Transcript Therapeutic developments of COPD

Chronic Obstructive Pulmonary Disease
(COPD)

A common preventable and treatable
disease, is characterized by persistent
airflow limitation that is usually progressive
and associated with an enhanced chronic
inflammatory response in the airways and
the lung to noxious particles or gases.
3
COPD will be the Fourth leading
cause of death in 2030
http://www.japi.org/february_2012_special_issue_copd/01_editorial.html
4
COPD is the 7th
leading cause of
death in Taiwan
5
Leading causes of mortality
Taiwan 2013
死亡
152,030
每十萬
人口
標準化
死亡率
462.4
42,559
16,513
10,823
9,081
9,047
6,726
5,984
5,153
4,631
4,368
132.2
47.9
31.3
26.9
24.8
24.1
16.2
16.5
12.9
12.6
死 亡 原 因
順位
人數
所有死亡原因
1
2
3
4
5
6
7
8
9
10
惡性腫瘤
心臟疾病（高血壓性疾病除外）
腦血管疾病
糖尿病
肺炎
事故傷害
慢性下呼吸道疾病
慢性肝病及肝硬化
高血壓性疾病
腎炎、腎病症候群及腎病變
死亡
百分比
%
100.0
28.0
10.9
7.1
6.0
6.0
4.4
3.9
3.4
3.0
2.9
Risk Factors for COPD
Genes
Infections
Socio- economic
status
Aging
Populations
© 2015 Global Initiative for Chronic Obstructive Lung Disease
7
11
Triggers
Viruses
Pollutants
Bacteria
Inflamed COPD airways
Effects
Greater airway inflammation
Systemic
inflammation
Bronchoconstriction
edema, mucus
Expiratory flow
limitation
Cardiovascular
comorbidity
Exacerbation
symptoms
Dynamic
hyperinflation
Wedzicha & Seemungal. Lancet 2007

Narrowing of peripheral airways leads to decreased
forced expiratory volume in 1 second (FEV1)

Peripheral airway obstruction and reduced elastic
recoil progressively trap air during expiration,
resulting in hyperinflation

Hyperinflation reduces inspiratory capacity
 functional residual capacity increases, particularly
during exercise (dynamic hyperinflation)
This results in dyspnea and limitation of exercise
capacity
NATURAL HISTORY OF COPD
Lung Function
Never smoked
Exacerbation
Smoker
Exacerbation
Exacerbation
Time (Years)
Fletcher C. BMJ 1977;1:1645-1648.
Exacerbations of COPD indicate
 instability or worsening of the clinical status
 progression of the disease
The development of complications
 an increased risk of subsequent exacerbations
 a worsening of coexisting conditions
 reduced health status and physical activity
 deterioration of lung function
 An increased risk of death
Exacerbations and comorbidities contribute
to the overall severity in individual patients.
 Assessment of COPD is based on the
patient’s level of symptoms, future risk of
exacerbations, the severity of spirometric
abnormality, and the identification of
comorbidities.

Classification of Severity of Airflow
Limitation in COPD
In patients with FEV1/FVC < 0.70:
GOLD
GOLD
GOLD
GOLD
1:
2:
3:
4:
Mild
Moderate
Severe
Very Severe
FEV1 > 80% predicted
50% < FEV1 < 80% predicted
30% < FEV1 < 50% predicted
FEV1 < 30% predicted
*Based on Post-Bronchodilator FEV1
(C)
(D)
>2
(B)
1
3
2
(A)
1
0
mMRC 0-1
CAT < 10
mMRC > 2
CAT > 10
Symptoms
(mMRC or CAT score)
(Exacerbation history)
4
Risk
(GOLD Classification of Airflow Limitation)
Risk
Combined Assessment of COPD
Modified MRC Questionnaire (mMRC)
COPD Assessment Test (CAT)
Use combined assessment
3
(C)
(D)
>2
2
(A)
(B)
1
0
1
(Exacerbation history)
4
Risk
(GOLD Classification of Airflow Limitation)
Risk
Combined Assessment of COPD
Patient is now in one of
four categories:
A: Les symptoms, low risk
B: More symtoms, low risk
C: Less symptoms, high risk
D: More Symtoms, high risk
mMRC 0-1
CAT < 10
mMRC > 2
CAT > 10
Symptoms
(mMRC or CAT score)
Manage Stable COPD: Pharmacologic Therapy
(Medications in each box are mentioned in alphabetical order, and therefore not
necessarily in order of preference.)
Patient
First choice
Second choice
Alternative Choices
A
SAMA prn
or
SABA prn
LAMA
or
LABA
or
SABA and SAMA
Theophylline
B
LAMA
or
LABA
LAMA and LABA
SABA and/or SAMA
Theophylline
LAMA and LABA
PDE4-inh.
SABA and/or SAMA
Theophylline
ICS and LAMA or
ICS + LABA and LAMA or
ICS+LABA and PDE4-inh. or
LAMA and LABA or
LAMA and PDE4-inh.
Carbocysteine
SABA and/or SAMA
Theophylline
C
D
ICS + LABA
or
LAMA
ICS + LABA
or
LAMA
Goal of COPD management
 Relieve symptoms
 Improve exercise tolerance
 Improve health status
 Prevent disease progression
 Prevent and treat exacerbations
Reduce
symptoms
Reduce
risk
 Reduce mortality
© 2015 Global Initiative for Chronic Obstructive Lung Disease

The main objectives of managing COPD
are a reduction in the severity of symptoms
and the prevention of exacerbations.
GOLD 2010~

Bronchodilator therapy is central to the
management of COPD.
GOLD COPD strategy
Bronchodilators are the cornerstone of treatment

Improved airflow

Reduction of dyspnea, improved quality of life

Improved hyperinflation and exercise capacity

Prevent exacerbations

May decrease mortality (UPLIFT, not primary
outcome)
GOLD 2010~





Inhaled therapy is preferred.
Give “as needed” to relive intermittent or worsening
symptoms, and on a regular basis to prevent or reduce
persistent symptoms.
The choice between β2-agonists, anticholinergics,
methylxanthines, and combination therapy depends on the
availability of medications and each patient`s individual
response in terms of both symptom relief and side effects.
Regular treatment with long-acting bronchodilators,
including nebulized formulations, is more effective and
convenient than treatment with short-acting bronchodilator.
Combining bronchodilators of different pharmacologic
classes may improve efficacy and decrease the side effects
compared to increasing the dose of a single bronchodilator.
Two classes of long-acting bronchodilators
 long-acting β2-agonists
 long-acting anticholinergic agents
Both have been shown to provide relief
from symptoms in patients with COPD.
Effects of long-term β2-agonists
The role of LABA in COPD






Decreased smooth muscle contraction
Increased muco-ciliary transport
Reduced Mucosal damage
Decreased numbers of inflammatory
cells/activation
- monocytes
- neutrophils
Reduced Airway fibrosis
Reduced Impaired skeletal muscle – weakness
Cholinergic regulation of airway
smooth muscle tone
Pre-ganglionic nerve
pre-synaptic
Nicotinic transmission
Parasympathetic
ganglion
M1 receptors facilitate
Post-ganglionic
nerve
Ideal anti-cholinergic
Pre-junctional
M2 receptors (–)
Neuromuscular
junction
ACh
Airway smooth muscle
Barnes PJ. Eur Respir Rev 1996;6:290–294
Post-junctional
M3 receptors (+)
Optimizing bronchodilation in COPD
Complimentary actions of β2-agonist and antimuscarinic
LABA
LAMA
2 receptor
s


 2 stimulation and
PKA-mediated inhibition
of MLCK directly
reduces smooth muscle
contraction
AC = adenylylcyclase
Ach = acetylcholine
cAMP = cyclic adenosine 3’,5’ monophosphate
MLCK = myosin light chain kinase
PKA = protein kinase A
PLC = Phospholipase C
ACh
M3 receptor
AC
PLC
cAMP
Ca2+
PKA
MLCK
 q

 Antagonism of
acetylcholine via M3
inhibits vagal tone
Smooth muscle contraction
Adapted from Cazzola & Molimard. Pulm Pharmacol Ther 2010
Rationale for Combination Therapy:
M3R/β2R cross-talk
TW1407224308
M3R
β2 AR
AC
P
αs γ β
cAMP
PKC
Protein kinase C
PLC
αq γ β
IP3
Ca2+
Relaxation
Contraction
Boterman et al., Eur J Pharmacol (2005) 516:85-92.
Rationale for Combination Therapy:
M3R/β2R cross-talk
TW1407224308
M3 antagonist
β2 AR
AC
P
αs γ β
cAMP
M3R
PKC
PLC
αq γ β
IP3
Ca2+
Relaxation
Relaxation
Contraction
Relaxation
Boterman et al., Eur J Pharmacol (2005) 516:85-92.
“Combining bronchodilators of different pharmacological
classes may improve efficacy and decrease the risk of side
effects compared to increasing the dose of a single
bronchodilator.”
GOLD 2015
TW1407224308
Rationale for LABA/LAMA combination
therapy: Functional Antagonism
Roffel et al., Br J Pharmacol (1995) 115:665-671.
Combined LABA/LAMA vs LAMA alone
INTRUST: Further improvements in lung function with
indacaterol + tiotropium vs tiotropium alone
FEV1 treatment difference (mL)
FEV1 AUC5 min–8 h and trough FEV1 at Week 12
INTRUST 1
160
140
120
INTRUST 2
***
130 mL
***
120 mL
100
***
80 mL
80
60
***
70 mL
40
20
0
FEV1 AUC5 min–8 h
(Primary endpoint)
***p<0.001 for indacaterol + tiotropium vs
tiotropium alone
Trough FEV1
(Key secondary endpoint)
Boterman et al., Eur J Pharmacol (2005) 516:85-92.
Combined LABA/LAMA vs LAMA alone
INTRUST: improves inspiratory capacity with
indacaterol + tiotropium vs tiotropium alone
IC treatment difference (mL)
Inspiratory capacity at serial time points post dose at Week 12
300
INTRUST 1
INTRUST 2
250
200
150
130 mL
100 mL
100
50
0
–50
-1
0
1
2
3
4
5
6
7
Time (hours)
8
Trough
(24 h post dose)
Study drug inhalation
Data are LSM and 95% CI for the treatment difference between indacaterol + tiotropium and tiotropium alone
All differences for indacaterol + tiotropium vs tiotropium alone significant at p<0.05
Between 99 and 124 patients per group were included at each time point
Mahler et al. Thorax 2012
Overview of LABA/LAMA fixed-dose
combinations in late-stage clinical
development
FDC
Development phase
Company
Pivotal trials
Indacaterol/
glycopyrronium
(QVA149)
110/50 μg filed
(EU, Japan)
Novartis
IGNITE program
11 trials, 11,198 patients
(target pop), 42 countries
Umeclidinium/
vilanterol
62.5/25 μg and
125/25 μg filed
(EU, US, Japan)
GSK,
Theravance
Phase III program
7 trials, 6000 patients,
worldwide
Olodaterol/
tiotropium
III
Boehringer
Ingelheim
TOviTO program
Aclidinium/
formoterol
III
Almirall, Forest
ACLIFORM (NCT01462942),
NCT01437397
Formoterol/
glycopyrrolate
II
AstraZeneca
Phase IIb trials completed
(e.g. NCT01587079)
Combined LABA/LAMA vs LABA alone
Combined LABA + LAMA (QVA149) is more efficacious
than higher dose LABA
Placebo
Indacaterol 300 µg
Indacaterol 600 µg
QVA 149 300/50 μg
1.7
FEV1 (L)
1.6
1.5
1.4
1.3
1.2
–2
0
2
4
6
8
10
12
Time (hours)
van Noord et al. Thorax 2010
14
16
18
20
22
24
Combined LABA/LAMA vs LABA alone
GLOW6: Further improvements in lung function with
indacaterol + glycopyrronium vs indacaterol alone
Walter Vincken et al. International Journal of COPD 2014:9 215–228
QVA149 IGNITE program
8trials completed during 2012 in more than 5700 patients
Long-term safety
(vs placebo)
Non-inferiority vs free combination
Japan pivotal safety
(vs tiotropium)
FEV1, TDI, SGRQ,
(vs glycopyrronium, indacaterol,
tiotropium and placebo)
FEV1, TDI, SGRQ
(vs fluticasone/salmeterol)
Exercise tolerance
(vs tiotropium and placebo)
Exacerbations
(vs glycopyrronium and tiotropium)
TDI/BDI
(vs tiotropium)
SHINE study design
Pivotal safety and efficacy study (USA, EU, Latin America, Asia)
 2144 patients randomized; 2135 included in full analysis

26-week, multicenter, randomized, double-blind, parallel-group,
placebo and active-controlled study
Pre-randomization period
Pre-screening
Run-in period
QVA149 110/50 μg q.d. via Breezhaler®
n=474
Indacaterol 150 μg q.d. via Breezhaler®
n=473
Glycopyrronium 50 μg q.d. via Breezhaler®
n=476
Open-label tiotropium 18 μg q.d. via HandiHaler® n=480
Placebo via Breezhaler®
Day −21 to Day −15
Day −14 to Day −1
Day 1 to Day 184
Randomization
Visit 1
Visit 2
Bateman et al. Eur Respir J 2013
Visit 3
n=232
Patient population
Inclusion criteria
Population
characteristics
 Post-bronchodilator FEV1
≥30% and <80% of
predicted normal
 Symptomatic patients,
defined as a total symptom
score (on daily eDiary) of
1 on at least 4 of the last 7
days prior to randomization
 Mean FEV1 % predicted:
55.2%
C
D
 Symptomatic:
Yes
Exclusion criteria
 COPD exacerbation
requiring treatment with
antibiotics, systemic
corticosteroids or
hospitalization within
6 weeks prior to study entry
or during screening/run in
Bateman et al. Eur Respir J 2013
 Exacerbations in
previous year:
1 (19.7%), ≥2 (5.7%)
A
B
Patients targeted by
inclusion criteria
QVA149 significantly improved
mean trough FEV1 at Week 26 vs all comparators
∆=200 mL, p<0.001
∆=80 mL, p<0.001
Least squares mean (SE)
trough FEV1 (L)
1.50
1.45
∆=90 mL, p<0.001
∆=70 mL, p<0.001
∆=130 mL, p<0.001
∆=120 mL, p<0.001
∆=130 mL, p<0.001
1.40
1.35
1.30
1.25
1.20
0.00
1.45
1.38
1.36
1.37
1.25
QVA149
110/50 μg q.d.
Indacaterol
150 μg q.d.
Glycopyrronium
50 μg q.d.
Open-label
tiotropium
18 μg q.d.
Placebo
Primary
Bateman et al. Eur Respir J 2013
endpoint
QVA149 provided significant improvements
in trough FEV1 regardless of disease severity
Favors placebo Favors active treatment
QVA149 110/50 μg q.d.
Indacaterol 150 μg q.d.
GOLD stage II
*†
Glycopyrronium 50 μg q.d.
*
OL Tiotropium 18 μg q.d.
*
*
GOLD stage III
–0.2
*p<0.001 vs placebo
†p<0.001 vs indacaterol,
glycopyrronium and
tiotropium
*†
0.0
0.2
0.4
0.6
Week 26 mean (95% CI) treatment difference
in trough FEV1 (L) vs placebo
Bateman et al. Eur Respir J 2013; Novartis data on file
SPARK study design
Pivotal exacerbation study (USA, EU, Latin America)
2224 patients randomized; 2205 included in modified full analysis set
Severe to very severe (GOLD stage III and IV) COPD and ≥1 COPD
exacerbation within 1 year of randomization



64-week, multicenter, randomized, double-blind, parallel-group and
active-controlled study
Pre-randomization period
Double-blind treatment period
Screening/
run-in
period
Prescreening
Day −21 to −15
Variable doubleblind treatment
period
QVA149 110/50 μg q.d. via Breezhaler®
n=729
Glycopyrronium 50 μg q.d. via Breezhaler®
n=740
Open-label tiotropium 18 μg q.d. via HandiHaler®
n=737
Day −14 to −1
Day 1 to 448
Day 448 to 532
Randomization
Visit 1
Visit 2
Visit 3
Visit 16
Visit 18
Wedzicha et al. Lancet Respir Med 2013
Patient population
Inclusion criteria
Population
characteristics
 Post-bronchodilator
FEV1 <50% of predicted
normal
 ≥1 documented COPD
exacerbation requiring
treatment with
antibiotics, systemic
corticosteroids or
hospitalization within
1 year of randomization
 Mean FEV1 % predicted:
37.2%
C
D
 Exacerbations in
previous year:
1 (76.2%), ≥2 (22.3%)
 Baseline ICS use:
75%
A
B
Patients targeted by
inclusion criteria
Wedzicha et al. Lancet Respir Med 2013
QVA149 significantly improved
mean trough FEV1 vs glycopyrronium and tiotropium
over 64 weeks (secondary objective)
*At all time points, p<0.001 vs glycopyrronium and open-label tiotropium
Least squares mean (SE)
trough FEV1 (L)
1.10
*
*
*
*
*
*
1.05
1.00
0.95
QVA149
110/50 μg q.d.
0.90
Glycopyrronium
50 μg q.d.
Open-label tiotropium
18 μg q.d.
0.00
Baseline
4
12
26
Week
Wedzicha et al. Lancet Respir Med 2013
38
52
64
QVA149 significantly reduced the rate of
moderate or severe COPD exacerbations vs
glycopyrronium over 64 weeks
 SPARK met its primary endpoint, demonstrating that QVA149 was superior to
glycopyrronium with regard to rate of moderate or severe COPD exacerbations
10% reduction, p=0.096
Annual rate of moderate or
severe COPD exacerbations
1.00
12% reduction, p=0.038 (primary endpoint)
0.95
0.90
0.85
0.80
QVA149
110/50 μg q.d.
Glycopyrronium
Open-label
50 μg q.d.
tiotropium 18 μg q.d.
Wedzicha et al. Lancet Respir Med 2013
Least squares mean (SE)
dynamic inspiratory capacity (L)
QVA149 significantly improved
dynamic* inspiratory capacity at Day 21
vs tiotropium and placebo ∆=320 mL, p<0.001
2.6
∆=140 mL, p=0.002
2.4
2.2
2.0
1.80
2.42
2.29
2.11
1
Tiotropium
18 μg q.d.
2
Placebo
QVA149
110/50 μg q.d.
*During exercise
3
Beeh et al. BTS 2012 Abstract
Patient population
Inclusion criteria
Population
characteristics
 Post-bronchodilator FEV1
≥30% and <80% of
predicted normal
 Symptomatic patients,
defined as Grade ≥2 on
the mMRC
 Mean FEV1 % predicted:
56.0%
C
D
Exclusion criteria
 COPD exacerbation
requiring treatment with
antibiotics, systemic
corticosteroids or
hospitalization within
6 weeks prior to Visit 1 or
between Visit 1 and Visit 3
 Exacerbations in
previous year:
1 (23.2%), ≥2 (6.9%)
 Symptomatic:
Yes
A
B
Patients targeted by
inclusion criteria
Mahler et al. Presented at ATS 2013
QVA149 significantly improved SAC TDI total
score vs tiotropium and placebo after 6 weeks
∆=1.37, p<0.001, primary endpoint
1.2
∆=0.49, p=0.021
Least squares mean (SE)
SAC TDI total score
1.0
0.8
∆=0.88, p<0.001
0.6
0.4
0.2
0
–0.2
0.88
0.39
Placebo
QVA149
110/50 μg q.d.
Blinded tiotropium
18 μg q.d.
–0.49
–0.4
–0.6
–0.8
Mahler et al. ATS 2013 Abstract
ILLUMINATE study design
Safety and efficacy study (EU, South Africa)
523 patients randomized; 522 included in full analysis set
Symptomatic patients with no history of exacerbations in the previous
year



26-week, multicenter, randomized, double-blind, parallel-group,
double-dummy study
Double-blind treatment period
(26 weeks)
Pre-randomization period
Prescreening
WASHOUT
Run-in
period
Day −21 to
Day −15
Day −14 to
Day −1
30-day postsafety follow-up
QVA149 110/50 μg q.d. via Breezhaler®
n=258
Fluticasone/salmeterol 500/50 µg
b.i.d. via Accuhaler®
n=264
Day 1 to Day 184
Randomization
Visit 1
Visit 2
Visit 3
Vogelmeier et al. Lancet Respir Med 2013
Visit 7
Patient population
Inclusion criteria
Population
characteristics
 Post-bronchodilator FEV1
40–80% of predicted normal
 Symptomatic patients,
defined as a total symptom
score (on daily eDiary) of
1 on at least 4 of the last 7
days prior to randomization
C
D
Exclusion criteria
 COPD exacerbation
requiring treatment with
antibiotics, systemic
corticosteroids or
hospitalization within
1 year of randomization;
history of asthma
A
B

Mean FEV1 % predicted:
60.2%

Exacerbations in
previous year:
No

Symptomatic:
Yes

ICS users at baseline
QVA149: 85/258 (32.9%)
Flut/Salm: 98/264 (37.1%)
Patients targeted by
inclusion criteria
Despite the specific exclusion criterion of no history of exacerbations in the previous year, meaning
patients should not have been receiving LABA/ICS, 35% were receiving ICS at baseline
Vogelmeier et al. Lancet Respir Med 2013
QVA149 significantly improved
FEV1 AUC0–12 h at Week 26 (primary endpoint)
vs Fluticasone/salmeterol
∆=138
Least squares mean (SE)
FEV1 AUC0–12 h (L)
1.8
mL, p<0.0001
1.7
1.6
1.5
0.0
1.4
1.70
1.56
QVA149
110/50 μg q.d.
Fluticasone/salmeterol
500/50 μg b.i.d.
Vogelmeier et al. Lancet Respir Med 2013
QVA149 significantly improved
mean trough FEV1 at Weeks 12 and 26
QVA149
110/50 μg q.d.
Fluticasone/salmeterol
500/50 μg b.i.d.
Least squares mean (SE)
trough FEV1 (L)
1.7
∆=92 mL, p<0.0001
∆=103 mL, p<0.0001
1.6
1.5
0.0
1.4
1.61
1.52
Week 12
Vogelmeier et al. Lancet Respir Med 2013
1.60
1.50
Week 26
BEACON study design
Primary objective: non-inferiority of QVA149 vs
concurrent administration of monocomponents

4-week, multicenter, randomized, double-blind, parallel-group study
Pre-randomization period
Screening
period
Double-blind treatment period
Run-in
period
QVA149 110/50 μg q.d. via Breezhaler®
Indacaterol
150 μg q.d. +
Glycopyrronium
50 μg q.d. via
Breezhaler®
Day −21 to −15
Visit 1
Indacaterol 150 μg q.d. +
Glycopyrronium 50 μg q.d. via Breezhaler®
Day −14 to −1
Visit 2
n=87
Visit 3
n=100
Day 1 to 28
Visit 6
Visit 7
Dahl et al. ERS 2013 Poster
QVA149 was non-inferior to
the free combination of indacaterol +glycopyrronium
for trough FEV1 at Week 4
∆=−5 mL (95% CI –0.051, 0.040)
Least squares mean (SE)
trough FEV1 (L)
1.60
1.40
1.20
1.00
0.80
0.60
0.40
0.20
n=81
n=96
QVA149
110/50 μg q.d.
Indacaterol 150 μg q.d. +
glycopyrronium 50 μg q.d.
0.00
Dahl et al. ERS 2013 Abstract
QVA149 significantly improved important
patient outcomes vs monotherapies and
LABA/ICS
Exacerbations
(vs glycopyrronium,
OL tiotropium)1
Rescue medication
Dyspnea
(vs glycopyrronium,
OL tiotropium,
salmeterol/fluticasone)2,3
(vs placebo,
glycopyrronium, tiotropium,
salmeterol/fluticasone)2,3,4
SGRQ
(vs placebo,
glycopyrronium,
OL tiotropium)1,2
1. Wedzicha et al. Lancet Respir Med 2013
2. Bateman et al. Eur Respir J 2012
3. Vogelmeier et al. Lancet Respir Med 2013
4. Mahler et al. ATS 2013 Abstract
TW1407225878
QVA149 AE profile vs individual
monocomponents, current standards of care
and placebo
QVA149
(n=1076)
Indacaterol
(n=476)
Glycopyrronium
(n=473)
Tiotropium
(n=519)
Salmeterol/
fluticasone
(n=264)
Placebo
(n=345)
Total
593
(55.1%)
291
(61.1%)
290
(61.3%)
295
(56.8%)
159
(60.2%)
190
(55.1%)
COPD worsening
248
(23.0%)
153
(32.1%)
150
(31.7%)
143
(27.6%)
62
(23.5%)
112
(32.5%)
Nasopharyngitis
91
(8.5%)
35
(7.4%)
46
(9.7%)
47
(9.1%)
29
(11.0%)
23
(6.7%)
Cough
43
(4.0%)
38
(8.0%)
18
(3.8%)
22
(4.2%)
5
(1.9%)
9
(2.6%)
Upper respiratory
tract infection
40
(3.7%)
32
(6.7%)
20
(4.2%)
28
(5.4%)
3
(1.1%)
18
(5.2%)
Total and most frequent AEs (≥3% in QVA149 arm), by preferred term;
pooled 6-month safety database
Welte et al. ERS 2013 Poster
SAEs, deaths and clinically significant
AEs vs individual monocomponents,
current standards of care and placebo
QVA149
(n=1076)
Indacaterol
(n=476)
Glycopyrronium
(n=473)
Tiotropium
(n=519)
SFC
(n=264)
Placebo
(n=345)
37 (3.4)
24 (5.0)
14 (3.0)
10 (1.9)
27 (10.2)
16 (4.6)
Total
59 (5.5)
26 (5.5)
29 (6.1)
20 (3.9)
14 (5.3)
19 (5.5)
COPD worsening
17 (1.6)
15 (3.2)
9 (1.9)
7 (1.3)
3 (1.1)
9 (2.6)
Deaths
3 (0.3)
2 (0.4)
1 (0.2)
3 (0.6)
1 (0.4)
0
CCV AEs
19 (1.8)
12 (2.5)
14 (3.0)
9 (1.7)
6 (2.3)
9 (2.6)
CCV SAEs
6 (0.6)
4 (0.8)
6 (1.3)
3 (0.6)
3 (1.1)
1 (0.3)
Total MACE events
3 (0.3)
2 (0.4)
3 (0.6)
3 (0.6)
1 (0.4)
0
Atrial fibrillation/flutter events
9 (0.8)
7 (1.5)
10 (2.1)
7 (1.3)
7 (2.7)
2 (0.6)
AEs leading to permanent
discontinuation of study drug
SAE
(≥1% patients in QVA149 group)
CCV = cardio-cerebral vascular
MACE = major adverse cardiac events
SFC= salmeterol/fluticasone
Ferguson et al. ERS 2013 Poster
Conclusions

The dual bronchodilator QVA149 was shown to
significantly improve lung function vs placebo,
monotherapy( LAMA or LABA ), and LABA/ICS

The safety of dual bronchodilation with
LABA/LAMA has been shown to be similar to
placebo, and LAMA and LABA monotherapies

These data support the use of dual
bronchodilation as a potential new treatment
option for patients with COPD
TW1407225878
Conclusion
Bronchodilation is the cornerstone of COPD
treatment.
 Combination therapy with two bronchodilators
that have different mechanisms of action has
been shown to provide significant benefits in
various lung function parameters vs
monotherapies
 ICS + LABA or LAMA +LABA as a Duo
bronchodilator, can do more than bronchodilation.
 LABA + LAMA improves lung function and reduce
rate of exacerbation in uncontrolled COPD.

Where is the ROLE of LAMA+LABA in GOLD?
4
ICS+LABA
(C)
或LAMA
ICS+LABA
(D)
或LAMA
>2
3
2
SABA 或 SAMA
(A)
LABA 或
LAMA(B)
1
mMRC 0-1
CAT < 10
mMRC > 2
CAT > 10
症狀
(mMRC 或CAT評分)
≤1
風險
（急性加重史）
風險
( 氣流受限的GOLD分級標準)
哪個首選: ICS＋LABA 或 LAMA?
Thank you for your attention!