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Genetically engineered drugs for treatment of bronchial asthma: recent achievements

https://doi.org/10.18093/0869-0189-2018-28-5-584-601

Abstract

Current population of patients with asthma is characterized by increasing resistance to standard pharmacotherapeutic agents such as inhaled corticosteroids, antileukotriene agents and anti-IgE antibodies. These findings were confirmed by international statistic data and indicate insufficient efficacy of the treatment. Asthma phenotyping encompassing a role of certain biomarkers for bronchial inflammation could contribute to achieving better response to treatment. Genetically engineered drugs could directly impact on mediators and modulators involved in the inflammation and bronchoconstriction. This is one of the most promising directions of the modern pharmacotherapy, particularly considering severe and difficult-to-treat asthma. A comparative analysis of efficacy and safety of currently available genetically engineered drug groups (monoclonal anti-IgE antibodies, monoclonal antibodies against interleukin (IL)-4/IL-13 and IL-5, and prostaglandin D2 receptor antagonists) was performed by the authors of this article on the basis of results of randomized controlled clinical trials (RCT). According to RCT results, omalizumab is still the leading genetically engineered drug. Moreover, evidence of efficacy and safety of novel agents has been published that allowed implementation these drugs in the routine clinical practice for treatment of severe eosinophilic asthma.

About the Authors

S. K. Zyryanov
The Peoples' Friendship University of Russia (Medical University); Moscow State Educational Government-Financed Institution City Clinical Hospital No.24 of Department of Health Care of the City of Moscow
Russian Federation

Sergey K. Zyryanov – Doctor of Medicine, Professor, Head of Department of General and Clinical Pharmacology, The Peoples' Friendship University of Russia, Deputy Chief Physician, State Educational Government-Financed Institution City Clinical Hospital No.24 of Department of Health Care of the City of Moscow

ul. Miklukho-Maklaya 6, Moscow, 117198, 

ul. Pistsovaya 10, Moscow, 127015



O. I. Butranova
The Peoples' Friendship University of Russia (Medical University); Moscow State Educational Government-Financed Institution City Clinical Hospital No.24 of Department of Health Care of the City of Moscow
Russian Federation

Olga I. Butranova – Candidate of Medicine, Assistant Professor of Chair of General and Clinical Pharmacology, Medical Institute, Federal State Autonomous Educational Institution for Higher Education Peoples' Friendship University of Russia, Deputy Chief Physician, State Educational Government-Financed Institution City Clinical Hospital No.24 of Department of Health Care of the City of Moscow

ul. Miklukho-Maklaya 6, Moscow, 117198, 

ul. Pistsovaya 10, Moscow, 127015



References

1. Demoly P., Annunziata K., Gubba E., Adamek L. Repeated cross-sectional survey of patient-reported asthma control in Europe in the past 5 years. Eur. Respir. Rev. 2012; 21 (123): 66–74. DOI: 10.1183/09059180.00008111.

2. Desai M., Oppenheimer J. Elucidating asthma phenotypes and endotypes: progress towards personalized medicine. Ann. Allergy Asthma Immunol. 2016; 116 (5): 394–401. DOI: 10.1016/j.anai.2015.12.024.

3. Wenzel S.E. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat. Med. 2012; 18 (5): 716–725. DOI: 10.1038/nm.2678.

4. Menzella F., Galeone C., Bertolini F. et al. Innovative treatments for severe refractory asthma: how to choose the right option for the right patient? J. Asthma Allergy. 2017; (10): 237–247. DOI: 10.2147/JAA.S144100.

5. Oettgen H.C. Fifty years later: Emerging functions of IgE antibodies in host defense, immune regulation, and allergic diseases. J. Allergy Clin. Immunol. 2016; 137 (6): 1631–1645. DOI: 10.1016/j.jaci.2016.04.009.

6. Bousquet J., Cabrera P., Berkman N. 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 (3): 302–308. DOI: 10.1111/j.1398-9995.2004.00770.x.

7. Humbert M., Beasley R., Ayres 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 (3): 309–316. DOI: 10.1111/j.1398-9995.2004.00772.x.

8. Brusselle G., Michils A., Louis R. et al. Real-life effectiveness of omalizumab in patients with severe persistent allergic asthma: The PERSIST study. Respir. Med. 2009; 103 (11):1633–1642. DOI: 10.1016/j.rmed.2009.06.014.

9. Braunstahl G.J., Chen C.W., Maykut R. et al. The eXpeRience registry: the 'real-world' effectiveness of omalizumab in allergic asthma. Respir. Med. 2013; 107 (8) 1141–1151. DOI: 10.1016/j.rmed.2013.04.017.

10. Milgrom H., Berger W., Nayak A. et al. Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics. 2001; 108 (2): e36. DOI: 10.1542/peds.108.2.e36.

11. Busse W.W., Morgan W.J., Gergen P.J. et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N. Engl. J. Med. 2011; 364 (11): 1005–1015. DOI: 10.1056/NEJMoa1009705.

12. Brodlie M., McKean M.C., Moss S., Spencer D.A. The oral corticosteroid-sparing effect of omalizumab in children with severe asthma. Arch. Dis. Child. 2012; 97 (7): 604–609. DOI: 10.1136/archdischild-2011-301570.

13. Odajima H., Ebisawa M., Nagakura T. et al. Omalizumab in Japanese children with severe allergic asthma uncontrolled with standard therapy. Allergol. Int. 2015; 64 (4): 364–370. DOI: 10.1016/j.alit.2015.05.006.

14. Odajima H., Ebisawa M., Nagakura T. et al. Long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with severe uncontrolled asthma. Allergol. Int. 2017; 66 (1): 106–115. DOI: 10.1016/j.alit.2016.06.004.

15. Deschildre A., Marguet C., Salleron J. et al. Add-on omalizumab in children with severe allergic asthma: a 1-year real life survey. Eur. Respir. J. 2013; 42 (5): 1224–1233. DOI: 10.1183/09031936.00149812.

16. Deschildre A., Marguet C., Langlois C. et al. Real-life long-term omalizumab therapy in children with severe allergic asthma. Eur. Respir. J. 2015; 46 (3): 856–859. DOI: 10.1183/09031936.00008115.

17. Campbell J.M., Wofford J.D., Knutsen A.P. Omalizumab treatment in children 6 to 18 years old with severe asthma at a children’s medical center. Pediatr. Allergy Immunol. Pulmonol. 2008; 21 (3): 123–148. DOI: 10.1089/pai.2008.0502.

18. Corren J., Kavati A., Ortiz B. et al. Efficacy and safety of omalizumab in children and adolescents with moderate-to-severe asthma: a systematic literature review. Allergy Asthma Proc. 2017; 38 (4): 250–263. DOI: 10.2500/aap.2017.38.4067.

19. Lanier B., Bridges T., Kulus M. et al. Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. J. Allergy Clin. Immunol. 2009; 124 (6): 1210–1216. DOI: 10.1016/j.jaci.2009.09.021.

20. Steiss J.O., Schmidt A., Nährlich L. et al. Immunoglobulin E monitoring and reduction of omalizumab therapy in children and adolescents. Allergy Asthma Proc. 2012; 33 (1): 77–81. DOI: 10.2500/aap.2012.33.3500.

21. Mansur A., Srivastava S., Mitchell V. et al. Longterm clinical outcomes of omalizumab therapy in severe allergic asthma: study of efficacy and safety. Respir. Med. 2017; 124: 36–43. DOI: 10.1016/j.rmed.2017.01.008.

22. Long A., Rahmaoui A., Rothman K.J. et al. Incidence of malignancy in patients with moderate-to-severe asthma treated with or without omalizumab. J. Allergy Clin. Immunol. 2014; 134 (3): 560–567. DOI: 10.1016/j.jaci.2014.02.007.

23. Harris J.M., Maciuca R., Bradley M.S. et al. A randomized trial of the efficacy and safety of quilizumab in adults with inadequately controlled allergic asthma. Respir. Res. 2016; (17): 29. DOI: 10.1186/s12931-016-0347-2.

24. Hanania N.A., Alpan O., Hamilos D.L. et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann. Intern. Med. 2011; 154 (9): 573–582. DOI: 10.7326/0003-4819-154-9-201105030-00002.

25. Gauvreau G.M., Arm J.P., Boulet L.P. et al. Efficacy and safety of multiple doses of QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergen-induced early asthmatic responses. J. Allergy Clin. Immunol. 2016; 138 (4): 1051-1059. DOI: 10.1016/j.jaci.2016.02.027.

26. Hanania N.A., Noonan M., Corren J. et al. Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. Thorax. 2015; 70 (8) 748–756. DOI: 10.1136/thoraxjnl-2014-206719.

27. Scheerens H., Arron J.R., Zheng Y. et al. The effects of lebrikizumab in patients with mild asthma following whole lung allergen challenge. Clin. Exp. Allergy. 2014; 44 (1): 38–46. DOI: 10.1111/cea.12220.

28. Hanania N.A, Korenblat P., Chapman K.R. 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 (10): 781–796. DOI: 10.1016/S2213-2600(16)30265-X.

29. Panettieri R.A. Jr, Wang M., Braddock M. et al. Tralokinumab for the treatment of severe, uncontrolled asthma: the ATMOSPHERE clinical development program. Immunotherapy. 2018; 10 (6): 473–490. DOI: 10.2217/imt-2017-0191.

30. Simpson E.L., Flohr C., Eichenfield L.F. et al. Efficacy and safety of lebrikizumab (an anti-IL-13 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical corticosteroids: a randomized, placebo-controlled phase II trial (TREBLE). J. Am. Acad. Dermatol. 2018; 78 (5): 863–871. DOI: 10.1016/j.jaad.2018.01.017.

31. Slager R.E., Otulana B.A., Hawkins G.A. 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 (2): 516–522. DOI: 10.1016/j.jaci.2012.03.030.

32. Shirley M. Dupilumab: First Global Approval. Drugs. 2017; 77 (10): 1115–1121. DOI: 10.1007/s40265-017-0768-3.

33. Gooderham M.J., Hong H.C., Eshtiaghi P., Papp K.A. Dupilumab: a review of its use in the treatment of atopic dermatitis. J. Am. Acad. Dermatol. 2018; 78 (3, Suppl.1): S28–S36. DOI: 10.1016/j.jaad.2017.12.022.

34. Pavord I.D., Korn S., Howarth P. et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012; 380 (9842): 651–659. DOI: 10.1016/S0140-6736(12)60988-X.

35. Varricchi G., Senna G., Loffredo S. et al. Reslizumab and eosinophilic asthma: one step closer to precision medicine? Front Immunol. 2017; (8): 242. DOI: 10.3389/fimmu.2017.00242.

36. Garcia G., Taille C., Laveneziana P. et al. Anti-interleukin-5 therapy in severe asthma. Eur. Respir. Rev. 2013; 22 (129): 251–257. DOI: 10.1183/09059180.00004013.

37. Ortega H.G., Liu M.C., Pavord I.D. et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N. Engl. J. Med. 2014; 371 (13): 1198–207. DOI: 10.1056/NEJMoa1403290.

38. Varricchi G., Bagnasco D., Ferrando M. et al. Mepolizumab in the management of severe eosinophilic asthma in adults: current evidence and practical experience. Ther. Adv. Respir. Dis. 2017; 11 (1): 40–45. DOI: 10.1177/1753465816673303.

39. Menzies-Gow A., Flood-Page P., Sehmi R. 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 (4): 714–719. DOI: 10.1067/mai.2003.1382.

40. Flood-Page P.T., Menzies-Gow A.N., Kay A.B., Robinson D.S. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am. J. Respir. Crit. Care Med. 2003; 167 (2): 199–204. DOI: 10.1164/rccm.200208-789OC.

41. Flood-Page P., Swenson C., Faiferman I. et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am. J. Respir. Crit. Care Med. 2007; 176 (11): 1062–1071. DOI: 10.1164/rccm.200701-085OC.

42. Haldar P., Brightling C. E., Hargadon B. et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N. Engl. J. Med. 2009; 360 (10): 973–984. DOI: 10.1056/NEJMoa0808991.

43. Nair P., Pizzichini M.M., Kjarsgaard M. et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N. Engl. J. Med. 2009; 360 (10): 985–993. DOI: 10.1056/NEJMoa0805435.

44. Pavord I.D., Korn S., Howarth P. et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012; 380 (9842): 651–659. DOI: 10.1016/S0140-6736(12)60988-X.

45. Bel E.H., Wenzel S.E., Thompson P.J. et al. SIRIUS Investigators. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N. Engl. J. Med. 2014; 371 (13): 1189–1197. DOI: 10.1056/NEJMoa1403291.

46. Haldar P., Brightling C.E., Singapuri A. et al. Outcomes after cessation of mepolizumab therapy in severe eosinophilic asthma: a 12-month follow-up analysis. J. Allergy Clin. Immunol. 2014; 133 (3): 921–923. DOI: 10.1016/j.jaci.2013.11.026.

47. Lugogo N., Domingo C., Chanez P. et al. Long-term efficacy and safety of mepolizumab in patients with severe eosinophilic asthma: a multi-center, open-label, phase IIIb study. Clin. Ther. 2016; 38 (9): 2058–2070. DOI: 10.1016/j.clinthera.2016.07.010.

48. Chupp G.L., Bradford E.S., Albers F.C. et al. 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. 2017; 5 (5): 390–400. DOI: 10.1016/S2213-2600(17)30125-X.

49. Yancey S.W., Ortega H.G., Keene O.N. et al. Meta-analysis of asthma-related hospitalization in mepolizumab studies of severe eosinophilic asthma. J. Allergy Clin. Immunol. 2017; 139 (4): 1167–1175. DOI: 10.1016/j.jaci.2016.08.008.

50. Castro M., Mathur S., Hargreave F. et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am. J. Respir. Crit. Care Med. 2011; 184 (10): 1125–1132. DOI: 10.1164/rccm.201103-0396OC.

51. Castro M., Zangrilli J., Wechsler M.E. 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 (5): 355–366. DOI: 10.1016/S2213-2600(15)00042-9.

52. Bjermer L., Lemiere C., Maspero J. et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest. 2016; 150 (4): 789–798. DOI: 10.1016/j.chest.2016.03.032.

53. Corren J., Weinstein S., Janka L. et al. Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. 2016; 150 (4): 799–810. DOI: 10.1016/j.chest.2016.03.018.

54. Pelaia C., Vatrella A., Bruni A. et al. Benralizumab in the treatment of severe asthma: design, development and potential place in therapy. Drug Des. Devel. Ther. 2018; 12: 619–628. DOI: 10.2147/DDDT.S155307.

55. Busse W.W., Katial R., Gossage D. 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 (6):1237–1244 e2. DOI: 10.1016/j.jaci.2010.04.005.

56. Laviolette M., Gossage D.L., Gauvreau G. et al. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J. Allergy Clin. Immunol. 2013; 132 (5): 1086–1096 e5. DOI: 10.1016/j.jaci.2013.05.020.

57. Park H.S., Kim M.K., Imai N. et al. 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. DOI: 10.1159/000444799.

58. Castro M., Wenzel S.E., Bleecker E.R. 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 (11): 879–890. DOI: 10.1016/S2213-2600(14)70201-2.

59. Nowak R.M., Parker J.M., Silverman R.A. et al. A randomized trial of benralizumab, an antiinterleukin 5 receptor α monoclonal antibody, after acute asthma. Am. J. Emerg. Med. 2015; 33 (1): 14–20. DOI: 10.1016/j.ajem.2014.09.036.

60. Bleecker E.R., FitzGerald J.M., Chanez P. et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016; 388 (10056): 2115–2127. DOI: 10.1016/S0140-6736(16)31324-1.

61. FitzGerald J.M., Bleecker E.R., Nair P. 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 (10056): 2128–2141. DOI: 10.1016/S0140-6736(16)31322-8.

62. Nair P., Wenzel S., Rabe K.F. et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N. Engl. J. Med. 2017; 376 (25): 2448–2458. DOI: 10.1056/NEJMoa1703501.

63. Ferguson G.T., FitzGerald J.M., Bleecker E.R. et al. Benralizumab for patients with mild to moderate, persistent asthma (BISE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir. Med. 2017; 5 (7): 568–576. DOI: 10.1016/S2213-2600(17)30190-X.

64. Matera M.G., Calzetta L., Rinaldi B., Cazzola M. Pharmacokinetic/pharmacodynamic drug evaluation of benralizumab for the treatment of asthma. Expert Opin. Drug Metab. Toxicol. 2017; 13 (9): 1007–1013. DOI: 10.1080/17425255.2017.1359253.

65. Liu T., Wang F., Wang G. et al. Efficacy and safety of benralizumab in patients with eosinophilic asthma: a meta-analysis of randomized placebo-controlled trials. Front Med. 2018; 12 (3): 340–349. DOI: 10.1007/s11684-017-0565-0.

66. FitzGerald J.M., Bleecker E.R., Menzies-Gow A. et al. Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies. Lancet Respir. Med. 2018; 6 (1): 51–64. DOI: 10.1016/S2213-2600(17)30344-2.

67. Chipps B.E., Newbold P., Hirsch I. et al. Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma. Ann. Allergy Asthma Immunol. 2018; 120 (5): 504–511. DOI: 10.1016/j.anai.2018.01.030.

68. Albers F.C., Müllerová H., Gunsoy N.B. et al. Biologic treatment eligibility for real-world patients with severe asthma: The IDEAL study. J. Asthma. 2017; 55 (2): 152–160. DOI: 10.1080/02770903.2017.1322611.

69. Albers F.C., Liu M.C., Chipps B.E. et al. Efficacy and safety of mepolizumab in uncontrolled patients with severe eosinophilic asthma following a switch from omalizumab (OSMO study): asthma control, quality of life and lung function outcomes. J. Allergy Clin. Immunol. 2018; 141 (2): AB408. DOI: 10.1016/j.jaci.2017.12.964.

70. Erpenbeck V.J., Popov T.A., Miller D. et al. The oral CRTh2 antagonist QAW039 (fevipiprant): a phase II study in uncontrolled allergic asthma. Pulm. Pharmacol. Ther. 2016; (39): 54–63. DOI: 10.1016/j.pupt.2016.06.005.

71. Gonem S., Berair R., Singapuri A. et al. Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: single-centre, randomised, double-blind, parallel-group, placebo controlled trial. Lancet Respir. Med. 2016; 4 (9): 699–707. DOI: 10.1016/S2213-2600(16)30179-5.

72. Bateman E.D., Guerreros A.G., Brockhaus F. et al. Fevipiprant, an oral prostaglandin DP2 receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled corticosteroids. Eur. Respir. J. 2017: 50 (2): pii: 1700670. DOI: 10.1183/13993003.00670-2017.


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Zyryanov S.K., Butranova O.I. Genetically engineered drugs for treatment of bronchial asthma: recent achievements. PULMONOLOGIYA. 2018;28(5):584-601. (In Russ.) https://doi.org/10.18093/0869-0189-2018-28-5-584-601

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