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 PDE4I Tiotropium
“Old” “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: Olodaterol, Vilanterol, Abediterol LAMAs: Umeclidinium LAMA/LABA combinations: Glycopyrronium/ Indacaterol (QVA149), Umeclidinium/ Vilanterol Tiotropium/ Olodaterol Aclidinium/ Formoterol Glycopyrronium bromide/ Formoterol (PT001) MABAs: 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 PDE4I LABA/LAMA Tiotropium 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 moderate- to-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)
Pulmonary function Whole body impedance/fat-free mass Chest computed tomography Exercise capacity Resting oxygen saturation Biomarkers – Blood samples – Induced sputum 3 years – Exhaled breath condensate Follow-up – 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% 52 Weeks Meds: SABA & SAMA Roflumilast: 500 ICS
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 Confirmatory early phase III studies 1-yr pivotal studies M2-111, M2-112 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% 52 Weeks IC: (+) C. Bronchitis Roflumilast: 500 (+) Sputum (+) Exacerbations Meds: Placebo No ICS (+) LABA (+) SAMA
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. Decline in Lung Function of COPD Patients Fletcher-Peto Curve vs ECLIPSE Curve Most Most 100 Rapid Rapid Never smoked Decline Decline or not susceptible (ECLIPSE) (Fletcher) to smoke 80
Smoked 50 regularly and susceptible to its effects
(% (% of at value25) age 30
1 FEV
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% 4 Years Meds allowed: SABA, LABA Tiotropium 18 ug OD ICS, Xanthine
Placebo
Yearly decline in Pre FEV1 Post FEV1 UPLIFT Decline in FEV1
N: All Subjects N: Subjects with moderate Obstruction
Tiotropium : 40±1 ml per year Tiotropium : 43±2 ml per year Placebo: 42±1 ml per year Placebo: 49±2 ml per year P = 0.21 P = 0.024
• 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 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 Real World
New Treatment Morbidity Better Outcome 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