Efficacy and safety of benralizumab in patients with eosinophilic asthma: a meta-analysis of randomized placebo-controlled trials

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

References

[1] Global Asthma Network. The Global Asthma Report 2014. Auckland, New Zealand: Global Asthma Network, 2014. Available: http://www.globalasthmareport.org/resources/Global_Asthma_Report_2014.pdf

[2] McIvor RA. Emerging therapeutic options for the treatment of patients with symptomatic asthma. Ann Allergy Asthma Immunol 2015; 115(4): 265–271.e5

[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

[4] Chung KF. Targeting the interleukin pathway in the treatment of asthma. Lancet 2015; 386(9998): 1086–1096

[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

[6] Aleman F, Lim HF, Nair P. Eosinophilic endotype of asthma. Immunol Allergy Clin North Am 2016; 36(3): 559–568

[7] Cardet JC, Israel E. Update on reslizumab for eosinophilic asthma. Expert Opin Biol Ther 2015; 15(10): 1531–1539

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[20] Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327(7414): 557–560

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[31] Juniper EF, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change in a disease-specific Quality of Life Questionnaire. J Clin Epidemiol 1994; 47(1): 81–87

Compliance with ethics guidelines

Ting Liu, Faping Wang, Geng Wang, and Hui Mao declare no conflict of interest. This manuscript does not involve any research protocols requiring approval by any relevant institutional review boards or ethics committees.

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2017 Higher Education Press and Springer-Verlag GmbH Germany