1. Bronchodilation is the cornerstone of treatment Pharmacological treatment of COPD

2. 2 GOLD 2014: treatment goals for stable COPD  Relieve symptoms  Improve exercise endurance  Improve health status REDUCE SYMPTOMS AND  Prevent disease progression  Prevent and treat exacerbations  Reduce mortality REDUCE RISK COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease GOLD 2014 (http://www.goldcopd.org/)http://www.goldcopd.org/

3. 3 The central role of airflow limitation leading to symptoms in COPD Disability Disease progressionDeath Air trapping Expiratory flow limitation Hyperinflation DeconditioningInactivity Reduced exercise capacity Exacerbations COPD Shortness of breath Quality of life Exercise COPD = chronic obstructive pulmonary disease Adapted from Cooper CB. Respir Med 2009;103:325–34.

4. 4 Early intervention may interrupt the downward spiral of activity-limiting symptoms Becomes more sedentary to avoid dyspnea-producing activity (decreases activity) Dyspnea with activities Deconditioning aggravates dyspnoea; patients adjust by reducing activity further The dyspnea–inactivity downward spiral Reardon JZ et al. Am J Med 2006;119(10 Suppl 1):32–72 ZuWallack R COPD 2007;4:293–7

5. 5 Bronchodilators are the cornerstone of COPD management  Bronchodilators are central to the management of symptomatic COPD and comprise three different classes Short-acting β 2 -agonists and muscarinic antagonists (SABAs and SAMAs) 1 Long-acting β 2 -agonists and muscarinic antagonists (LABAs and LAMAs) 1  Long-acting agents are more effective and convenient in maintenance control of symptoms, improving HRQoL, and preventing exacerbations than short-acting agents 1–9  Drugs from different classes can be used alone or in combination 1 COPD = chronic obstructive pulmonary disease; HRQoL = health-related quality of life; LABA = long-acting β 2 -agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting β 2 -agonist; SAMA = short-acting muscarinic antagonist 1. GOLD 2014 (http://www.goldcopd.org/); 2. Dahl R et al. Am J Respir Crit Care Med 2001;164:778–84; 3. Mahler D et al. Chest 1999;115:957–65; 4. Szafranski W et al. Eur Respir J 2003;21:74–81; 5. Calverley PMA et al. Eur Respir J 2003;22:912–9; 6. Rennard S et al. Am J Respir Crit Care Med 2001;163:1087–92; 7. Brusasco V et al. Thorax 2003;58:399–404; 8. Rutten van-Molken MPMH et al. Eur J Heath Econ 2007;8:123–35; 9. Vogelmeier C et al. N Engl J Med 2011;364:1093–103http://www.goldcopd.org/

6. 6 Mechanism of action of bronchodilators  Alter airway smooth muscle tone, widening airways 1 Improves expiratory flow 1  Reduce air trapping and improve lung emptying 1–4 Improves symptoms and exercise capacity 1–4  Additional non-bronchodilator effects Improves skeletal muscle function and mucociliary clearance 5 1. GOLD 2014 (http://www.goldcopd.org/); 2. Hasegawa M et al. Thorax 2009;64:332–8; 3. Cooper CB. Respir Med 2009;103:325–34; 4. Calverley PMA. Eur Respir J 2005;26:190–1; 5. Johnson M, Rennard S. Chest 2001;120:258–70http://www.goldcopd.org/

7. 7 Mechanism of action of LABAs and LAMAs  β 2 -adrenergic agonists Stimulate β 2 -adrenergic receptors on airway smooth muscle 1 -Causes muscle relaxation (i.e. bronchodilation) 1 -Increases cAMP, antagonizing bronchoconstriction 1  Anticholinergics Block M 3 receptors 1 -Inhibits ACh-induced bronchoconstriction of airway smooth muscle 2,3 -Inhibits mucus secretion at mucus glands 2,3 Non-selective agents also block M 1 and M 2 receptors 1 -M 2 receptor blockade may diminish original bronchodilatory effects, and produce adverse cardiac and urinary effects 4–6 ACh = acetylcholine; cAMP = cyclic adenosine monophosphate; LABA = long-acting β 2 -agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting β 2 -agonist; SAMA = short-acting muscarinic antagonist 1.GOLD 2014 (http://www.goldcopd.org/)http://www.goldcopd.org/ 2.Barnes PJ. Life Sci 1993;52:521–7 3.Eglen RM et al. Pharmacol Rev 1996;48:531–65 4.Van Noord JA. Drugs 2002;62:1204–5 5.Caulfield MP and Birdsall NJM. Pharmacol Rev 1998;50:279–90 6.Hegde SS and Eglen RM. Life Sci 1999;64:419–28

8. 8 Targeting two bronchodilatory pathways to improve bronchodilation  Targeting two bronchodilatory pathways can provide greater bronchodilation than one pathway alone 1–3  Targeting two bronchodilatory pathways may also address diurnal variations in symptoms Sympathetic activity may be more prominent during the day, and parasympathetic activity more prominent during the night 4–6 Considerable intra-patient variability in reversibility testing has been observed 7,8 1.COMBIVENT Inhalation Solution Study Group. Chest 1997;112:1514–21 2.Mahler DA et al. Thorax 2012;67:781–8 3.van Noord JA et al. Eur Respir J 2005;26:214–22 4.Postma DS et al. Clin Sci 1985;69:251–8 5.Gaultier C et al. Respir Physiol 1977;31:169–82 6.Furlan R et al. Circulation 1990;81:537–47 7.Calverley PM et al. Thorax. 2003;58:659–64 8.Anthonisen N and Wright E. Am Rev Respir Dis 1986;133:814–9

9. 9 GOLD 2014 Pharmacological management of COPD* Based on combined assessment of airflow limitation, symptoms and exacerbation risk Risk Exacerbation history Risk GOLD classification of airflow limitation GOLD Grade 4 GOLD Grade 2 GOLD Grade 1 GOLD Grade 3 GOLD Group C ICS + LABA, or LAMA LAMA + LABA or LAMA + PDE-4i or LABA + PDE-4i LAMA or LABA LAMA + LABA SAMA or SABA p.r.n. LAMA or LABA or SABA + SAMA ICS + LABA +/or LAMA ICS + LABA + LAMA or ICS + LABA + PDE-4i or LAMA + LABA or LAMA + PDE-4i Recommended first choice Alternative choice GOLD Group D GOLD Group AGOLD Group B ≥2 or ≥1 leading to hospital admission 1 (not leading to hospital admission) Symptoms CAT ≥10CAT <10 mMRC 0  1 mMRC ≥2 Breathlessness *Medications in each box are in alphabetical order, and not necessarily in order of preference. Other possible treatments are not shown, but can be used alone or in combination with other options in the Recommended first choice and Alternative choice boxes. CAT = COPD Assessment Test; COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease; HRQoL = health-related quality of life; ICS = inhaled corticosteroids; LABA = long-acting β 2 -agonist; LAMA = long-acting muscarinic antagonist; mMRC = modified Medical Research Council; PDE-4i = phosphodiesterase type 4 inhibitor; SABA = short-acting β 2 -agonist; SAMA = short-acting muscarinic antagonist GOLD 2014 (http://www.goldcopd.org/)http://www.goldcopd.org/

10. 10 LAMA therapies are established in COPD and can improve a range of clinical outcomes  Lung function 1–7  Inspiratory capacity 8–11  Exercise capacity 9–11  Effectiveness of pulmonary rehabilitation 12  Shortness of breath 1,2,4–7,9  HRQoL* 1–7  Exacerbations 1,3,6,7,13 *St George's Respiratory Questionnaire 1-7 and Short Form 36 Health Survey 1 COPD = chronic obstructive pulmonary disease; HRQoL = health-related quality of life; LAMA = long-acting muscarinic antagonist 1. Casaburi R et al. Eur Respir J 2002;19:217–24; 2. Donohue J et al. Chest 2002;122:47–55; 3. Tashkin DP et al. N Engl J Med 2008;359:1543–54; 4. Kerwin EM et al. COPD 2012;9:90–101; 5. Jones PW et al. Eur Respir J 2012;40:830–6; 6. D'Urzo A et al. Respir Res 2011;12:156; 7. Kerwin E et al. Eur Respir J 2012;40:1106–14; 8. Celli B et al. Chest 2003;124:1743–8; 9. O’Donnell DE et al. Eur Respir J 2004;23:832–40; 10. Maltais F et al. Chest 2005;128:1168–78; 11. Beeh KM et al. Int J Chron Obstruct Pulmon Dis 2012;7:503–13; 12. Casaburi R et al. Chest 2005;127:809–17; 13. Niewoehner DE et al. Ann Intern Med 2005;143:317–26

11. 11 LAMAs have demonstrated ability to reduce the risk of exacerbation vs placebo  Both glycopyrronium and tiotropium significantly reduced the risk of exacerbation (in terms of time to first moderate-to-severe exacerbation) vs placebo (p=0.001) 100 Patients exacerbation-free (%) Time to first exacerbation (weeks) 90 80 70 60 50 0 0481216202428323640444852 Glycopyrronium 50 μg o.d. Tiotropium Placebo  Glycopyrronium significantly reduced the rate of moderate-to-severe COPD exacerbations vs placebo CI = confidence interval; COPD = chronic obstructive pulmonary disease; HR = hazard ratio; RR, rate ratio. Kerwin E et al. Eur Respir J 2012;40:1106–14 Glycopyrronium vs placebo: HR 0.66 (95% CI 0.520–0.850); p=0.001 Tiotropium vs placebo: HR 0.61 (95% CI, 0.456–0.821); p=0.001

12. 12  Improvements in trough FEV 1 were statistically significant with indacaterol + glycopyrronium* vs indacaterol at Day 1 and Week 12 (both p<0.001) Δ 74 † mL Δ 64 † mL Trough FEV 1 (L) 0 LAMA and LABA combination significantly improved lung function after first dose (Day 1) and at Week 12 vs LABA alone *Open-label indacaterol and double-blind glycopyrronium were co-administered via separate Breezhaler ® devices. Indacaterol 150 µg o.d.+ glycopyrronium 50 µg o.d.*Indacaterol 150 µg o.d.+ placebo † p<0.001. Data are least squares mean ± standard error;. FEV 1 = forced expiratory volume in 1s; o.d.,= once daily Vincken et al. Int J Chron Obstruct Pulmon Dis 2014 (in press)

13. 13 Inhaled corticosteroids do not improve symptoms of breathlessness Fluticasone propionate Mean breathlessness symptom score after 52 weeks Placebo p=ns ns = not significant Calverley PMA et al. Lancet 2003;361:449–56

14. 14 Despite recommendations, ICS used often in early-stage COPD  ICS plus LABA recommended for use only in patients in Groups C and D 1  However, many patients in Groups A and B are treated with ICS 2,3 Data were drawn from the Adelphi Respiratory Disease Specific Programme, a large multinational (France, Germany, Italy, Spain, UK, USA) cross-sectional survey generating real-world data based on actual clinical practice. N=1508. 2,3 GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting β 2 -agonist. GOLD Group C 13 patients 54% using ICS 739 patients 38% using ICS 152 patients 33% using ICS 604 patients 51% using ICS GOLD Group D GOLD Group AGOLD Group B 1. GOLD 2014 (http://www.goldcopd.org/)http://www.goldcopd.org/ 2. Small M et al. Thorax 2012;67:A144–A145 3. Higgins V et al. COPD8 2012. (Poster)

15. 15 Increased risk of pneumonia with ICS use in patients with COPD: meta-analysis  Significantly increased risk of serious pneumonia for ICS vs placebo: risk ratio 1.51 (95%CI 1.08–2.10) 285 events/3,881 patients vs 180 events/3,633 patients ICS + LABA vs LABA: risk ratio 1.72 (95%CI 1.28–2.30) 356 events/4,754 patients vs 217 events/4,728 patients Total: ICS vs no ICS: risk ratio 1.60 (95%CI 1.33–1.92) 641 events/8,635 patients vs 397 events/8,361 patients Singh S, et al. Arch Intern Med 2009;169:219–29 CI, confidence interval; COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid; LABA, long-acting β 2 -agonist.

16. 16 Conclusions  The key treatment goals for stable COPD are: 1 Reduce symptoms (improve symptoms, exercise endurance and health status) Reduce risk (prevent progression, prevent/treat exacerbations, reduce mortality)  Early intervention may interrupt the downward spiral of activity-limiting symptoms in COPD 13,14(2,3)  Bronchodilators are central to the management of symptomatic COPD 1 Long-acting bronchodilators (LABAs and LAMAs) are preferred over short-acting agents  Long-acting bronchodilators have been shown to : reduce airflow limitation 2,3 (4,5) reduce hyperinflation and exercise endurance 4 (6) improve HRQoL 5(7) reduce exacerbations 6–12(8-14)  Administration of a LAMA and a LABA provides incremental benefit on lung function (trough FEV 1 ) compared with LABA alone (15)  ICS may reduce the risk of exacerbations in patients with severe COPD, 15(16) but may also increase the risk of pneumonia 16(17)  ICS are only recommended for high-risk patients 1 COPD = chronic obstructive pulmonary disease; LABA = long-acting β 2 -agonist; LAMA = long-acting muscarinic antagonist; ICS = inhaled corticosteroids 1. GOLD 2014 (http://www.goldcopd.org/); 2. Reardon JZ et al. Am J Med 2006; 3. ZuWallack R COPD 2007; 4. Dahl R. et al. Am J Respir Crit Care Med 2001; 5. Donohue J et al. Chest 2002; 6. O’Donnell D et al. Eur Respir J 2004; 7. Calverley PMA et al. Eur Respir J 2003; 8. Calverley PMA et al. Lancet 2003; 9. Calverley PMA et al. New Engl J Med 2007; 10. Casaburi R, et al.. Eur Respir J 2002; 11. Vogelmeier C, et al. N Engl J Med 2011; 12. Vincken W, et al. Eur Respir J 2002; 13. Wedzicha JA, et al. Am J Respir Crit Care Med 2008; 14. Tashkin DP, et al. N Engl J Med 2008; 15. Vincken et al. Int J Chron Obstruct Pulmon Dis 2014 (in press); 16. Agarwal R, et al. Chest 2010; 17. Singh S, et al. Arch Intern Med 2009;http://www.goldcopd.org/