Advancing COPD treatment strategies with evidencebased. 17:15 19:15 Monday 11 September 2017 ERS 2017, Milan, Italy

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1 Advancing COPD treatment strategies with evidencebased approaches 17:15 19:15 Monday 11 September 2017 ERS 2017, Milan, Italy

2 Increasing understanding of COPD and the effect on guideline evolution. GOLD 2017: the what, the why and the how Nicolas Roche, Respiratory and Intensive Care Medicine Cochin Hospital, AP-HP University Paris Descartes, France September 2017 GLRESP/COPD/0246m Novartis Pharma AG

3 Disclosures Activity Board membership Consultancy Grants and unrestricted funding for investigator-initiated studies Lectures Manuscript preparation Development of educational materials Travel/accommodation/meeting registration Mundipharma Novartis Pfizer Sandoz Sanofi Teva Zambon Company Mundipharma, Boehringer Ingelheim, TEVA, Pfizer, Novartis 3M, Sanofi, Sandoz, GSK Boehringer Ingelheim, Pfizer, Novartis Boehringer Ingelheim, Novartis, AstraZeneca, GSK, Chiesi, Cipla, Pfizer Novartis, AstraZeneca Zambon Boehringer Ingelheim, Novartis, AstraZeneca, GSK, Chiesi GOLD Science Committee

4 A historical perspective focused on treatment indications

5 As a preamble: old and new GOLD COPD definition GOLD < Chronic Obstructive Pulmonary Disease (COPD), a common preventable and treatable disease that is: characterized by persistent airflow limitation usually progressive associated with an enhanced chronic inflammatory response to noxious particles or gases in the airways and the lung GOLD Chronic Obstructive Pulmonary Disease (COPD) is a common, preventable and treatable disease that is: characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases 1. GOLD Available from: 2. GOLD Available from:

6 Back to basics: goals of COPD management Symptoms Reduce symptoms Exercise tolerance Health status Reduce risk Progression Exacerbations Mortality GOLD

7 Available medications (2001) Short-acting bronchodilators LABA ICS monotherapy was available, but indicated in very few countries for COPD Theophylline Mucoactive agents* *Not indicated for the long-term treatment of COPD ICS = inhaled corticosteroids; LABA = long-acting b 2 agonist

8 GOLD (2001) FVC = forced vital capacity; FEV 1 = forced expiratory volume in 1 second Pauwels RA, et al. Am J Respir Crit Care Med 2001;163:

9 GOLD (2007) Severity (all: FEV 1 /FVC <0.7) I: mild FEV 1 : >80% II: moderate FEV 1 : 50/60 80% III: severe FEV 1 : 30 50/60% IV: very severe FEV 1 <30% Risk factors avoidance; vaccines + prn short-acting bronchodilator + regular long-acting bronchodilator(s) + rehabilitation + fixed ICS-LABA combination if repeated exacerbations Roflumilast if CB + exacerbations ± LTOT surgery CB = chronic bronchitis; LTOT = long-term oxygen therapy ; prn = pro re nata (as needed) Rabe KF, et al. Am J Respir Crit Care Med 2007;176:532 55

10 Available medications (2017) Short-acting bronchodilators LABA LAMA LAMA+ICS In most countries, ICS are not indicated outside of fixed dose combinations LABA+LAMA LABA+ICS LAMA+LABA+ICS Theophylline Mucoactive agents* Roflumilast Macrolides* *Not indicated for the-long term treatment of COPD GOLD Available from:

11 A benefit-risk approach to treatment recommendations Individual presentation and underlying mechanisms Individual risk factors and comorbidities Expected Benefits Individualizing treatment choices in COPD Current COPD pharmacological treatments Expected Risks ALSO CONSIDER COSTS AND PREFERENCES Woodruff PG, et al. Lancet 2015;385:

12 GOLD (2011) GOLD 4 GOLD 3 C ICS/LABA or LAMA D ICS/LABA and/or LAMA 2 or more exacerbations/ year GOLD 2 GOLD 1 A SABA or SAMA prn B LABA or LAMA Less than 2 exacerbations/ year mmrc 0 1 CAT <10 mmrc 2 CAT 10 CAT = COPD Assessment Test; mmrc = modified Medical Research Council dyspnea scale Vestbo J, et al. Am J Respir Crit Care Med 2013;187:347 65

13 GOLD C and D patients were not the same! % of the population Exacerbations/year C1 (FEV 1 ) 4% 0.58 C2 (exacerbations) 1% 0.55 C3 (both) <1% 1.39 D1 (FEV 1 ) 26% 0.89 D2 (exacerbations) 6% 1.34 D3 (both) 9% 1.86 N=4,484 Han MK, et al. Lancet Respir Med 2013;1:43 50

14 GOLD 2017: the refined ABCD assessment tool Risk (GOLD classification of airflow limitation, FEV 1 % pred) Risk (exacerbation history in previous year) Exacerbation history 4 (<30) 3 (30 49) C D 2 or 1 leading to hospital admission 2 or 1 leading to hospital admission C D 2 (50 79) 1 ( 80) A B CAT <10 CAT 10 Symptoms mmrc 0 1 mmrc 2 Breathlessness 0 or 1 (not leading to hospital admission) 0 or 1 (not leading to hospital admission) A mmrc 0 1 CAT < 10 Symptoms B mmrc 2 CAT 10 CCQ = clinical COPD questionnaire 1. GOLD Available from: 2. GOLD Available from: ( 2017 Global Strategy for Diagnosis, Management and Prevention of COPD all rights reserved. Use is by express license from the owner)

15 Don t forget that COPD care begins with spirometry! Spirometrically confirmed diagnosis ROLES OF SPIROMETRY: Diagnosis FEV 1 (% predicted) Assessment of severity of airflow obstruction (prognosis) Post-bronchodilator GOLD 1 80 Follow-up FEV 1 /FVC assessment <0.7 GOLD Therapeutic decisions: - pharmacological changes - consideration of alternative diagnoses Assessment of airflow limitation GOLD GOLD 4 <30 - non-pharmacological treatments (e.g. interventional) Identification of rapid decline Exacerbation history 2 or 1 leading to hospital admission 0 or 1 (not leading to hospital admission) Assessment of symptoms/risk of exacerbations C A mmrc 0 1 CAT < 10 Symptoms D B mmrc 2 CAT Global Strategy for Diagnosis, Management and Prevention of COPD all rights reserved. Use is by express license from the owner. Available from:

16 GOLD 2017: new pharmacological treatment recommendations Group C Group D LAMA+LABA LABA+ICS Consider roflumilast if FEV 1 <50% pred. and patient has chronic bronchitis Consider macrolide (in former smokers) Further exacerbation(s) LAMA Further exacerbation(s) Further exacerbation(s) LAMA LAMA+LABA +ICS LAMA+LABA Persistent symptoms/further exacerbations LABA+ICS Group A Group B Continue, stop or try alternative class of bronchodilator LAMA+LABA Evaluate effect Persistent symptoms Preferred treatment A bronchodilator A long-acting bronchodilator (LABA or LAMA) 2017 Global Strategy for Diagnosis, Management and Prevention of COPD all rights reserved. Use is by express license from the owner. Available from:

17 GOLD A therapeutic recommendations Group A Continue, stop or try alternative class of bronchodilator Evaluate effect A bronchodilator 2017 Global Strategy for Diagnosis, Management and Prevention of COPD all rights reserved. Use is by express license from the owner). Available from:

18 GOLD B therapeutic recommendations Group B LAMA+LABA Persistent symptoms A long-acting bronchodilator (LABA or LAMA) 2017 Global Strategy for Diagnosis, Management and Prevention of COPD all rights reserved. Use is by express license from the owner). Available from:

19 GOLD C therapeutic recommendations Group C LAMA+LABA LABA+ICS Further exacerbation(s) LAMA 2017 Global Strategy for Diagnosis, Management and Prevention of COPD all rights reserved. Use is by express license from the owner). Available from:

20 GOLD D therapeutic recommendations Group D Consider roflumilast if FEV 1 <50% pred. and patient has chronic bronchitis Consider macrolide (in former smokers) Further Exacerbation(s) Further Exacerbation(s) LAMA+LABA+ICS Persistent symptoms/further exacerbations Until 2016: exacerbations ICS 2017 onwards: 1st line = long-acting bronchodilator(s) LAMA LAMA+LABA LABA+ICS 2017 Global Strategy for Diagnosis, Management and Prevention of COPD all rights reserved. Use is by express license from the owner). Available from:

21 What about triple therapy? What we know: triple vs: Placebo LAMA (added value of LABA+ICS) LABA+ICS (added value of the LAMA) What we don t have: triple vs LABA+LAMA Added value of the ICS Clinicaltrials.gov IMPACT: triple vs LABA+LAMA vs LABA+ICS 1 TRIBUTE: triple vs LABA+LAMA 2 ETHOS: triple vs LABA+LAMA vs LABA+ICS 3 SUNSET: triple vs LABA+LAMA 4 1. ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT

22 Personalizing pharmacological therapy for COPD

23 COPD endotypes for personalized/precision medicine Biomarker-directed personalized medicines approaches Endotypes COPD with persistent systemic inflammation Eosinophilic or Th2 high COPD Endotype COPD with persistent pathogenic bacterial colonization Infection (variable) Exposome Inflammation (variable) Cellular and matrix changes Extracellular matrix destruction; abnormal cell repair or apoptosis; ciliary dysfunction, mucus Endotype α-1 antitrypsin deficiency Structural changes Airways remodeling; alveolar destruction Biomarker-directed personalized medicines approaches Genetics Physiological dysfunction Clinical manifestations of COPD Woodruff PG, et al. Lancet. 2015;385:

24 The Blood Eosinophil Debate 4 studies/analyses ICS/LABA vs LABA or LABA/LAMA - SFC vs salmeterol 1 - FF/VI vs VI 2,3 - BDP/FOR vs FOR 4 - SFC+Tio vs Tio+salmeterol 5,6 BUT ICS vs no ICS - FP vs placebo 7 ICS/LABA vs LABA/LAMA - SFC vs IND/GLY 8 Blood eosinophils identify patients in whom ICS + long-acting bronchodilator(s) are superior to long-acting bronchodilator(s) alone Contradictory evidence BDP = beclomethasone dipropionate; IND/GLY=indacaterol/glycopyrronium; TIO = tiotropium 1. Pavord ID, et al. Thorax 2016;71:118 25; 2. Pascoe S, et al. Lancet Respir Med 2015;3:435 42; 3. Hinds DR, et al. BMJ Open 2016;6:e010099; 4. Siddiqui SH, et al. Am J Respir Crit Care Med 2015; 192:523 25; 5. Calverley PMA, et al. Am J Respir Crit Care Med 2017 [Epub ahead of print]; 6. Watz H, et al. Lancet Respir Med 2016;4:390 8; 7. Barnes NC, et al. Eur Respir J 2016;47: Roche N, et al. Am J Respir Crit Care Med 2017;195: ;

25 What about ACO? WARNING! Many ACO sub-phenotypes 1 Don t put all patients in the «ACO basket»! 2 Don t forget to think: differential diagnosis is essential GINA = Global Initiative for Asthma 1. Diagnosis of Diseases of Chronic Airflow Limitation: Asthma, COPD and Asthma-COPD Overlap Syndrome (ACOS) GINA. Global strategy for asthma management and prevention Available from:

26 When should phenotyping occur?

27 COPD: Official diagnosis and treatment guidelines of the Czech Pneumological and Phthisiological Society Risk elimination (U)-LAMA ± (U)-LABA REHAB Mandatory treatment ICS/LABA Roflumilast BLVR/LVRS AAT ABT Mucoactive Rx Phenotypic treatment LTOT HOME NIV LuTX Palliative care Respiratory failure Rx and terminal care Smoking cessation Elimination of other Risks Regular walking Vaccination Checking inhaler technique AAT = alpha 1-antitrypsin; ABT= antibiotic therapy; BLVR = bronchoscopic lung volume reduction; LuTX = lung transplantation; LVRS = lung volume reduction surgery; NIV = non-invasive ventilation; rehab = rehabilitation Koblizek V, et al. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2013;157:

28 Inhaled therapy for COPD: don t forget the patient! PROBLEM : Preference Abilities Technique The ideal inhaler Do Treatment not effectiveness exist! Adherence The ideal healthcare professional The ideal patient GOLD

29 Overall, no improvement in inhaler technique over time! Sanchis J, et al. Chest 2016;150:

30 Device handling errors are common 212 GPs and 50 pulmonologists assessed the handling of 3,993 devices used for continuous treatment of COPD in 2,935 patients Device A B C D E F Total # Devices, n ,393 No error 36.5 ( ) 29.2 ( ) 10.7 ( ) 16.4 ( ) 23.0 ( ) 30.5 ( ) 25.3 ( ) Deviceindependent errors 53.5 ( ) 50.9 ( ) 54.8 ( ) 53.8 ( ) 56.8 ( ) 51.9 ( ) 53.8 ( ) Device-dependent errors 15.4 ( ) 29.2 ( ) 75.3 ( ) 70.1 ( ) 50.6 ( ) 32.1 ( ) 43.1 ( ) At least one critical error 15.4 ( ) 21.2 ( ) 29.3 ( ) 43.8 ( ) 46.9 ( ) 32.1 ( ) 30.0 ( ) *Errors were considered critical if they could have substantially affected dose delivery to the lungs; # total number of evaluated devices Adapted from Molimard M, et al. Eur Respir J 2017;49(2)

31 Conclusions The past: few available treatments, pessimistic view of their effects The present: hierarchized treatment options with demonstrated efficacy The future: tools for personalized care The what: personalized medicine for COPD The why: increasing understanding of treatment effects and their determinants The how: possible yield of biomarkers