Biologic agents for asthma treatment

Sung-Ryeol Kim; Jae-Hyun Lee

doi:10.4168/aard.2019.7.1.3

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Kim and Lee: Biologic agents for asthma treatment

Review

Allergy Asthma Respir Dis 2019;7(1):3-12.

Published online: 12 January 2019

DOI: https://doi.org/10.4168/aard.2019.7.1.3

Biologic agents for asthma treatment

Sung-Ryeol Kim, Jae-Hyun Lee

^¹Division of Allergy and Immunology, Department of Internal Medicine, Institute of Allergy, Yonsei University College of Medicine, Seoul Korea

Correspondence to: Jae-Hyun Lee https://orcid.org/0000-0002-0760-0071 Division of Allergy and Immunology, Department of Internal Medicine, Yonsei University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Korea Tel: +82-2-2228-1987, Fax: +82-2-393-6884, E-mail: jhleemd@yuhs.ac

• This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (Ministry of Science, ICT & Future Planning) (No. 2015R1C1A1A02036533).

Received 26 June 2018 Revised 28 January 2019 Accepted 18 January 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Most treatment strategies for asthma currently include inhaled corticosteroids, with the addition of long-acting beta-2-agonists or leukotriene modifiers, if necessary. However, some patients may not respond to conventional treatment. A better understanding of the pathophysiology of asthma has recently led to the development of biological agents, which have shown promising results for symptom control and future risk reduction in severe asthmatics. This article reviews currently available biologic agents, introduces related studies, and describes the subgroup of patients benefitting from each of biologic agents in the view point of precision medicine.

Keywords: Asthma, Biologic therapy, Precision medicine, Personalized medicine

References

1. Wurth M, Papantonakis CM, Nevel RJ, Thomas CS, Sokolow AG, Moore PE, et al. Risk factors associated with asthma development and control in children. Mouse infestation, antipyretics, respiratory viruses, and allergic sensitization. Am J Respir Crit Care Med. 2017; 196:1605–7.

2. Masoli M, Fabian D, Holt S, Beasley R. Global Initiative for Asthma (GINA) Program. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy. 2004; 59:469–78.

3. Kim BK, Kim JY, Kang MK, Yang MS, Park HW, Min KU, et al. Allergies are still on the rise? A 6-year nationwide population-based study in Korea. Allergol Int. 2016; 65:186–91.

4. Pelaia G, Vatrella A, Maselli R. The potential of biologics for the treatment of asthma. Nat Rev Drug Discov. 2012; 11:958–72.

5. Sokol CL, Barton GM, Farr AG, Medzhitov R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Immunol. 2008; 9:310–8.

6. Brusselle GG, Maes T, Bracke KR. Eosinophils in the spotlight: eosinophilic airway inflammation in nonallergic asthma. Nat Med. 2013; 19:977–9.

7. Davies DE, Wicks J, Powell RM, Puddicombe SM, Holgate ST. Airway remodeling in asthma: new insights. J Allergy Clin Immunol. 2003; 111:215–25.

8. Lötvall J, Akdis CA, Bacharier LB, Bjermer L, Casale TB, Custovic A, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011; 127:355–60.

9. Tabatabaian F, Ledford DK, Casale TB. Biologic and new therapies in asthma. Immunol Allergy Clin North Am. 2017; 37:329–43.

10. Katial RK, Bensch GW, Busse WW, Chipps BE, Denson JL, Gerber AN, et al. Changing paradigms in the treatment of severe asthma: the role of biologic therapies. J Allergy Clin Immunol Pract. 2017; 5:S1–14.

11. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012; 18:716–25.

12. Kuhl K, Hanania NA. Targeting IgE in asthma. Curr Opin Pulm Med. 2012; 18:1–5.

13. Busse W, Corren J, Lanier BQ, McAlary M, Fowler-Taylor A, Cioppa GD, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol. 2001; 108:184–90.

14. Fahy JV, Fleming HE, Wong HH, Liu JT, Su JQ, Reimann J, et al. The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am J Respir Crit Care Med. 1997; 155:1828–34.

15. Humbert M, Beasley R, Ayres J, Slavin R, Hébert J, Bousquet J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy. 2005; 60:309–16.

16. Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014; CD00:3559.

17. Bousquet J, Cabrera P, Berkman N, Buhl R, Holgate S, Wenzel S, et al. The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthma. Allergy. 2005; 60:302–8.

18. Brusselle G, Michils A, Louis R, Dupont L, Van de Maele B, Delobbe A, et al. “Real-life” effectiveness of omalizumab in patients with severe persistent allergic asthma: The PERSIST study. Respir Med. 2009; 103:1633–42.

19. Braunstahl GJ, Chen CW, Maykut R, Georgiou P, Peachey G, Bruce J. The eXpeRience registry: the ‘real-world' effectiveness of omalizumab in allergic asthma. Respir Med. 2013; 107:1141–51.

20. Humbert M, Busse W, Hanania NA, Lowe PJ, Canvin J, Erpenbeck VJ, et al. Omalizumab in asthma: an update on recent developments. J Allergy Clin Immunol Pract. 2014; 2:525–36.

21. Busse W, Spector S, Rosén K, Wang Y, Alpan O. High eosinophil count: a potential biomarker for assessing successful omalizumab treatment effects. J Allergy Clin Immunol. 2013; 132:485–6.

22. Lanier B, Bridges T, Kulus M, Taylor AF, Berhane I, Vidaurre CF. Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. J Allergy Clin Immunol. 2009; 124:1210–6.

23. Corren J, Casale T, Deniz Y, Ashby M. Omalizumab, a recombinant humanized anti-IgE antibody, reduces asthma-related emergency room visits and hospitalizations in patients with allergic asthma. J Allergy Clin Immunol. 2003; 111:87–90.

24. Busse W, Buhl R, Fernandez Vidaurre C, Blogg M, Zhu J, Eisner MD, et al. Omalizumab and the risk of malignancy: results from a pooled analysis. J Allergy Clin Immunol. 2012; 129:983–9.

25. Long A, Rahmaoui A, Rothman KJ, Guinan E, Eisner M, Bradley MS, et al. Incidence of malignancy in patients with moderate-to-severe asthma treated with or without omalizumab. J Allergy Clin Immunol. 2014; 134:560–7.

26. Cox L, Lieberman P, Wallace D, Simons FE, Finegold I, Platts-Mills T, et al. American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma & Immunology Omalizumab-Associated Anaphylaxis Joint Task Force follow-up report. J Allergy Clin Immunol. 2011; 128:210–2.

27. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002; 360:1715–21.

28. Jayaram L, Pizzichini MM, Cook RJ, Boulet LP, Lemière C, Pizzichini E, et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J. 2006; 27:483–94.

29. Chlumský J, Striz I, Terl M, Vondracek J. Strategy aimed at reduction of sputum eosinophils decreases exacerbation rate in patients with asthma. J Int Med Res. 2006; 34:129–39.

30. Takatsu K, Nakajima H. IL-5 and eosinophilia. Curr Opin Immunol. 2008; 20:288–94.

31. Shardonofsky FR, Venzor J 3rd, Barrios R, Leong KP, Huston DP. Therapeutic efficacy of an anti-IL-5 monoclonal antibody delivered into the respiratory tract in a murine model of asthma. J Allergy Clin Immunol. 1999; 104:215–21.

32. Flood-Page P, Menzies-Gow A, Phipps S, Ying S, Wangoo A, Ludwig MS, et al. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J Clin Invest. 2003; 112:1029–36.

33. Menzies-Gow A, Flood-Page P, Sehmi R, Burman J, Hamid Q, Robinson DS, et al. Anti-IL-5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics. J Allergy Clin Immunol. 2003; 111:714–9.

34. Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009; 360:985–93.

35. Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009; 360:973–84.

36. Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012; 380:651–9.

37. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014; 371:1198–207.

38. Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014; 371:1189–97.

39. Haldar P, Brightling CE, Singapuri A, Hargadon B, Gupta S, Monteiro W, et al. Outcomes after cessation of mepolizumab therapy in severe eosinophilic asthma: a 12-month follow-up analysis. J Allergy Clin Immunol. 2014; 133:921–3.

40. Castro M, Mathur S, Hargreave F, Boulet LP, Xie F, Young J, et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, place-bo-controlled study. Am J Respir Crit Care Med. 2011; 184:1125–32.

41. Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, et al. 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; 3:355–66.

42. Corren J, Weinstein S, Janka L, Zangrilli J, Garin M. Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. 2016; 150:799–810.

43. Bjermer L, Lemiere C, Maspero J, Weiss S, Zangrilli J, Germinaro M. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest. 2016; 150:789–98.

44. Ghazi A, Trikha A, Calhoun WJ. Benralizumab–a humanized mAb to IL-5Rα with enhanced antibody-dependent cell-mediated cytotoxicity–a novel approach for the treatment of asthma. Expert Opin Biol Ther. 2012; 12:113–8.

45. Busse WW, Katial R, Gossage D, Sari S, Wang B, Kolbeck R, et al. 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; 125:1237–44.

46. Laviolette M, Gossage DL, Gauvreau G, Leigh R, Olivenstein R, Katial R, et al. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol. 2013; 132:1086–96.

47. Castro M, Wenzel SE, Bleecker ER, Pizzichini E, Kuna P, Busse WW, et al. Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med. 2014; 2:879–90.

48. FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, et al. Benralizumab, an anti-interleukin-5 receptor α 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; 388:2128–41.

49. Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, et al. Oral Glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med. 2017; 376:2448–58.

50. Blanchard C, Mishra A, Saito-Akei H, Monk P, Anderson I, Rothenberg ME. Inhibition of human interleukin-13-induced respiratory and oesophageal inflammation by anti-human-interleukin-13 antibody (CAT-354). Clin Exp Allergy. 2005; 35:1096–103.

51. Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011; 365:1088–98.

52. Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet. 2007; 370:1422–31.

53. Slager RE, Otulana BA, Hawkins GA, Yen YP, Peters SP, Wenzel SE, et al. IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti-IL-4 receptor α antagonist. J Allergy Clin Immunol. 2012; 130:516–22.

54. Hanania NA, Noonan M, Corren J, Korenblat P, Zheng Y, Fischer SK, et al. Lebrikizumab in moderate-to-severe asthma: 9 pooled data from two randomised placebo-controlled studies. Thorax. 2015; 70:748–56.

55. Hanania NA, Korenblat P, Chapman KR, Bateman ED, Kopecky P, Paggiaro P, et al. 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. 2016; 4:781–96.

56. Piper E, Brightling C, Niven R, Oh C, Faggioni R, Poon K, et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J. 2013; 41:330–8.

57. Brightling CE, Chanez P, Leigh R, O'Byrne PM, Korn S, She D, et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med. 2015; 3:692–701.

58. Panettieri RA Jr, Wang M, Braddock M, Bowen K, Colice G. Tralokinumab for the treatment of severe, uncontrolled asthma: the ATMOSPHERE clinical development program. Immunotherapy. 2018; 10:473–90.

59. Tomkinson A, Tepper J, Morton M, Bowden A, Stevens L, Harris P, et al. Inhaled vs subcutaneous effects of a dual IL-4/IL-13 antagonist in a monkey model of asthma. Allergy. 2010; 65:69–77.

60. Otulana BA, Wenzel SE, Ind PW, Bowden A, Puthukkeril S, Tomkinson A, et al. A phase 2b study of inhaled pitrakinra, an IL-4/IL-13 antagonist, successfully identified responder subpopulations of patients with uncontrolled asthma. D101. Am J Respir Crit Care Med. 2011; 183:A6179.

61. Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013; 368:2455–66.

62. Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016; 388:31–44.

63. Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016; 375:2335–48.

64. Simpson EL, Gadkari A, Worm M, Soong W, Blauvelt A, Eckert L, et al. Dupilumab therapy provides clinically meaningful improvement in patient-reported outcomes (PROs): a phase IIb, randomized, placebo-controlled, clinical trial in adult patients with moderate to severe atopic dermatitis (AD). J Am Acad Dermatol. 2016; 75:506–15.

65. Blauvelt A, de Bruin-Weller M, Gooderham M, Cather JC, Weisman J, Pariser D, et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIB-ERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet. 2017; 389:2287–303.

66. Bachert C, Mannent L, Naclerio RM, Mullol J, Ferguson BJ, Gevaert P, et al. Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial. JAMA. 2016; 315:469–79.

67. Gonem S, Berair R, Singapuri A, Hartley R, Laurencin MFM, Bacher G, et al. Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial. Lancet Respir Med. 2016; 4:699–707.

68. Erpenbeck VJ, Popov TA, Miller D, Weinstein SF, Spector S, Magnusson B, et al. The oral CRTh2 antagonist QAW039 (fevipiprant): a phase II study in uncontrolled allergic asthma. Pulm Pharmacol Ther. 2016; 39:54–63.

69. Holgate ST, Noonan M, Chanez P, Busse W, Dupont L, Pavord I, et al. Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial. Eur Respir J. 2011; 37:1352–9.

70. Wenzel SE, Barnes PJ, Bleecker ER, Bousquet J, Busse W, Dahlén SE, et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factoralpha blockade in severe persistent asthma. Am J Respir Crit Care Med. 2009; 179:549–58.

71. Ying S, O'Connor B, Ratoff J, Meng Q, Mallett K, Cousins D, et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol. 2005; 174:8183–90.

72. Gauvreau GM, O'Byrne PM, Boulet LP, Wang Y, Cockcroft D, Bigler J, et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med. 2014; 370:2102–10.

73. Oh CK, Leigh R, McLaurin KK, Kim K, Hultquist M, Molfino NA. A randomized, controlled trial to evaluate the effect of an anti-interleukin-9 monoclonal antibody in adults with uncontrolled asthma. Respir Res. 2013; 14:93.

74. Busse WW, Israel E, Nelson HS, Baker JW, Charous BL, Young DY, et al. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial. Am J Respir Crit Care Med. 2008; 178:1002–8.

75. Kon OM, Sihra BS, Compton CH, Leonard TB, Kay AB, Barnes NC. Randomised, dose-ranging, placebo-controlled study of chimeric antibody to CD4 (keliximab) in chronic severe asthma. Lancet. 1998; 352:1109–13.

76. Busse WW, Holgate S, Kerwin E, Chon Y, Feng J, Lin J, et al. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med. 2013; 188:1294–302.

Table 1.

Biologic therapies for severe asthma^9,60

FDA approved
Drug	Mechanism of action	Approval	Dose & route	Potential biomarkers	Effect
Omalizumab	Blocks IgE interaction with Fcε RI	Ages 6 and older	150–375 mg subcutaneous (SC) every 2–4 wk; frequency based on IgE and body weight	Elevated IgE. Patients with higher FeNO and blood eosinophils >300 cells/μL	Decrease asthma exacerbations
Mepolizumab	IL-5 antagonist	Ages 12 and older	100 mg SC every 4 wk	Peripheral eosinophil count of >150 cells/μL or 300 cells/μL	Decrease in asthma exacerbations improvement in prepostbronchodilator FEV₁
Reslizumab	IL-5 antagonist	Ages 18 and older	3 mg/kg IV every 4 wk	Peripheral eosinophil count of >400 cells/μL	Decrease in asthma exacerbations and improvement in FEV₁
Benralizumab	IL-5 receptor α antagonists	Ages 12 and older	20–100 mg every 4–8 wk	Elevated peripheral blood eosinophil count	Decreased asthma exacerbations and in small study used in ER visit setting administration contributed to a 50% drop in exacerbation over 12 wk
Dupilumab	Inhibits IL-13 and IL-4 by targeting IL-4 α, a common receptor domain for both cytokines	Ages 12 and older	200 mg SC every 2 wk or 300 mg SC every 4 wk	Peripheral eosinophil count of >300 cells/μL or sputum >3%	Decrease in asthma exacerbations and improvement in FEV₁
In clinical trials
Tralokinumab	IL-13 antagonist	Phase 2b trials	NA	Elevated periostin and DDP-4	Decreased in asthma exacerbations and improvement in FEV₁
Pitrakinra	Blocking IL-4 receptor α	Phase 2b trials	NA	Peripheral eosinophil count of >300 cells/μL Elevated FeNO IL-4 receptor rs8832 SNP GG genotype	Decreased in asthma exacerbations

FDA, U.S. Food and Drug Administration; FeNO, Fractional exhaled nitric oxide; IL, interleukin; ER, emergency room; FEV₁, forced expiratory volume in 1 second; NA, not applicable.

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