1
Double Bronchodilatation in
COPD
Bartolome R. Celli, M.D.
Brigham and Women’s Hospital
Professor of Medicine
Harvard Medical School
50 years Trend in Smoking
Related Mortality US
Thun M et al NEJM 2013;368:351
Global Burden of Disease
Murray and Lopez NEJM 2013;369:448
Deaths from COPD Worldwide
Territories are sized in proportion to the absolute
number of people who died from chronic obstructive
pulmonary disease in one year.
Objective
• COPD progresses over a long period of
time
• Reasoning for BD
• Patients respond to therapy
• Bronchodilators
• New agents
Objective
• COPD progresses over a long period of
time
• Reasoning for BD
• Patients respond to therapy
• Bronchodilators
• New agents
The Natural History of Chronic Bronchitis and Emphysema
LHS
POET
TORCH
UPLIFT
Fletcher and Peto BMJ 1976
Objective
• COPD progresses over a long period of
time
• Reasoning for BD
• Patients respond to therapy
• Bronchodilators
• New agents
Mechanism of action of β2-agonists
β2-agonist
Extracellular
β2R
β2R
Gs
Gs
AC
Airway smooth muscle
Intracellular
cAMP
PKA
(active)
ATP
PK
(inactive)
Relaxation
•
Stimulation of β2-adrenoreceptors results in activation of adenylate cyclase,
increased intracellular cAMP and subsequent airway smooth muscle relaxation
AC, adenylyl cyclase; ATP, adenosine triphosphate; β2R, β2 receptor;
cAMP, cyclic AMP; Gs, stimulatory G protein; PKA, protein kinase A
Tashkin DP, Fabbri LM, Respir Res. 2010;11:149.
Mechanism of action of muscarinic antagonists
Parasympathetic
ganglion
Preganglionic
nerve
ACh
MA
Postganglionic
nerve
M1
• Muscarinic antagonists block M1
and M3 receptors, thus
preventing binding of
acetylcholine and inhibiting
airway smooth muscle
contraction
M2
ACh
ACh, acetylcholine; Mx, muscarinic receptor; MA, muscarinic antagonist
MA
M3
Airway smooth muscle
Tashkin DP, Fabbri LM, Respir Res. 2010;11:149.
Objective
• COPD progresses over a long period of
time
• Patients respond to therapy
• Anti-inflammatories
• Bronchodilators
• New agents
Benefits of maximal bronchodilation
on clinical outcomes
Correlation between change in FEV1 and outcomes
5
P<0.0001, r2=8.2%
P<0.0001, r2=10%
Number of
exacerbations per year
5
4
0
SGRQ
TDI
3
2
1
0
-5
-10
-1
-250
0
250
500
1
0
0
-500
P<0.002, r2=5.6%
2
-500
-250
0
250
500
-250
0
250
500
FEV1 (mL)
FEV1 (mL)
FEV1 (mL)
-500
ICS severe
ICS moderate
No ICS severe
No ICS moderate
Correlation analysis of pooled data from three indacaterol studies (N=3313)
Jones PW et al, Respir Res 2011;12:161.
Objective
• COPD progresses over a long period of
time
• Reasoning for BD
• Patients respond to therapy
• Bronchodilators
• New agents
Ultra LABA
Ultra LABA
Aclidinium
Tiotropium
LAMA’s
Umeclidinium
Glycopirronium
FEV1 over 24 Hours Following
Single Dosing of Olodaterol
1.25
Olodaterol 20 µg
Olodaterol 10 µg
Olodaterol 5 µg
Olodaterol 2 µg
Placebo
FEV1 (L)
1.15
1.05
0.95
0.85
0.51
2 3
6
9
12
15
18
21 22 23 24
Time (h)
van Noord JA et al. Pulm Pharmacol Ther. 2011;24)6):666-672.
Long term efficacy and safety of
Indacaterol
N = 412
FEV1 = 1.5 L DB,R, PC.
26 weeks Two doses versus placebo
No important adverse side effects
Decreased exacerbations by 14%
USA FDA approved 75 mcg
Chapman K et al CHEST 2011;140:68
Indacaterol versus Tiotropium
n = 1600
FEV1 = 1.5 l
12 weeks
Indacaterol 150 mcg
Tiotropium 18 mcg
Outcomes
spirometry
SGRQ
TDI
Buhl et al Eur Respir J 2011: 28:797
Efficacy and safety of Aclidinium
The ATTAIN Study
N = 824
FEV1 = 1.5 L DB,R, PC.
24 weeks 2 doses versus placebo
No difference in side effects versus placebo
TDI was also improved
Jones P et al Eur Respir J 2012 e published March 22
Aclidinium BID versus Tiotropium
and Placebo
N = 30
FEV1 = 1.7 L
R, PC.
15 days 2 medications versus placebo
Furh R et al CHEST 2012;141:745
Efficacy of Glycopirronium : GLOW study
Patients = 657
Glycopirronium = 327
Tiotropium = 328
Duration = 12 weeks
Outcomes:
FEV1
AUC
Chapman K et al BMC Pulm Med 2014;14:4
Conclusions I
• Bronchodilators do bronchodilate.
• The Ultra-LABA and LAMA increase FEV1
between 120 and 200 ml
• The improve Qol and dyspnea
• Decrease exacerbations. All better than
placebo
Bronchodilator response
Distribution in UPLIFT
Percent of patients
53%
30
25
20
n= 5881
FEV1 = 1.1 L
15
10
5
0
-300
-200
-100
0
100
FEV1 ml change
Tashkin e al ERJ 2008
200
300
UPLIFT: FEV1 versus FVC response
FVC, but not
FEV1 response
FEV1, but not
FVC response
Stage III
Stage IV
Stage II
50
50
40
40
% of responders
% of responders
Stage II
30
20
20
10
0
0
Tashkin e al ERJ 2008
≥12% + ≥200 mL
Stage IV
30
10
≥15%
Stage III
≥15%
≥12% + ≥200 mL
Are 2 better than 1?
Comparison T versus F bid and
both combined qd
n = 71 FEV1=1.04L Cross-over 3 X 6 weeks periods T, T+ F qd and F bid
T+ F qd
T
F bid
Van Noord J et al ERJ 2005;26:214
Indacaterol plus tiotropium vs tiotropium plus placebo
FEV1 at Week 12 (The INTRUST Studies)
Study 1
FEV1 treatment difference (mL)
180
Study 2
160
140
120
100
80
60
40
Study drug inhalation
20
0
0
1
2
FEV1, forced expiratory volume in 1 second
3
4 5 6
Time (h)
7
8
23 24
Mahler et al. Thorax. 2012;67:781-788.
LAMA/LABA (tiotropium/salmeterol): Improvement
in dyspnea and reliever medication use
3.0
TDI focal score
*
3.5
*
TDI focal score
2.5
2.0
1.5
MCID
1.0
Reliever medication use
3.0
0.5
Reliever medication use
(puffs/24 hours)
3.5
2.5
2.0
*
*
1.5
1.0
0.5
0.0
Tiotropium
0.0
Tiotropium + salmeterol qd
Salmeterol bid
Tiotropium + salmeterol bid
*P<0.001 compared to either single agent alone
van Noord JA et al. Respir Med 2010;104:995.
LAMA/LABA (tiotropium / formoterol): Improvement in
constant work rate exercise tolerance
Δ rest to isotime inspiratory
capacity (L)
% CWR exercise time
140
Δ rest to isotime inspiratory capacity (L)
0.2
% CWR exercise time
120
100
80
60
40
20
P=<0.05
0.0
Formoterol bid
Crossover study of 33 COPD subjects; FEV1=47%pred
0.0
P=<0.05
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
Tiotropium qd + formoterol bid
Berton et al. Respir Med 2010; 104:1288.
Umeclidinium + Salmeterol versus
S, Tiotropium or Placebo
N = 47 FEV1 = 1.5 L
R,PC,Crossover
1 week
705 50 mcg + S
705 20 mcg + S
Tio
S
Placebo
Beier J et al Intl J COPD 2012;7:153
LAMA + LABA (tiotropium + olodaterol)
4 week, crossover studies (n=232)
Olodaterol 5 μg
Olodaterol 10 μg
FEV1 (L) at 4 weeks
+Tiotropium 5 μg*
+Tiotropium 2.5 μg*
+Tiotropium 1.25 μg*
Olodaterol 5 μg
1.75
1.70
1.65
1.60
1.55
1.50
1.45
1.40
1.35
1.30
1.25
+Tiotropium 5 μg*
+Tiotropium 2.5 μg*
+Tiotropium 1.25 μg*
Olodaterol 10 μg
1.75
1.70
1.65
1.60
1.55
1.50
1.45
1.40
1.35
1.30
1.25
~0.34 L
mean baseline
-1.00 0.00 1.00 2.00 3.00 4.00 5.00 6.00
Time
•
~0.36 L
mean baseline
-1.00 0.00 1.00 2.00 3.00 4.00 5.00 6.00
Time
Addition of tiotropium to olodaterol significantly improved FEV1 versus olodaterol alone
* via Respimat SMI
Aalbers et al. Eur Resp J 2012;40(Suppl 56): 525s (P2882).
Companies
Products
FDA
LABA + LAMA
Combined in one dispenser
Overview of inhaled LABA/LAMA
in development
Drug
combinations
Frequency
Development stage
Company
Formoterol/
aclidinium
Twice daily
Phase III*
Almirall/Forest
Formoterol/
glycopyrrolate
Twice daily
Phase II
Pearl
Therapeutics
Olodaterol/
tiotropium
Once a day
Phase III
BI
Umeclidinium/
vilanterol
Once a day
Phase III*
Theravance/GSK
Indacaterol/
glycopyrronium
Once a day
(QVA149)
*Detailed data have not been presented publicly
Phase III
Novartis
LAMA / LABA
Effect on lung function (SHINE study)
Least Square Mean of FEV1 (L)
1.60
QVA149 (n=59)
Indacaterol (n=55)
Glycopyrronium (n=63)
Tiotropium (n=66)
Placebo (n=27)
1.55
1.50
1.45
1.40
1.35
1.30
1.25
1.20
1.15
1.10
1.05
1.00
5m 1h 2h
4h
8h
Serial spirometry substudy
QVA110/50μg, indacaterol 150 μg, glycopyrronium 50 μg, and tiotropium
18 μg, all administered once daily
12h
16h
22h 23h 45m
Bateman E. et al. Eur Respir J. 2013 Epub ahead of print
LAMA / LABA
Effect on lung function
(SHINE
study)
0.08***
0.09***
Trough FEV1 at
Week 26 (L)
0.07***
Placebo
Open-label
tiotropium
18 μg qd
Glycopyrronium
50 μg qd
Indacaterol QVA149
150 μg qd 110/50 μg qd
0.13***
0.12***
0.13***
0.20***
***P<0.001 QVA149,
glycopyrronium plus
indacaterol
26-week randomized, controlled SHINE study in patients with moderate-to-severe COPD (n=2144)
Bateman et al, Eur Resp J 2013 [Epub ahead of print]
Umeclidinium/ Vilanterol vs. each one
FEV1
Celli et al CHEST 2014
QVA149 improves TDI focal
score versus placebo and tiotropium at Week 26
∆=1.09, P<0.001
∆=0.51, P<0.01
∆=0.21,P=ns
∆=0.26, P=ns
∆=0.84, P<0.001
∆=0.89, P<0.001
∆=0.58; P<0.05
Values are leastsquares mean±
standard error
Placebo
Open-label
tiotropium
18 μg qd
Glycopyrronium
50 μg qd
Indacaterol
150 μg qd
QVA149
110/50 μg qd
Bateman et al, Eur Resp J 2013 [Epub ahead of print]
QVA149 improves SGRQ total score
versus placebo and open-label tiotropium at Week 26
∆=–3.01, P<0.01
∆=–1.92, P=0.065
∆=–1.83, P=0.078
∆=–0.88, P=ns
∆=–2.13, P=0.01
SGRQ total score
∆=–1.18; P=ns
∆=–1.09; P=ns
Placebo
Open-label Glycopyrronium Indacaterol
tiotropium
50 μg q.d.
150 μg q.d.
18 μg q.d.
QVA149
110/50 μg q.d.
Bateman et al, Eur Resp J 2013 [Epub ahead of print]
QVA149 significantly reduces the rate of moderate or
severe COPD exacerbations versus glycopyrronium
Annual rate of moderate
or severe COPD exacerbations
1
12% reduction, P=0.038
10% reduction, P=0.096
0.95
0.9
0.85
0.8
Glycopyrronium
50 μg q.d.
Glycopyrronium
50 μg qd
Tiotropium
18 μg q.d.
Open-label
tiotropium 18 μg qd
QVA149
QVA149150/50
110/50μg
μgq.d.
qd
Wedzicha J. et al, Lancet Respir Med 2013;1(3):199-209
Improved lung function with FDC glycopyrronium /
indacaterol qd versus monotherapy and SFC
FEV1 over 12 hours postdose at wk 26
Trough FEV1
1.85
0.1****
QVA149 110/50 μg qd
SFC 50/500 μg bid
Trough FEV1 at Week 26 (L)
1.80
FEV1 at Week 26 (L)
1.75
1.70
1.65
1.60
1.55
1.50
1.45
1.40
0
QVA149
110/50 μg qd
SFC
50/500 μg bid
0
1
2
4
8
Time postdose (hours)
12
26-week randomized, controlled ILLUMINATE study in patients with moderate-to-severe COPD (n=523)
****P<0.0001; P<0.0001 at each time point over 12 hours
Vogelmeier et al, Lancet Respir Med 2013;1(1):51-60
Improvement of mean SGRQ-C
total score
Improvement
Data are LSM (SE); Mean difference in SGRQ-C total score for QVA149 versus SFC at Week 26
was –1·24 (P=0·245)
Vogelmeier et al, Lancet Respir Med 2013;1(1):51-60
Withdrawal of ICS and Exacerbations of COPD
DB, Parallel group
12 months
2485 patients
Age = 63
FEV1 = 0.98 L
Tio + F + S
Over 18 weeks d/c S
Outcome:
Exacerbations
FEV1
QoL
Magnussen H et al NEJM 2014;371:1285
Withdrawal of ICS and Exacerbations of COPD
Magnussen H et al NEJM 2014;371:1285
Are 3 better than 2?
Tiotropium + (Placebo, Salmeterol, or S/F) in COPD
n = 449
1 year
FEV1 = 1.02 L
Primary Outcome
Pre- BD FEV1 (L)
1.2
T+P
T+S
T + SF
1.15
1.1
p = 0.049
1.05
Exacerbations
1
0
4
20
36
52
Time weeks
Aaron S et al Ann Intern Med 2007;146:545
Tiotropium vs Tio/Bud/Formoterol
n = 660
12 weeks
T + B/F
FEV1 = 1.1 L
62%
Outcome
lung function
T + Placebo
QoL
Exacerbations
Welte et al AJRCCM 2009;180:741
Objective
• COPD progresses over a long period of
time
• Reasoning for BD
• Patients respond to therapy
• Bronchodilators
• New agents
MABA
Muscarinic-receptor Antagonists
Beta(2)-Adrenergic receptor agonists
Conclusions
• Several long acting bronchodilators are
reaching the market.
• Combinations are already here, of which
LAMA+LABA are attractive
• Two BD are more effective than one in
lung function, mild exacerbations and QoL
• Head to head comparisons are needed
• MABA coming?????
Occurring as we speak