1. 1 COPD Phenotypes Stephen I Rennard University of Nebraska Florianopolis, Brazil October 2009

2. COPD Phenotypes: Studies ECLIPSE N= 2,165 COPDgene N= 10,000 SPIROMICS N= 3,200 Others

3. “COPD HETEROGENEITY” PT # 1 58 y FEV1: 28 % PT # 2 62 y FEV1: 33% PT # 3 69 y FEV1: 35% PT # 4 72 y FEV1: 34% Cote & Celli

4. “COPD HETEROGENEITY” PT # 1 58 y FEV1: 28 % MRC: 2/4 PaO2: 70 mmHg 6MWD: 540 mt BMI: 30 PT # 2 62 y FEV1: 33% MRC: 2/4 PaO2: 57 mmHg 6MWD: 400 m BMI: 21 PT # 3 69 y FEV1: 35% MRC: 3/4 PaO2: 66 mmHg 6MWD: 230 m BMI: 34 PT # 4 72 y FEV1: 34% MRC: 4/4 PaO2: 60 mmHg 6MWD: 154 m BMI: 24 Cote & Celli

5. BODE Index Scoring Celli et al. New Engl. J. Med. 350: 1005, 2004

6. “COPD HETEROGENEITY” PT # 1 58 y FEV1: 28 % MRC: 2/4 PaO2: 70 mmHg 6MWD: 540 mt BMI: 30 SCORE3 SCORE: 3 PT # 2 62 y FEV1: 33% MRC: 2/4 PaO2: 57 mmHg 6MWD: 400 m BMI: 21 SCORE: 6 PT # 3 69 y FEV1: 35% MRC: 3/4 PaO2: 66 mmHg 6MWD: 230 m BMI: 34 SCORE: 7 PT # 4 72 y FEV1: 34% MRC: 4/4 PaO2: 60 mmHg 6MWD: 154 m BMI: 24 SCORE: 9 Cote & Celli

7. COPD is a Collection of Syndromes/Diseases Many little COPDs COPD = ∑ (copd) n John Reilly n=1 ?

8. Lessons From Breast Cancer: Better with Sub-phenotyping Predict prognosis: homogeneous Assess treatments: smaller numbers Implement treatments: smaller numbers needed to treat

9. Breast Cancer Phenotypes Diaz et al. Adv. Anat. Pathol. 14: 419, 2007 Triple Negative Breast Cancers Breast Cancer 1Basal Phenotype

11. Breast Cancer Phenotypes Diaz et al. Adv. Anat. Pathol. 14: 419, 2007 Triple Negative Breast Cancers Breast Cancer 1Basal Phenotype

12. Breast Cancer: Molecular Phenotype and Prognosis Rakha et al. Cancer 109: 25, 2007 1726 cases Phenotype Estrogen receptor Progesterone receptor HER2 Triple negative = 282 (16.3%) Overall survival

13. Lessons From Breast Cancer: Better with Sub-phenotyping Predict prognosis: homogeneous Assess treatments: smaller numbers Implement treatments: smaller numbers needed to treat

14. Neutrophils in Bronchial Lavage Thompson et al. Am. Rev. Resp. Dis. 140: 1527, 1989

15. Neutrophils in Bronchial Lavage: predictor Research subjects Lung function Bronchoscopy Bronchial lavage (first 20 ml aliquot) Follow up 41 subjects Mean 11.4 years Lung function Induced sputum Hepp et al. Decline in FEV1 (ml/year) Bronchial PMNs (%) at first visit) p =0.0119 r 2 =0.1514

16. 162 subjects FEV1/FVC < 0.7 FEV1 40-80% predicted <10% and <200 ml increase after BD Randomize: placebo vs. salmeterol/fluticasone (50/500) Induced sputum Biopsy Anti-inflammatory Effects of Salmeterol/Fluticasone Propionate in Chronic Obstructive Pulmonary Disease Barnes, N. et al. Am. J. Res. Crit Care Med. 173: 736, 2006

17. Anti-inflammatory Effects of Salmeterol/Fluticasone Propionate in Chronic Obstructive Pulmonary Disease n = 59 n = 50 > 10% reduction 6 (10%) 19 (38%) > 35% reduction 2 (3%) 5 (10%) Barnes, N. et al. Am. J. Res. Crit Care Med. 173: 736, 2006 Magnitude Control Sal/flutic

18. Neutrophils in Bronchial Lavage Thompson et al. Am. Rev. Resp. Dis. 140: 1527, 1989

19. New Therapies: What are we doing?

20. Roflumilast Improves FEV 1 in COPD Patients * p <.0001 vs placebo. Placebo Roflumilast 250 µg Roflumilast 500 µg Time, weeks LS mean difference in post-bronchodilator FEV 1 (T last ), mL * * Endpoint -50 -25 0 25 50 75 100 04812162024 * * * * * * * * * * * p < 0.03 vs placebo *  97 mL  74 mL Placebo Roflumilast 250 µg Roflumilast 500 µg * Rabe et al. Lancet 366: 563, 2005

21. Effect of Roflumilast in COPD: 1 year trial COPD Smokers, ex-smokers FEV1 < 50% Outcome FEV1 Exacerbations Moderate exacerbations = change in medications Severe = hospitalization 0 0.25 0.5 0.75 1 Moderate or Severe Exacerbations Systemic steroids Roflumilast Placebo All p=0.451 p=0.183 Calverley et al. Am. J. Resp. Crit. Care Med. 176: 154, 2007

22. Effect of Roflumilast in COPD: 1 year trials COPD Smokers, ex-smokers FEV1 < 50% Chronic cough and sputum At least one exacerbation requiring systemic glucocorticoids or hospitalization in the previous year Outcome Moderate exacerbations = systemic glucocorticoids Severe = hospitalization Calverley et al. Lancet 374: 685, 2009

23. Effect of Roflumilast in COPD: 1 year trials COPD Smokers, ex-smokers FEV1 < 50% Chronic cough and sputum At least one exacerbation requiring systemic glucocorticoids or hospitalization in the previous year Outcome Moderate exacerbations = systemic glucocorticoids Severe = hospitalization 0 0.5 1 1.5 M2-124M2-125 Roflumilast Placebo p=0.0278 p=0.0035 Moderate or Severe Exacerbations Calverley et al. Lancet 374: 685, 2009

24. Effect of Roflumilast in COPD: 1 year trials COPD Smokers, ex-smokers FEV1 < 50% Chronic cough and sputum At least one exacerbation requiring systemic glucocorticoids or hospitalization in the previous year Outcome Moderate exacerbations = systemic glucocorticoids Severe = hospitalization 0 0.5 1 1.5 M2-124M2-125 Roflumilast Placebo p=0.0240 p=0.0055 Exacerbations: Glucocorticoids or Antibiotics Calverley et al. Lancet 374: 685, 2009

25. Lessons From Breast Cancer: Better with Sub-phenotyping Predict prognosis: homogeneous Assess treatments: smaller numbers Implement treatments: smaller numbers needed to treat

26. Research Activity: Disease and Phenotyping

27. Medline Papers CancerBreast CancerCOPD 100 1000 10000 100000 1000000 10000000 2,262,114 201,112 26,278

28. Research Activity: Disease and Phenotyping Medline Papers CancerBreast CancerCOPD 100 1000 10000 100000 1000000 10000000 CancerBreast CancerCOPD Medline Phenotype Papers 2,262,114 201,112 26,278 57,389 5,601 363

29. COPD is a Collection of Syndromes/Diseases Many little COPDs COPD = ∑ (copd) n John Reilly n=1 ? Defining COPD subsets: natural history treatment