Treatment Options for the Symptomatic Asthma Patient Paul M O’Byrne EJ Moran Campbell Professor of Medicine Firestone Institute for Respiratory Health, St. Joseph’s Healthcare and McMaster University, Hamilton, Ontario, Canada

Potential for Conflict of Interest Advisory Boards: Abbott, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Medimmune, Merck. Speakers Fees: AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Takeda. Grants-in-Aid: Amgen, AstraZeneca, Axican, Genentech, GlaxoSmithKline, Novartis, Sanofi. Employed by McMaster University

The Goals of Asthma Management Overall Asthma Control achieving reducing Current control Future risk defined by defined by Symptoms Reliever use Instability/ worsening Exacerbations Activity Lung function Loss of lung function Adverse effects of medication NAEPP. Expert Panel Report 3. 2007 Taylor DR, et al. Eur Respir J 2008; 32:545–554

Asthma Paradox Effective and safe treatments: Inhaled corticosteroids Short-acting inhaled β2-agonists ICS/LABA combinations Leukotriene receptor antagonists Anti-IgE hMab 23% 59% 18% Chapman KR, et al. Eur Respit J 2008; 31:320-5

KEYPAD QUESTION

Evaluation of Uncontrolled Asthma Adherence, adherence, adherence (50%: 50%: 50%) Co-morbidities Rhino-sinusitis Allergic bronchopulmonary aspergillosis GERD Obesity Bronchiectasis Vocal cord dysfunction Smoking Psychopathology Persistent allergen/occupational exposure Incorrect diagnosis Severe refractory disease

Krishnan JA, et al. Am J Respir Crit Care Med 2004; 170:1281-5

1 year risk of discontinuation: Age <55 years Female sex Previous β2-agonist use No other drugs used Higher co-payment

Study Subjects n Intervention Results Rasmussen et al. JACI 2005 300 Internet-based management tool Better adherence, lung function, symptoms and QOL Araujo et al. J Invest All Clin Immunol 2012 21 Web-based management tool Better QOL only Vollmer et al. Am J Manag Care 2011 8517 Interactive voice recognition calls Better adherence, better asthma control Wilson et al. AJRCCM 2010 612 Shared decision making Better adherence. Some improvement AQLQ Clark et al. Chron Resp Dis 2012 808 Asthma Care Plan developed with physician Gamble et al. Respir Med 2011 239 Educational visit with specialist nurse Better adherence. Less OCS use Ulrik et al. Clin Respir Dis 2009 361 Compliance enhancement training sessions No improvement in asthma control Barnes CB, Ulrik S. Respir Care 2014: in press

GINA 2014 *For children 6-11 years, theophylline is not recommended, and preferred Step 3 is medium dose ICS **For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy

Well-controlled patients (%) Poorly-controlled patients (%) FACET: Well vs Poorly Controlled Patients Well-controlled patients (%) Poorly-controlled patients (%) 80 20 62% 60 15 14% 46% 40% 40 37% 10 7% 6% 20 5 3% BUD 200 BUD 800 BUD 200+ F BUD 800+ F BUD 200 BUD 800 BUD 200+ F BUD 800+ F O’Byrne PM, et al. Chest 2008; 134:1192-99

KEYPAD QUESTION

The Goal of Asthma Management is: Overall Asthma Control achieving reducing Current Control Future Risk defined by defined by Symptoms Reliever use Instability/ worsening Exacerbations Activity Lung function Lung function loss Medication adverse effects GINA 2006; NIH/NAEPP Expert Report No.3 2007; ATS/ERS Task Force on Asthma Severity & Control 2008

Sears MR et al. New Engl J Med 2003;349:1414-22.

START – study outline Part A Part B 1 2 3 Year 4 5 Visit 1 2 3 4 5 6 7 Children 11+ yrs and Adults Budesonide 400 µg ONCE DAILY + usual therapy Part B Children < 11 yrs Children 11+ yrs and Adults Budesonide 200 µg ONCE DAILY + usual therapy Budesonide 400 µg ONCE DAILY + usual therapy Children < 11 yrs Budesonide 200 µg ONCE DAILY + usual therapy START – study outline START is a multinational, multicentre, double-blind, parallel group study lasting for 3 years, followed by a 2-year open-label study. During the first 3 years (Part A), patients received Pulmicort once daily or placebo once daily, in addition to their usual asthma therapy. In the final 2 years (Part B), all patients receive Pulmicort once daily, in addition to their usual asthma therapy. Adults and Children Placebo ONCE DAILY + usual therapy 1 2 3 Year 4 5 Visit 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

NoSARE is the subgroup with no Severe Asthma Related Event. n=3284 (Budesonide), n=3178 (Placebo) SCS is the subgroup with at least one systemic corticosteroid course due to asthma. n=543 (Budesonide), n=808 (Placebo) (p<0.001) SARE is the subgroup with at least one Severe Asthma Related Event requiring hospital management. n=116 (Budesonide), n=192 (Placebo) (p<0.01)

START: 3-year change in post-bd FEV1% O’Byrne PM, et al. Am J Respir Crit Care Med 2009; 179:19-24

Tailoring treatment for asthma Chung et al, Lancet Respir 2013

Ortega HG et al. N Engl J Med 2014:371:1189-97 Asthma Exacerbations and FEV1 at 32 Weeks. Figure 2. Asthma Exacerbations and FEV1 at 32 Weeks. Panel A shows the numbers of asthma exacerbations in patients receiving either intravenous or subcutaneous mepolizumab or placebo. The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Panel B shows the mean forced expiratory volume in 1 second (FEV1) as a percentage of the predicted value. At week 32, there was greater improvement from baseline in the two mepolizumab groups than in the placebo group — a 100-ml greater increase in the intravenous-mepolizumab group than in the placebo group (P=0.02) and a 98-ml greater increase in the subcutaneous-mepolizumab group than in the placebo group (P=0.03). The I bars indicate 95% confidence intervals. Ortega HG et al. N Engl J Med 2014:371:1189-97

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.

Thymic Stromal Lymphopoietin (TSLP) Activated Dendritic Cell OX40 OX40L TSLP Naïve T cell Th2 Cell Memory T Cell IL-5 IL-9 IL-4/IL-13/IL-9 B Cell Eosinophil Goblet Cell POLARIZE ACTIVATE Epithelium Smooth Muscle

12-Week Treatment Period Screening Period Placebo Dose AMG 157 IV 700 mg Allergen Challenge Day: -28 -15 -14 -13 1 8 15 29 36 41 42 43 57 71 83 84 85 113 169 SI* AHR SI 12-Week Treatment Period PB Follow Up FENO Gauvreau GM, et al. N Engl J Med 2014: 370:2102-10.

Percent Change in FEV1 (%) Time Post-Allergen Challenge (Hours) Day -14 Day 42 Day 84 * * * * Percent Change in FEV1 (%) AMG 157 Placebo Mean ±SEM percent FEV1-time curve at screening, day 42 and day 84. AMG 157 treatment significantly attenuated the early and late allergen-induced fall in FEV1 at days 42 and 84. *P<0.05 AMG 157 compared to placebo Time Post-Allergen Challenge (Hours) Gauvreau GM, et al. N Engl J Med 2014: 370:2102-10.

* * * * * * * * * * * * * * * * * * * * * A B C AMG 157 Placebo Blood Eosinophils (x106/L) -15 15 29 43 57 85 . B * * * Sputum Eosinophils (%) * * -15 -14 -13 1 41 42 43 83 84 85 . * C * Mean±SEM. Red arrows denote dosing, black arrows denote allergen inhalation challenge. *P<0.05 AMG 157 compared to placebo * * * * * * * * * * Fractional Exhaled Nitric Oxide (ppb) -15 -14 -13 1 8 15 29 36 41 42 43 57 71 83 84 85 . Study Day

CXCR1/2 Receptors and Neutrophil Activity GRO-a GRO-b ENA-78 GCP2 Pharmacol Rev 2004; 56:515-548

Median % change from baseline Sputum neutrophils 10.00 0.00 -10.00 -20.00 Median % change from baseline -30.00 -40.00 -50.00 Placebo SCH 527123 -60.00 Week 2 Week 4 Nair P, et al. Clin Exp Allergy 2012: 42:1097-1103

Anti-CXCR2 results CXCR2 antagonist Placebo Baseline End of study TCC (106/g) 4.6 3.1 5.5 Sputum NEUTR (%) 69.589 44.442 67.200 75.1* Blood NEUTR (x109/L) 4.928 5.288 5.759 5.565 Sputum EOS (%) 3.321 13.026 10.355 8.91 FEV1 post bd (L) 2.197 2.054 1.851 1.681 FEV1 post bd (% pred) 67.995 63.775 60.421 54.50 PEF (am), L/min 315.45 303.43 316.04 285.82 ACQ 2.159 1.946 2.298 2.524 SABA (Puffs/day) 1.70 1.59 2.10 2.47 Mild exacerbations 1.3 2.25* Nair P, et al. Clin Exp Allergy 2012: 42:1097-1103

Brusselle G, et al. Thorax 2013; 68:322-9

The Goals of Asthma Management Despite effective asthma treatments, many asthmatics remain uncontrolled The most common reason for poor asthma control is poor adherence Poor asthma control is associated with increased risk of asthma exacerbations Asthma exacerbations can cause a decline in lung function New asthma treatments should improve current symptom control, and/or reduce future risks of asthma exacerbations Overall Asthma Control achieving reducing Current control Future risk defined by defined by Symptoms Reliever use Instability/ worsening Exacerbations Activity Lung function Loss of lung function Adverse effects of medication NAEPP. Expert Panel Report 3. 2007 Taylor DR, et al. Eur Respir J 2008; 32:545–554