Five molecules for targeted biological therapy of severe bronchial asthma: realities and perspectives


DOI: https://dx.doi.org/10.18565/therapy.2020.5.195-205

Malyavin A.G., Kozulina I.E., Sharapova Yu.A.

1) A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Ministry of Healthcare of Russia; 2) GlaxoSmithKline Trading JSC, Moscow; 3) N.N. Burdenko Voronezh State Medical University of the Ministry of Healthcare of Russia
Biological therapy has opened a new era in the treatment of patients with severe bronchial asthma. Today, there are already 5 molecules acting on different links of pathogenesis of this disease. The article provides data on all currently existing biological targeted drugs, the results of basic clinical trials to assess the effectiveness and safety of these drugs, as well as data on the priority areas of clinical research.
Keywords: severe bronchial asthma, T2 phenotype, T2-asthma, eosinophilia, FeNO, IgE, omalizumab, reslizumab, mepolizumab, benralizumab, dupilumab, targeted therapy, biological therapy
Read entire article

Literature


  1. Agache I., Beltran J., Akdis C. et al. Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI Guidelines – recommendations on the use of biologicals in severe asthma. Allergy. 2020; 75: 1023–42. doi: 10.1111/all.14221.

  2. Papi A., Brightling C., Pedersen S.E., Reddel H.K. Asthma. Lancet. 2018; 391(10122): 783–800. doi: 10.1016/S0140-6736(17)33311-1.

  3. Settipane R.A., Kreindler J.L., Chung Y., Tkacz J. Evaluating direct costs and productivity losses of patients with asthma receiving GINA 4/5 therapy in the United States. Ann Allergy Asthma Immunol. 2019; 123(6): 564–72.e3. doi: 10.1016/j.anai.2019.08.462.

  4. Perez de Llano L., Martinez-Moragon E., Plaza Moral V. et al. Unmet therapeutic goals and potential treatable traits in a population of patients with severe uncontrolled asthma in Spain. ENEAS study. Respir Med. 2019; 151: 49–54. doi: 10.1016/j.rmed.2019.03.006.

  5. Chung K.F., Wenzel S.E., Brozek J.L. et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014; 43(2): 343–73. doi: 10.1183/09031936.00202013.

  6. Caminati M., Cegolon L., Vianello A. et al. Mepolizumab for severe eosinophilic asthma: a real-world snapshot on clinical markers and timing of response. Expert Rev Respir Med. 2019; 13(12): 1205–12. doi: 10.1080/17476348.2019.1676734.

  7. Fahy J.V. Type 2 inflammation in asthma – present in most, absent in many. Nat Rev Immunol. 2015; 15(1): 57–65. doi: 10.1038/nri3786.

  8. Seys S.F., Scheers H., Van den Brande P. et al. Cluster analysis of sputum cytokine-high profiles reveals diversity in T(h)2-high asthma patients. Respir Res. 2017; 18(1): 39. doi: 10.1186/s12931-017-0524-y.

  9. Karlen S., De Boer M.L., Lipscombe R.J. et al. Biological and molecular characteristics of interleukin-5 and its receptor. Int Rev Immunol. 1998; 16 (3–4): 227–47. doi: 10.3109/08830189809042996.

  10. Gour N., Wills-Karp M. IL-4 and IL-13 signaling in allergic airway disease. Cytokine. 2015; 75(1): 68–78. doi: 10.1016/j.cyto.2015.05.014.

  11. Corren J. New targeted therapies for uncontrolled asthma. J Allergy Clin Immunol Pract. 2019; 7(5): 1394–403. doi: 10.1016/j.jaip.2019.03.022.

  12. Froidure A., Mouthuy J., Durham S. et al. Asthma phenotypes and IgE-responses. Eur Respir J. 2016; 47(1): 304–19. doi: 10.1183/13993003.01824-2014

  13. Wu L.C., Zarrin A.A. The production and regulation of IgE by the immune system. Nat Rev Immunol. 2014; 14(4): 247–59. doi: 10.1038/nri3632.

  14. Kawakami T., Blank U. From IgE to omalizumab. J Immunol. 2016; 197(11): 4187–92. doi:10.4049/jimmunol.1601476.

  15. Fajt M.L., Wenzel S.E. Asthma phenotypes and the use of biologic medications in asthma and allergic disease: the next steps toward personalized care. J Allergy Clin Immunol. 2015; 135(2): 299–310; quiz 311. doi: 10.1016/j.jaci.2014.12.1871.

  16. Busse W., Corren J., Lanier B.Q. et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol. 2001; 108(2): 184–90. doi: 10.1067/mai.2001.117880.

  17. 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): 1141–51. doi: 10.1016/j.rmed.2013.04.017.

  18. Samitas K., Radinger M., Bossios A. Current update on eosinophilic lung diseases and anti-IL-5 treatment. Recent Pat Antiinfect Drug Discov. 2011; 6(3): 189–205. doi: 10.2174/157489111796887855.

  19. Walsh G.M. An update on emerging drugs for asthma. Expert Opin Emerg Drugs. 2012; 17(1): 37–42. doi: 10.1517/14728214.2012.657625.

  20. Bel E.H., Wenzel S.E., Thompson P.J. et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014; 371(13): 1189–97. doi: 10.1056/NEJMoa1403291.

  21. Ortega H.G., Yancey S.W., Mayer B. et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med. 2016; 4(7): 549–56. doi: 10.1016/S2213-2600(16)30031-5.

  22. 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. Lancet Respir Med. 2015; 3(5): 355–66. doi: 10.1016/S2213-2600(15)00042-9.

  23. Khatri S., Moore W., Gibson P.G. et al. Assessment of the long-term safety of mepolizumab and durability of clinical response in patients with severe eosinophilic asthma. J Allergy Clin Immunol. 2019; 143(5): 1742–51.e7. doi: 10.1016/j.jaci.2018.09.033.

  24. 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): 2058–70.e1. doi: 10.1016/j.clinthera.2016.07.010.

  25. Difficult-to-treat and severe asthma in adolescence and adult patients. Diagnosis and management. GINA. V 2.0 April 2019. Available at: https://ginasthma.org/wp-content/uploads/2019/04/GINA-Severe-asthma-Pocket-Guide-v2.0-wms-1.pdf (date of access – 01.08.2020).

  26. Chapman K.R., Albers F.C., Chipps B. et al. The clinical benefit of mepolizumab replacing omalizumab in uncontrolled severe eosinophilic asthma. Allergy. 2019; 74(9): 1716–26. doi: 10.1111/all.13850.

  27. Li J., Wang F., Lin C. et al. The efficacy and safety of reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: a systematic review and meta-analysis. J Asthma. 2017; 54(3): 300–07. doi: 10.1080/02770903.2016.1212371.

  28. Weinstein S., Katial R., Bardin F. et al. Effects of reslizumab on asthma outcomes in a subgroup of eosinophilic asthma patients with self-reported chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol Pract. 2019; 7(2): 589–96. doi: 10.1016/j.jaip.2018.08.021.

  29. Deeks E.D., Brusselle G. Reslizumab in eosinophilic asthma: a review. Drugs. 2017; 77(7): 777–84. doi: 10.1007/s40265-017-0740-2.

  30. Tian B.P., Zhang G.S., Lou J. et al. Efficacy and safety of benralizumab for eosinophilic asthma: a systematic review and meta-analysis of randomized controlled trials. J Asthma. 2018; 55(9): 956–65. doi: 10.1080/02770903.2017.1379534.

  31. Goldman M., Hirsch I., Zangrilli J.G. et al. The association between blood eosinophil count and benralizumab efficacy for patients with severe, uncontrolled asthma: subanalyses of the Phase III SIROCCO and CALIMA studies. Curr Med Res Opin. 2017; 33(9): 1605–13. doi: 10.1080/03007995.2017.1347091.

  32. Nair P., Wenzel S., Rabe K. et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med. 2017; 376(25): 2448–58. doi: 10.1056/NEJMoa1703501.

  33. Liu W., Ma X., Zhu W. Adverse events of benralizumab in moderate to severe eosinophilic asthma. A meta-analysis. Medicine. 2019; 98(22): e15868. doi: 10.1097/MD.0000000000015868.

  34. Wenzel S., Castro M., Corren J. 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(10039): 31–44. doi: 10.1016/S0140-6736(16)30307-5.

  35. Rabe K.F., Nair P., Brusselle G. et al. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med. 2018; 378(26): 2475–85. doi: 10.1056/NEJMoa1804093.

  36. 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): 2115–27. doi: 10.1016/S0140-6736(16)31324-1.

  37. 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): 2128–41. doi: 10.1016/S0140-6736(16)31322-8.

  38. Castro M., Corren J., Pavord I.D. et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018; 378(26): 2486–96. doi: 10.1056/NEJMoa1804092.

  39. 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.

  40. 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.

  41. Krings J.G., McGregor M.C., Bacharier L.B., Castro M. Biologics for severe asthma: treatment-specific effects are important in choosing a specific agent. J Allergy Clin Immunol Pract. 2019; 7(5): 1379–92. doi: 10.1016/j.jaip.2019.03.008.

  42. Ando K., Tanaka A., Sagara H. Comparative efficacy and safety of dupilumab and benralizumab in patients with inadequately controlled asthma: a systematic review. Int J Mol Sci. 2020; 21(3): 889. doi: 10.3390/ijms21030889.

  43. Higgins J.P., Altman D.G., Gotzsche P.C. et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011; 343: d5928. doi: 10.1136/bmj.d5928.

  44. ClinicalTrial.gov. https://clinicaltrials.gov/


About the Autors

Andrey G. Malyavin, MD, professor, professor of the Department of phthisiology and pulmonology of A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Ministry of Healthcare of Russia, RSMSIM general secretary, chief freelance pulmonologist of Central Federal District of the Ministry of Healthcare of Russia. Address: 107150, Moscow, 39/2 Losinoostrovskaya Str. E-mail: maliavin@mail.ru
Irina E. Kozulina, PhD, medical advisor of GlaxoSmithKline Trading JSC. Address: 125167, Moscow, 37A/4 Leningradsky Prospect
Yulia A. Sharapova, PhD, chief physician of the Department of Healthcare of the Voronezh Region, associate professor of Department of hospital therapy and endocrinology of N.N. Burdenko Voronezh State Medical University of the Ministry of Healthcare of Russia. Address: 394066, Voronezh, 151 Moskovsky Prospect

Back to Content

Бионика Медиа