Abstract
Background
Several new biologics have been studied in patients with eosinophilic asthma with varying degrees of response on clinical outcomes. No head-to-head trial has directly compared the efficacy of these drugs.
Objective
To synthesize data on the relative efficacy of benralizumab, dupilumab, lebrikizumab, mepolizumab, reslizumab, and tralokinumab using network meta-analysis.
Data sources
We searched PubMed from inception to December 15th, 2017.
Data extraction and synthesis
We used the ‘frequentist’ methodology with random effect models using primarily ‘netmeta’ function in R to generate network meta-analysis results. Outcomes assessed included changes in forced expiratory volume-in 1 s (FEV1), asthma control questionnaire (ACQ), and asthma quality of life questionnaire (AQLQ). We also separately analyzed the annualized rate ratios for asthma exacerbations for each drug and compared to placebo. For all outcomes assessed, all drugs were superior to placebo except tralokinumab. In terms of magnitude of effect, dupilumab, followed by reslizumab and benralizumab showed the greatest increase in FEV1, 0.16L (95% CIs: 0.08–0.24), 0.13L (0.10–0.17), and 0.12L (0.08–0.17), compared to placebo. While mepolizumab, followed by dupliumab, benralizumab, and reslizumab showed reductions in ACQ scores, in order of magnitude of effect, dupilumab, followed by mepolizumab, benralizumab, and reslizumab showed the greatest increase in AQLQ scores. All drugs decreased asthma exacerbations but the results were only significant for reslizumab and dupilumab.
Conclusions
All drugs except for tralokinumab showed improvements in FEV1, ACQ, and AQLQ. Only reslizumab and dupilumab were associated with statistically significant reductions in asthma exacerbation rates.
Similar content being viewed by others
References
McGrath KW, Icitovic N, Boushey HA, Lazarus SC, Sutherland ER, Chinchilli VM, Fahy JV, Asthma Clinical Research Network of the National Heart, Lung, and Blood Institute (2012) A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med 185:612–619
Carr TF, Zeki AA, Kraft M (2018) Eosinophilic and noneosinophilic asthma. Am J Respir Crit Care Med 197:22–37
Lambrecht BN, Hammad H (2015) The immunology of asthma. Nat Immunol 16:45–56
Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, Adcock IM, Bateman ED, Bel EH, Bleecker ER et al (2014) International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 43:343–373
Kumar R, Singh J (2014) Biosimilar drugs: current status. Int J Appl Basic Med Res 4:63–66
McCracken JL, Veeranki SP, Ameredes BT, Calhoun WJ (2017) Diagnosis and management of asthma in adults: a review. JAMA 318:279–290
Ghazi A, Trikha A, Calhoun WJ (2012) Benralizumab–a humanized mAb to IL-5Ralpha with enhanced antibody-dependent cell-mediated cytotoxicity–a novel approach for the treatment of asthma. Expert Opin Biol Ther 12:113–118
Vatrella A, Fabozzi I, Calabrese C, Maselli R, Pelaia G (2014) Dupilumab: a novel treatment for asthma. J Asthma Allergy 7:123–130
Humbert M, Busse W, Hanania NA (2018) Controversies and opportunities in severe asthma. Curr Opin Pulm Med 24:83–93
Hanania NA, Korenblat P, Chapman KR, Bateman ED, Kopecky P, Paggiaro P, Yokoyama A, Olsson J, Gray S, Holweg CT et al (2016) Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respir Med 4:781–796
Iftikhar IH, Alghothani L, Sardi A, Berkowitz D, Musani AI (2017) Transbronchial lung cryobiopsy and video-assisted thoracoscopic lung biopsy in the diagnosis of diffuse parenchymal lung disease. a meta-analysis of diagnostic test accuracy. Ann Am Thorac Soc 14:1197–1211
Iftikhar IH, Alghothani L, Trotti LM (2017) Gabapentin enacarbil, pregabalin and rotigotine are equally effective in restless legs syndrome: a comparative meta-analysis. Eur J Neurol 24:1446–1456
Higgins JPT, Green S (eds) (2011) Cochrane handbook for systematic reviews of interventions version 5.1.0 (updated March 2011). The Cochrane Collaboration. Available from http://www.cochrane-handbook.org
Rucker G (2012) Network meta-analysis, electrical networks and graph theory. Res Synth Methods 3:312–324
Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, Sproule S, Gilmartin G, Aurivillius M, Werkstrom V et al (2016) Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet 388:2115–2127
Ferguson GT, FitzGerald JM, Bleecker ER, Laviolette M, Bernstein D, LaForce C, Mansfield L, Barker P, Wu Y, Jison M et al (2017) Benralizumab for patients with mild to moderate, persistent asthma (BISE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med 5:568–576
FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, Ferguson GT, Busse WW, Barker P, Sproule S et al (2016) Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 388:2128–2141
Corren J, Weinstein S, Janka L, Zangrilli J, Garin M (2016) Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest 150:799–810
Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, Harris JM, Scheerens H, Wu LC, Su Z et al (2011) Lebrikizumab treatment in adults with asthma. N Engl J Med 365:1088–1098
Castro M, Wenzel SE, Bleecker ER, Pizzichini E, Kuna P, Busse WW, Gossage DL, Ward CK, Wu Y, Wang B et al (2014) Benralizumab, an anti-interleukin 5 receptor alpha monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med 2:879–890
Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, Ioannidis JP, Straus S, Thorlund K, Jansen JP et al (2015) The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med 162:777–784
Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, Barker P, Sproule S, Ponnarambil S, Goldman M et al (2017) Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med 376:2448–2458
Nowak RM, Parker JM, Silverman RA, Rowe BH, Smithline H, Khan F, Fiening JP, Kim K, Molfino NA (2015) A randomized trial of benralizumab, an antiinterleukin 5 receptor alpha monoclonal antibody, after acute asthma. Am J Emerg Med 33:14–20
Park HS, Kim MK, Imai N, Nakanishi T, Adachi M, Ohta K, Tohda Y (2016) Asian benralizumab study G: a phase 2a study of benralizumab for patients with eosinophilic asthma in South Korea and Japan. Int Arch Allergy Immunol 169:135–145
Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, Pirozzi G, Sutherland ER, Evans RR, Joish VN et al (2016) 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 388:31–44
Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, Wang L, Kirkesseli S, Rocklin R, Bock B et al (2013) Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 368:2455–2466
Hanania NA, Noonan M, Corren J, Korenblat P, Zheng Y, Fischer SK, Cheu M, Putnam WS, Murray E, Scheerens H et al (2015) Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. Thorax 70:748–756
Noonan M, Korenblat P, Mosesova S, Scheerens H, Arron JR, Zheng Y, Putnam WS, Parsey MV, Bohen SP, Matthews JG (2013) Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids. J Allergy Clin Immunol 132:567–574 e512
Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, Ortega HG, Pavord ID, Investigators S (2014) Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 371:1189–1197
Chupp GL, Bradford ES, Albers FC, Bratton DJ, Wang-Jairaj J, Nelsen LM, Trevor JL, Magnan A, Ten Brinke A (2017) Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med 5:390–400
Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick L, Robinson D, Wenzel S, Busse W, Hansel TT et al (2007) A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med 176:1062–1071
Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall RP, Bradding P, Green RH, Wardlaw AJ et al (2009) Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 360:973–984
Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, Hargreave FE, O’Byrne PM (2009) Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 360:985–993
Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, Humbert M, Katz LE, Keene ON, Yancey SW et al (2014) Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 371:1198–1207
Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, Ortega H, Chanez P (2012) Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 380:651–659
Bjermer L, Lemiere C, Maspero J, Weiss S, Zangrilli J, Germinaro M (2016) Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest 150:789–798
Castro M, Mathur S, Hargreave F, Boulet LP, Xie F, Young J, Wilkins HJ, Henkel T, Nair P (2011) Res-5—study G: reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med 184:1125–1132
Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, Murphy K, Maspero JF, O’Brien C, Korn S (2015) 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 3:355–366
Brightling CE, Chanez P, Leigh R, O’Byrne PM, Korn S, She D, May RD, Streicher K, Ranade K, Piper E (2015) Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med 3:692–701
Piper E, Brightling C, Niven R, Oh C, Faggioni R, Poon K, She D, Kell C, May RD, Geba GP et al (2013) A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J 41:330–338
Hastie AT, Moore WC, Li H, Rector BM, Ortega VE, Pascual RM, Peters SP, Meyers DA, Bleecker ER, National Heart L et al (2013) Biomarker surrogates do not accurately predict sputum eosinophil and neutrophil percentages in asthmatic subjects. J Allergy Clin Immunol 132:72–80
Wagener AH, de Nijs SB, Lutter R, Sousa AR, Weersink EJ, Bel EH, Sterk PJ (2015) External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma. Thorax 70:115–120
Zhang XY, Simpson JL, Powell H, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, Jenkins C, Peters MJ et al (2014) Full blood count parameters for the detection of asthma inflammatory phenotypes. Clin Exp Allergy 44:1137–1145
Christensen RD, Hill HR (1987) Exercise-induced changes in the blood concentration of leukocyte populations in teenage athletes. Am J Pediatr Hematol Oncol 9:140–142
Dahl R (1977) Diurnal variation in the number of circulating eosinophil leucocytes in normal controls and asthmatics. Acta Allergol 32:301–303
Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS (2003) Eosinophil’s role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med 167:199–204
Leckie MJ, ten Brinke A, Khan J, Diamant Z, O’Connor BJ, Walls CM, Mathur AK, Cowley HC, Chung KF, Djukanovic R et al (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356:2144–2148
Koczulla AR, Vogelmeier CF, Garn H, Renz H (2017) New concepts in asthma: clinical phenotypes and pathophysiological mechanisms. Drug Discov Today 22:388–396
Choy DF, Hart KM, Borthwick LA, Shikotra A, Nagarkar DR, Siddiqui S, Jia G, Ohri CM, Doran E, Vannella KM et al (2015) TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma. Sci Transl Med 7:301ra129
Funding
This study was not sponsored by any funding agency or pharmaceutical company.
Author information
Authors and Affiliations
Contributions
IHI had full access to all of the extracted data in the network meta-analysis and takes responsibility for the integrity of the data and the accuracy of the data analysis. IHI conceptualized and designed the study protocol, conducted the analyses and wrote the first draft manuscript. IHI, MS, WB, and CS contributed to assessment of study quality. All authors contributed substantially to the interpretation of analyses and in revisions of manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Iftikhar, I.H., Schimmel, M., Bender, W. et al. Comparative Efficacy of Anti IL-4, IL-5 and IL-13 Drugs for Treatment of Eosinophilic Asthma: A Network Meta-analysis. Lung 196, 517–530 (2018). https://doi.org/10.1007/s00408-018-0151-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00408-018-0151-5