Traiter l asthme sévère par le phénotype. Dr. Alain Michils CUB-Hôpital Erasme

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1 Traiter l asthme sévère par le phénotype Dr. Alain Michils CUB-Hôpital Erasme Darwin 25 mars 2017

2 Step 5 treatment (GINA 2016) STEP 5 STEP 4 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Low dose ICS STEP 3 Low dose ICS/LABA** Med/high ICS/LABA Refer for add-on treatment e.g. tiotropium,* omalizumab, mepolizumab* Other controller options RELIEVER Consider low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* As-needed short-acting beta 2 -agonist (SABA) Med/high dose ICS Low dose ICS+LTRA (or + theoph*) Add tiotropium* High dose ICS + LTRA (or + theoph*) As-needed SABA or low dose ICS/formoterol # Add low dose OCS

3 The prevalence of severe uncontrolled asthma 7 A Dutch prevalence study BE/NLA/0011/16a Sept 2016 For external use and distribution ER: GlaxoSmithKline Pharmaceuticals s.a./n.v. Site Apollo Avenue Pascal, Wavre Belgium

4 Severe asthma: definition Chung KF et al. Eur Resp J 2014 International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

5 Heterogeneity of severe asthma: A major barrier to improved outcomes Severe asthma is now accepted to comprise different patients phenotypes and endotypes, with distinct pathogenic mechanisms A broad spectrum approach to therapy is problematic due to potential lack of efficacy and adverse effects Highly selected therapy

6 Phenotyping asthma Gauthier M et al. AJRCCM 2015 Timeline showing major events in the understanding of asthma and phenotyping

7 The umbrella term asthma : the concept Wenzel. Nature Med 2012; 18:

8 The umbrella term asthma : the concept Age of onset (40 y.o.) Wenzel. Nature Med 2012; 18:

9 The umbrella term asthma : the concept Age of onset (40 y.o.) Severity Wenzel. Nature Med 2012; 18:

10 The umbrella term asthma : the concept Age of onset (40 y.o.) Severity Inflammatory characteristics Wenzel Nature Med 2012; 18:

11 Type 2 Hi asthma Early-onset allergic (TH 2 ) asthma Ray et al. Am J Physiol Lung Cell Mol Physiol 2015; 308: L130-L140 Early childhood Associated with other atopic diseases Family history Mild to severe (progression?) Severity related to the number of IgE sensitivities Genes associated are epithelial genes rather than allergy genes Higher numbers of TH2 genes products associated with severity Biomarkers: FeNO, eosinophils, periostin, IgE?

12 Type 2 Hi asthma Late-onset persistent eosinophilic asthma Ray et al. Am J Physiol Lung Cell Mol Physiol 2015; 308: L130-L140 Late onset Severe from the onset No clinical allergy No family history Association with AERD Refractoriness to CS Biomarkers: IL-5; IL-13;FeNO; periostin, eosinophils (>2% IS, >220/µL blood)

13 Two mechanisms for eosinophilic inflammation Type 2 (T2) asthma: allergic vs nonallergic Brusselle et al. Nature Med 2013; 19:

14 Allergic Early onset Non allergic Late onset Ray A Am J Physiol Lung Cell Mol Physiol 2015

15 Belgian Severe Asthma Registry (BSAR) results Schleich et al. Respir Med 2014; 108:

16 International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma Chung et al. Eur Respir J 2014; 43:

17 Omalizumab Mode of action IgE Omalizumab Regio C 3

18 Omalizumab Mode of action Allergen IgE Omalizumab Regio C 3 Fixation site Receptor Fc RI Mastocyte

19 Omalizumab Brusselle et al. Respir Med 2009 Significant reduction in severe exacerbation rate in patients suffering from severe allergic asthma treated with Omalizumab 3,5 3-65,0 % 2,7-57,2 % 3,2 Previous 12 months PP 2,5 Omalizumab PP 2 1,5 1 0,5 0,4 0,9 1,3 0,5 0 Non Severe Severe Total

20 Type 2 biomarkers Hanania N et al. AJRCCM 2013 Omalizumab effect greater in high baseline biomarker subgroups compared to low baseline biomarker subgroups Bousquet et al. Chest 2004 Best clinical predictors of response to Omalizumab: low FEV 1 and high ICS dosage

21 Anti-IgE mab therapy for severe asthma: determinants of response Type 2 molecular markers Low FEV1

22 International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma Chung et al. Eur Respir J 2014; 43:

23 Mepolizumab (Nucala) Reslizumab Benralizumab

24 Effect of mepolizumab on inflammatory markers 1,11,12 Geometric mean eosinophil counts in blood Mepolizumab reduced the geometric mean eosinophil counts in blood by 84 % vs. placebo 1 Placebo (+ usual treatment) Mepolizumab SC (+ usual treatment) Mepolizumab IV 75mg is a non licensed drug used in clinical trials. 1. Nucala SmPC 11. Ortega et al. N Engl J Med 2014; 371; Ortega et al. N Engl J Med 2014; 371; Supplementary appendix 24 BE/NLA/0011/16a Sept 2016 For external use 24 and distribution ER: GlaxoSmithKline Pharmaceuticals s.a./n.v. Site Apollo Avenue Pascal, Wavre Belgium

25 Mean rate MENSA 11 Significant Reduction in Clinically Significant Exacerbations Primary Endpoint 2 1,6 1,75 47% (95% CI, 29, 61) a p<0,001 53% (95% CI, 37, 65) a p<0,001 1,2 0,8 0,93 0,81 0,4 0 Placebo N=191 Mepolizumab 75 mg IV N = 191 Mepolizumab 100 mg SC N = 194 a The between-group difference in this category is the percent reduction as compared with the placebo group. Mepolizumab 75mg IV is not licensed dose/route of administration Ortega HG, et al. N Engl J Med. 2014;371: BE/NLA/0011/16a Sept 2016 For external use and distribution ER: GlaxoSmithKline Pharmaceuticals s.a./n.v. Site Apollo Avenue Pascal, Wavre Belgium

26 Anti-IL-5 mab therapy for severe asthma: determinants of response Age of onset Exacerbation number Eosinophils

27 Treatment Step 5: asthma phenotypes and monoclonal antibodies (GINA 2016) In patients with more severe asthma, some phenotypeguided treatments are available (p 14): Add-on omalizumab (anti-ige) treatment : for patients with (moderate* or) severe allergic asthma that is uncontrolled on Step 4 treatment (Evidence A) (p 47). Add-on mepolizumab (anti-interleukin-5 treatment) : for patients with severe eosinophilic asthma that is uncontrolled on Step 4 treatment (Evidence B) (p 47). * moderate : US label only, adapted from

28 Phenotypes-endotypes and add-on treatments Froidure et al. Eur Respir J 2016; 47: Omalizumab: early-onset severe allergic asthma with strong IgE response with or without eosinophils (TH2 domninant) Mepolizumab: late-onset eosinophilic asthma with or without IgE (ILC2 dominant)

29 Anti-IgE (Anti-IL-4/13) Bronchial thermoplasty? Anti-IL-5 (Anti-IL-4/13) Weight loss Marcrolides Anti-IL-23 Wenzel. Nature Med 2012; 5: