Evaluation and Treatment of Patients with Severe Asthma

Home , Daclizumab, Lebrikizumab, Reslizumab

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

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

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. 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.