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Lung

, Volume 196, Issue 5, pp 517–530 | Cite as

Comparative Efficacy of Anti IL-4, IL-5 and IL-13 Drugs for Treatment of Eosinophilic Asthma: A Network Meta-analysis

  • Imran H. Iftikhar
  • Mathew Schimmel
  • William Bender
  • Colin Swenson
  • David Amrol
ASTHMA

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.

Keywords

Eosinophilic asthma Benralizumab Dupilumab Mepolizumab Reslizumab 

Notes

Author 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.

Funding

This study was not sponsored by any funding agency or pharmaceutical company.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

408_2018_151_MOESM1_ESM.docx (431 kb)
Supplementary material 1 (DOCX 430 KB)

References

  1. 1.
    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 185:612–619CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Carr TF, Zeki AA, Kraft M (2018) Eosinophilic and noneosinophilic asthma. Am J Respir Crit Care Med 197:22–37CrossRefPubMedGoogle Scholar
  3. 3.
    Lambrecht BN, Hammad H (2015) The immunology of asthma. Nat Immunol 16:45–56CrossRefPubMedGoogle Scholar
  4. 4.
    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 43:343–373CrossRefGoogle Scholar
  5. 5.
    Kumar R, Singh J (2014) Biosimilar drugs: current status. Int J Appl Basic Med Res 4:63–66CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    McCracken JL, Veeranki SP, Ameredes BT, Calhoun WJ (2017) Diagnosis and management of asthma in adults: a review. JAMA 318:279–290CrossRefPubMedGoogle Scholar
  7. 7.
    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 12:113–118CrossRefPubMedGoogle Scholar
  8. 8.
    Vatrella A, Fabozzi I, Calabrese C, Maselli R, Pelaia G (2014) Dupilumab: a novel treatment for asthma. J Asthma Allergy 7:123–130CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Humbert M, Busse W, Hanania NA (2018) Controversies and opportunities in severe asthma. Curr Opin Pulm Med 24:83–93CrossRefPubMedGoogle Scholar
  10. 10.
    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 4:781–796CrossRefGoogle Scholar
  11. 11.
    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 14:1197–1211PubMedGoogle Scholar
  12. 12.
    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 24:1446–1456CrossRefPubMedGoogle Scholar
  13. 13.
    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
  14. 14.
    Rucker G (2012) Network meta-analysis, electrical networks and graph theory. Res Synth Methods 3:312–324CrossRefPubMedGoogle Scholar
  15. 15.
    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 388:2115–2127CrossRefGoogle Scholar
  16. 16.
    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 5:568–576CrossRefPubMedGoogle Scholar
  17. 17.
    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 388:2128–2141CrossRefGoogle Scholar
  18. 18.
    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 150:799–810CrossRefPubMedGoogle Scholar
  19. 19.
    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 365:1088–1098CrossRefGoogle Scholar
  20. 20.
    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 2:879–890CrossRefGoogle Scholar
  21. 21.
    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 162:777–784CrossRefPubMedGoogle Scholar
  22. 22.
    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 376:2448–2458CrossRefPubMedGoogle Scholar
  23. 23.
    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 33:14–20CrossRefPubMedGoogle Scholar
  24. 24.
    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 169:135–145CrossRefPubMedGoogle Scholar
  25. 25.
    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 388:31–44CrossRefPubMedGoogle Scholar
  26. 26.
    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 368:2455–2466CrossRefGoogle Scholar
  27. 27.
    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 70:748–756CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    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 e512CrossRefPubMedGoogle Scholar
  29. 29.
    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 371:1189–1197CrossRefGoogle Scholar
  30. 30.
    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 5:390–400CrossRefPubMedGoogle Scholar
  31. 31.
    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 176:1062–1071CrossRefPubMedGoogle Scholar
  32. 32.
    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 360:973–984CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    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 360:985–993CrossRefGoogle Scholar
  34. 34.
    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 371:1198–1207CrossRefGoogle Scholar
  35. 35.
    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 380:651–659CrossRefGoogle Scholar
  36. 36.
    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 150:789–798CrossRefPubMedGoogle Scholar
  37. 37.
    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 184:1125–1132CrossRefGoogle Scholar
  38. 38.
    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 3:355–366CrossRefPubMedGoogle Scholar
  39. 39.
    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 3:692–701CrossRefGoogle Scholar
  40. 40.
    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 41:330–338CrossRefGoogle Scholar
  41. 41.
    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 132:72–80CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    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 70:115–120CrossRefPubMedGoogle Scholar
  43. 43.
    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 44:1137–1145CrossRefPubMedGoogle Scholar
  44. 44.
    Christensen RD, Hill HR (1987) Exercise-induced changes in the blood concentration of leukocyte populations in teenage athletes. Am J Pediatr Hematol Oncol 9:140–142CrossRefPubMedGoogle Scholar
  45. 45.
    Dahl R (1977) Diurnal variation in the number of circulating eosinophil leucocytes in normal controls and asthmatics. Acta Allergol 32:301–303CrossRefPubMedGoogle Scholar
  46. 46.
    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 167:199–204CrossRefPubMedGoogle Scholar
  47. 47.
    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 356:2144–2148CrossRefPubMedGoogle Scholar
  48. 48.
    Koczulla AR, Vogelmeier CF, Garn H, Renz H (2017) New concepts in asthma: clinical phenotypes and pathophysiological mechanisms. Drug Discov Today 22:388–396CrossRefPubMedGoogle Scholar
  49. 49.
    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 7:301ra129CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Imran H. Iftikhar
    • 1
  • Mathew Schimmel
    • 1
  • William Bender
    • 1
  • Colin Swenson
    • 1
  • David Amrol
    • 2
  1. 1.Division of Pulmonary, Allergy, Critical Care & Sleep MedicineEmory University School of MedicineAtlantaUSA
  2. 2.Division of Allergy and ImmunologyUniversity of South Carolina School of MedicineColumbiaUSA

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