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Evaluation and Treatment of Patients with Severe Asthma

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Evaluation and Treatment of Patients with Severe Asthma Evaluation and Treatment of Patients with Severe Asthma Paul M. O’Byrne, MD Associate Professor of Pediatrics EJ Moran Campbell Professor of Medicine Firestone Institute for Respiratory Health, St. Joseph’s Healthcare and McMaster University, Hamilton, Ontario, Canada Faculty Disclosure for Paul M. O’Byrne For the 12 months preceding this CME activity, I disclose the following types of financial relationships: Honoraria received from: AstraZeneca, Boehringer Ingelheim, Chiesi Ltd., GlaxoSmithKline, Takeda Pharmaceutical Company Consulted for: AstraZeneca, Boehringer Ingelheim, Forest, GlaxoSmithKline, Merck, Verona Pharma Held common stock in: None Research, clinical trial, or drug study funds received from: AIM, Amgen, AstraZeneca, Axcan Pharma Inc., Genentech, GlaxoSmithKline, Novartis, Ono Pharmaceutical I will be discussing products that are investigational or not labeled for the use under discussion. The Goals of Asthma Management Overall Asthma Control achieving reducing Current control Future risk defined by defined by Instability/ Symptoms Reliever use Exacerbations worsening Loss of Adverse effects Activity Lung function lung function of medication NAEPP. Expert Panel Report 3. 2007 Taylor DR, et al. Eur Respir J 2008; 32:545–554 Severe refractory asthma makes up 5-10% asthma population Uncontrolled asthma and high exacerbation risk despite maximal conventional therapy Evaluation of Severe Refractory Asthma • Adherence, adherence, adherence • Co-morbidities – Rhino-sinusitis – GERD – Obesity – Bronchiectasis – Vocal cord dysfunction • Smoking • Psychopathology • Persistent allergen/occupational exposure • Incorrect diagnosis • Severe refractory disease Canadian Consensus Guidelines Lougheed D, et al. Can Respir J 2012; 19:127-64 Asthma Phenotypes/Endotypes Wenzel SE. Pul Pharm Ther 2013; 26: 710 - 715 Asthma Phenotypes Haldar P, et al. Am J Respir Crit Care Med 2008; 178:218-24 Inflammatory Phenotype: Induced Sputum O’Byrne PM, Nair P. Lancet 2006; 368:794-308 Current and Experimental Treatments for Severe Asthma Approach Drug/Treatment Oral corticosteroids Prednisone, Medrol Anti-IgE Mab Omalizumab Bronchial smooth muscle Bronchial Thermoplasty Once daily ICS/LABA Relvar Anticholinergics Tiotropium Anti-IL5 Mab Mepolizumab, Reslizumab Anti-IL5R Mab Benzralizumab Anti-IL4Rα MAb Dupilimab Anti-IL13 Mab Lebrikizumab, Tralokinumab Macrolide antibiotics Several C-kit & PDGFR tryosine kinase inhibitor Masitinib Anti-IL2Rα Mab Daclizumab CXCR2 receptor antagonist SCH527123 CRTh2 Several Anti-TNFα Golimumab Bronchial Thermoplasty • Catheter has an expandable wire Radiofrequency energy that is array at the tip converted to heat in the airway wall Monopolar radiofrequency (RF) energy Temperature controlled: 65 °C 10 seconds Signal for successful activation Multiple safety algorithms to ensure controlled energy delivery Bronchial Thermoplasty Miller J D et al. Chest 2005;127:1999-2006 Pavord I, et al. Am J Respir Crit Care Med 2007; 176:1185-91 Bronchial Thermoplasty in Difficult-to-Control Asthma Pavord I, et al. Am J Respir Crit Care Med 2007; 176:1185-91 Current and Experimental Treatments for Severe Asthma Approach Drug/Treatment Oral corticosteroids Prednisone, Medrol Anti-IgE Mab Omalizumab Bronchial smooth muscle Bronchial Thermoplasty Once daily ICS/LABA Relvar Anticholinergics Tiotropium Anti-IL5 Mab Mepolizumab, Reslizumab Anti-IL5R Mab Benzralizumab Anti-IL4Rα MAb Dupilimab Anti-IL13 Mab Lebrikizumab, Tralokinumab Macrolide antibiotics Several C-kit & PDGFR tryosine kinase inhibitor Masitinib Anti-IL2Rα Mab Daclizumab CXCR2 receptor antagonist SCH527123 CRTh2 Several Anti-TNFα Golimumab Kerstjens HAM, et al. J Allergy Clin Immunol 2011; 128:308-14 Kerstjens HAM, et al. New Engl J Med 2012; 367:1198-207 Tiotropium in Poorly Controlled Asthma Kerstjens HAM, et al. New Engl J Med 2012; 367:1198-207 Once Daily ICS/LABAs O’Byrne PM et al. Eur Respir J 2013: in press Woodruff PG, et al. Am J Respir Crit Care Med 2009; 180:388-95 Nair P, et al. N Engl J Med 2009; 360:985-93 Prednisone Reduction n=9 n=10 100 80 prednisone reduction as % of maximum possible 60 reduction 40 20 0 mepolizumab placebo p<0.05 Nair P, et al. N Engl J Med 2009; 360:985-93 . Asthma Exacerbations NAIR P, et al. N Engl J Med 2009; 360:985-93. Haldar P et al. N Engl J Med 2009; 360:973-984 DREAM Study n= 621 Pavord I, et al. Lancet 2012; 380:651-9 Anti-IL5Rα Ghazi A, et al. Expert Opin Biol Ther 2012; 12:113-8 Laviolette M, et al. J Allergy Clin Immunol 2013; 132:1086-96. IL-4 and IL-13 Ingram JL, Kraft M. J Allergy Clin Immunol 2012130:829-42 Anti-IL-13 Treatment in Adults with Asthma Corren J et al. N Engl J Med 2011;365:1088-1098. Severe Exacerbations P=0.08 Rate Corren J et al. N Engl J Med 2011;365:1088-1098. P=0.375 P=0.072 Study Design Wenzel S, et al. N Engl J Med 2013; 368:2455-66. Anti-IL4Rα in Asthma Wenzel S, et al. N Engl J Med 2013; 368:2455-66. Anti-IL4Rα in Asthma Wenzel S, et al. N Engl J Med 2013; 368:2455-66. Conclusion: Despite statistically significant associations, FENO levels, IgE levels, blood eosinophil and neutrophil counts, FEV1 percent predicted, and age are poor surrogates, both separately and combined, for accurately predicting sputum eosinophil and neutrophil percentages. (J Allergy Clin Immunol 2013;132:72-80.) FEV1 PEF Reiter J, et al. Allergy 2013; 68:1040-9 Symptom scores AQL Reiter J, et al. Allergy 2013; 68:1040-9 Brusselle G, et al. Thorax 2013; 68:322-9 Conclusions • Patients with severe refractory asthma are uncontrolled despite optimal therapy with ICS/LABA . • Tiotropium improves lung function in refractory asthma and slightly reduce asthma exacerbation risk. • Treatment with anti –IL-5 hMab reduces asthma exacerbations in patients with airway eosinophilia, but the effect on lung function has been variable. • Treatment with anti-IL-13 or IL-4Rα improved lung function and may reduce asthma exacerbations. • Treatment with macrolides may reduce asthma exacerbations in non-eosinophilic asthma. .
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