2012 Research Highlights
Despite the availability of effective and safe drugs to treat asthma,1 the most important of which are inhaled corticosteroids, either alone or in combination with long-acting inhaled β2-agonists, many patients have poorly controlled asthma.2 The most important reason for poor disease control is low adherence to treatment regimens. However, a subset of asthmatic patients do not achieve well-controlled asthma despite treatment with optimum doses of drugs, and are at high risk of severe exacerbations. These patients are regarded as severe refractory asthmatics, and represent 5–10% of all patients with asthma.3 In 2012, several reports were published of new treatment approaches for patients with asthma, including for patients with severe refractory asthma. The new treatments involve targeted therapy against specific inflammatory cell types thought to be important in asthma persistence or in severe asthma exacerbations. One of these new approaches was developed as a result of the identification of a population of patients with severe refractory asthma and persistent airway eosinophilia. Previous studies have suggested that inhibition of airway eosinophilia with mepolizumab, a humanised monoclonal antibody against interleukin-5, reduced the risk of severe asthma exacerbations. In a subsequent double-blind, placebo-controlled trial, investigators reported the effects of mepolizumab treatment in 621 patients with a history of recurrent severe asthma exacerbations and evidence of eosinophilic inflammation.4 Patients were given one of three different doses of intravenous mepolizumab or placebo during the course of a year. The rate of severe asthma exacerbations was reduced by between 39% and 52% with mepolizumab treatment, with no evidence of increased benefit with higher treatment doses. However, mepolizumab administration did not substantially improve other asthma outcomes, such as lung function or asthma control. Despite the success of a focused treatment approach for patients with persisting airway eosinophilia, investigators have identified that about half of patients with mild-to-moderate asthma have persistent noneosinophilic airway inflammation, which is often neutrophilic.5 However, whether neutrophils contribute to poor asthma control, or to exacerbations, is unclear. Neutrophil migration is mediated partly by activation www.thelancet.com/respiratory Vol 1 March 2013
of the chemokine receptor CXCR2, which is a G-proteincoupled receptor amenable to antagonism by lowmolecular-weight antagonists and by several agonists, including interleukin-8, growth-regulated oncogene α, and growth-regulated oncogene β. One antagonist (SCH527123) was studied in a small, randomised, double-blind, 4-week study of 32 patients with severe refractory asthma and airway neutrophilia.6 Treatment with SCH527123 substantially reduced the amount of both blood and sputum neutrophils, with a notable decrease in mild exacerbations and a trend towards improvement in asthma control questionnaire score. These results suggest that airway neutrophils might have a role in the persistence of severe refractory asthma in some patients, but larger studies of longer duration are needed to assess their effect on other asthma outcomes, including severe exacerbations. CRTH2 is another G-protein-coupled receptor that has been implicated in asthma, through the activation of T-helper 2 lymphocytes, eosinophils, and basophils by prostaglandin D2. In a double-blind, placebo-controlled, 28-day study, investigators assessed the potential benefit of a selective CRTH2 antagonist (OC000459) in asthma.7 By contrast with the studies described previously, the patients enrolled in this trial were not using regular inhaled corticosteroids to manage their asthma. Treatment with the antagonist significantly improved the forced expiratory volume in 1 s compared with placebo (9·2% vs 1·8%, p=0·037), but only in the per-protocol population. Substantial improvements in quality-of-life scores and night-time symptoms were also recorded. The magnitude of clinical benefit is probably smaller than that which would be seen with low doses of inhaled corticosteroids in this patient population; additional larger studies of longer duration will be necessary to clarify whether this treatment approach will be useful in asthma. Another new treatment approach for patients with asthma who are uncontrolled while on treatment with combinations of inhaled corticosteroids and long-acting β2-agonists has been the assessment of inhaled long-acting muscarinic antagonists, which are a mainstay of treatment for chronic obstructive pulmonary disease but have not yet been shown to be useful in asthma. In two replicate, randomised,
Ian Hooton/Science Photo Library
Asthma: management of severe disease
Published Online January 14, 2013 http://dx.doi.org/10.1016/ S2213-2600(12)70062-0
e3
2012 Research Highlights
placebo-controlled trials, the benefit of the longacting muscarinic antagonist tiotropium for 48 weeks compared with placebo was investigated, when added to combination therapy treatment, in terms of its effect on lung function and asthma exacerbations.8 Treatment with tiotropium substantially improved the trough (pre-dose) forced expiratory volume in 1 s from baseline in both studies when compared with placebo, and substantially reduced the risk of severe asthma exacerbations. Thus, tiotropium will probably be a useful third-line drug to add to the combination of inhaled corticoisteroids and long-acting β2-agonists in these patient populations. The US Food and Drug Administration has recommended the withdrawal of long-acting β2-agonists from treatment combinations of inhaled corticosteroids and long-acting β2-agonists when asthma is controlled by the combination treatment, because of concerns about their safety. However, the results of a metaanalysis did not favour this step-off approach.9 When long-acting β2-agonists were discontinued, asthma quality of life and asthma control deteriorated, the number of symptom-free days decreased, and the risk of withdrawal increased due to low efficacy. These findings suggest that cessation of long-acting β2-agonist treatment and maintenance of inhaled corticosteroids alone, while patients still need moderate-to-high-dose combination treatment for asthma control, should not be recommended. These studies offer future hope for the management of severe refractory asthma. The studies of mepolizumab and the CXCR2 antagonist suggest that phenotyping of patients on the basis of airway inflammatory cell type will be useful for the decision of whether to start treatment with these compounds. The value of CRTH2 antagonists in asthma management is unclear. Tiotropium will probably be used as an add-on
e4
to inhaled corticosteroids and long-acting β2-agonists, since most patients with severe refractory asthma have airflow obstruction. Finally, if asthma control is achieved from treatment with inhaled corticosteroids and long-acting β2-agonists, the long-acting β2-agonist component should not be discontinued until asthma control is maintained with the lowest doses of the combination treatment. *Paul M O’Byrne, Nizar Naji Firestone Institute of Respiratory Health, St Joseph’s Healthcare and Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON, Canada [email protected] PMO’B has been on advisory boards for AIM, Asmacure, AstraZeneca, Boehringer, GlaxoSmithKline, and Merck, and has received lecture fees from these and other pharmaceutical companies, including Chiesi. Additionally, he has received grants-in-aid for research studies from AIM, Amgen, AstraZeneca, Genentech, GlaxoSmithKline, Novartis, and Ono. NN declares that he has no conflicts of interest. 1
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Bateman ED, Hurd SS, Barnes PJ, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 2008; 31: 143–78. Demoly P, Annunziata K, Gubba E, Adamek L. Repeated cross-sectional survey of patient-reported asthma control in Europe in the past 5 years. Eur Respir Rev 2012; 21: 66–74. Bousquet J, Mantzouranis E, Cruz AA, et al. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol 2010; 126: 926–38. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012; 380: 651–59. McGrath KW, Icitovic N, Boushey HA, et al. A large subgroup of mild-tomoderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med 2012; 185: 612–19. Nair P, Gaga M, Zervas E, et al. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial. Clin Exp Allergy 2012; 42: 1097–103. Barnes N, Pavord I, Chuchalin A, et al. A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma. Clin Exp Allergy 2012; 42: 38–48. Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 2012; 367: 1198–207. Brozek JL, Kraft M, Krishnan JA, et al. Long-acting beta2-agonist step-off in patients with controlled asthma: systematic review with meta-analysis. Arch Intern Med 2012; 172: 1365–75.
www.thelancet.com/respiratory Vol 1 March 2013
Despite the availability of effective and safe drugs to treat asthma,1 the most important of which are inhaled corticosteroids, either alone or in combination with long-acting inhaled β2-agonists, many patients have poorly controlled asthma.2 The most important reason for poor disease control is low adherence to treatment regimens. However, a subset of asthmatic patients do not achieve well-controlled asthma despite treatment with optimum doses of drugs, and are at high risk of severe exacerbations. These patients are regarded as severe refractory asthmatics, and represent 5–10% of all patients with asthma.3 In 2012, several reports were published of new treatment approaches for patients with asthma, including for patients with severe refractory asthma. The new treatments involve targeted therapy against specific inflammatory cell types thought to be important in asthma persistence or in severe asthma exacerbations. One of these new approaches was developed as a result of the identification of a population of patients with severe refractory asthma and persistent airway eosinophilia. Previous studies have suggested that inhibition of airway eosinophilia with mepolizumab, a humanised monoclonal antibody against interleukin-5, reduced the risk of severe asthma exacerbations. In a subsequent double-blind, placebo-controlled trial, investigators reported the effects of mepolizumab treatment in 621 patients with a history of recurrent severe asthma exacerbations and evidence of eosinophilic inflammation.4 Patients were given one of three different doses of intravenous mepolizumab or placebo during the course of a year. The rate of severe asthma exacerbations was reduced by between 39% and 52% with mepolizumab treatment, with no evidence of increased benefit with higher treatment doses. However, mepolizumab administration did not substantially improve other asthma outcomes, such as lung function or asthma control. Despite the success of a focused treatment approach for patients with persisting airway eosinophilia, investigators have identified that about half of patients with mild-to-moderate asthma have persistent noneosinophilic airway inflammation, which is often neutrophilic.5 However, whether neutrophils contribute to poor asthma control, or to exacerbations, is unclear. Neutrophil migration is mediated partly by activation www.thelancet.com/respiratory Vol 1 March 2013
of the chemokine receptor CXCR2, which is a G-proteincoupled receptor amenable to antagonism by lowmolecular-weight antagonists and by several agonists, including interleukin-8, growth-regulated oncogene α, and growth-regulated oncogene β. One antagonist (SCH527123) was studied in a small, randomised, double-blind, 4-week study of 32 patients with severe refractory asthma and airway neutrophilia.6 Treatment with SCH527123 substantially reduced the amount of both blood and sputum neutrophils, with a notable decrease in mild exacerbations and a trend towards improvement in asthma control questionnaire score. These results suggest that airway neutrophils might have a role in the persistence of severe refractory asthma in some patients, but larger studies of longer duration are needed to assess their effect on other asthma outcomes, including severe exacerbations. CRTH2 is another G-protein-coupled receptor that has been implicated in asthma, through the activation of T-helper 2 lymphocytes, eosinophils, and basophils by prostaglandin D2. In a double-blind, placebo-controlled, 28-day study, investigators assessed the potential benefit of a selective CRTH2 antagonist (OC000459) in asthma.7 By contrast with the studies described previously, the patients enrolled in this trial were not using regular inhaled corticosteroids to manage their asthma. Treatment with the antagonist significantly improved the forced expiratory volume in 1 s compared with placebo (9·2% vs 1·8%, p=0·037), but only in the per-protocol population. Substantial improvements in quality-of-life scores and night-time symptoms were also recorded. The magnitude of clinical benefit is probably smaller than that which would be seen with low doses of inhaled corticosteroids in this patient population; additional larger studies of longer duration will be necessary to clarify whether this treatment approach will be useful in asthma. Another new treatment approach for patients with asthma who are uncontrolled while on treatment with combinations of inhaled corticosteroids and long-acting β2-agonists has been the assessment of inhaled long-acting muscarinic antagonists, which are a mainstay of treatment for chronic obstructive pulmonary disease but have not yet been shown to be useful in asthma. In two replicate, randomised,
Ian Hooton/Science Photo Library
Asthma: management of severe disease
Published Online January 14, 2013 http://dx.doi.org/10.1016/ S2213-2600(12)70062-0
e3
2012 Research Highlights
placebo-controlled trials, the benefit of the longacting muscarinic antagonist tiotropium for 48 weeks compared with placebo was investigated, when added to combination therapy treatment, in terms of its effect on lung function and asthma exacerbations.8 Treatment with tiotropium substantially improved the trough (pre-dose) forced expiratory volume in 1 s from baseline in both studies when compared with placebo, and substantially reduced the risk of severe asthma exacerbations. Thus, tiotropium will probably be a useful third-line drug to add to the combination of inhaled corticoisteroids and long-acting β2-agonists in these patient populations. The US Food and Drug Administration has recommended the withdrawal of long-acting β2-agonists from treatment combinations of inhaled corticosteroids and long-acting β2-agonists when asthma is controlled by the combination treatment, because of concerns about their safety. However, the results of a metaanalysis did not favour this step-off approach.9 When long-acting β2-agonists were discontinued, asthma quality of life and asthma control deteriorated, the number of symptom-free days decreased, and the risk of withdrawal increased due to low efficacy. These findings suggest that cessation of long-acting β2-agonist treatment and maintenance of inhaled corticosteroids alone, while patients still need moderate-to-high-dose combination treatment for asthma control, should not be recommended. These studies offer future hope for the management of severe refractory asthma. The studies of mepolizumab and the CXCR2 antagonist suggest that phenotyping of patients on the basis of airway inflammatory cell type will be useful for the decision of whether to start treatment with these compounds. The value of CRTH2 antagonists in asthma management is unclear. Tiotropium will probably be used as an add-on
e4
to inhaled corticosteroids and long-acting β2-agonists, since most patients with severe refractory asthma have airflow obstruction. Finally, if asthma control is achieved from treatment with inhaled corticosteroids and long-acting β2-agonists, the long-acting β2-agonist component should not be discontinued until asthma control is maintained with the lowest doses of the combination treatment. *Paul M O’Byrne, Nizar Naji Firestone Institute of Respiratory Health, St Joseph’s Healthcare and Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON, Canada [email protected] PMO’B has been on advisory boards for AIM, Asmacure, AstraZeneca, Boehringer, GlaxoSmithKline, and Merck, and has received lecture fees from these and other pharmaceutical companies, including Chiesi. Additionally, he has received grants-in-aid for research studies from AIM, Amgen, AstraZeneca, Genentech, GlaxoSmithKline, Novartis, and Ono. NN declares that he has no conflicts of interest. 1
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Bateman ED, Hurd SS, Barnes PJ, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 2008; 31: 143–78. Demoly P, Annunziata K, Gubba E, Adamek L. Repeated cross-sectional survey of patient-reported asthma control in Europe in the past 5 years. Eur Respir Rev 2012; 21: 66–74. Bousquet J, Mantzouranis E, Cruz AA, et al. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol 2010; 126: 926–38. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012; 380: 651–59. McGrath KW, Icitovic N, Boushey HA, et al. A large subgroup of mild-tomoderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med 2012; 185: 612–19. Nair P, Gaga M, Zervas E, et al. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial. Clin Exp Allergy 2012; 42: 1097–103. Barnes N, Pavord I, Chuchalin A, et al. A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma. Clin Exp Allergy 2012; 42: 38–48. Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 2012; 367: 1198–207. Brozek JL, Kraft M, Krishnan JA, et al. Long-acting beta2-agonist step-off in patients with controlled asthma: systematic review with meta-analysis. Arch Intern Med 2012; 172: 1365–75.
www.thelancet.com/respiratory Vol 1 March 2013
