1. COPD 2014 Alejandro C. Arroliga, M.D. Chairman and Professor Dr. A. Ford Wolf and Brooksie Nell Boyd Wolf Centennial Chair of Medicine

2. Organization of the talk A.- Inflammation B.- Brief review of therapy including for exacerbation (recent papers in red) COPD is a systemic disease 2

3. PLATINO: COPD in LatinAmerica Brazil (São Paulo) Uruguay (Montevideo) Venezuela (Caracas) Mexico (Mexico city) Chile (Santiago) Menezes A, et al. Lancet 2005 12,1%!!!

4. COPD is a progressive disease with inflammation as a key process

5. 1. Snoeck-Stroband JB et al. Respir Res 2006; 7: 140. 2. Parr DG et al. Respir Research 2006; 7: 136 (online journal). Understanding inflammation Airway inflammation negatively affects health status of COPD patients 1 Higher levels of certain inflammatory markers are associated with a decline in lung function and subsequent disease progression 2

6. Airway inflammation is characterised by increased numbers of neutrophils, macrophages and CD8+ lymphocytes 1,2 Infiltration of inflammatory cells into the airways occurs in both early and late stages of COPD 3 As the disease progresses, the small airways fill with inflammatory mucus exudates 3 The presence of inflammation in the airways provides a rationale for using inhaled corticosteroids and long-acting beta 2 -agonists to treat the disease 1. Gold Guideline http://goldcopd.com 2007. 2. Barnes NC et al. Am J Respir Crit Care Med 2006; 173: 736–743. 3. Hogg JC et al. New Eng J Med 2004; 350: 2645–2653. Inflammation is present even in the early stages of COPD

7. Percentage change from baseline in biopsy and sputum endpoints 1. Barnes NC et al. Am J Respir Crit Care Med 2006; 173: 736–743. CD8 p=0.001 CD68 p=0.288 CD45 p=0.001 CD4 p=0.002 Mast cells p=0.022 TNF-  p=0.007 IFN-  p=0.055 Change favours SFC Change favours placebo 30 20 10 0 -10 -20 -30 -40 -50 -60 -70 -80 SFC 50/500 – placebo (%)

8. The Anti-inflammatory Effect Is Associated With A Reduced Rate In The FEV1 Decline Ann Intern Med. 2009;151:517-527.

9. 1. Bourbeau J et al. Thorax 2007; 62: 938–943. 2. Kardos P et al. Am J Respir Crit Care Med 2007; 175:144–149. 3. Mahler DA et al. Am J Respir Crit Care Med 2002 166: 1084 – 1091; 4. Calverley PMA et al. Lancet 2003; 361: 449 – 456. 5. Calverley PMA et al. New Eng J Med 2007; 356: 775–789. 6. Johnson M. Proc Am Thor Soc 2004; 1: 200–206 7. Adcock IM. J Allergy Clin Immunol 2002; 110(6 Suppl): s261–s268. Synergistic effects of SFC Bourbeau et al suggest that combination therapy has anti-inflammatory effects, not seen with inhaled corticosteroids alone 1 Compared with monotherapy, enhanced effects for combination are consistent not only with clinical data but also with in vitro data 2–5 Bourbeau et al propose that the anti-inflammatory activity seen with SFC but not FP may be due to additive or synergistic effects at the receptor level 1 Corticosteroids may regulate  2 receptor function by increasing expression of the receptor, and inhibiting  2 receptor down-regulation 6,7

10. COPD 2013 “patients who benefit the most from inhaled bronchodilators seem to be those who have respiratory symptoms and airflow obstruction with an FEV1 less than 60% predicted” “monotherapy using either long acting inhaled anticholinergics or long acting beta agonists(but not inhaled steroids as monotherapy) for symptomatic patients with an FEV1 of less than 60% predicted is recommended Courtesy of Frank Perez-Guerra, M.D.

12. Summary of data of different therapeutic studied in patients with COPD UPLIFT (Tiotropium achieves improvement in lung function over time, although rate of decline not reduced; reduction in frequency of exacerbations and in hospitalizations; no difference in mortality between tiotropium and placebo TORCH- reduction in the rate of decline in airflow limitation in the salmeterol/fluticasone arm compared to placebo INSPIRE – comparison of SFC versus tiotropium in severe COPD – no difference in exacerbation frequency between the two treatments. Question of better quality of life and reduced mortality risk with SFC.

13. Tiotropium/formoterol (Foradil) vs salmeterol(Serevent)/fluticasone in moderate COPD – TF superior in lung function over the day compared to SF (this study appeals to me, Chest 2008;134:255) OPTIMAL (Tiotopium/placebo, T plus salmeterol, T plus salmeterol/fluticasone) – patients treated with T/F/S had significantly better disease specific quality of life and fewer hospitalizations compared to T/placebo, however these improvements in health outcomes were associated with increased costs. Monotherapy with T most economically attractive. Exacerbation rate did not differ Summary of data of different therapeutic studied in patients with COPD

14. Others therapy Immunizations – both Pneumovax and influenza (this is an “accepted” recommendation) Testing for alpha-one-anti-trypsin deficiency – Lung volume reduction surgery (or “medical treatment utilizing valves”) - not a common procedure, but may be considered in very symptomatic patients with well documented predominant upper lobe emphysema with an FEV1 and DlCO of more than 20% of predicted Transplantation - LVRS may be a bridge to this. When to refer – BODE index of over 5, post dilator FEV1 of less than 20% predicted, resting hypoxemia, hypercapnia, secondary PH, accelerated decline in FEV1 – but…is there a survival benefit?

15. Global Strategy for Diagnosis, Management and Prevention of COPD Manage Stable COPD: Non-pharmacologic Patient Group EssentialRecommendedDepending on local guidelines A Smoking cessation (can include pharmacologic treatment) Physical activity Flu vaccination Pneumococcal vaccination B, C, D Smoking cessation (can include pharmacologic treatment) Pulmonary rehabilitation Physical activity Flu vaccination Pneumococcal vaccination © 2013 Global Initiative for Chronic Obstructive Lung Disease Courtesy of Shirley Jones, M.D.

16. COPD 2013 Roflumilast – this is a PDE-4 inhibitor (PDE-4 inhibition decreases inflammation and promotes airway smooth muscle relaxation) Approved for COPD patients with a history of exacerbations – the experience is limited, but this agent may be useful perhaps not only in COPD, but in asthma, bronchiectasis, etc – time will tell Mucoactive agents- the jury is out, but some patients may improve, some even think that they are better than the inhaled medications (but this is doubtful)

17. GOLD Assessment Severity of Airflow Obstruction Worse obstruction More severe Exacerbations Frequent exacerbations D Severe Obstruction Severe Symptoms ++ Exacerbations High Risk Symptoms C Severe Obstruction Minimal Symptoms ++ Exacerbations A Mild-Mod Obstruction Minimal Symptoms Few Exacerbations B Mild-Mod Obstruction Severe Symptoms Few Exacerbations GOLD Website. http://www.goldcopd.com. Updated December 2011http://www.goldcopd.com

18. Survival shown as Kaplan-Meier curves Lange et al AJRCCM 2012; 186: 975–981 Groups C and D experienced a higher incidence of exacerbations in the following year and a higher average number of exacerbations per year than groups A and B.

19. Exacerbations per year > 2 1 0 mMRC 0-1 CAT < 10 Risk FEV 1 GOLD 4 or mMRC > 2 CAT > 10 GOLD 3 GOLD 2 or GOLD 1 SAMA prn or SABA prn LABA or LAMA ICS + LABA or LAMA COPD: Pharmacologic Therapy (FIRST CHOICE) AB DC ICS + LABA or LAMA In alphabetical order Symptoms Risk

20. Exacerbations Are Not Random Events

21. Gold StageAECOPD Rate in Yr 1 II0.85 III1.34 IV2.00 Risks of COPD Exacerbations Strongest predictor of an AECOPD in a given year was the presence of an exacerbation in the previous year Hurst JR et al. N Engl J Med 2010; 363:1128-1138

22. 22 Agusti A, et al. Eur Respir J 2013; 42: 636

23. PA:A ratio of more than 1 at baseline was associated with future exacerbations of COPD, particularly those requiring hospitalization 23 The PA:A ratio also appears to outperform many established risk factors for exacerbation including GERD, SGRQ score, breathlessness, chronic bronchitis, and FEV1,as well as recently identified CT predictors.

24. 0.029%SFC vs FP 0.00212%SFC vs sal <0.00125%SFC vs placebo SFC significantly reduces exacerbations and severity of exacerbations over 3 years (TORCH) p-valueTreatment effect 0 0.2 0.4 0.6 0.8 1 1.2 Placebo Annualised exacerbation rate SalFPSFC 25% (p<0.001) 1.13 0.97 0.93 0.85 1. Calverley PMA et al. New Eng J Med 2007; 356: 775–789.

25. Treatment of ambulatory exacerbations of mild- moderate COPD is more effective with antibiotic vs. placebo Primary and Secondary Outcomes AMX (500/125 mg/8 hrs) % N=158 PBO % N= 152 P value Clinical cure days 9-11*74590.016 Clinical cure at day 2081670.006 Days until exacerbation, median 233 (110-365)160 (66-365)0.015 Peak expiratory flow from basal, L/min 52380.039 25 The NNT is seven Llor C, et al Am J Respir Crit Care Med 2012; 186: 716

26. In patients presenting to the ER with acute exacerbation, 5-day treatment of prednisone (40mg daily) was noninferior to 14-day treatment Non inferiority was defined as a 15% absolute difference in % of patients with a re-exacerbation (6 months) Average FEV1 was 31% and 87% were GOLD 3 or 4 26 End pointConventional treatment (n=155) Short- term (n= 156) Comparison measure (95%CI) P value Reexacerbations (ITT) 36%35%HR 0.95 (0.70-1.29)0.006 Deaths follow up8%7%HR 0.93 (0.40-2.20).87 Need for MV13%11%OR 0.78 (0.37-1.63).49 Cumulative dose, median, mg 560 (560-773)200 (200- 310) <0.001 Leuppi JD, et al. JAMA 2013; 309: 2223-2231

27. COPD affects more than the lungs!

28. TORCH overall causes of death as adjudicated by the Clinical Endpoint Committee Unknown 7% Cardiac 27% Cancer 21% Other 10% Respiratory 35% 1. Calverley PMA et al. New Eng J Med 2007; 356: 775–789.

29. 84% of COPD patients in TORCH study had comorbidities in at least one body system n=6112

30. Clinical consequences of osteoporosis Acute and chronic pain Kyphosis Loss of height Loss of mobility Bulging abdomen, reflux and other GI symptoms Breathing difficulties Depression Loss of independence REDUCED QUALITY OF LIFE Courtesy of Tony Anzueto, M.D.

31. What Do COPD Patients Die From? Mannino et al. Thorax. 2003;58:388-393. 100020406080 Severe COPD GOLD Stage III Moderate COPD GOLD Stage II No COPD GOLD Stage 0 COPDASCVDLung CancerPneum/InfOther Patients (%) Courtesy of Tony Anzueto, M.D.

32. Prevalence of CVD in COPD Curkendall et al, AEP 2006 Angina Other Cardiovascular Disease Pulmonary Embolism Stroke Acute Myocardial Infarction Arrhythmia Odds ratio Congestiv e Heart Failure 0 1 2 3 4 5 6 7 8 Courtesy of Tony Anzueto, M.D.

33. β-blockers can be used in patients with COPD and heart failure To explore the interaction of β-blocker selectivity and outcomes the authors queried the OPTIMIZE-HF registry 33 Mentz RJ, Am J Cardiol 2013; 111: 582-87

34. 34 β-blockers can be used in patients with COPD and heart failure Mentz RJ, Am J Cardiol 2013; 111: 582-87

35. 35 Mentz RJ, Am J Cardiol 2013; 111: 582-87

36. Conclusions The burden of COPD is high and is rising 1 COPD is a multicomponent disease with inflammation at its core 2 It is important to treat the underlying inflammation, which is present even in the early stages of the disease 3,4 Patients on SFC have significantly improved lung function and quality of life, and a significant reduction in exacerbations compared with components or placebo 5 1. Murray CJL et al. Lancet 1997; 349:1498–1504. 2. Agusti AGN et al. Eur Respir J 2005; 99: 670–682. 3. Hogg JC et al. New Eng J Med 2004; 350: 2645– 2653. 4. Barnes NC et al. Am J Respir Crit Care Med 2006; 173: 736–743. 5. Calverley PMA et al. New Eng J Med 2007; 356: 775–789.

37. Conclusions Exacerbations are common. Patients with previous exacerbations are more likely to have more. Presence of cough and sputum production are associated with more exacerbations Antibiotics are useful to treat exacerbations in patients with mild to moderate COPD Prednisone 40 mg daily for 5 days is enough Use of β-blockers in patients with HF, even non selective are well tolerated and may be associated with improve survival

38. 38

39. COPD : a vision for the next 10 years  Understanding airway obstruction  Improved drug delivery  New LABAs and LAMAs  Combinations LAMA + LABA

40. Ultra long-acting β 2 agonists under development Vilanterol Olodaterol Abediterol (LAS-100977) AZD3199 PF-610355 (?)

41. NEW LABAs  Cazzola M, et al. Respir Med 2013

42. Disease Severity: BDs +/- ICS  Decramer M, et al. Respir Med 2013

43. New LABA’s  van Noord JA, et al. Pulm Pharmacol Ther 2011 n=35 FEV1: 37 ± 9% TBD: 21 ± 8% Respimat n=35 FEV1: 37 ± 9% TBD: 21 ± 8% Respimat

44. Long-acting antimuscarinic agents Glycopyrronium (NVA-237) Umeclidinium (GSK-573719) Aclidinium TD-4208 CHF 5407 QAT370 BEA-2180BR Trospium Dexpirronium AZD8683 PF-3715455 or PF-3635659

45. New LABA - NAV 237  Kerwin E, et al; GLOW2. Eur Respir J 2012 n=1066 FEV1: 55,7 ± 13% TBD: 16 ± 15% Breezhaler n=1066 FEV1: 55,7 ± 13% TBD: 16 ± 15% Breezhaler

46. New LAMA’s Jones PW, et al; ATTAIN. Eur Respir J 2012 n=828 FEV1: 53 ± 14% TBD: – Genuair n=828 FEV1: 53 ± 14% TBD: – Genuair

47. COPD : a vision for the next 10 years  Understanding airway obstruction  Improved drug delivery  New LABAs and LAMAs  Combinations LAMA + LABA

48. The present and future LAMAs Tiotropium Glycopyrronium (NVA237) Umeclidinium bromide Aclidinium bromide LABAs Oledanterol Indacaterol Vilanterol Carmoterol Formoterol Salmeterol Fixed - Combinations - Olodaterol/ tiotropium -Umeclidinium/ vilanterol -- Indacaterol/ glycopyrronium - Formoterol/aclidinium -Formoterol/glycopyrrolate

49. Rationale for combining long-acting bronchodilators Inhaled bronchodilators are the foundation of COPD treatment Most patients with COPD improve with bronchodilation Maximal bronchodilation is not achieved using clinically approved doses of 1 class of bronchodilator alone There could be synergistic interactions between  2-agonists and anticholinergics Cazzola M, Molimard M. Pulm Pharmacol Ther 2010;23:257-67

50. Ipratropium + Albuterol Combination short acting therapy 40 50 60 70 80 90 100 0153045607590105120 % Responding AlbuterolIpratropium Minutes post-drug administration Dorinsky PM, et al. Chest. 1999;115:966–971.

51. Combining tiotropium and formoterol (dosed once or twice daily): FEV 1 1.5 1.4 1.3 1.2 1.1 0.9 1.0 024681012141618202224 9 AM3 PM9 PM3 AM9 AM FEV 1 (L) van Noord JA et al. Chest 2006;129:509-17 Time (hours) Tiotropium qd + formoterol bid Tiotropium qd + formoterol qd Tiotropium qd + placebo bid 24-hour base

52. Effects of tiotropium and formoterol on dynamic hyperinflation and exercise endurance in COPD time to exercise intolerance FEV1 Berton et al. Respiratory Medicine 2010; 104: 1288-96

53. Combination: LABA + LAMA

54. Nuevas evidencias en LABA-LAMA 2 Bateman E, et al; SHINE. ERS Congress 2012 5m1h2h4h8h16h22h24\912h Time 1.60 1.55 1.45 1.40 1.35 1.30 1.25 1.20 1.15 1.10 1.05 1.00 LS mean of FEV 1 (L) QVA149IndacaterolGlycopyrroniumOpen-label tiotropiumPlacebo 54/46

55. LABA + LAMA vs ICS/LABA  Vogelmeier CF, et al; ILLUMINATE. Lancet 2012

56. Four weeks once daily treatment with tiotropium + olodaterol fixed dose combination compared with tiotropium in COPD patients * * * * Maltais et al, ERS Congress 2010

57. FEV 1 after 4 weeks of treatment a Mean values adjusted for baseline, treatment and centre 1.20 1.30 1.40 1.50 1.60 0123456 Time (hours) FEV 1 (L) a T+O (5 / 10 µg) T+O (5 / 5 µg) T+O (5 / 2 µg) T (5 µg) Maltais F et al. P5557 presented at ERS 2010

58. 28-day safety and tolerability of umeclidinium in combination with vilanterol in COPD Change from baseline in 0–6 h weighted mean pulse rate Feldman et al, Pulm Pharmacol Ther 2012

59. (Ultra) LABA/ICS combinations in clinical development Formoterol + mometasone (MFF258) Formoterol + fluticasone propionate Formoterol + ciclesonide Indacaterol + mometasone (QMF-149) Indacaterol + QAE-397 Vilanterol + fluticasone furoate GS-424020 (novel mutual prodrug of salmeterol and desisobutrylciclesonide)

60. Cazzola et al, Expert Opin Pharmacother 2012 Triple combination therapies in Phase I and II clinical trials

61. COPD: Drug Combinations (in alphabetical order) PatientFirst choiceSecond choiceAlternative Choices A SAMA prn or SABA prn LAMA or LABA or SABA and SAMA Theophylline B LAMA or LABA LAMA and LABA SABA and/or SAMA Theophylline C ICS + LABA or LAMA LAMA and LABA PDE4-inh. SABA and/or SAMA Theophylline D ICS + LABA or LAMA ICS and LAMA or ICS + LABA and LAMA or ICS+LABA and PDE4-inh. or LAMA and LABA or LAMA and PDE4-inh. Carbocysteine SABA and/or SAMA Theophylline

62. MABA: LABAS + LAMA LABA Long-acting beta agonist LABA Long-acting beta agonist LAMA Long-acting muscarinic antagonist LAMA Long-acting muscarinic antagonist MABA Muscarinic antagonist and beta agonist MABA Muscarinic antagonist and beta agonist  Hughes AD, et al. Prog Med Chem 2012

63. Astra Zeneca – PATHOS Study Objectives: – To investigate exacerbation rates in primary care patients with COPD treated with BF vs FS. Methods: – Data from primary care medical records. – Pairwise (1:1) propensity score matching. Results – Matching of 9893 patients (7155 BF; 2738 FS yielded two cohorts of 2734 patients), comprising 19,170 patient-years. – The exacerbation rates were 0.80 and 1.09 per patient-year BF and FS – Yearly rates for COPD-related hospitalizations were 0.15 and 0.21, respectively Conclusions – Long-term treatment with fixed-combination BF was associated with fewer exacerbations than FS in patients with moderate and severe COPD. Journal of Internal Medicine 2013 in press.

64. New ICS-LABAS combination Martinez F et al Respiratory Medicine 2013; 107: 550

65. Inhibition of release of inflammatory mediators by p38 inhibitors - Signalling through p38 mitogen-activated protein kinase (p38- MAPK) is required for the expression of a range of inflammatory mediators associated with COPD such as tumor necrosis factor α, interleukin-1 (IL-1), IL-6 and IL-8. - PH-797804 is a potent, selective p38-MAPK MacNee W, et al. Thorax 2013

66. Novel classes of bronchodilators Selective phosphodiesterase inhibitors K + channel openers Vasoactive intestinal peptide analogs Rho kinase inhibitors Brain natriuretic peptide and analogs Nitrix oxide donors E-prostanoid receptor 4 agonists Bitter taste receptor agonists Cazzola et al, Pharmacol Rev 2012

67. COPD : a vision for the next 10 years Further understanding of the impact of long acting bronchodilators. Demonstrate the efficacy of intervention in milder disease. New delivery systems Provide maximum bronchodilation - combination therapy – LABA-LAMA New molecules