0
Editorials: Point and Counterpoint |

COUNTERPOINT: Will New Anti-eosinophilic Drugs Be Useful in Asthma Management? No FREE TO VIEW

Peter J. Barnes, DM, Master FCCP
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURE: The authors have reported to CHEST the following: P. J. B. has served on the scientific advisory boards of AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Glenmark, Johnson & Johnson, Napp, Novartis, Takeda, Pfizer, Prosonix, Respivert, Teva, and Zambon and has received research funding from AstraZeneca, Boehringer-Ingelheim, Chiesi, Novartis, and Takeda.

Airway Disease Section, National Heart and Lung Institute, Imperial College, London, England

CORRESPONDENCE TO: Peter J. Barnes, DM, Master FCCP, Airway Disease Section, National Heart and Lung Institute, Dovehouse St, London SW3 6LY, UK


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


Chest. 2017;151(1):17-20. doi:10.1016/j.chest.2016.09.023
Text Size: A A A
Published online

Recently there has been great interest in the development of precision medicines that target a specific underlying disease mechanism so that responders will have a better therapeutic response and less adverse effects compared with the nonspecific therapies that are currently used. This approach has been very promising in the treatment of cancer, in which specific anticancer therapies have been targeted to particular molecular abnormalities identified in the cancer. The same approach is now being applied to complex inflammatory diseases, such as asthma and COPD, but so far with less success.

The greatest advance in precision medicine for asthma has been the development of specific anti-eosinophil treatments, which target mediators involved in eosinophil inflammation in the airways. Asthma is usually characterized by chronic inflammation of the airways, with an infiltration of activated eosinophils orchestrated by dendritic cells that interact with T helper 2 (Th2) cells or from nonallergic mechanisms that lead to activation of innate type 2 lymphocytes (ILC2). Th2 and ILC2 cells express the transcription factor GATA3, which results in the synthesis of IL-5, which is required for eosinophil differentiation, proliferation, and survival. Anti-IL-5 blocking antibodies, which were remarkably effective in animal models of allergic asthma, are therefore a logical approach to the treatment of inflammation in asthma. The first human study of an anti-IL-5 antibody (mepolizumab) showed a profound and prolonged fall in circulating eosinophils and a marked reduction in sputum eosinophils after allergen challenge in patients with mild asthma. Yet there was no reduction in the early or late response to inhaled allergen or in airway hyperresponsiveness, which is probably explained by the fact that there was no effect on mast cell activation, which is thought to mediate many of the day-to-day symptoms of asthma. In unselected patients with asthma whose asthma was not controlled by inhaled corticosteroids (ICS), there was no clinical improvement despite a marked reduction in eosinophils in blood and sputum. Since then, several clinical studies have been performed in selected patients with refractory asthma as well as persistent eosinophils in sputum and a history of frequent exacerbations. These studies consistently show a reduction, but not elimination, of exacerbations, with little effect on symptoms, lung function, or quality of life. Thus anti-IL-5 therapy would not be a sufficient treatment alone, probably because it does not affect the mast cell activation that produces most asthma symptoms. It seems that patient selection is very important, but patients with refractory asthma that is not controlled by maximal inhaled therapy or oral corticosteroids and who have increased eosinophils in sputum and a history of frequent exacerbations are relatively uncommon and usually explained by poor adherence to ICS. Another anti-IL-5 antibody, reslizumab, and an anti-IL-5 receptor antibody (IL-5Rα), benralizumab, have clinical effects similar to those of mepolizumab., Anti-IL-5 treatments have now been approved for use in refractory eosinophilic asthma, although in the United Kingdom, the National Institute for Health and Care Excellence has not approved mepolizumab on cost-effectiveness grounds.

Corticosteroids are the most effective treatment against eosinophilic inflammation, probably mediated by their potent inhibitory effect on GATA3, which is important for the release of IL-5 (and IL-4/13) from Th2 and ILC2 cells. In the real world, asthma is often poorly controlled, and a recent survey of European patients with asthma showed that almost half had poor asthma control, despite being prescribed ICS, usually in combination with a long-acting β2-agonist (LABA). In a community study of patients with asthma (ascertained through their prescriptions), almost all patients with asthma that was classified as severe and who were receiving maximal ICS and LABA therapy had poor adherence or poor inhaler use, or both. This reflects the very poor adherence to ICS among patients with asthma, even when they have severe disease. This is confirmed by another study showing that of the 20% of patients classified as having severe refractory asthma, the true prevalence of severe asthma is less than 4% of patients overall. To use an expensive antibody treatment as a substitute for taking regular ICS would impose an enormous financial burden in view of the high prevalence of asthma. It would be much more cost-effective to use other strategies to address poor adherence with ICS, such as using an asthma-reliever medication that contains a corticosteroid, eg, maintenance and reliever therapy using ICS/formoterol combination inhalers, or by electronic monitoring of ICS use with an audiovisual reminder.

In addition to anti-IL-5, there are other specific approaches that target eosinophilic inflammation in asthma. Anti-IL-13 blocking antibodies, such as lebrikizumab and tralokinumab, provide relatively little clinical benefit in patients with refractory asthma., Dupilumab, a monoclonal antibody that blocks IL-4Rα, the common receptor for IL-4 and IL-13, appears to be more effective in improving symptoms and lung function and preventing exacerbations in patients with uncontrolled asthma, although it is not certain whether these clinical benefits are due to reduced eosinophil levels. Theoretically, blocking IL-4/IL-13 will also reduce IgE formation and have effects on airway mucus secretion and structural changes. Thymic stromal lymphopoietin (TSLP) is an upstream cytokine that drives eosinophilic inflammation, and an anti-TSLP antibody (AMG 157) reduces early and late responses to inhaled allergen in mild asthma, with a reduction in blood and sputum eosinophil levels. Targeting GATA3, which also drives eosinophilic inflammation, has recently become possible with a GATA3-specific DNAzyme (SB010), which has a small effect on the early and late responses to allergen in patients with asthma. Yet another approach is blocking prostaglandin D2 receptors (also known as CRTh2), which are expressed on Th2 and ILC2 cells. Orally administered CRTh2 antagonists provide a small clinical improvement in severe allergic asthma. Whether these early findings translate into useful clinical improvement in refractory asthma with eosinophilia remains to be determined, however.

Although important advances have been made in the development of specific anti-eosinophilic therapies, it is unlikely that these drugs will have a major impact on asthma, since eosinophilic inflammation is usually responsive to corticosteroids, and the main reason for poor control of asthma is poor adherence to ICS therapy or poor inhaler technique. Anti-eosinophil treatments may be more useful in other eosinophilic diseases, such as hypereosinophilic syndromes or eosinophilic esophagitis, to avoid the need for long-term oral corticosteroids. Patients with severe asthma may have noneosinophilic inflammation, with a predominance of neutrophils or macrophages that will require different therapies, such as macrolides. These patients who are poorly responsive to corticosteroids are more challenging to treat, and it is these patients in whom new and more specific antiinflammatory therapies are needed. I conclude that specific anti-eosinophilic therapies will provide clinical benefit for only a small number of patients with severe asthma, and their likely high cost will be a disincentive to their use in most countries.

Martinez-Gonzalez I. .Steer C.A. .Takei F. . Lung ILC2s link innate and adaptive responses in allergic inflammation. Trends Immunol. 2015;36:189-195 [PubMed]journal. [CrossRef] [PubMed]
 
Leckie M.J. .ten Brincke A. .Khan J. .et al Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness and the late asthmatic response. Lancet. 2000;356:2144-2148 [PubMed]journal. [CrossRef] [PubMed]
 
Barnes P.J. . Pathophysiology of allergic inflammation. Immunol Rev. 2011;242:31-50 [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]
 
Powell C. .Milan S.J. .Dwan K. .Bax L. .Walters N. . Mepolizumab versus placebo for asthma. Cochrane Database Syst Rev. 2015;:Cd010834- [PubMed]journal
 
Khorasanizadeh M. .Eskian M. .Assa'ad A.H. .Camargo C.A. Jr..Rezaei N. . Efficacy and safety of benralizumab, a monoclonal antibody against IL-5Rα, in uncontrolled eosinophilic asthma. Int Rev Immunol. 2016;35:294-311 [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:e15- [PubMed]journal. [CrossRef]
 
Maneechotesuwan K. .Yao X. .Ito K. .et al Suppression of GATA-3 nuclear import and phosphorylation: a novel mechanism of corticosteroid action in allergic disease. PLoS Med. 2009;6:e1000076- [PubMed]journal. [CrossRef] [PubMed]
 
Price D. .Fletcher M. .van der Molen T. . Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. NPJ Prim Care Respir Med. 2014;24:14009- [PubMed]journal. [PubMed]
 
Armour C.L. .Lemay K. .Saini B. .et al Using the community pharmacy to identify patients at risk of poor asthma control and factors which contribute to this poor control. J Asthma. 2011;48:914-922 [PubMed]journal. [CrossRef] [PubMed]
 
McNicholl D.M. .Stevenson M. .McGarvey L.P. .Heaney L.G. . The utility of fractional exhaled nitric oxide suppression in the identification of nonadherence in difficult asthma. Am J Respir Crit Care Med. 2012;186:1102-1108 [PubMed]journal. [CrossRef] [PubMed]
 
Hekking P.P. .Wener R.R. .Amelink M. .Zwinderman A.H. .Bouvy M.L. .Bel E.H. . The prevalence of severe refractory asthma. J Allergy Clin Immunol. 2015;135:896-902 [PubMed]journal. [CrossRef] [PubMed]
 
Naji N. .O'Byrne P.M. . Asthma maintenance and reliever therapy. Ann Allergy Asthma Immunol. 2012;109:388-391 [PubMed]journal. [CrossRef] [PubMed]
 
Chan A.H. .Stewart A.W. .Harrison J. .Camargo C.A. Jr..Black P.N. .Mitchell E.A. . The effect of an electronic monitoring device with audiovisual reminder function on adherence to inhaled corticosteroids and school attendance in children with asthma: a randomised controlled trial. Lancet Respir Med. 2015;3:210-219 [PubMed]journal. [CrossRef] [PubMed]
 
Hanania N.A. .Noonan M. .Corren J. .et al Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. Thorax. 2015;70:748-756 [PubMed]journal. [CrossRef] [PubMed]
 
Piper E. .Brightling C. .Niven R. .et al A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J. 2013;41:330-338 [PubMed]journal. [CrossRef] [PubMed]
 
Gauvreau G.M. .O'Byrne P.M. .Boulet L.P. .et al Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med. 2014;370:2102-2110 [PubMed]journal. [CrossRef] [PubMed]
 
Krug N. .Hohlfeld J.M. .Kirsten A.M. .et al Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N Engl J Med. 2015;372:1987-1995 [PubMed]journal. [CrossRef] [PubMed]
 
Erpenbeck V.J. .Popov T.A. .Miller D. .et al The oral CRTh2 antagonist QAW039 (fevipiprant): a phase II study in uncontrolled allergic asthma. Pulm Pharmacol Ther. 2016;39:54-63 [PubMed]journal. [CrossRef] [PubMed]
 
Brusselle G.G. .Vanderstichele C. .Jordens P. .et al Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68:322-329 [PubMed]journal. [CrossRef] [PubMed]
 
Barnes P.J. . Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2013;131:636-645 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Martinez-Gonzalez I. .Steer C.A. .Takei F. . Lung ILC2s link innate and adaptive responses in allergic inflammation. Trends Immunol. 2015;36:189-195 [PubMed]journal. [CrossRef] [PubMed]
 
Leckie M.J. .ten Brincke A. .Khan J. .et al Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness and the late asthmatic response. Lancet. 2000;356:2144-2148 [PubMed]journal. [CrossRef] [PubMed]
 
Barnes P.J. . Pathophysiology of allergic inflammation. Immunol Rev. 2011;242:31-50 [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]
 
Powell C. .Milan S.J. .Dwan K. .Bax L. .Walters N. . Mepolizumab versus placebo for asthma. Cochrane Database Syst Rev. 2015;:Cd010834- [PubMed]journal
 
Khorasanizadeh M. .Eskian M. .Assa'ad A.H. .Camargo C.A. Jr..Rezaei N. . Efficacy and safety of benralizumab, a monoclonal antibody against IL-5Rα, in uncontrolled eosinophilic asthma. Int Rev Immunol. 2016;35:294-311 [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:e15- [PubMed]journal. [CrossRef]
 
Maneechotesuwan K. .Yao X. .Ito K. .et al Suppression of GATA-3 nuclear import and phosphorylation: a novel mechanism of corticosteroid action in allergic disease. PLoS Med. 2009;6:e1000076- [PubMed]journal. [CrossRef] [PubMed]
 
Price D. .Fletcher M. .van der Molen T. . Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. NPJ Prim Care Respir Med. 2014;24:14009- [PubMed]journal. [PubMed]
 
Armour C.L. .Lemay K. .Saini B. .et al Using the community pharmacy to identify patients at risk of poor asthma control and factors which contribute to this poor control. J Asthma. 2011;48:914-922 [PubMed]journal. [CrossRef] [PubMed]
 
McNicholl D.M. .Stevenson M. .McGarvey L.P. .Heaney L.G. . The utility of fractional exhaled nitric oxide suppression in the identification of nonadherence in difficult asthma. Am J Respir Crit Care Med. 2012;186:1102-1108 [PubMed]journal. [CrossRef] [PubMed]
 
Hekking P.P. .Wener R.R. .Amelink M. .Zwinderman A.H. .Bouvy M.L. .Bel E.H. . The prevalence of severe refractory asthma. J Allergy Clin Immunol. 2015;135:896-902 [PubMed]journal. [CrossRef] [PubMed]
 
Naji N. .O'Byrne P.M. . Asthma maintenance and reliever therapy. Ann Allergy Asthma Immunol. 2012;109:388-391 [PubMed]journal. [CrossRef] [PubMed]
 
Chan A.H. .Stewart A.W. .Harrison J. .Camargo C.A. Jr..Black P.N. .Mitchell E.A. . The effect of an electronic monitoring device with audiovisual reminder function on adherence to inhaled corticosteroids and school attendance in children with asthma: a randomised controlled trial. Lancet Respir Med. 2015;3:210-219 [PubMed]journal. [CrossRef] [PubMed]
 
Hanania N.A. .Noonan M. .Corren J. .et al Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. Thorax. 2015;70:748-756 [PubMed]journal. [CrossRef] [PubMed]
 
Piper E. .Brightling C. .Niven R. .et al A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J. 2013;41:330-338 [PubMed]journal. [CrossRef] [PubMed]
 
Gauvreau G.M. .O'Byrne P.M. .Boulet L.P. .et al Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med. 2014;370:2102-2110 [PubMed]journal. [CrossRef] [PubMed]
 
Krug N. .Hohlfeld J.M. .Kirsten A.M. .et al Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N Engl J Med. 2015;372:1987-1995 [PubMed]journal. [CrossRef] [PubMed]
 
Erpenbeck V.J. .Popov T.A. .Miller D. .et al The oral CRTh2 antagonist QAW039 (fevipiprant): a phase II study in uncontrolled allergic asthma. Pulm Pharmacol Ther. 2016;39:54-63 [PubMed]journal. [CrossRef] [PubMed]
 
Brusselle G.G. .Vanderstichele C. .Jordens P. .et al Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68:322-329 [PubMed]journal. [CrossRef] [PubMed]
 
Barnes P.J. . Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2013;131:636-645 [PubMed]journal. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

CHEST Journal Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543