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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2018, Vol. 12 Issue (3) : 340-349    https://doi.org/10.1007/s11684-017-0565-0
LETTER TO FRONTIERS OF MEDICINE |
Efficacy and safety of benralizumab in patients with eosinophilic asthma: a meta-analysis of randomized placebo-controlled trials
Ting Liu, Faping Wang, Geng Wang, Hui Mao()
Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
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Abstract

Benralizumab is a monoclonal antibody that targets interleukin-5 receptor α to deplete blood eosinophils and improve the clinical outcomes of allergic asthma. We conducted a meta-analysis to evaluate the safety and efficacy of different doses of benralizumab in patients with eosinophilic asthma. All randomized controlled trials involving benralizumab treatment for patients with eosinophilic asthma, which were searched in PubMed, Embase, and the Cochrane Library published until January 2017, as well as the rate of asthmatic exacerbation, pulmonary functionality, asthma control, quality of life scores, and adverse events were included. Randomized-effect models were used in the meta-analysis to calculate the pooled mean difference, relative risks, and 95% confidence intervals. Five studies involving 1951 patients were identified. Compared with the placebo, benralizumab treatment demonstrated significant improvements in the forced expiratory volume in 1?s (FEV1), Asthma Quality of Life Questionnaire scores, decreased asthmatic exacerbation and Asthma Control Questionnaire-6 (ACQ-6) scores. Benralizumab treatment was also not associated with increased adverse events. These findings indicated that benralizumab can be safely used to improve FEV1, enhance patient symptom control and quality of life, and reduce the risk of exacerbations and ACQ-6 scores in patients with eosinophilic asthma. Furthermore, our meta-analysis showed that benralizumab with 30 mg (every eight weeks) dosage can improve the health-related quality of life and appear to be more effective than 30 mg (every four weeks) dosage. Overall, data indicated that the optimal dosing regimen for benralizumab was possibly 30 mg (every eight weeks).

Keywords benralizumab      anti-interleukin-5      monoclonal antibody      eosinophilic asthma      meta-analysis     
Corresponding Authors: Hui Mao   
Just Accepted Date: 06 September 2017   Online First Date: 31 October 2017    Issue Date: 04 May 2018
 Cite this article:   
Ting Liu,Faping Wang,Geng Wang, et al. Efficacy and safety of benralizumab in patients with eosinophilic asthma: a meta-analysis of randomized placebo-controlled trials[J]. Front. Med., 2018, 12(3): 340-349.
 URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-017-0565-0
http://academic.hep.com.cn/fmd/EN/Y2018/V12/I3/340
Fig.1  Flow chart identifying the studies included in the analysis.
Reference Study design No. of subjects (treatment/placebo) Age (year) Doses of benralizumab used Routine Treatment duration Outcomes Follow-up
Laviolette et al., 2013 [21]a mRCT 4/5 18–65 100 mg Q4W SC 8 weeks Blood, sputum eosinophils; adverse events 20 weeks
Castro et al., 2014 [22]b mRCT 244/80 18–75 2, 20, 100 mg Q8W SC 52 weeks Blood eosinophils; asthma exacerbations; FEV1 52 weeks
Park et al., 2016 [23]b mRCT 60/21 20–75 2, 20, 100 mg Q8W SC 40 weeks Blood eosinophils; asthma exacerbations; FEV1; PEF; ACQ-6 52 weeks
FitzGerald et al., 2016 [24]b mRCT 480/248 12–75 30 mg Q4W or 30 mg Q8W SC 56 weeks Asthma exacerbations; FEV1; ACQ-6; AQLQ 56 weeks
Bleecker et al., 2016 [14]a mRCT 542/267 12–75 30 mg Q4W or 30 mg Q8W SC 48 weeks Asthma exacerbations; FEV1; ACQ-6; AQLQ 48 weeks
Tab.1  Characteristics of the randomized controlled trials included in the meta-analysis
Fig.2  Risk of bias summary of the included studies.
Fig.3  Funnel plot of the five studies that evaluated the effect of benralizumab on FEV1.
Fig.4  Forest plot of the effect of benralizumab treatment on asthma exacerbations versus the placebo. Fixed-effect model. SE, standard error; IV, inverse variance; CI, confidence interval.
Fig.5  Effect of benralizumab treatment versus the placebo on FEV1. SD, standard deviation; IV, inverse variance; CI, confidence interval; Std. Mean Difference, standardized mean difference.
Fig.6  Effect of benralizumab treatment versus the placebo on the ACQ-6 score. SD, standard derivation; IV, inverse variance; CI, confidence interval.
Fig.7  Effect of benralizumab treatment versus the placebo on the AQLQ score. SD, standard derivation; IV, inverse variance; CI, confidence interval.
Fig.8  Forest plot of the effect of benralizumab treatment on adverse events versus the placebo. M-H, Mantel–Haenszel; CI, confidence interval.
1 Global Asthma Network. The Global Asthma Report 2014. Auckland, New Zealand: Global Asthma Network, 2014. Available:
2 McIvor RA. Emerging therapeutic options for the treatment of patients with symptomatic asthma. Ann Allergy Asthma Immunol 2015; 115(4): 265–271.e5
https://doi.org/10.1016/j.anai.2015.07.011 pmid: 26254973
3 Torrego A, Solà I, Munoz AM, Roqué I Figuls M, Yepes-Nuñez JJ, Alonso-Coello P, Plaza V. Bronchial thermoplasty for moderate or severe persistent asthma in adults. Cochrane Database Syst Rev 2014; (3): CD009910
pmid: 24585221
4 Chung KF. Targeting the interleukin pathway in the treatment of asthma. Lancet 2015; 386(9998): 1086–1096
https://doi.org/10.1016/S0140-6736(15)00157-9 pmid: 26383000
5 Mitchell PD, El-Gammal AI, O’Byrne PM. Emerging monoclonal antibodies as targeted innovative therapeutic approaches to asthma. Clin Pharmacol Ther 2016; 99(1): 38–48
https://doi.org/10.1002/cpt.284 pmid: 26502193
6 Aleman F, Lim HF, Nair P. Eosinophilic endotype of asthma. Immunol Allergy Clin North Am 2016; 36(3): 559–568
https://doi.org/10.1016/j.iac.2016.03.006 pmid: 27401626
7 Cardet JC, Israel E. Update on reslizumab for eosinophilic asthma. Expert Opin Biol Ther 2015; 15(10): 1531–1539
https://doi.org/10.1517/14712598.2015.1090972 pmid: 26372797
8 Khorasanizadeh M, Eskian M, Assa’ad AH, Camargo CA Jr, Rezaei N. Efficacy and safety of benralizumab, a monoclonal antibody against IL-5Ra, in uncontrolled eosinophilic asthma. Int Rev Immunol 2016; 35(4): 294–311
https://doi.org/10.3109/08830185.2015.1128901 pmid: 27119985
9 Wu Y, Li JJ, Kim HJ, Liu X, Liu W, Akhgar A, Bowen MA, Spitz S, Jiang XR, Roskos LK, White WI. A neutralizing antibody assay based on a reporter of antibody-dependent cell-mediated cytotoxicity. AAPS J 2015; 17(6): 1417–1426
https://doi.org/10.1208/s12248-015-9798-5 pmid: 26205082
10 Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, Ortega H, Chanez P. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012; 380(9842): 651–659
https://doi.org/10.1016/S0140-6736(12)60988-X pmid: 22901886
11 Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, Ortega HG, Pavord ID; SIRIUS Investigators. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014; 371(13): 1189–1197
https://doi.org/10.1056/NEJMoa1403291 pmid: 25199060
12 Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, Humbert M, Katz LE, Keene ON, Yancey SW, Chanez P; MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014; 371(13): 1198–1207
https://doi.org/10.1056/NEJMoa1403290 pmid: 25199059
13 Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, Murphy K, Maspero JF, O’Brien C, Korn S. 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(5): 355–366
https://doi.org/10.1016/S2213-2600(15)00042-9 pmid: 25736990
14 Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, Sproule S, Gilmartin G, Aurivillius M, Werkström V, Goldman M; SIROCCO study investigators. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting b2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet 2016; 388(10056): 2115–2127
https://doi.org/10.1016/S0140-6736(16)31324-1 pmid: 27609408
15 Ghazi A, Trikha A, Calhoun WJ. Benralizumab—a humanized mAb to IL-5Ra with enhanced antibody-dependent cell-mediated cytotoxicity—a novel approach for the treatment of asthma. Expert Opin Biol Ther 2012; 12(1): 113–118
https://doi.org/10.1517/14712598.2012.642359 pmid: 22136436
16 Busse WW, Katial R, Gossage D, Sari S, Wang B, Kolbeck R, Coyle AJ, Koike M, Spitalny GL, Kiener PA, Geba GP, Molfino NA. Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti-IL-5 receptor alpha antibody, in a phase I study of subjects with mild asthma. J Allergy Clin Immunol 2010; 125(6): 1237–1244.e2
https://doi.org/10.1016/j.jaci.2010.04.005 pmid: 20513521
17 Menzella F, Lusuardi M, Galeone C, Facciolongo N, Zucchi L. The clinical profile of benralizumab in the management of severe eosinophilic asthma. Ther Adv Respir Dis 2016; 10(6): 534–548
https://doi.org/10.1177/1753465816667659 pmid: 27612492
18 Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1. 0. The Cochrane Collaboration, 2011
19 Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savović J, Schulz KF, Weeks L, Sterne JA; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928
https://doi.org/10.1136/bmj.d5928 pmid: 22008217
20 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327(7414): 557–560
https://doi.org/10.1136/bmj.327.7414.557 pmid: 12958120
21 Laviolette M, Gossage DL, Gauvreau G, Leigh R, Olivenstein R, Katial R, Busse WW, Wenzel S, Wu Y, Datta V, Kolbeck R, Molfino NA. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol 2013; 132(5): 1086–1096.e5
https://doi.org/10.1016/j.jaci.2013.05.020 pmid: 23866823
22 Castro M, Wenzel SE, Bleecker ER, Pizzichini E, Kuna P, Busse WW, Gossage DL, Ward CK, Wu Y, Wang B, Khatry DB, van der Merwe R, Kolbeck R, Molfino NA, Raible DG. Benralizumab, an anti-interleukin 5 receptor a monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med 2014; 2(11): 879–890
https://doi.org/10.1016/S2213-2600(14)70201-2 pmid: 25306557
23 Park HS, Kim MK, Imai N, Nakanishi T, Adachi M, Ohta K, Tohda Y; Asian Benralizumab Study Group. A phase 2a study of benralizumab for patients with eosinophilic asthma in South Korea and Japan. Int Arch Allergy Immunol 2016; 169(3): 135–145
https://doi.org/10.1159/000444799 pmid: 27097165
24 FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, Ferguson GT, Busse WW, Barker P, Sproule S, Gilmartin G, Werkström V, Aurivillius M, Goldman M; CALIMA study investigators. Benralizumab, an anti-interleukin-5 receptor a monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2016; 388(10056): 2128–2141
https://doi.org/10.1016/S0140-6736(16)31322-8 pmid: 27609406
25 Hilvering B, Xue L, Pavord ID. Evidence for the efficacy and safety of anti-interleukin-5 treatment in the management of refractory eosinophilic asthma. Ther Adv Respir Dis 2015; 9(4): 135–145
https://doi.org/10.1177/1753465815581279 pmid: 25900924
26 Rudulier CD, Larché M, Moldaver D. Treatment with anti-cytokine monoclonal antibodies can potentiate the target cytokine rather than neutralize its activity. Allergy 2016; 71(3): 283–285
https://doi.org/10.1111/all.12816 pmid: 26619376
27 Pham TH, Damera G, Newbold P, Ranade K. Reductions in eosinophil biomarkers by benralizumab in patients with asthma. Respir Med 2016; 111: 21–29
https://doi.org/10.1016/j.rmed.2016.01.003 pmid: 26775606
28 Ortega HG, Yancey SW, Mayer B, Gunsoy NB, Keene ON, Bleecker ER, Brightling CE, Pavord ID. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med 2016; 4(7): 549–556
https://doi.org/10.1016/S2213-2600(16)30031-5 pmid: 27177493
29 Cabon Y, Molinari N, Marin G, Vachier I, Gamez AS, Chanez P, Bourdin A. Comparison of anti-interleukin-5 therapies in patients with severe asthma: global and indirect meta-analyses of randomized placebo-controlled trials. Clin Exp Allergy 2017; 47(1): 129–138
https://doi.org/10.1111/cea.12853 pmid: 27859832
30 Wang B, Yan L, Hutmacher M, White W, Ward CK, Nielsen J, Wu Y, Goldman M, Raible DG, Roskos L. Exposure-response analysis for determination of benralizumab optimal dosing regimen in adults with asthma. Am J Respir Crit Care Med 2014; 189: A1324
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