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

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

“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

“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

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

“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

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

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

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

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

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

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

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

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 = r 2 =0.1514

162 subjects FEV1/FVC < 0.7 FEV % 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

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

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

New Therapies: What are we doing?

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 * * * * * * * * * * * p < 0.03 vs placebo *  97 mL  74 mL Placebo Roflumilast 250 µg Roflumilast 500 µg * Rabe et al. Lancet 366: 563, 2005

Effect of Roflumilast in COPD: 1 year trial COPD Smokers, ex-smokers FEV1 < 50% Outcome FEV1 Exacerbations Moderate exacerbations = change in medications Severe = hospitalization 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

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

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 M2-124M2-125 Roflumilast Placebo p= p= Moderate or Severe Exacerbations Calverley et al. Lancet 374: 685, 2009

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 M2-124M2-125 Roflumilast Placebo p= p= Exacerbations: Glucocorticoids or Antibiotics Calverley et al. Lancet 374: 685, 2009

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

Research Activity: Disease and Phenotyping

Medline Papers CancerBreast CancerCOPD ,262, ,112 26,278

Research Activity: Disease and Phenotyping Medline Papers CancerBreast CancerCOPD CancerBreast CancerCOPD Medline Phenotype Papers 2,262, ,112 26,278 57,389 5,

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