Session on COPD: Novel Concepts and Promising New Drugs Topic: New Treatment = Better Outcome? Through a CME Grant sponsored by
New Treatment = Better Outcome? Tim S. Trinidad, MD
Disclosure Present: COPD Advisory Board Member & Lecturer Novartis Astra Zeneca UAP Past: COPD Lecturer Nycomed Takeda Boehringer Ingelheim Glaxo Smith Kline
Scope of the Discussion New Treatment = Better Outcome? Pharmacologic Non-pharmacologic Risk reduction Vaccination Rehab or Physical Activity Invasive (surgical or non-bronchoscopic LVRS)
Reference Point for New (2001) (2004) (2011) (2014) LABA/ ICS Tiotropium Old PDE4I New
Pharmacologic Agents: Recently approved in some countries or Undergoing clinical development (Not listed in GOLD 2014) TNF-a inhibitors: Infliximab, PKF242-484, PKF241-466 IL-6 inhibitors: Tocilizumab Chemokine antagonists: ADZ8309, SCH-527123, SB-656933 NF-kB inhibitors: IMD-0354, IMD-0650, BMS-345541, SC-514, AS602868 p38 MAPK inhibitors: SB681323, PH797804, PF03715455, GSK681323 PI3K inhibitors: PI3K-g inhibitors, TG100-115 JAK/STAT inhibitors: Tofacitinib Ngkelo, A. et al. New treatments for COPD. Current Opinion in Pharmacology 2013, 13:362 369
Pharmacologic Agents: Recently approved in some countries or Undergoing clinical development (Not listed in GOLD 2014)) LABA/ICS combination: Mometasone/ Indacaterol (QMF149) LAMA/LABA/ICS triple combination inhalers : Ciclesonide/ Tiotropium/ Formoterol Beclomethasone/ Formoterol/ Glycopyrronium QMF149/Glycopyrronium Umeclidinium/ Vilanterol/ Fluticasone furoate GSK961081/ Fluticasone Ngkelo, A. et al. New treatments for COPD. Current Opinion in Pharmacology 2013, 13:362 369
LABAs: LAMAs: Olodaterol, Vilanterol, Abediterol Umeclidinium LAMA/LABA combinations: MABAs: Glycopyrronium/ Indacaterol (QVA149), Umeclidinium/ Vilanterol Tiotropium/ Olodaterol Aclidinium/ Formoterol Glycopyrronium bromide/ Formoterol (PT001) GSK-961081, AZD2115 Ngkelo, A. et al. New treatments for COPD. Current Opinion in Pharmacology 2013, 13:362 369
New Pharmacologic Treatment (UPDATE 2015) (2001) (2004) (2011) (2014) (2015) LABA/ ICS Tiotropium PDE4I LABA/LAMA
Reference Point for Better Outcome (GOLD Treatment Goals) Reduce symptoms Relieve symptoms Improve exercise tolerance Improve health status Prevent future risks Prevent and treat exacerbations Prevent disease progression Reduce mortality GOLD 2014. Available from: http://www.goldcopd.com.
LABA/ ICS & Treatment Goals Relieve symptoms Improve health status Prevent and treat exacerbations Improve exercise tolerance X Reduce mortality? Prevent disease progression Calverley, P et al. Salmeterol and Fluticasone Propionate and Survival in Chronic Obstructive Pulmonary Disease. N Engl J Med 2007;356:775-89. Cochrane Database of Systematic Reviews, Issue 4, 2008
Tiotropium & Treatment Goals Relieve symptoms Improve health status Prevent and treat exacerbations Improve exercise tolerance? Reduce mortality X Prevent disease progression Tashkin, D et al. A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease. N Engl J Med 2008;359: 1543-54. The Cochrane Library 2012, Issue 7
Unmet needs in COPD management
Infliximab (TNF-A Inhibitor) X CRQ X Pre-FEV1 X 6-MWT X SF-36 X TDI (?) Cancer (?) Pneumonia Rennard SI, et al. The safety and efficacy of infliximab in moderateto-severe COPD. Am J Respir Crit Care Med 2007; 175: 926 34.
ABX vs IL-8 TDI X FEV1 X SGRQ X 6MWT Mahler DA et al. Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study. Chest 2004; 126: 926 34.
PDE4I: Roflumilast Achieved GOLD guidelines recommendations and FDA approval in several countries Anti-inflammatory drug: used for ECOPD prevention In comparison to other (old) drugs (NNT) LAMA: 16 LABA/ ICS: 20 General COPD Roflumilast: 3-4 Cochrane Database Syst Rev. 2012 Jul 11; 7:CD009285. Nannini LJ, et al. Cochrane Database of Systematic Reviews 2012, Issue 9 Bateman, E et al. Roflumilast with long-acting β2-agonists for COPD: influence of exacerbation history. ERJ September 1, 2011 vol. 38 no. 3 553-560
We continue to know more
Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) 3 years Follow-up Pulmonary function Whole body impedance/fat-free mass Chest computed tomography Exercise capacity Resting oxygen saturation Biomarkers Blood samples Induced sputum Exhaled breath condensate Blood and urine metabolomics Health outcomes Blood samples for genetic markers Vestbo J, et al. Am J of Resp & Crit Care Med Vol. 189 Num. 9 May 1 2014
COPD is very heterogeneous clinical presentation Some patients are frequent exacerbator others are not Some patients have severe inflammation others have less inflammation Some patients are rapid FEV1 decliners others are not For those rapid decliners, the greatest decline occurs in the moderate to severe stage Vestbo J, et al. Am J of Resp & Crit Care Med Vol. 189 Num. 9 May 1 2014
COPD phenotype A single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes : Symptoms Exacerbations Response to therapy Rate of disease progression Death
COPD Phenotype Application Roflumilast Story
Design OPUS ( 111) / RATIO (112) Study N: 2,686 FEV1: <50% Meds: SABA & SAMA ICS 52 Weeks Roflumilast: 500 Placebo
Rate Ratio of Exacerbation (moderate & severe) Study Favors Roflumilast Favors Placebo iexacerb. Rate (%) M2-111 -14.0 M2-112 -15.2 Why? 0.50 0.75 1.00 1.25 1.50 Rate Ratio
Post-hoc Analysis: Who are the responders?
Identification of Patient Target Population Subgroup analyses of early phase III studies M2-111, M2-112 Confirmatory 1-yr pivotal studies M2-124, M2-125 Severe/very severe COPD Severe/very severe COPD Hx chronic cough & sputum Hx chronic cough & sputum Hx of exacerbations
Pivotal Study M2-124/ M2-125 N: 3,091 FEV1: <50% IC: (+) C. Bronchitis (+) Sputum (+) Exacerbations Meds: No ICS (+) LABA (+) SAMA 52 Weeks Roflumilast: 500 Placebo Calverley PMA, Rabe, KF et al. Lancet 2009;374:685 694.
Rate Ratio of Exacerbation (moderate & severe) Study Favors Roflumilast Favors Placebo iexacerb. Rate (%) M2-111 -14.0 M2-112 -15.2 M2-124 -14.9 M2-125 -18.5 0.50 0.75 1.00 1.25 1.50 Rate Ratio Calverley PMA, Rabe, KF et al. Lancet 2009;374:685 694.
GOLD: Statements on Roflumilast The phosphodiesterase 4 inhibitor (Roflumilast) may also be used to reduce exacerbations for patients with chronic bronchitis, severe and very severe airflow limitation, and frequent exacerbations that are not adequately controlled by long- acting bronchodilators. GOLD 2014. Available from: http://www.goldcopd.com.
FEV 1 (% of value at age 25) Decline in Lung Function of COPD Patients Fletcher-Peto Curve vs ECLIPSE Curve 100 80 Most Rapid Decline (ECLIPSE) Most Rapid Decline (Fletcher) Never smoked or not susceptible to smoke 50 30 Smoked regularly and susceptible to its effects 0 25 50 75 Age (years) Vestbo J, et al. Am J of Resp & Crit Care Med Vol. 189 Num. 9 May 1 2014
Do we have a better response if we give the drugs during the early stage? Tiotropium UPLIFT Story
UPLIFT Study N: 4,383 FEV1: <70% Meds allowed: SABA, LABA ICS, Xanthine 4 Years Tiotropium 18 ug OD Placebo Yearly decline in Pre FEV1 Post FEV1
Tashkin, D et al. A 4-Year Trial of Tiotropium in COPD. N Engl J Med 2008;359: 1543-54. Decramer, M. et al. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet 2009; 374: 1171 78 UPLIFT Decline in FEV1 N: All Subjects N: Subjects with moderate Obstruction Tiotropium : 40±1 ml per year Placebo: 42±1 ml per year P = 0.21 Tiotropium : 43±2 ml per year Placebo: 49±2 ml per year P = 0.024
Clinical Trials in COPD FEV1 Inclusion Criteria Study FEV1 % predicted inclusion criteria TORCH (2003-06) < 60% UPLIFT (2004-08) < 70% Glycopyronium/ Indacaterol < 80% and 30% Umeclidinium/ Vilanterol 70% Glycopyrrolate/ Formoterol < 80% and 30% Tiotropium/ Olodaterol < 80% http://www.clinicaltrials.gov
LAMA/ LABA FDC for COPD: Approved or Under Investigation Banerji, D. et al. Dual bronchodilation for the treatment of chronic obstructive pulmonary disease: a review of the latest clinical data. Clin. Invest. (2014) 4(6), 511 533
Banerji, D. et al. Dual bronchodilation for the treatment of chronic obstructive pulmonary disease: a review of the latest clinical data. Clin. Invest. (2014) 4(6), 511 533
Banerji, D. et al. Dual bronchodilation for the treatment of chronic obstructive pulmonary disease: a review of the latest clinical data. Clin. Invest. (2014) 4(6), 511 533
Banerji, D. et al. Dual bronchodilation for the treatment of chronic obstructive pulmonary disease: a review of the latest clinical data. Clin. Invest. (2014) 4(6), 511 533
Banerji, D. et al. Dual bronchodilation for the treatment of chronic obstructive pulmonary disease: a review of the latest clinical data. Clin. Invest. (2014) 4(6), 511 533
New Treatment = Better Outcome? Yes, but there is room for improvement.
Medicines in Development COPD: 2012 Report America s biopharmaceutical research companies
Medicines in Development COPD: 2012 Report America s biopharmaceutical research companies
New Treatment = Better Outcome? (part 2) PCCP Mid-year 2018 Version
New Treatment = Better Outcome? We know more about COPD. Beginning to know: Who and when to give the drug. Yes, new treatment = better outcome but we need more. More drugs in development.
RCT New Treatment Better Outcome Real World Morbidity Mortality Health providers General population Patient Diagnose early COPD Spirometry facility Increase awareness How to recognize How to treat Why & how to use inhalers
Thank you very much for your attention
Session on COPD: Novel Concepts and Promising New Drugs Topic: New Treatment = Better Outcome? Through a CME Grant sponsored by