New Treatment Options for COPD: Phenotypes, Endotypes or Treatable Traits? Conflict of Interest Statement 2018 Speakers Bureau Astra Zeneca Boehringer Ingelheim Genentech Sunovion Ron Balkissoon MD DIH MSc. FRCP(C) Associate Professor National Jewish Health University of Colorado School of Medicine Advisory Boards Astra Zeneca Genentech Glaxo Smith Kline Sanofi Sunovion Research Grants by Pharmaceutical Companies None Changing Epidemiology: Quick Facts During the year 2000 1.5 million emergency department visits 8 million physician office and hospital outpatient visits The Majority of Healthcare Costs for Managing COPD Are Associated With Exacerbations Total costs for COPD were estimated to be $49.9 billion in 2010 1 $29.5 billion in direct costs Over.75 million hospitalizations 119,000 deaths 50%-75% of direct costs for COPD are for services associated with exacerbations 2 Despite its ease of diagnosis, COPD remains an underdiagnosed disease, chiefly in its milder and more treatable form. Centers for Disease Control and Prevention Mannino et al. COPD disease surveillance United States, 1971 2000. MMWR. 2002;51(SS 6):1 16. 1. National Institutes of Health, National Heart, Lung & Blood Institute. Morbidity and Mortality: 2009 chart book on cardiovascular, lung and blood diseases. www.nhlbi.nih.gov/resources/docs/cht-book.htm. Accessed January 18, 2012. 2. American Thoracic Society/European Respiratory Society. Standards for the diagnosis and management of patients 4 with COPD. Updated 2005. Version 1.2. www.thoracic.org/go/copd. Accessed January 18, 2012. 1
Current GOLD Paradigm for COPD Precision Medicine in United Airway Disease: A treatable traits approach. Yii et al;allergy. 2018;00:1 15 Endotype and Phenotype Phenotype Definition: Current and proposed COPD Phenotypes An observable characteristic or trait of a disease without any implication of a mechanism. Prospective validation of COPD phenotypes against clinical outcomes or response to treatment is essential in defining a phenotype Accepted Phenotypes 1. Alpha 1 AT Deficiency 2. Emphysema/hyperinflation 3. Frequent Exacerbator Proposed Phenotypes 1. Non smokers 2. Rapid decliners 3. Asthma/COPD overlap 4. Eosinophilic 5. Mild airflow obstruction/severe dyspnea 6. Chronic bronchitis 7. GERD comorbidity 8. Cardiovascular co morbidity 9. OSA comorbidity 10. CT Phenotypes 2
Phenotype Clusters and Networks Many overlaps and connections are endless OSA comorbidity Pulmonary hypertension CT Phenotypes Alpha 1 AT Deficiency Lung Cancer Non smokers Eosinophilic Asthma/COPD overlap Chronic bronchitis Frequent Exacerbator Rapid decliners Microbiome changes GERD comorbidity Phenotype Treatable Traits Emphysema/ hyperinflation Mild airflow obstruction/ severe dyspnea Cardiovascular co morbidity Obesity Comorbidity Endotypes Smoking Status Endotype Definition Endotype: Subtype of a condition, defined by a distinct functional or pathobiological mechanism. It is envisaged that patients with a specific endotype present themselves within phenotypic clusters of diseases. Precision Medicine: Treatable Traits Precision medicine is defined as treatments targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish a given patient from other patients with similar clinical patients Agusti, et al. ERJ 2016;47:359 361. 3
Biologics? Non pharmacological COPD Treatment Options Smoking cessation Education, self management Cardiopulmonary rehabilitation Pneumococcal and influenza vaccination Long term oxygen therapy Long term non invasive ventilation for history of hopitalization for acute respiratory failure Bronchoscopic or surgical lung volume reduction Airway Clearance for significant bronchorrhea Stepwise management pharmacotherapy UPDATED 2017 Diagnosis Symptom control & risk factors (including lung function) Inhaler technique & adherence Patient preference BIOLOGICS IN ASTHMA Symptoms Exacerbations Side-effects Patient satisfaction Lung function Asthma medications Non-pharmacological strategies Treat modifiable risk factors STEP 5 STEP 4 PREFERRED CONTROLLER CHOICE Other controller options RELIEVER STEP 1 STEP 2 Low dose ICS Consider low Leukotriene receptor antagonists (LTRA) dose ICS Low dose theophylline* As-needed short-acting beta2-agonist (SABA) STEP 3 Refer for *Not for children <12 years add-on **For children 6-11 years, the treatment preferred Step 3 treatment is e.g. Med/high tiotropium,* medium dose ICS ICS/LABA anti-ige, # Low dose anti-il5* For patients prescribed BDP/formoterol or BUD/ ICS/LABA** formoterol maintenance and reliever therapy Med/high dose ICS Add tiotropium* Add low Low dose ICS+LTRA High dose ICS dose OCS Tiotropium by mist inhaler is (or + theoph*) + LTRA an add-on treatment for (or + theoph*) patients 12 years with a As-needed SABA or history of exacerbations low dose ICS/formoterol # GINA 2017, Box 3-5 (2/8) (upper part) 4
Biologics and chronic obstructive pulmonary disease: Pavord et al JACI 2018: 141; 1983 1991 Biologic Drugs: A new Target Therapy in COPD Yousef A et al JCOPD:2018;15(2)99 107 T2 high COPD vs Non T2 COPD Benralizumab for COPD and Sputum Eosinophilia: a randomized, double blind, placebo controlled, phase 2a study Brightling et al Lancet Respir. Med 2014;2:891 901 BIOLOGICS IN TH 2 high COPD 101 patients At least 1 exacerbation in previous year Eosinophils > 3% in sputum Benralizumab 100 mg SQ vs placebo Did not meet primary outcome in reducing exacerbations with eosinophilic COPD Post hoc analysis suggested efficacy in FEV 1 and exacerbations for Blood eos > 250 cells/μl or sputum eos > 2%. 5
Benralizumab for COPD and Sputum Eosinophilia: a randomized, double blind, placebo controlled, phase 2a study Brightling et al Lancet Respir. Med 2014;2:891 901 Benralizumab for COPD and Sputum Eosinophilia: a randomized, double blind, placebo controlled, phase 2a study Brightling et al Lancet Respir. Med 2014;2:891 901 Benralizumab for COPD and Sputum Eosinophilia: a randomized, double blind, placebo controlled, phase 2a study Brightling et al Lancet Respir. Med 2014;2:891 901 Change in Eosinophils over time Benralizumab for COPD and Sputum Eosinophilia: a randomized, double blind, placebo controlled, phase 2a study Brightling et al Lancet Respir. Med 2014;2:891 901 Adverse Events at least 5% and more common than in placebo group Placebo (n=50) Benralizumab (n=51) TEAE 240 282 Serious TEAE 16 25 TEAE leading to D/C 2 (4%) 3 (65) Injection site reactions 4(8%) 13(25%) infections 10 (20%) 16 (31%) Skin reactions 6(12%) 10(20%) Cardiac disorders 2 (4%) 7(14%) Renal Disorders 2(4%) 3(6%) 6
Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease Phase 3 DBRCT parallel group Metrex conducted in 16 countries Mepolizumab 100 mg or placebo Triple inhaler therapy Q 4 week injection X 52 weeks + 8 wk. follow up Metreo in 15 countries Mepolizumab 100, Mepolizumab 300, Placebo Triple inhaler therapy Q 4 week injection x 52 weeks + 8 wk. Follow up Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease Population: > 40 years old on triple therapy at least ICS+/ LABA, +/ LAMA, +/ PDE4 +/ methylxanthine X 12 months On LABA/ICS/LAMA for at least 3 months prior to entry Diagnosed with COPD > 1 year FEV 1 /FVC < 0.70 PBD FEV 1 80 20% predicted 2 or more moderate exacerbations or at least 1 severe exacerbation (hospitalization) in previous 12 months Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease Primary Endpoint: Annual Rate of exacerbations (moderate or severe) Secondary endpoints Time to first moderate or severe exacerbation Annual rate of exacerbations leading to ER or hospitalization or both Change in COPD Assessment Test Score Change St. George Respiratory Questionnaire Score 7
Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease Metrix Study Modified Intention to treat with an Eosinophilic phenotype Metreo Study Modified Intention to treat population Oral corticosteroids with or without antibiotics Antibiotics alone Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease Exacerbation Rate Ratio According to Eosinophil Count 8
Biologics and chronic obstructive pulmonary disease: Pavord et al JACI 2018: 141; 1983 1991 BIOLOGIC TARGETS FOR NON T2 COPD CXCR 2 Receptor Antagonist MK7123: Phase 2 Proof of Concept Trial for COPD Rennard et al AJRCCM 191:9 1001 111 2015 CXCR 2 Receptor Antagonist MK7123: Phase 2 Proof of Concept Trial for COPD Rennard et al AJRCCM 191:9 1001 111 2015 CXCR 2 Receptor Antagonist MK7123: Phase 2 Proof of Concept Trial for COPD Rennard et al AJRCCM 191:9 1001 111 2015 Change in FEV1 over 26 weeks 9
CXCR 2 Receptor Antagonist MK7123: Phase 2 Proof of Concept Trial for COPD Rennard et al AJRCCM 191:9 1001 111 2015 Small improvement in FEV 1 in 50 mg dose group only 160 cc improvement versus placebo in current smokers only Study terminated early at 12 months due to subject attrition Higher rate of infection in treatment arms than placebo for those staying in trial > 6 months Further research not progressing Other Anti Neutrophilic (Non T2) Candidate Biologics Cytokine Population Study Sample size IL 8 Mod severe IL 8 mab 800 mg loading dose then 400 mg/month x 2 months 1 Clinical Outcomes 109 +ve TDI score. ve for PFT, 6MW, rescue Albuterol 234 Negative: CRQ TNFα Mod severe Anti TNFα 3 mg/kg or 5 mg/kg x 44 weeks 2 PFT QOL Exacerbations IL 1β IL 1α IL 6 IL 17 Moderate to very severe No studies to date No studies to date AntiIL1R 3 324 ve Mod severe exacerbations ve SGRQ 1. Mahler et al. Chest.2004;126(3):926 34 2. Rennard et al. AJRCCM 2007, may;175(9):926 34 3. Calverley et al. Respir Res 2017;18(1):153 No benefit in Asthma trials Secondary outcomes and Adverse Events Increased cancer risks Increased infections Neutrophilic (Non T2) Candidate Biologics Considerations Clinical safety of neutrophil reduction is uncertain Neutrophil subtypes have different functions CXCR 2 and macrolides both reduce neutrophils CXCR 2 reduces exacerbations better in smokers Macrolides reduce exacerbations better in exsmokers Suggests 2 different types of neutrophilic inflammation in COPD Current Smoker Neutrophil Endotypes? Ex Smoker Microbiome Adapted from Pavord,I. et al JACI 2018: 141; 1983 1991 10
Non Biologic Alternatives for Neutrophil Inflammation Macrolide Antibiotics PDE4 inhibitors (Roflumilast) PDE3/PDE4 combination Macrolides Antimicrobial Anti inflammatory Augment Macrophage function Enhance Steroid efficacy Azithromycin: Mechanisms of action and their relevance for clinical applications. Parnham et al Pharmacology&Therapeutics 143(2014)225 245 Azithromycin for Prevention of Exacerbations of COPD Albert et al NEJM 2011 Aug 25;365(8):689 98 DESIGN: azithromycin, 250 mg daily (570 participants) vs placebo (572 participants) 1 year in addition to their usual care. follow up: 89% in the azithromycin group; 90% in the placebo group. RESULTS: The median time to the first exacerbation was Azithromycin: 266 days (95% confidence interval [CI], 227 to 313) azithromycin Placebo: 174 days (95% CI, 143 to 215) (P<0.001). The frequency of exacerbations: exacerbations per patient year Azithromycin: 1.48 vs Placebo: 1.83 (P=0.01) Hazard ratio for having an acute exacerbation of COPD per patient year azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). 11
Azithromycin for Prevention of Exacerbations of COPD Albert et al NEJM 2011 Aug 25;365(8):689 98 1.0 0.9 0.8 0.7 Azithromycin Placebo Azithromycin for Prevention of Exacerbations of COPD Albert et al NEJM 2011 Aug 25;365(8):689 98 Secondary Outcomes St. George's Respiratory Questionnaire: % subjects with > MCID of 4 units. 43% in the azithromycin group 36% in the placebo group (P=0.03). Proportion free of COPD Exacerbations 0.6 0.5 0.4 0.3 0.2 0.1 p= 0.001 by log rank test and Wilcoxon signed rank test ADVERSE EVENTS: 1. Hearing decrements: azithromycin group vs placebo group (25% vs. 20%, P=0.04). 2. Azithromycin Resistance Not detected in this study but inconclusive 0.0 0.0 40 80 120 160 200 240 280 320 360 Follow up (days) Effect of Roflumilast and Inhaled Corticosteroid/Long ActingB2 Agonists on Chronic Obstructive Lung Disease Exacerbations )RE 2 SPOND Martinez, et al. AJRCCM 2016;194(5): 559. Effect of Roflumilast and Inhaled Corticosteroid/Long ActingB2 Agonists on Chronic Obstructive Lung Disease Exacerbations )RE 2 SPOND Martinez, et al. AJRCCM 2016;194(5): 559. (n=1,178) (n=1,174) 0.61 (0.39,0.95)* p = 0.030 0.99(0.77,1.27)* P=0.921 * Rate Ratio (95% CI) 0.96(0.83,1.11)* P= 0.586 Martinez, et al. AJRCCM 2016;194(5): 559. 12
PDE3/PDE4 Inhibitor Inhaled agent PDE3 smooth muscle relaxant PDE4 anti inflammatory with effects on neutrophils The short term bronchodilator effects of the dual PDE3 and PDE4 inhibitor RPL554 in COPD Singh et al ERJ Aug 2018 (Early view) Two Phase 2 4 week multicenter trial dose ranging 6 way cross over study Dose range (0.75 mg, 1.5 mg, 3 mg, or 6 mg) Compared to: 1. Study 1: Salbutamol 200 µg and Ipratropium Bromide 40 µg 2. Study 2: Tiotropium (18 µg) The short term bronchodilator effects of the dual PDE3 and PDE4 inhibitor RPL554 in COPD Singh et al ERJ Aug 2018 (Early view) The short term bronchodilator effects of the dual PDE3 and PDE4 inhibitor RPL554 in COPD Singh et al ERJ Aug 2018 (Early view) Study 1 13
The short term bronchodilator effects of the dual PDE3 and PDE4 inhibitor RPL554 in COPD Singh et al ERJ Aug 2018 (Early view) The short term bronchodilator effects of the dual PDE3 and PDE4 inhibitor RPL554 in COPD Singh et al ERJ Aug 2018 (Early view) This study did not look at exacerbations Future studies will examine this important component of this combination therapy. Clusters and Networks Phenotype, Endotype or Treatable Traits? Precision medicine in united airway disease: A treatable traits approach. Yii et al;allergy. 2018;00:1 15 OSA comorbidity Lung Cancer Chronic bronchitis Rapid decliners Pulmonary hypertension CT Phenotypes Eosinophilic Asthma/COPD overlap Frequent Exacerbator Microbiome changes Alpha 1 AT Deficiency Non smokers GERD comorbidity Emphysema/ hyperinflation Mild airflow obstruction/ severe dyspnea Cardiovascular co morbidity Obesity Smoking Status Precision medicine in united airways disease: A treatable traits approach, First published: 05 June 2018, DOI: (10.1111/all.13496) 14
COPD Assessment Control Panel Lange P. et al Int.J.COPD (First World lung disease Summit 2016:11;3 12) New Treatment Options for COPD: Phenotypes, Endotypes or Treatable Traits? SUMMARY COPD patients are a heterogeneous population with a wide array of variable characteristics that can impact response to treatment Phenotypes lack precision to find one intervention that will address all components of their COPD Identifying treatable traits is the most practical approach Identifying endotypes will allow for greater precision in treatment Managing co morbidities is often as important as managing their COPD 15