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Editorials: Point and Counterpoint |

POINT: Will New Anti-eosinophilic Drugs Be Useful in Asthma Management? Yes FREE TO VIEW

Paul M. O'Byrne, MBBCh, FCCP
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following: P. M. O. has held grants-in aid from GSK for the investigation of mepolizumab and from Medimmune for the investigation of benralizumab. He also reports consulting fees from AstraZeneca, Chiesi, Boehringer Ingelheim, GSK, Medimmune, Merck, Takeda, and Abbott and grants-in-aid from AstraZeneca, Amgen, Genentech, Novartis Axican, and Alakos.

Firestone Institute of Respiratory Health and the Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada

CORRESPONDENCE TO: Paul M. O’Byrne, MBBCh, FCCP, Room 3W10, McMaster University Medical Center, 1280 Main St W, Hamilton, ON, L8S 4K1, Canada


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2017;151(1):14-17. doi:10.1016/j.chest.2016.09.021
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Over the past 10 years, the aims of asthma management have focused on achieving overall asthma control, which consists of two domains: current (day-to-day) control of symptoms, minimizing the use of asthma relievers, maintaining activities of daily living, and reducing future risk of severe asthma exacerbations and asthma instability, preventing the decline in lung function that occurs in some patients with asthma and preventing side effects from the medications used to treat asthma.

Inhaled corticosteroids (ICS) are the mainstay of asthma treatment. This is because ICS improve all the important outcomes in asthma. These include improving current asthma control, reducing future risk (particularly of severe asthma exacerbations), preventing the decline in FEV1 associated with severe asthma exacerbations, improving the other cardinal physiological feature of asthma, ie, airway hyperresponsiveness to both direct and indirect stimuli such as exercise, and improving airway inflammation and some of the pathologic features of airway remodeling. If ICS alone are not sufficient to achieve overall asthma control, ICS and long-acting inhaled β2-agonists combinations in low to medium doses are recommended. ICS/long-acting inhaled β2-agonist combinations improve lung function and further reduce asthma exacerbation risk.

Despite the widespread availability of effective and generally very safe medications, asthma is often uncontrolled. There is a range of reasons for this. They include adherence to maintenance asthma treatments, which is by far the most important reason for poorly controlled asthma and comorbidities that can worsen asthma control, including rhinosinusitis, allergic bronchopulmonary aspergillosis, gastroesophageal reflux, obesity, bronchiectasis, vocal cord dysfunction, smoking, psychopathology, persistent allergen/occupational exposure, and an incorrect diagnosis of asthma.

Once the causes of poorly controlled asthma have been assessed, 5% to 8% of patients have asthma that is poorly controlled. These are considered patients with severe refractory asthma. These patients not only have poor current asthma control but also are at the greatest risk of severe asthma exacerbations. Treatment options have until recently been very limited for this patient population and consist of oral corticosteroids, or anti-IgE humanized monoclonal antibody (hMab)(omalizumab) for patients with severe refractory allergic asthma. Omalizumab is effective in reducing exacerbation risks in patients with severe refractory allergic asthma and was the first biologic agent to be approved for use in this patient population.

Patients with severe refractory asthma do not have a single phenotype. The evaluation of these patients, using inflammatory biomarkers, particularly with induced sputum, has determined that some patients (up to 50%) have persistent airway eosinophilia despite using high doses of ICS, which are usually very effective in resolving airway eosinophilia; some have elevated airway neutrophilia, whereas a small number have no evidence of an increase in airway inflammatory cells (paucigranulocytic).

IL-5 is an inflammatory cytokine that is critical for the development, maturation, and survival of eosinophils. In 1999, two anti-IL-5 hMabs were described—mepolizumab and reslizumab, which bind to the IL-5 protein and prevent subsequent binding to the IL-5 receptor. Initial studies of both hMabs in severe refractory asthma were disappointing., This is because they were initially evaluated in unselected patients with severe refractory asthma, many of whom did not have persistent airway eosinophilia. As a result of the identification of patient populations with severe refractory eosinophilic asthma, more focused studies were initiated. One of these studies examined the benefit of mepolizumab in patients with prednisone-dependent severe eosinophilic asthma. This study showed that treatment with mepolizumab for 6 months allowed reduction (and discontinuation in most patients) of prednisone without loss of asthma control or asthma exacerbation. A second study confirmed a benefit in patients with severe eosinophilic asthma, with a 50% reduction of severe asthma exacerbations over 1 year of treatment. Mepolizumab subsequently went into clinical trials with much larger populations of patients with severe eosinophilic asthma; it was confirmed that it produced a benefit for reducing severe asthma exacerbations (Fig 1), reduced oral steroid requirements, and slightly improved FEV1 values (Fig 1)., Similarly, with the second anti-IL-5 hMab, reslizumab, studies in patients with severe refractory asthma showed a significant reduction in asthma exacerbations and improvement in lung function.

Figure 1
Figure Jump LinkFigure 1 A, Number of asthma exacerbations in patients receiving either IV or subcutaneous mepolizumab or placebo. The rate of exacerbations was reduced by 47% (95% CI, 28-60) among patients receiving IV mepolizumab and by 53% (95% CI, 36-65) among those receiving subcutaneous mepolizumab, compared with those receiving placebo (P < .001 for both comparisons). B, Mean FEV1 as a percentage of the predicted value. At week 32, there was greater improvement from baseline in the two mepolizumab groups than in the placebo group—a 100-mL greater increase in the IV mepolizumab group than in the placebo group (P = .02) and a 98-mL greater increase in the subcutaneous mepolizumab group than in the placebo group (P = .03). The bars indicate 95% CIs.Grahic Jump Location

Another treatment approach to blocking the effects of IL-5 is an hMab that binds to the IL-5 receptor (anti-IL-5Rα)(benralizumab). This antibody is fucosylated, which results in apoptosis of eosinophils in tissues. Once again, treatment with benralizumab in patients with severe eosinophilic asthma demonstrated a reduction in severe asthma exacerbations and a reduction in hospitalizations due to asthma. Taken together, these studies are remarkably consistent in demonstrating that blocking IL-5 improves some components of asthma control and reduces severe asthma exacerbation risk.

Other hMabs that provide benefits to patients with severe refractory eosinophilic asthma are directed against IL-4 and IL-13. These cytokines have pleomorphic effects in causing type 2 airway inflammation. Three different hMabs have been evaluated in patients with severe refractory asthma. They are lebrikizumab and tralokinumab, which bind to IL-13 protein, and dupilumab, which binds to the common subunit of the IL-4 and IL-13 receptor (IL-4Rα). The evaluation of lebrikizumab and tralokinumab have consistently shown benefits for improving FEV1 in patients with biomarker evidence of increased IL-13 levels in the airways, as measured by increases in serum periostin (a protein released from airway epithelial cells after stimulation with IL-13) or increased IL-13 levels in sputum. However, the studies have not shown a consistent effect in reducing severe asthma exacerbations. In contrast, treatment with dupilumab in patients with severe refractory eosinophilic asthma improved FEV1 but also reduced severe asthma exacerbations between 33% and 70%, depending on the dose administered (Fig 2). It is unclear why there has been a lack of consistency in blocking this pathway for the attenuation of severe asthma exacerbations.

Figure 2
Figure Jump LinkFigure 2 The effect of the anti-IL-4Rα monoclonal antibody dupilumab on severe exacerbation event rates estimated from the 24-week treatment period in the overall population. Error bars indicate point estimate from adjusted annualized severe exacerbation event rates in the 24-week treatment period. (P < .01; P < .001; P < .05 vs placebo.Grahic Jump Location

The results of the efficacy studies targeting IL-5 in patients with severe refractory eosinophilic asthma have been very consistent in demonstrating a 50% reduction in severe asthma exacerbations (Fig 1), allowing a reduction (and often a discontinuation) of oral corticosteroids and, in some studies, an improvement in FEV1 (Fig 1). Similar benefits are described with the anti-IL4Rα hMab. Severe asthma exacerbations are the most important clinical outcome to improve with biologic anti-asthma treatments. This is because severe exacerbations are the time of greatest risk to patients with asthma, the greatest cause of anxiety to patients and their families, the greatest stress to health care professionals, and the greatest cost to health care systems in managing asthma and are associated with an irreversible decline in pulmonary function. Thus, the high costs of using biologic agents in the management of severe refractory asthma are most easily justified when the risks and direct and indirect costs of severe asthma exacerbations are mitigated. For many patients, the added benefit of reducing the need for oral corticosteroids and their associated side effects is immensely important. The magnitude of benefit that has been shown for mepolizumab and reslizumab in phase III pivotal clinical trials has resulted in their regulatory approval in many jurisdictions and the inclusion of this treatment approach in the most recent iteration of the Global Initiative for Asthma strategy document for the treatment of severe refractory eosinophilic asthma. However, there remain patients with severe refractory asthma who do not have persistent airway eosinophilia and for whom there are no currently available effective additional asthma treatment options.

Global Strategy for Asthma Management and Prevention.www.ginasthma.org. Accessed October 20, 2016.
 
Chapman K.R. .Boulet L.P. .Rea R.M. .et al Suboptimal asthma control: prevalence, detection and consequences in general practice. Eur Respir J. 2008;31:320-325 [PubMed]journal. [CrossRef] [PubMed]
 
Chung K.F. .Wenzel S.E. .Brozek J.L. .et al International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43:343-373 [PubMed]journal. [CrossRef] [PubMed]
 
Hanania N.A. .Alpan O. .Hamilos D.L. .et al Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med. 2011;154:573-582 [PubMed]journal. [CrossRef] [PubMed]
 
Pizzichini M.M. .Popov T.A. .Efthimiadis A. .et al Spontaneous and induced sputum to measure indices of airway inflammation in asthma. Am J Respir Crit Care Med. 1996;154:866-869 [PubMed]journal. [CrossRef] [PubMed]
 
Wenzel S.E. .Schwartz L.B. .Langmack E.L. .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;160:1001-1008 [PubMed]journal. [CrossRef] [PubMed]
 
Zia-Amirhosseini P. .Minthorn E. .Benincosa L.J. .et al Pharmacokinetics and pharmacodynamics of SB-240563, a humanized monoclonal antibody directed to human interleukin-5, in monkeys. J Pharmacol Exp Ther. 1999;291:1060-1067 [PubMed]journal. [PubMed]
 
Egan R.W. .Athwal D. .Bodmer M.W. .et al Effect of SCH 55700, a humanized monoclonal antibody to human interleukin-5, on eosinophilic responses and bronchial hyperreactivity. Arzneimittelforschung. 1999;49:779-790 [PubMed]journal. [PubMed]
 
Kips J.C. .O'Connor B.J. .Langley S.J. .et al Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am J Respir Crit Care Med. 2003;167:1655-1659 [PubMed]journal. [CrossRef] [PubMed]
 
Flood-Page P. .Swenson C. .Faiferman I. .et al A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med. 2007;176:1062-1071 [PubMed]journal. [CrossRef] [PubMed]
 
Nair P. .Pizzichini M.M. .Kjarsgaard M. .et al Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360:985-993 [PubMed]journal. [CrossRef] [PubMed]
 
Haldar P. .Brightling C.E. .Hargadon B. .et al Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360:973-984 [PubMed]journal. [CrossRef] [PubMed]
 
Ortega H.G. .Liu M.C. .Pavord I.D. .et al Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-1207 [PubMed]journal. [CrossRef] [PubMed]
 
Bel E.H. .Wenzel S.E. .Thompson P.J. .et al Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189-1197 [PubMed]journal. [CrossRef] [PubMed]
 
Castro M. .Zangrilli J. .Wechsler M.E. .et al Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3:355-366 [PubMed]journal. [CrossRef] [PubMed]
 
Nowak R.M. .Parker J.M. .Silverman R.A. .et al A randomized trial of benralizumab, an antiinterleukin 5 receptor alpha monoclonal antibody, after acute asthma. Am J Emerg Med. 2015;33:14-20 [PubMed]journal. [CrossRef] [PubMed]
 
Corren J. .Lemanske R.F. .Hanania N.A. .et al Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365:1088-1098 [PubMed]journal. [CrossRef] [PubMed]
 
Brightling C.E. .Chanez P. .Leigh R. .et al Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med. 2015;3:692-701 [PubMed]journal. [CrossRef] [PubMed]
 
Wenzel S. .Ford L. .Pearlman D. .et al Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368:2455-2466 [PubMed]journal. [CrossRef] [PubMed]
 
Wenzel S. .Castro M. .Corren J. .et al Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting beta2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388:31-44 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 A, Number of asthma exacerbations in patients receiving either IV or subcutaneous mepolizumab or placebo. The rate of exacerbations was reduced by 47% (95% CI, 28-60) among patients receiving IV mepolizumab and by 53% (95% CI, 36-65) among those receiving subcutaneous mepolizumab, compared with those receiving placebo (P < .001 for both comparisons). B, Mean FEV1 as a percentage of the predicted value. At week 32, there was greater improvement from baseline in the two mepolizumab groups than in the placebo group—a 100-mL greater increase in the IV mepolizumab group than in the placebo group (P = .02) and a 98-mL greater increase in the subcutaneous mepolizumab group than in the placebo group (P = .03). The bars indicate 95% CIs.Grahic Jump Location
Figure Jump LinkFigure 2 The effect of the anti-IL-4Rα monoclonal antibody dupilumab on severe exacerbation event rates estimated from the 24-week treatment period in the overall population. Error bars indicate point estimate from adjusted annualized severe exacerbation event rates in the 24-week treatment period. (P < .01; P < .001; P < .05 vs placebo.Grahic Jump Location

Tables

References

Global Strategy for Asthma Management and Prevention.www.ginasthma.org. Accessed October 20, 2016.
 
Chapman K.R. .Boulet L.P. .Rea R.M. .et al Suboptimal asthma control: prevalence, detection and consequences in general practice. Eur Respir J. 2008;31:320-325 [PubMed]journal. [CrossRef] [PubMed]
 
Chung K.F. .Wenzel S.E. .Brozek J.L. .et al International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43:343-373 [PubMed]journal. [CrossRef] [PubMed]
 
Hanania N.A. .Alpan O. .Hamilos D.L. .et al Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med. 2011;154:573-582 [PubMed]journal. [CrossRef] [PubMed]
 
Pizzichini M.M. .Popov T.A. .Efthimiadis A. .et al Spontaneous and induced sputum to measure indices of airway inflammation in asthma. Am J Respir Crit Care Med. 1996;154:866-869 [PubMed]journal. [CrossRef] [PubMed]
 
Wenzel S.E. .Schwartz L.B. .Langmack E.L. .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;160:1001-1008 [PubMed]journal. [CrossRef] [PubMed]
 
Zia-Amirhosseini P. .Minthorn E. .Benincosa L.J. .et al Pharmacokinetics and pharmacodynamics of SB-240563, a humanized monoclonal antibody directed to human interleukin-5, in monkeys. J Pharmacol Exp Ther. 1999;291:1060-1067 [PubMed]journal. [PubMed]
 
Egan R.W. .Athwal D. .Bodmer M.W. .et al Effect of SCH 55700, a humanized monoclonal antibody to human interleukin-5, on eosinophilic responses and bronchial hyperreactivity. Arzneimittelforschung. 1999;49:779-790 [PubMed]journal. [PubMed]
 
Kips J.C. .O'Connor B.J. .Langley S.J. .et al Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am J Respir Crit Care Med. 2003;167:1655-1659 [PubMed]journal. [CrossRef] [PubMed]
 
Flood-Page P. .Swenson C. .Faiferman I. .et al A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med. 2007;176:1062-1071 [PubMed]journal. [CrossRef] [PubMed]
 
Nair P. .Pizzichini M.M. .Kjarsgaard M. .et al Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360:985-993 [PubMed]journal. [CrossRef] [PubMed]
 
Haldar P. .Brightling C.E. .Hargadon B. .et al Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360:973-984 [PubMed]journal. [CrossRef] [PubMed]
 
Ortega H.G. .Liu M.C. .Pavord I.D. .et al Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-1207 [PubMed]journal. [CrossRef] [PubMed]
 
Bel E.H. .Wenzel S.E. .Thompson P.J. .et al Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189-1197 [PubMed]journal. [CrossRef] [PubMed]
 
Castro M. .Zangrilli J. .Wechsler M.E. .et al Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3:355-366 [PubMed]journal. [CrossRef] [PubMed]
 
Nowak R.M. .Parker J.M. .Silverman R.A. .et al A randomized trial of benralizumab, an antiinterleukin 5 receptor alpha monoclonal antibody, after acute asthma. Am J Emerg Med. 2015;33:14-20 [PubMed]journal. [CrossRef] [PubMed]
 
Corren J. .Lemanske R.F. .Hanania N.A. .et al Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365:1088-1098 [PubMed]journal. [CrossRef] [PubMed]
 
Brightling C.E. .Chanez P. .Leigh R. .et al Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med. 2015;3:692-701 [PubMed]journal. [CrossRef] [PubMed]
 
Wenzel S. .Ford L. .Pearlman D. .et al Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368:2455-2466 [PubMed]journal. [CrossRef] [PubMed]
 
Wenzel S. .Castro M. .Corren J. .et al Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting beta2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388:31-44 [PubMed]journal. [CrossRef] [PubMed]
 
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