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Omalizumab in Severe Asthma: Effect on Oral Corticosteroid Exposure and Remodeling. A Randomized Open-Label Parallel Study

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Abstract

Introduction

Data on the clinical efficacy and remodeling of omalizumab therapy in patients on oral corticosteroids (OC) are limited.

Objective

The purpose of the study is to show that in patients with corticosteroid-dependent asthma, omalizumab is a corticosteroid-sparing therapy able to inhibit airway remodeling and to reduce disease burden (lung function impairment, exacerbations).

Methods

This study is a randomised open-label study evaluating the addition of omalizumab to the standard of care in patients with severe asthma receiving oral corticosteroids. The primary endpoint was represented by the change in OC monthly dose by the end of treatment and secondary endpoints included spirometry changes, airway inflammation (FeNO), number of exacerbations and airways remodelling assessed by bronchial biopsies studied by transmission electron microscopy. As a safety variable, adverse effects were recorded.

Results

Efficacy was assessed for 16 patients in the omalizumab group and 13 in the control group. The final cumulative mean monthly OC doses were 34.7 mg and 217 mg for the omalizumab and control group, respectively; the mean difference between groups adjusted for baseline was −148.1 [95% confidence interval (CI) −243.6, −52.5; p = 0.004]. OC withdrawal of 75% versus 7.7% (p = 0.001) was observed in the omalizumab and control group, respectively. Omalizumab provided a slowing of forced expiratory volume in one second (FEV1) loss (70 mL versus 260 mL), a significant decrease in FeNO values and a reduction in the annual relative risk of clinically significant exacerbations of 54%. The treatment was well tolerated. The morphological study showed a significant decrease in basement membrane thickness in the omalizumab group (6.7 µm versus 4.6 µm) compared with controls (6.9 µm versus 7 µm) [mean difference between groups adjusted for baseline was −2.4 (95% CI −3.7, −1.2; p < 0.001], as well as a decrease in intercellular spaces (1.18 µm versus 0.62 µm and 1.21 µm versus 1.20 µm, p = 0.011, respectively). A qualitative improvement was also observed in the treated group.

Conclusions

Omalizumab showed a marked OC-sparing capacity and was associated with an improvement in clinical management that correlated with bronchial epithelial repair. In OC-dependent asthma, reversibility of remodelling is possible; the concepts that basement membrane enlargement is detrimental and that chronic airway obstruction is systematically irreversible are outdated (EudraCT: 2009-010914-31).

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References

  1. Domingo C, Pacheco A, Hinojosa M, Bosque M. The relevance of IgE in the pathogenesis of allergy: the effect of an anti-IgE drug in asthma and other diseases. Recent Pat Inflamm Allergy Drug Discov. 2007;1(2):151–64.

    Article  CAS  PubMed  Google Scholar 

  2. Domingo C. Omalizumab for severe asthma: efficacy beyond the atopic patient? Drugs. 2014;74(5):521–33.

    Article  CAS  PubMed  Google Scholar 

  3. Holgate S, Bousquet J, Wenzel S, Fox H, Liu J, Castellsague J. Efficacy of omalizumab, an anti-immunoglobulin E antibody, in patients with allergic asthma at high risk of serious asthma-related morbidity and mortality. Curr Med Res Opin. 2001;17(4):233–40.

    Article  CAS  PubMed  Google Scholar 

  4. Busse W, Corren J, Lanier BQ, 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.

    Article  CAS  PubMed  Google Scholar 

  5. Solèr M, Matz J, Townley R, et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J. 2001;18(2):254–61.

    Article  PubMed  Google Scholar 

  6. Buhl R, Solèr M, Matz J, et al. Omalizumab provides long-term control in patients with moderate-to-severe allergic asthma. Eur Respir J. 2002;20(1):73–8.

    Article  CAS  PubMed  Google Scholar 

  7. Domingo C. Overlapping effects of new monoclonal antibodies for severe asthma. Drugs. 2017;77(16):1769–87.

    Article  CAS  PubMed  Google Scholar 

  8. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189–97.

    Article  PubMed  Google Scholar 

  9. Nair P, Wenzel S, Rabe KF, et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med. 2017;376:2448–58.

    Article  CAS  PubMed  Google Scholar 

  10. Rabe KF, 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.

    Article  CAS  PubMed  Google Scholar 

  11. Sullivan P, Stephens D, Ansari T, Costello J, Jeffery P. Variation in the measurements of basement membrane thickness and inflammatory cell number in bronchial biopsies. Eur Respir J. 1998;12(4):811–5.

    Article  CAS  PubMed  Google Scholar 

  12. Johannessen R, Skogaker N, Halgunset J, Petersen H, Kleveland PM. A standardized method for measuring intercellular spaces in esophageal biopsies in patients with suspected gastroesophageal reflux disease (the intercellular space ratio). Scand J Gastroenterol. 2013;48(11):1235–41.

    Article  PubMed  Google Scholar 

  13. R Core Team. R: A language and environment for statistical computing [Internet]. Vienna, Austria: R Foundation for Statistical Computing; 2022. https://www.R-project.org/.

  14. Rizopoulos D (2022). GLMMadaptive: generalized linear mixed models using adaptive Gaussian quadrature. https://drizopoulos.github.io/GLMMadaptive/, https://github.com/drizopoulos/GLMMadaptive.

  15. Thomas WY (2022). VGAM: vector generalized linear and additive models. R package version 1.1-6. https://CRAN.R-project.org/package=VGAM.

  16. Venables WN, Ripley BD. Modern Applied Statistics with S. Fourth Edition. Springer, New York, 2002. https://www.stats.ox.ac.uk/pub/MASS4/.

  17. Wickham H. ggplot2: elegant graphics for data analysis. Springer, New York, 2016. https://ggplot2.tidyverse.org.

  18. Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;1:CD003559.

    Google Scholar 

  19. Siergiejko Z, Świebocka E, Smith N, et al. Oral corticosteroid sparing with omalizumab in severe allergic (IgE-mediated) asthma patients. Curr Med Res Opin. 2011;27(11):2223–8.

    Article  CAS  PubMed  Google Scholar 

  20. Braunstahl G-J, Chen C-W, Maykut R, Georgiou P, Peachey G, Bruce J. The eXpeRience registry: the “real-world” effectiveness of omalizumab in allergic asthma. Respir Med. 2013;107(8):1141–51.

    Article  PubMed  Google Scholar 

  21. Barnes N, Menzies-Gow A, Mansur AH, et al. Effectiveness of omalizumab in severe allergic asthma: a retrospective UK real-world study. J Asthma. 2013;50(5):529–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Domingo C, Moreno A, Jose Amengual M, Monton C, Suarez D, Pomares X. Omalizumab in the management of oral corticosteroid-dependent IGE-mediated asthma patients. Curr Med Res Opin. 2011;27(1):45–53.

    Article  CAS  PubMed  Google Scholar 

  23. 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):309–16.

    Article  CAS  PubMed  Google Scholar 

  24. Korn S, Thielen A, Seyfried S, Taube C, Kornmann O, Buhl R. Omalizumab in patients with severe persistent allergic asthma in a real-life setting in Germany. Respir Med. 2009;103(11):1725–31.

    Article  CAS  PubMed  Google Scholar 

  25. Molimard M, de Blay F, Didier A, Le Gros V. Effectiveness of omalizumab (Xolair) in the first patients treated in real-life practice in France. Respir Med. 2008;102(1):71–626.

    Article  PubMed  Google Scholar 

  26. Jeffery PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB. Bronchial biopsies in asthma. An ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis. 1989;140(6):1745–53.

    Article  CAS  PubMed  Google Scholar 

  27. Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics. Lancet (Lond, Engl). 1989;1(8637):520–4.

    Article  CAS  Google Scholar 

  28. Riccio AM, Dalnegro RW, Micheletto C, et al. Omalizumab modulates bronchial reticular basement membrane thickness and eosinophil infiltration in severe persistent allergic asthma patients. Int J Immunopathol Pharmacol. 2012;25(2):475–84.

    Article  CAS  PubMed  Google Scholar 

  29. Domingo C, Pomares X, Navarro A, et al. A step-down protocol for omalizumab treatment in oral corticosteroid-dependent allergic asthma patients. Br J Clin Pharmacol. 2018;84(2):339–48.

    Article  CAS  PubMed  Google Scholar 

  30. Domingo C, Pomares X, Morón A, Sogo A. Dual monoclonal antibody therapy for a severe asthma patient. Front Pharmacol. 2020;11:587621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Redhu NS, Shan L, Al-Subait D, et al. IgE induces proliferation in human airway smooth muscle cells: role of MAPK and STAT3 pathways. Allergy Asthma Clin Immunol. 2013;9(1):41.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Roth M, Zhong J, Zumkeller C, S’ng CT, Goulet S, Tamm M. The role of IgE-receptors in IgE-dependent airway smooth muscle cell remodelling. PLoS One. 2013;8(2):e56015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Roth M, Zhao F, Zhong J, Lardinois D, Tamm M. Serum IgE induced airway smooth muscle cell remodeling is independent of allergens and is prevented by omalizumab. PLoS One. 2015;10(9):e0136549.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kistemaker LEM, Oenema TA, Meurs H, Gosens R. Regulation of airway inflammation and remodeling by muscarinic receptors: perspectives on anticholinergic therapy in asthma and COPD. Life Sci. 2012;91:1126–33.

    Article  CAS  PubMed  Google Scholar 

  35. Hoshino M, Ohtawa J. Effects of adding omalizumab, an anti-immunoglobulin E antibody, on airway wall thickening in asthma. Respiration. 2012;83(6):520–8.

    Article  CAS  PubMed  Google Scholar 

  36. Solidoro P, Patrucco F, de Blasio F, et al. Predictors of reversible airway obstruction with omalizumab in severe asthma: a real-life study. Ther Adv Respir Dis. 2019;13:1753466619841274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Domingo C, Mirapeix RM. From the allergic cascade to the epithelium-driven disease: the long road of bronchial asthma. Int J Mol Sci. 2023;2:2716. https://doi.org/10.3390/ijms24032716.

    Article  Google Scholar 

  38. Pavord I, Gardiner F, Heaney LG, Domingo C, Price RG, Pullan A, et al. Remission outcomes in severe eosinophilic asthma with mepolizumab therapy: analysis of the REDES study. Front Immunol. 2023;14:1150162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Anna Garrit for her technical assistance in electron microscopy laboratory (Department of Morphological Sciences-UAB), Natàlia Martínez, nurse at the Respiratory Service (Corporació Parc Taulí-UAB) and Dr. Vicente Marco-Molina (Servei d’Anatomía Patològica, Hospital Quirón, Barcelona).

Author information

Author notes

  1. Christian Domingo and Rosa M. Mirapeix contributed equally to this work.

Authors and Affiliations

  1. Pulmonary Service, Corporació Sanitària Parc Taulí, Parc Taulí s/n, 08208 Sabadell, Barcelona, Spain

    Christian Domingo

  2. Departament of Medicine, Medical School, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain

    Christian Domingo

  3. Department of Morphological Sciences, Medical School, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain

    Rosa M. Mirapeix

  4. Translational Research In Airway Diseases Group (TRIAD), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain

    Francisco-Javier González-Barcala

  5. CIBER Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain

    Francisco-Javier González-Barcala

  6. Departamento de Medicina, Universidad de Santiago de Compostela, Santiago de Compostela, Spain

    Francisco-Javier González-Barcala

  7. Servicio de Neumología, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain

    Francisco-Javier González-Barcala

  8. Heorfy Consulting, Lleida, Spain

    Carles Forné

  9. Department of Basic Medical Sciences, University of Lleida, Lleida, Spain

    Carles Forné

  10. Servei d’Anatomía Patològica, Hospital Quirón (Barcelona), Barcelona, Spain

    Felip García

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Corresponding author

Correspondence to Christian Domingo.

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Funding

Grants from SEPAR 845-2009/ FUCAP 2008/FUCAP 2009.

Conflicts of Interest

C.D. declares having received financial aid for travel support and speakers bureaus from Novartis, Sanofi, GSK, TEVA, MSD, Esteve, Almirall, Astra-Zeneca, Chiesi, Menarini, Pfizer, Ferrer, Stallergenes, ALK-Abelló, Allergy therapeutics, Hall Allergy, Inmunotek and Roxall. R.M.M., C.F. and F.G. declare that they have no conflicts of interest. No authors have any conflict of interest in relation to this study.

Availability of data and material

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Ethics approval

The study was approved by the Institutional Review Boards of both hospitals. Written informed consent was obtained from all patients. The study was registered with EudraCT number 2009-010914-31. The study was performed in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Consent to participate

Written informed consent was obtained from all patients.

Consent for publication

Written informed consent was obtained from all patients.

Authors’ contributions

C.D.: conceptualization, funding acquisition, data curation, methodology, project administration, resources, supervision, verification, visualization and writing original draft. R.M.M: conceptualization, data curation, methodology, resources, supervision, verification, visualization and writing original draft. F.J.G.B.: data curation, resources, verification and writing—review and editing. C.F.: formal analysis, methodology, visualization and writing—review and editing. F.P.: data curation, resources, verification and writing—review and editing. All authors have read and approved the final version of the manuscript, and agree to be accountable for the work.

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Domingo, C., Mirapeix, R.M., González-Barcala, FJ. et al. Omalizumab in Severe Asthma: Effect on Oral Corticosteroid Exposure and Remodeling. A Randomized Open-Label Parallel Study. Drugs 83, 1111–1123 (2023). https://doi.org/10.1007/s40265-023-01905-5

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