0
Editorial |

Anti-IL-5 for Severe Asthma: Aiming High to Achieve Success FREE TO VIEW

Richard Russell, MBBS; Christopher E. Brightling, PhD, FCCP
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following: C. E. B. has received, through his institution, grant and or consultancy funding, or both, from AZ/MedImmune, GSK, Novartis, Roche/Genentech, Chiesi, Pfizer, Theravance, and Vectura. None declared (R. R.).

Department of Infection, Immunity and Inflammation, Institute for Lung Health, Glenfield Hospital, University of Leicester, Leicester, England

CORRESPONDENCE TO: Christopher E. Brightling, PhD, FCCP, University of Leicester, Glenfield General Hospital, Leicester, LE3 9QP, UK


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


Chest. 2016;150(4):766-768. doi:10.1016/j.chest.2016.06.013
Text Size: A A A
Published online

Asthma affects > 300 million people worldwide and is severe in 10% of these individuals. Advances in approaches to phenotype the heterogeneity of severe asthma have established the importance of eosinophilic inflammation, and several new therapies beyond corticosteroids and anti-immunoglobulin E are designed to target type 2-mediated immunity to inhibit this inflammation, with the aim of reducing exacerbation frequency. Current therapies against type 2 immunity include anti-IL-4Rα, IL-5, IL-5R, IL-13, and the type 2 prostaglandin D2 receptor.

FOR RELATED ARTICLES SEE PAGES 789, 799

The most advanced therapeutic target is IL-5, which is an attractive target because it is an obligate cytokine for eosinophil maturation and survival. Its inhibition is thus predicted to reduce bone marrow production of eosinophils and promote apoptosis. Persistent eosinophilic inflammation is present in approximately half of individuals with severe asthma. In those without eosinophilic inflammation, about half have emergent eosinophilic inflammation following corticosteroid reduction, suggesting that this phenotype is very common. Eosinophilic inflammation is present with or without atopy, as a type 2-mediated response can occur following allergic sensitization, with consequent release of IL-5 from Th2 cells, or in response to airway damage and infection through activation of the type 2 innate lymphoid cells.

The IL-5 neutralizing antibodies mepolizumab and reslizumab were licensed in the United States and Europe in 2015 following successful phase III studies demonstrating reductions in severe exacerbations. Benralizumab, an anti-IL-5R biologic, was also successful in its pivotal phase III studies. Although all these anti-IL5R approaches consistently reduce exacerbations, beneficial effects on lung function, asthma control, and health status are more variable. Small effects on lung function were observed in the phase III study for mepolizumab, which were not seen in a phase II study, whereas effects on these outcomes were more robustly observed following treatment with reslizumab and benralizumab. Whether these larger effects on lung function and symptoms in response to reslizumab and benralizumab are real or chance observations is unclear. However, the limited bronchoscopic biopsy data suggest that benralizumab reduces bronchial mucosal eosinophilia to a greater extent than does mepolizumab. This raises the intriguing possibility that improvements in lung function might be related to the magnitude of the reduction in the airway eosinophilia. To date, no biopsy studies have been reported for reslizumab.

In all the late-phase anti-IL5R, studies, the blood eosinophil count has been a valuable biomarker. In this issue of CHEST, Bjermer et al and Corren et al undertook two similarly designed randomized placebo-controlled trials of reslizumab administered IV every 4 weeks for 16 weeks in patients with poorly controlled asthma. Corren et al included individuals with asthma with and without an elevated blood eosinophil count (≥ 400 cells/μL), whereas Bjermer et al included two doses of reslizumab and only patients with asthma with an elevated blood eosinophil count. In the former study, the subgroup of patients with, but not those without, an elevated baseline blood eosinophil count showed improvements in lung function and asthma control following treatment with reslizumab when compared with placebo, even though no significant relationship was detected between baseline blood eosinophil levels and a change in lung function. Likewise, Bjermer et al showed that reslizumab significantly improved lung function and asthma control vs placebo, with greater effects seen with the higher dose. These findings support the view that an elevated blood eosinophil count is associated with a good clinical response but did not find a clear correlation between the intensity of the baseline eosinophil count and response. In contrast, improvements in exacerbation frequency observed following treatment with mepolizumab were related to the baseline blood eosinophil count with clinical benefit in asthmatics with a blood eosinophil count ≥ 150 cells/μL. Thus, the best cutoff for the blood eosinophil count to apply clinically remains uncertain. From a patient perspective, there is an argument to select a low or no cutoff, as there is some benefit even with low baseline eosinophil counts, whereas from a payer’s perspective, the health economic benefit is better with a higher cutoff. Post-licensing studies will need to continue to address the effectiveness of these therapies in real-world studies.

In the next few years, it is likely that we shall have several new therapies for severe asthma. For the clinician to understand how to select the right therapy for the right patient, we shall need to better understand the phenotype-specific mechanistic role of different elements of the immune response and to have biomarkers of these mechanisms, as it is likely that some changes in airway inflammation and remodeling will contribute more to exacerbation risk, whereas others might be more related to symptoms or lung function. For example, in contrast to the success of anti-IL5R in phase III studies, the anti-IL-13 biologic lebrikizumab was only successful in achieving its primary outcome of reducing asthma exacerbations in one of two pivotal phase III studies. However, lebrikizumab has consistently improved lung function, perhaps in part due to its effects on airway smooth muscle rather than eosinophilic inflammation, and improvements were greatest in those patients with an activated IL-13 pathway, as evidenced by increased blood levels of periostin. The outcome of phase III studies of another anti-IL-13 therapy, tralokinumab, are awaited, but earlier studies again demonstrated a more consistent effect on lung function, with the greatest reductions in exacerbations observed in those with bronchodilator reversibility and elevated blood periostin or dipeptidyl-peptidase-4 levels. Dupilumab shows promise and targets both IL-4 and IL-13 signaling through anti-IL4Rα, which might have a more profound effect on airway inflammation. Importantly, it is unknown whether these approaches reduce eosinophilic airway inflammation. Fevipiprant, a small-molecule type 2 prostaglandin D2 receptor inhibitor, has demonstrated beneficial effects on lung function and eosinophilic inflammation in sputum and bronchial biopsy samples. Whether this translates into a benefit in exacerbation frequency is unknown, and findings from phase III studies are awaited.

We are moving into a new era of type 2 immunity-mediated therapies that will bring new opportunities for clinicians and our patients, but with this opportunity comes new challenges. Biomarkers will increase in importance to help drive precision medicine, but we need to understand how to use them, and in particular what cut points to apply. For anti-IL-5 approaches we probably need to look toward elevated blood eosinophil counts, as aiming for a high cutoff is most likely the best way we shall achieve success.

References

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]
 
Russell R. .Brightling C. . Mepolizumab for the reduction of exacerbations in severe eosinophilic asthma. Expert Rev Respir Med. 2016;10:607-617 [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]
 
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]
 
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]
 
Castro M. .Wenzel S.E. .Bleecker E.R. .et al Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med. 2014;2:879-890 [PubMed]journal. [CrossRef] [PubMed]
 
Laviolette M. .Gossage D.L. .Gauvreau G. .et al Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol. 2013;132:1086-1096.e5 [PubMed]journal. [CrossRef] [PubMed]
 
Bjermer L. .Lemiere C. .Maspero J. .Weiss S. .Zangrilli J. .Germinaro M. . Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest. 2016;150:789-798 [PubMed]journal
 
Corren J. .Weinstein S. .Janka L. .Zangrilli J. .Garin M. . Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. 2016;150:799-810 [PubMed]journal
 
Ortega HG, Yancey SW, Mayer B, et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies [published online ahead of print May 10, 2016].Lancet Respir Med.http://dx.doi.org/10.1016/S2213-2600(16)30031-5.
 
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]
 
Berair R. .Gonem S. .Singapuri A. .et al Effect of QAW039, an oral prostaglandin D2 receptor (DP2/CRTH2) antagonist, upon sputum and bronchial eosinophilic inflammation and clinical outcomes in treatment-resistant asthma: A phase 2a randomized placebo-controlled trial. Am J. Respir Crit Care Med. 2015;191:A6361- [PubMed]journal
 

Figures

Tables

References

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]
 
Russell R. .Brightling C. . Mepolizumab for the reduction of exacerbations in severe eosinophilic asthma. Expert Rev Respir Med. 2016;10:607-617 [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]
 
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]
 
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]
 
Castro M. .Wenzel S.E. .Bleecker E.R. .et al Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med. 2014;2:879-890 [PubMed]journal. [CrossRef] [PubMed]
 
Laviolette M. .Gossage D.L. .Gauvreau G. .et al Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol. 2013;132:1086-1096.e5 [PubMed]journal. [CrossRef] [PubMed]
 
Bjermer L. .Lemiere C. .Maspero J. .Weiss S. .Zangrilli J. .Germinaro M. . Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest. 2016;150:789-798 [PubMed]journal
 
Corren J. .Weinstein S. .Janka L. .Zangrilli J. .Garin M. . Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. 2016;150:799-810 [PubMed]journal
 
Ortega HG, Yancey SW, Mayer B, et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies [published online ahead of print May 10, 2016].Lancet Respir Med.http://dx.doi.org/10.1016/S2213-2600(16)30031-5.
 
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]
 
Berair R. .Gonem S. .Singapuri A. .et al Effect of QAW039, an oral prostaglandin D2 receptor (DP2/CRTH2) antagonist, upon sputum and bronchial eosinophilic inflammation and clinical outcomes in treatment-resistant asthma: A phase 2a randomized placebo-controlled trial. Am J. Respir Crit Care Med. 2015;191:A6361- [PubMed]journal
 
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.

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