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The Current State of Biologic Therapies for Treatment of Refractory Asthma

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Abstract

Asthma is a heterogeneous disease, with the immune processes behind the chronic inflammation underlying this disorder differing between the various identified asthma endotypes. In addition to heterogeneity in underlying disease pathophysiology, asthmatics fall across a broad spectrum of disease severity and can vary greatly in their response to convention asthma therapies. A small percentage of patients with severe persistent asthma will remain uncontrolled despite treatment with high-dose inhaled corticosteroids and a long-acting beta-agonist. Less than two decades ago, there were few options for these treatment-refractory asthmatics beyond chronic systemic steroids, with their myriad of treatment-limiting side effects. However, in recent years, there have been a growing number of Food and Drug Administration (FDA)–approved biologic medications with targets that include immunoglobulin E (IgE), interleukin-5 (IL-5), the IL-5 receptor and the IL-4/IL-13 receptor-alpha subunit. The current FDA-approved biologics for severe persistent asthma are omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab. These monoclonal antibodies have been shown to improve asthma control, decrease asthma exacerbations and decrease glucocorticoid dependence in certain subsets of patients with asthma. The optimal biologic for treatment of severe asthma varies from patient to patient, depending on the underlying pathophysiology of the patient’s disease. For each of these medications, there are certain biomarkers that can help predict whether a patient is likely to respond favorably to the medication. This review will discuss the currently approved biologics for severe persistent asthma, including their indications, efficacy and side effects.

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References

  1. Broaddus VC et al (2016) Chapter 38 Asthma. In: Murray & Nadel's textbook of respiratory medicine. Elsevier/Saunders, Philadelphia, PA, p 1 online resource

    Google Scholar 

  2. Adkinson NF et al (2014) Chapter 38: Epidemiology of Asthma and Allergic Airway Diseases. In: Middleton's allergy: principles and practice. Elsevier/Saunders, Philadelphia, PA (xxvii, 1690 pages)

    Google Scholar 

  3. Muraro A et al Precision medicine in patients with allergic diseases: Airway diseases and atopic dermatitis—PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol 137(5):1347–1358

  4. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2017. Available from: www.ginasthma.org

  5. Good JT Jr et al Refractory Asthma. CHEST 141(3):599–606

  6. Barrett, M.L., L.M. Wier, and R. Washington, Trends in Pediatric and Adult Hospital Stays for Asthma, 2000–2010: Statistical Brief #169, in Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. 2006: Rockville (MD)

  7. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, Pedersen SE, GOAL Investigators Group (2004) Can guideline-defined asthma control be achieved? The gaining optimal asthma control study. Am J Respir Crit Care Med 170(8):836–844

    Article  Google Scholar 

  8. Busse W et al Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 108(2):184–190

  9. Chipps BE, Lanier B, Milgrom H, Deschildre A, Hedlin G, Szefler SJ, Kattan M, Kianifard F, Ortiz B, Haselkorn T, Iqbal A, Rosén K, Trzaskoma B, Busse WW (2017) Omalizumab in children with uncontrolled allergic asthma: review of clinical trial and real-world experience. J Allergy Clin Immunol 139(5):1431–1444

    Article  CAS  Google Scholar 

  10. McKeage K (2013) Omalizumab: a review of its use in patients with severe persistent allergic asthma. Drugs 73(11):1197–1212

    Article  CAS  Google Scholar 

  11. Strunk RC, Bloomberg GR (2006) Omalizumab for asthma. N Engl J Med 354(25):2689–2695

    Article  CAS  Google Scholar 

  12. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, Adcock IM, Bateman ED, Bel EH, Bleecker ER, Boulet LP, Brightling C, Chanez P, Dahlen SE, Djukanovic R, Frey U, Gaga M, Gibson P, Hamid Q, Jajour NN, Mauad T, Sorkness RL, Teague WG (2014) International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 43(2):343–373

    Article  CAS  Google Scholar 

  13. Milgrom H, Berger W, Nayak A, Gupta N, Pollard S, McAlary M, Taylor AF, Rohane P (2001) Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics 108(2):E36

    Article  CAS  Google Scholar 

  14. Holgate ST, Chuchalin AG, Hébert J, Lötvall J, Persson GB, Chung KF, Bousquet J, Kerstjens HA, Fox H, Thirlwell J, Cioppa GD, Omalizumab 011 International Study Group (2004) Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma. Clin Exp Allergy 34(4):632–638

    Article  CAS  Google Scholar 

  15. Soler M et al (2001) The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J 18(2):254–261

    Article  CAS  Google Scholar 

  16. Deschildre A, Marguet C, Salleron J, Pin I, Rittié JL, Derelle J, Taam RA, Fayon M, Brouard J, Dubus JC, Siret D, Weiss L, Pouessel G, Beghin L, Just J (2013) Add-on omalizumab in children with severe allergic asthma: a 1-year real life survey. Eur Respir J 42(5):1224–1233

    Article  CAS  Google Scholar 

  17. Hanania NA, Wenzel S, Rosén K, Hsieh HJ, Mosesova S, Choy DF, Lal P, Arron JR, Harris JM, Busse W (2013) Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med 187(8):804–811

    Article  CAS  Google Scholar 

  18. Humbert M, Busse W, Hanania NA, Lowe PJ, Canvin J, Erpenbeck VJ, Holgate S (2014) Omalizumab in asthma: an update on recent developments. J Allergy Clin Immunol Pract 2(5):525–36 e1

    Article  Google Scholar 

  19. Yancey SW, Ortega HG, Keene ON, Mayer B, Gunsoy NB, Brightling CE, Bleecker ER, Haldar P, Pavord ID (2017) Meta-analysis of asthma-related hospitalization in mepolizumab studies of severe eosinophilic asthma. J Allergy Clin Immunol 139(4):1167–1175 e2

    Article  CAS  Google Scholar 

  20. Teach SJ et al Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. J Allergy Clin Immunol 136(6):1476–1485

  21. Maselli DJ et al (2013) Efficacy of omalizumab in asthmatic patients with IgE levels above 700 IU/mL: a retrospective study. Ann Allergy Asthma Immunol 110(6):457–461

    Article  CAS  Google Scholar 

  22. Wang KY, Sindher SB, Stinson R, DaVeiga S (2018) Efficacy and safety of omalizumab in pediatric patients with high immunoglobulin E levels: a case series. Allergy Asthma Proc 39(4):289–291

    Article  CAS  Google Scholar 

  23. Iribarren C, Rahmaoui A, Long AA, Szefler SJ, Bradley MS, Carrigan G, Eisner MD, Chen H, Omachi TA, Farkouh ME, Rothman KJ (2017) Cardiovascular and cerebrovascular events among patients receiving omalizumab: results from EXCELS, a prospective cohort study in moderate to severe asthma. J Allergy Clin Immunol 139(5):1489–1495 e5

    Article  CAS  Google Scholar 

  24. Namazy J, Cabana MD, Scheuerle AE, Thorp JM Jr, Chen H, Carrigan G, Wang Y, Veith J, Andrews EB (2015) The Xolair pregnancy registry (EXPECT): the safety of omalizumab use during pregnancy. J Allergy Clin Immunol 135(2):407–412

    Article  CAS  Google Scholar 

  25. Zazzali JL, Raimundo KP, Trzaskoma B, Rosén KE, Schatz M (2015) Changes in asthma control, work productivity, and impairment with omalizumab: 5-year EXCELS study results. Allergy Asthma Proc 36(4):283–292

    Article  CAS  Google Scholar 

  26. Bachert C, Sousa AR, Lund VJ, Scadding GK, Gevaert P, Nasser S, Durham SR, Cornet ME, Kariyawasam HH, Gilbert J, Austin D, Maxwell AC, Marshall RP, Fokkens WJ (2017) Reduced need for surgery in severe nasal polyposis with mepolizumab: randomized trial. J Allergy Clin Immunol 140(4):1024–1031 e14

    Article  CAS  Google Scholar 

  27. Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick L, Robinson D, Wenzel S, Busse W, Hansel TT, Barnes NC, International Mepolizumab Study Group (2007) A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med 176(11):1062–1071

    Article  CAS  Google Scholar 

  28. Zeiger RS et al Blood eosinophil count and outcomes in severe uncontrolled asthma: a prospective study. J Allergy Clin Immunol Pract 5(1):144–153.e8

  29. 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(10):985–993

    Article  CAS  Google Scholar 

  30. Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, Ortega HG, Pavord ID, SIRIUS Investigators (2014) Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 371(13):1189–1197

    Article  Google Scholar 

  31. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald J, Chetta A, Humbert M, Katz LE, Keene ON, Yancey SW, Chanez P, MENSA Investigators (2014) Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 371(13):1198–1207

    Article  Google Scholar 

  32. Abonia JP, Putnam PE (2011) Mepolizumab in eosinophilic disorders. Expert Rev Clin Immunol 7(4):411–417

    Article  CAS  Google Scholar 

  33. Cinqair [prescribing information]. Frazer, Pa: Teva Respiratory, LLC; 2016

  34. Fowler SJ, Tavernier G, Niven R High blood eosinophil counts predict sputum eosinophilia in patients with severe asthma. J Allergy Clin Immunol 135(3):822–824.e2

  35. 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(5):355–366

    Article  CAS  Google Scholar 

  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(4):789–798

    Article  Google Scholar 

  37. Kolbeck R et al MEDI-563, a humanized anti–IL-5 receptor α mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol 125(6):1344–1353.e2

  38. Bleecker ER, FitzGerald J, Chanez P, Papi A, Weinstein SF, Barker P, Sproule S, Gilmartin G, Aurivillius M, Werkström V, Goldman M, SIROCCO study investigators (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(10056):2115–2127

    Article  CAS  Google Scholar 

  39. FitzGerald JM 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(10056):2128–2141

    Article  CAS  Google Scholar 

  40. Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, Barker P, Sproule S, Ponnarambil S, Goldman M, ZONDA Trial Investigators (2017) Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med 376(25):2448–2458

    Article  CAS  Google Scholar 

  41. 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(1):14–20

    Article  Google Scholar 

  42. Busse WW et al Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti–IL-5 receptor α antibody, in a phase I study of subjects with mild asthma. J Allergy Clin Immunol 125(6):1237–1244.e2

  43. Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, Pirozzi G, Sutherland ER, Evans RR, Joish VN, Eckert L, Graham NM, Stahl N, Yancopoulos GD, Louis-Tisserand M, Teper A (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(10039):31–44

    Article  CAS  Google Scholar 

  44. Dupixent (dupilumab). Tarrytown, NY: Regeneron Pharmaceuticals, 2017 (package insert)

  45. Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, Wang L, Kirkesseli S, Rocklin R, Bock B, Hamilton J, Ming JE, Radin A, Stahl N, Yancopoulos GD, Graham N, Pirozzi G (2013) Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 368(26):2455–2466

    Article  CAS  Google Scholar 

  46. Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, van der Merwe R (2017) Tezepelumab in adults with uncontrolled asthma. N Engl J Med 377(10):936–946

    Article  CAS  Google Scholar 

  47. Bel EH (2017) Moving upstream - anti-TSLP in persistent uncontrolled asthma. N Engl J Med 377(10):989–991

    Article  Google Scholar 

  48. Xolair (omalizumab). San Francisco: Genentech, 2003 (package insert)

  49. Nucala [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2015

  50. Fasenra (benralizumab) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017

  51. Whittington MD et al (2017) Assessing the value of mepolizumab for severe eosinophilic asthma: a cost-effectiveness analysis. Ann Allergy Asthma Immunol 118(2):220–225

    Article  CAS  Google Scholar 

  52. Ehteshami-Afshar S, FitzGerald J, Doyle-Waters MM, Sadatsafavi M (2016) The global economic burden of asthma and chronic obstructive pulmonary disease. Int J Tuberc Lung Dis 20(1):11–23

    Article  CAS  Google Scholar 

  53. Zafari Z, Sadatsafavi M, Mark FitzGerald J (2018) Cost-effectiveness of tiotropium versus omalizumab for uncontrolled allergic asthma in US. Cost Eff Resour Alloc 16:3

    Article  Google Scholar 

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Mavissakalian, M., Brady, S. The Current State of Biologic Therapies for Treatment of Refractory Asthma. Clinic Rev Allerg Immunol 59, 195–207 (2020). https://doi.org/10.1007/s12016-020-08776-8

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