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COPD phenotypes: Clinical and pathobiological implications Fernando J. Martinez, M.D., M.S. University of Michigan Health System

What is a phenotype?  ‘The observable structural and functional characteristics of an organism determined by its genotype and modulated by its environment’ Schultze & McMahon. Human Hered. 2004; 58: Must be complete, valid and reliable  Endophenotype - ‘clinical entities associated with a disease but closer to the underlying biology than the symptoms usually used to define a case’

COPD: A syndrome with multiple components  Chronic airflow obstruction characterized by – parenchymal abnormality (emphysema) – large airway abnormality (‘chronic bronchitis’) – small airway abnormality – vascular defects – systemic manifestations

Genetic associations with functional parameters in emphysema patients  304 subjects from NETT – Maximal output on CPET Microsomal epoxide hydrolase (EPHX1) Microsomal epoxide hydrolase (EPHX1) Latent transforming growth factor-  binding protein-4 (LTBP4) Latent transforming growth factor-  binding protein-4 (LTBP4) – Six minute walk distance LTBP4 LTBP4 Surfactant protein B (SFTPB) Surfactant protein B (SFTPB) – DL CO EPHX1 EPHX1 – Dyspnea Transforming growth factor-  1 Transforming growth factor-  1 Hersh CP et al. AJRCCM. 2006; 173:

COPD candidate genes associate with CT phenotypic findings in NETT Emphysema GeneSNPP-value EPHX1rs rs SERPINE2rs rs rs rs rs GSTP1rs AWT Pi-10mm GeneSNPP-value TGFB1rs rs rs EPHX1rs rs SERPINE2rs ADRB2rs rs Kim WJ et al. ERJ; 2011; 37: 39-43

Han et al, AJRCCM 2010; 182:

Health related quality of life (SGRQ) varies by the extent of CT emphysema in severe COPD FeatureParameter estimate 95% CIP value BODE , 4.34< Age (yrs) , -0.28< Whole lung emphysema (-910 HU) , -6.42< Pack yrs , Female gender , Martinez et al. AJRCCM 2007; 176:

Emphysema and airway structure interact in influencing AECOPD rate in COPDgene ® cohort Han MLK et al. in review

CT phenotype and clinical correlates Han et al. COPD 2009; 6: FactorEstimate p value Age Gender Cigs Pack yrs 0.006<0.001 Emp%0.04< RUL AS WA%

Predictors of mortality in patients with severe emphysema* Predictors of mortality in patients with severe emphysema* * Adjusted for all listed factors † women <25 watts, men < 40 watts Risk Factor Relative Risk 95%CI P O 2 use RV (> 262 % pred) TLC (> 140% pred) Age(> 70) < Difference in emphysema (UL-LL < -0.8) CPET Watts † Modified BODE (>7) Martinez FJ et al. AJRCCM. 2006; 173: DLCO ( <21% pred)

CT emphysema is associated with significant comorbidity  Lung cancer 1,2,3  Cardiovascular disease 4,5,6  Osteoporosis 7,9  Fat free mass loss 9 1 Wilson DO et al. AJRCCM. 2008; 178: ; 2 de Torres JP et al. Chest. 2007; 132: ; 3 Li et al. Cancer Prev Res (Phila) 2011; 4: 43-50; 4 Barr RG et al. AJRCCM. 2007; 176: ; 5 Barr et al. NEJM 2010; 362: ; 6 Dransfield et al. COPD 2010; 7: ; 7 Ohara et al, Chest 2008; 134: ; 8 Bon et al. AJRCCM 2010 [epub ahead of pring Oct 8]; 9 Kurosaki et al, Inter Med 2009; 48: 41-8

Severe COPD Symptomatic despite maximal medical Rx and pulmonary rehabilitation FEV 1 < 15% pred FEV % pred Consider Lung transplantation Consider LVRS FEV 1 < 25% pred & D L CO < 20% pred or Homogeneous emphysema Meets NETT Criteria? Non-upper lobe emphysema and low exercise capacity Non-upper lobe emphysema and high exercise capacity Upper lobe emphysema and low exercise capacity Upper lobe emphysema and high exercise capacity No Yes BODE > 7 and other criteria? Yes No Adapted from Nathan; Chest 2005; 127: ?

Pooled effect of roflumilast on exacerbation rate from early studies Rennard S et al. Respir Res (in press)

Main Criteria for Inclusion  Age > 40 years  History of chronic obstructive pulmonary disease associated with chronic bronchitis for at least 12 months prior to baseline  FEV 1 /FVC ratio (post-bronchodilator)  70%  FEV 1 (post-bronchodilator)  50% of predicted  At least one documented moderate and/or severe COPD exacerbation within one year prior to study  Not suffering from any concomitant disease that might interfere with study procedures or evaluation  Current or former smoker with a smoking history of at least 20 pack years Calverley PMA, Rabe, KF, et al. Lancet 2009;374:685–694

COPD Exacerbations, Moderate or severe, pooled analysis Mean rate of exacerbations per patient per year RR = - 17% p = placeboroflumilast 500µg Calverley PMA, Rabe, KF, et al. Lancet 2009;374:685–694

ECLIPSE subjects with > 2 exacerbations were more likely to experience exacerbations in subsequent year Hurst JR et al. N Engl J Med 2010;363: Year 2Year 3

Greatest benefit of roflumilast seen in patients with a history of frequent exacerbations ≥2 exacerbations in previous year <2 exacerbations in previous year M2-124 & M2-125 – pooled post-hoc analysis BATEMAN ED ET AL. ABSTRACT PRESENTED AT EUROPEAN RESPIRATORY SOCIETY ANNUAL CONGRESS P4003

Severe COPD Symptomatic despite maximal medical Rx and pulmonary rehabilitation FEV 1 < 15% pred Adapted from Nathan; Chest 2005; 127: Consider Lung transplantation

FEV 1 < 20% pred & D L CO < 20% pred or Homogeneous emphysema Severe COPD Symptomatic despite maximal medical Rx and pulmonary rehabilitation FEV 1 < 15% pred FEV % pred Naunheim et al. Ann Thorac Surg; 2006; 82: Adapted from Nathan; Chest 2005; 127:

BODE > 7 and other criteria? Meets NETT Criteria? No Adapted from Nathan; Chest 2005; 127: Severe COPD Symptomatic despite maximal medical Rx and pulmonary rehabilitation FEV 1 < 15% pred FEV % pred Consider Lung transplantation FEV 1 < 20% pred & DL CO < 20% pred or Homogeneous emphysema Yes

Martinez et al, AJRCCM 2006; 173: Adapted from Nathan; Chest 2005; 127: BODE > 7 and other criteria? Meets NETT Criteria? No Severe COPD Symptomatic despite maximal medical Rx and pulmonary rehabilitation FEV 1 < 15% pred FEV % pred Consider Lung transplantation FEV 1 < 20% pred & DL CO < 20% pred or Homogeneous emphysema Yes

Severe COPD Symptomatic despite maximal medical Rx and pulmonary rehabilitation FEV 1 < 15% pred FEV % pred Consider Lung transplantation FEV 1 < 20% pred & DL CO < 20% pred or Homogeneous emphysema Meets NETT Criteria? BODE > 7 and other criteria? No Yes No Adapted from Nathan; Chest 2005; 127:

Upper lobe emphysema and low exercise capacity Upper lobe emphysema and high exercise capacity Non-upper lobe emphysema and low exercise capacity Non-upper lobe emphysema and high exercise capacity Yes Severe COPD Symptomatic despite maximal medical Rx and pulmonary rehabilitation FEV 1 < 15% pred FEV % pred Consider Lung transplantation FEV 1 < 20% pred & DL CO < 20% pred or Homogeneous emphysema Meets NETT Criteria? BODE > 7 and other criteria? No Yes No

Upper lobe emphysema and low exercise capacity Upper lobe emphysema and high exercise capacity Non-upper lobe emphysema and low exercise capacity Non-upper lobe emphysema and high exercise capacity Yes Severe COPD Symptomatic despite maximal medical Rx and pulmonary rehabilitation FEV 1 < 15% pred FEV % pred Consider Lung transplantation FEV 1 < 20% pred & DL CO < 20% pred or Homogeneous emphysema Meets NETT Criteria? BODE > 7 and other criteria? No Yes No Adapted from Nathan; Chest 2005; 127:

Upper lobe emphysema and high exercise capacity Upper lobe emphysema and low exercise capacity Non-upper lobe emphysema and low exercise capacity Non-upper lobe emphysema and high exercise capacity Yes Severe COPD Symptomatic despite maximal medical Rx and pulmonary rehabilitation FEV 1 < 15% pred FEV % pred Consider Lung transplantation FEV 1 < 20% pred & DL CO < 20% pred or Homogeneous emphysema Meets NETT Criteria? BODE > 7 and other criteria? No Yes No Adapted from Nathan; Chest 2005; 127:

Consider LVRS Adapted from Nathan; Chest 2005; 127: Upper lobe emphysema and low exercise capacity Upper lobe emphysema and high exercise capacity Non-upper lobe emphysema and low exercise capacity Non-upper lobe emphysema and high exercise capacity Yes Severe COPD Symptomatic despite maximal medical Rx and pulmonary rehabilitation FEV 1 < 15% pred FEV % pred Consider Lung transplantation FEV 1 < 20% pred & D L CO < 20% pred or Homogeneous emphysema Meets NETT Criteria? BODE > 7 and other criteria? No Yes No Airway valve?

Improvement in FEV1 at 6 months: VENT trial Impact of Lobar Exclusion and Fissure Integrity Modified from Sciurba (with permission)

Non-upper lobe emphysema and low exercise capacity Non-upper lobe emphysema and high exercise capacity Severe COPD Symptomatic despite maximal medical Rx and pulmonary rehabilitation FEV 1 < 15% pred FEV % pred Consider Lung transplantation Consider LVRS FEV 1 < 20% pred & D L CO < 20% pred or Homogeneous emphysema Meets NETT Criteria? BODE > 7 and other criteria? Upper lobe emphysema and low exercise capacity Upper lobe emphysema and high exercise capacity No Yes No Adapted from Nathan; Chest 2005; 127:

Non-upper lobe emphysema and high exercise capacity Non-upper lobe emphysema and low exercise capacity Severe COPD Symptomatic despite maximal medical Rx and pulmonary rehabilitation FEV 1 < 15% pred FEV % pred Consider Lung transplantation Consider LVRS FEV 1 < 20% pred & D L CO < 20% pred or Homogeneous emphysema Meets NETT Criteria? BODE > 7 and other criteria? Upper lobe emphysema and low exercise capacity Upper lobe emphysema and high exercise capacity No Yes No Adapted from Nathan; Chest 2005; 127:

Non-upper lobe emphysema and low exercise capacity Non-upper lobe emphysema and high exercise capacity Severe COPD Symptomatic despite maximal medical Rx and pulmonary rehabilitation FEV 1 < 15% pred FEV % pred Consider Lung transplantation Consider LVRS FEV 1 < 20% pred & D L CO < 20% pred or Homogeneous emphysema Meets NETT Criteria? BODE > 7 and other criteria? Upper lobe emphysema and low exercise capacity Upper lobe emphysema and high exercise capacity No Yes No Adapted from Nathan; Chest 2005; 127:

Severe COPD Symptomatic despite maximal medical Rx and pulmonary rehabilitation FEV 1 < 15% pred FEV % pred Consider Lung transplantation Consider LVRS FEV 1 < 25% pred & D L CO < 20% pred or Homogeneous emphysema Meets NETT Criteria? BODE > 7 and other criteria? Non-upper lobe emphysema and low exercise capacity Non-upper lobe emphysema and high exercise capacity Non-upper lobe emphysema and low exercise capacity Non-upper lobe emphysema and high exercise capacity No Yes No ? BODE > 7 & other risk factors Adapted from Nathan; Chest 2005; 127:

Primary hypotheses of SPIROMICS  1) phenotypic/clinical parameters and biological markers will enable COPD patients to be divided into homogeneous subgroups  2) the same, or a different subgroup, of phenotypic/clinical and biological markers can be used as intermediate outcomes for use as clinical trial endpoints

SPIROMICS Visit Schedule

Assessments  Physiology – ● Lung function testing – ● BMI, body composition – ● Exercise + – ● Vascular function (endo-PAT) +  Imaging – ● Serial CT scans – ● Dynamic CT scans +  Induced Sputum  Patient reported outcomes  Bronchoscopy* – BAL – Endobronchial bx – Protected brush – Immunophenotyping Blood & Sputum Blood & Sputum  Mucociliary clearance +  Exacerbations* – ● EXACT-PRO – ● Unscheduled visit – ● Biospecimens * Sub-study + Potential Future Study

Clinical & Core Sites University of Utah U. of Utah Hospital and Clinics VAMC Salt Lake Intermountain MC UC San Francisco Moffitt/Long Kaiser Permanente UC Los Angeles Ronald Reagan-UCLA Santa Monica-UCLA Harbor-UCLA Olive View MC VA GLAHCS University of Iowa Radiology Reading Center Columbia University Columbia UMC Weill-Cornell New York-Prespyterian Johns Hopkins University of Michigan UM-Taubman Health Care Detroit Medical Center VAMC Ann Arbor Temple University Wake Forest University Wake Forest University of North Carolina at Chapel Hill Genomics and Informatics Center National Heart, Lung and Blood Institute Foundation for the National Institutes of Health