Pharmacol Ther

    (2004)
  • SE Dahlen

    Treatment of asthma with antileukotrienes: first line or last resort therapy?

    Eur J Pharmacol

    (2006)
  • DA Medina-Tato et al.

    Leukocyte navigation mechanisms as targets in airway diseases

    Drug Discov Today

    (2006)
  • AJ Ravensberg et al.

    Eotaxin-2 and eotaxin-3 expression is associated with persistent eosinophilic bronchial inflammation in patients with asthma after allergen challenge

    J Allergy Clin Immunol

    (2005)
  • PJ Barnes

    New molecular targets for the treatment of neutrophilic diseases

    J Allergy Clin Immunol

    (2007)
  • MJ Leckie et al.

    Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response

    Lancet

    (2000)
  • LC Borish et al.

    Efficacy of soluble IL-4 receptor for the treatment of adults with asthma

    J Allergy Clin Immunol

    (2001)
  • K Tomita et al.

    Attenuated production of intracellular IL-10 and IL-12 in monocytes from patients with severe asthma

    Clin Immunol

    (2002)
  • S Lim et al.

    Haplotype associated with low interleukin-10 production in patients with severe asthma

    Lancet

    (1998)
  • SA Bryan et al.

    Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response

    Lancet

    (2000)
  • V Norris et al.

    Effect of IVL745, a VLA-4 antagonist, on allergen-induced bronchoconstriction in patients with asthma

    J Allergy Clin Immunol

    (2005)
  • W Feleszko et al.

    Toll-like receptors—novel targets in allergic airway disease (probiotics, friends and relatives)

    Eur J Pharmacol

    (2006)
  • DB Solit et al.

    Development and application of Hsp90 inhibitors

    Drug Discov Today

    (2008)
  • IM Adcock et al.

    Kinase inhibitors and airway inflammation

    Eur J Pharmacol

    (2006)
  • LB Li et al.

    Superantigen-induced corticosteroid resistance of human T cells occurs through activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK-ERK) pathway

    J Allergy Clin Immunol

    (2004)
  • AR Sousa et al.

    In vivo resistance to corticosteroids in bronchial asthma is associated with enhanced phosyphorylation of JUN N-terminal kinase and failure of prednisolone to inhibit JUN N-terminal kinase phosphorylation

    J Allergy Clin Immunol

    (1999)
  • P Nath et al.

    Potential role of c-Jun NH2-terminal kinase in allergic airway inflammation and remodelling: effects of SP600125

    Eur J Pharmacol

    (2005)
  • EO Meltzer et al.

    An intranasal Syk-kinase inhibitor (R112) improves the symptoms of seasonal allergic rhinitis in a park environment

    J Allergy Clin Immunol

    (2005)
  • M Masoli et al.

    The global burden of asthma: executive summary of the GINA Dissemination Committee report

    Allergy

    (2004)
  • PJ Barnes et al.

    The costs of asthma

    Eur Respir J

    (1996)
  • KF Chung et al.

    Difficult/therapy-resistant asthma: the need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies

    Eur Respir J

    (1999)
  • ST Holgate

    Pathogenesis of asthma

    Clin Exp Allergy

    (2008)
  • PJ Barnes

    Inhaled glucocorticoids for asthma

    N Engl J Med

    (1995)
  • R Horne

    Compliance, adherence, and concordance: implications for asthma treatment

    Chest

    (2006)
  • KF Chung et al.

    Combination therapy of long-acting beta2-adrenoceptor agonists and corticosteroids for asthma

    Treat Respir Med

    (2004)
  • DS Postma et al.

    Inhaled corticosteroids and long-acting beta-agonists in adult asthma: a winning combination in all?

    Naunyn Schmiedebergs Arch Pharmacol

    (2008)
  • ED Bateman et al.

    Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study

    Am J Respir Crit Care Med

    (2004)
  • MF Moffatt et al.

    Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma

    Nature

    (2007)
  • The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. European Network for Understanding Mechanisms of Severe Asthma

    Eur Respir J

    (2003)
  • N Kamel et al.

    The Innovative Medicines Initiative (IMI): a new opportunity for scientific collaboration between academia and industry at the European level

    Eur Respir J

    (2008)
  • L Cohen et al.

    Epithelial cell proliferation contributes to airway remodeling in severe asthma

    Am J Respir Crit Care Med

    (2007)
  • AR Brasier et al.

    Molecular phenotyping of severe asthma using pattern recognition of bronchoalveolar lavage-derived cytokines

    J Allergy Clin Immunol

    (2008)
  • P Haldar et al.

    Cluster analysis and clinical asthma phenotypes

    Am J Respir Crit Care Med

    (2008)
  • SE Wenzel et al.

    Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics

    Am J Respir Crit Care Med

    (1999)
  • MG Matera et al.

    Ultra-long-acting beta2-adrenoceptor agonists: an emerging therapeutic option for asthma and COPD?

    Drugs

    (2007)
  • H Derendorf

    Pharmacokinetic and pharmacodynamic properties of inhaled ciclesonide

    J Clin Pharmacol

    (2007)
  • OS Usmani et al.

    Glucocorticoid receptor nuclear translocation in airway cells after inhaled combination therapy

    Am J Respir Crit Care Med

    (2005)
  • HM Reichardt et al.

    Repression of inflammatory responses in the absence of DNA binding by the glucocorticoid receptor

    EMBO J

    (2001)
  • JN Miner et al.

    Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein-protein interaction profile

    Proc Natl Acad Sci USA

    (2007)
  • Cited by (213)

    View all citing articles on Scopus
    View full text