Topic: New Treatment = Better Outcome? · PDF fileTopic: New Treatment = Better Outcome? ......
Transcript of Topic: New Treatment = Better Outcome? · PDF fileTopic: New Treatment = Better Outcome? ......
Through a CME Grant sponsored by
Session on COPD: Novel Concepts
and Promising New Drugs
Topic: New Treatment = Better Outcome?
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)
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
LABA/ ICS Tiotropium
PDE4I LABA/LAMA
(2001) (2004) (2011) (2014) (2015)
(UPDATE 2015)
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
• 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
Relieve symptoms
Improve exercise tolerance
Improve health status Prevent and treat exacerbations
X Reduce mortality ? Prevent disease progression
Tiotropium & Treatment Goals
• 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
Relieve symptoms
Improve exercise tolerance
Improve health status Prevent and treat exacerbations
? Reduce mortality X Prevent disease progression
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.
Infliximab (TNF-A Inhibitor)X CRQX Pre-FEV1X 6-MWTX SF-36 X TDI(?) Cancer(?) Pneumonia
Mahler DA et al. Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study. Chest 2004; 126: 926–34.
ABX vs IL-8 TDIX FEV1X SGRQX 6MWT
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
– 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
“General COPD”
Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points(ECLIPSE)
3 yearsFollow-up
Vestbo J, et al. Am J of Resp & Crit Care Med Vol. 189 Num. 9 | May 1 2014
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
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
Design OPUS ( 111) / RATIO (112) Study
N: 2,686
FEV1: <50%
Meds:
SABA & SAMA
ICSRoflumilast: 500
Placebo
52 Weeks
Rate Ratio of Exacerbation (moderate & severe)
0.75 1.00 1.25
Rate Ratio
0.50 1.50
Favors Roflumilast Favors PlaceboStudy iExacerb. Rate (%)
M2-111 -14.0
M2-112 -15.2
Why?
Identification of Patient Target Population
Confirmatory 1-yr pivotal studiesM2-124, M2-125
Severe/very severe COPD
Hx chronic cough & sputum
Hx of exacerbations
Hx chronic cough & sputum
Subgroup analyses ofearly phase III studies
M2-111, M2-112
Severe/very severe COPD
N: 3,091
FEV1: <50%
IC:
(+) C. Bronchitis
(+) Sputum
(+) Exacerbations
Meds:
No ICS
(+) LABA
(+) SAMA
Pivotal Study M2-124/ M2-125
Roflumilast: 500
Placebo
52 Weeks
Calverley PMA, Rabe, KF et al. Lancet 2009;374:685–694.
Rate Ratio of Exacerbation (moderate & severe)
0.75 1.00 1.25
Rate Ratio
0.50 1.50
Favors Roflumilast Favors Placebo
M2-124 -14.9
M2-125 -18.5
Study iExacerb. Rate (%)
M2-111 -14.0
M2-112 -15.2
Calverley PMA, Rabe, KF et al. Lancet 2009;374:685–694.
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: Statements on Roflumilast
GOLD 2014. Available from: http://www.goldcopd.com.
Decline in Lung Function of COPD Patients Fletcher-Peto Curve vs ECLIPSE Curve
FE
V1
(% o
f va
lue
at
ag
e 2
5)
25 50 75
Age (years)
100
80
50
30
0
Smoked
regularly and
susceptible to
its effects
Never smoked
or not susceptible
to smoke
Most Rapid
Decline(Fletcher)
Most Rapid
Decline(ECLIPSE)
Vestbo J, et al. Am J of Resp & Crit Care Med Vol. 189 Num. 9 | May 1 2014
UPLIFT Study
N: 4,383
FEV1: <70%
Meds allowed:
SABA, LABA
ICS, XanthineTiotropium 18 ug OD
Placebo
4 Years
Yearly decline in Pre FEV1Post FEV1
UPLIFT Decline in FEV1
N: All Subjects N: Subjects with moderate Obstruction
Tiotropium : 40±1 ml per yearPlacebo: 42±1 ml per yearP = 0.21
Tiotropium : 43±2 ml per yearPlacebo: 49±2 ml per yearP = 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
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
Clinical Trials in COPD FEV1 Inclusion Criteria
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
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
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.
New Treatment Better Outcome
RCT
Morbidity Mortality
Real World
Health providers
General population
Patient
• Diagnose early COPD• Spirometry facility• Increase awareness• How to recognize • How to treat• Why & how to use inhalers