recent in copd
TRANSCRIPT
Recent in COPD
Gamal Rabie Agmy, MD,FCCP Professor of Chest Diseases, Assiut university
Presentation1.lnk
LUNG INFLAMMATION
COPD PATHOLOGY
Oxidative
stress Proteinases
Repair
mechanisms
Anti-proteinases Anti-oxidants
Host factors
Amplifying mechanisms
Cigarette smoke Biomass particles
Particulates
Source: Peter J. Barnes, MD
Pathogenesis of COPD
4 4
Apoptotic Pathways in COPD
Demedts IK, et al. Respir Res. 2006;7:53. Reproduced with permission from Biomed Central.
Survival factor Granzyme B Perforin
TNF-α sFasL
cytoplasm
nucleus
ER Stress
Apoptosome
Apaf 1 Procasp-9
Procasp-9 Casp-9
Casp-8 CAD CAD
ICAD
Casp-8
Procasp-8 Procasp-8
FADD Bid tBid
Bax
Bak
Cyt C
ER stress
DNA fragmentation
1 2
4
3
5
?
Fas
COPD Pathogenesis
6 6
Angiogenesis in COPD
Reprinted f rom International Journal of COPD, 2, Siafakas NM, et al., Role of angiogenesis and vascular remodeling in
chronic obstructive pulmonary disease, 453-462, Copyright 2007, with permission f rom Dove Medical Press Ltd.
extravasated
plasma proteins
Inflammatory cells (Mac, Neu, Epith, Lymph)
Release of angiogenic
mediators
Fibrinogen products
Inflammation Tissue
hypoxia
Airway
fibrosis
Mechanical
Injury
Increased
blood flow
Vessel growth
Angiogenesis
Vascular remodeling
Up-regulation of
Angiogenic factors
Shear stress
on the endothelium
COPD Pathogenesis
7 7
Angiogenic and Angiostatic Factors in COPD
Angiogenic CXC Chemokines, CC Chemokines, and Growth Factors:
– CXCL1
– CXCL5
– CXCL8
– CCL2
– VEGF
– bFGF
– Angiopoietin-1
– HGF
– EGF
Angiostatic CXC Chemokines, CC Chemokines, and Growth Factors:
– CXCL10
– CXCL11
Siafakas NM, et al. Int J Chron Obstruct Pulmon Dis. 2007;2:453-462.
COPD Pathogenesis
Disrupted alveolar attachments
Inflammatory exudate in lumen
Peribronchial fibrosis
Lymphoid
follicle
Thickened wall with inflammatory cells
- macrophages, CD8+ cells, fibroblasts
Changes in Small Airways in COPD Patients
Source: Peter J. Barnes, MD
9
Alveolar wall destruction
Loss of elasticity
Destruction of pulmonary
capillary bed
↑ Inflammatory cells
macrophages, CD8+ lymphocytes
Changes in the Lung Parenchyma in COPD
Source: Peter J. Barnes, MD
10
Normal
Inspiration
Expiration
alveolar attachments
Mild/moderate
COPD
loss of elasticity
Severe
COPD
loss of alveolar attachments
closure
small airway
Dyspnea
↓ Exercise capacity Air trapping
Hyperinflation
↓ Health
status
Source: Peter J. Barnes, MD
Air trapping in COPD
Dr.Sarma@works 11
CLINICAL FEATURES
Dr.Sarma@works 12
CHRONIC BRONCHITIS EMPHYSEMA
1. Mild dyspnea
2. Cough before dyspnea starts
3. Copious, purulent sputum
4. More frequent infections
5. Repeated resp. insufficiency
6. PaCO2 50-60 mmHg
7. PaO2 45-60 mmHg
8. Hematocrit 50-60%
9. DLCO is not that much ↓
10. Cor pulmonale common
1. Severe dyspnea
2. Cough after dyspnea
3. Scant sputum
4. Less frequent infections
5. Terminal RF
6. PaCO2 35-40 mmHg
7. PaO2 65-75 mmHg
8. Hematocrit 35-45%
9. DLCO is decreased
10. Cor pulmonale rare.
Dr.Sarma@works 13
CHRONIC BRONCHITIS EMPHYSEMA
BLUE BLOTTER PINK PUFFER
ALPHA1 ANTITRYPSIN ↓ EMPHYSEMA
Specific circumstances of Alpha 1- AT↓include.
• Emphysema in a young individual (< 35)
• Without obvious risk factors (smoking etc)
• Necrotizing panniculitis, Systemic vasculitis
• Anti-neutrophil cytoplasmic antibody (ANCA)
• Cirrhosis of liver, Hepatocellular carcinoma
• Bronchiectasis of undetermined etiology
• Otherwise unexplained liver disease, or a
• Family history of any one of these conditions
• Especially siblings of PI*ZZ individuals.
• Only 2% of COPD is alpha 1- AT ↓
Patterns of Abnormality
Restriction low FEV1 & FVC, high FEV1%FVC
Recorded Predicted SR %Pred
FEV 1 1.49 2.52 -2.0 59
FVC 1.97 3.32 -2.2 59
FEV 1 %FVC 76 74 0.3 103
PEF 8.42 7.19 1.0 117
Obstructive low FEV1 relative to FVC, low PEF, low FEV1%FVC
Recorded Predicted SR %Pred
FEV 1 0.56 3.25 -5.3 17
FVC 1.65 4.04 -3.9 41
FEV 1 %FVC 34 78 -6.1 44
PEF 2.5 8.28 -4.8 30
high PEF early ILD
low PEF late ILD
Patterns of Abnormality
Upper Airway Obstruction low PEF relative to FEV1
Recorded Predicted SR %Pred
FEV 1 2.17 2.27 -0.3 96
FVC 2.68 2.70 0.0 99
FEV 1 %FVC 81 76 0.7 106
PEF 2.95 5.99 -3.4 49
FEV 1 /PEF 12.3
Discordant PEF and FEV1
High PEF versus FEV1 = early interstitial lung disease (ILD)
Low PEF versus FEV1 = upper airway obstruction
Concordant PEF and FEV1
Both low in airflow obstruction, myopathy, late ILD
Bronchiolitis
obliterans
β2-adrenergic receptors
• High concentration in lung
tissue
• Density in airway smooth
muscle does not change at
different airway levels
• Bronchioles have a
similar density to large
airways.
Muscarinic
(cholinergic) receptors
• In smooth muscle
of all airways
• Higher density
in larger airways
β2-agonists and muscarinic antagonists provide bronchodilation with complementary modes and
sites of action
Muscarinic antagonists
• Prevent acetylcholine
binding to muscarinic
receptors that make
muscle contract
β2-agonists
• Promote muscle relaxation
by stimulating c-AMP,
providing functional
antagonism to
bronchoconstriction
Barnes PJ. Distribution of receptor targets in the lung. PATS 2004;1:345–51.
Influencing the bronchial tone
Bronchodilation may, therefore, be
obtained either by directly relaxing the
smooth muscle through stimulation of the
b2-AR with b2-AR agonists, or/and by
inhibiting the action of ACh at mAChRs.
Bronchodilators
Indacterol Glycopyrronium bromide
Olodaterol Aclidinium bromide
Vilanterol
Xanthines
Influencing the bronchial tone
Inhibitory NANC (iNANC) system is considered to be
the main neural mechanism mediating ASM relaxation
by releasing of vasoactive intestinal peptide (VIP), VIP
structure-related peptides and nitric oxide (NO) .
On the other hand, excitatory NANC (eNANC) system
mediates bronchial contraction activating the efferent
functions of bronchopulmonary-sensitive sensory
nerves. These nerves release tachykinins, such as
substance P and neurokinin A, which in turn activate
neurokinin-1 (NK-1) and NK-2 receptors located on the
ASM membrane, thus inducing bronchoconstriction
Influencing the bronchial tone
Bronchodilation may, therefore, be
obtained either by directly relaxing the
smooth muscle through stimulation of the
b2-AR with b2-AR agonists, or/and by
inhibiting the action of ACh at mAChRs.
Furthermore, an alternative approach
could be the modulation of the NANC
system.
Global Strategy for Diagnosis, Management and Prevention of COPD
Definition of COPD
◙ 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.
◙ Exacerbations and comorbidities contribute to the overall severity in individual patients.
28
COPDforum is
supported by
Inflammatory Cells in Stable COPD
Gamal Agmy 2-5-2014
Inflammation in COPD
29 29
Neutrophils in COPD
Mucous hypersecretion
Serine proteases Neutrophil Elastase
Cathepsin G
Proteinase-3
O2-
MPO
LTB4, IL-8, GRO-
LTB4, IL-8
Adapted f rom Barnes PJ. N Engl J Med. 2000; 343: 269-280
Adapted f rom Barnes PJ, et al. Eur Respir J. 2003; 22: 672-688
Emphysema
Severe emphysema
Images courtesy R Buhl.
Inflammation in COPD
30 30
Sputum Neutrophil Count
Correlates With Declining Lung Function
Reproduced with permission of Thorax f rom “Airways obstruction, chronic expectoration and rapid decline of FEV1 in smokers are
associated with increased levels of sputum neutrophils,” Stanescu et al, Vol 51, Copyright © 1996; permission conveyed through
Copyright Clearance Center, Inc.
> 30 < 20
100
0
Ne
utr
op
hils in
iIn
du
ce
d s
pu
tum
(%
)
90
20 – 30
80
60
70
50
40
FEV1 decline (mL/year)
P<0.01
Inflammation in COPD
31 31
Neutrophils Infiltrating Bronchial
Glands in COPD
Saetta M, et al. Am J Respir Crit Care Med. 1997;156:1633-1639. Reproduced with permission f rom American Thoracic Society.
Copyright © 1997
Inflammation in COPD
32 32
Reduction in Neutrophil Apoptosis in COPD
Adapted f rom Brown V, et al. Respir Res. 2009;10:24.
Apoptotic neutrophils
(arrows)
*P<0.05
*P<0.01
Morphology Tunel
NS
HS
COPD
60
50
40
30
20
10
0
Apoptotic
neutrophils [%]
Image courtesy of R Buhl.
NS: nonsmoking controls (n=9) HS:
healthy smoking controls (n=9)
TUNEL: the terminal transferase-
mediated dUTP nick end-labeling method
Inflammation in COPD
33 33
Alveolar Macrophages in COPD
Phagocytosis
Cigarette smoke
Wood smoke
Elastolysis MMP-9, MMP-12
Cathepsins K, L, S
Emphysema
Steroid resistance
NO
ROS ONOO-
HDAC Steroid
response
Monocytes
MCP-1
GRO-
Neutrophils
LTB4
IL-8 GRO-
CD8+ Cells
IP-10 Mig I-TAC
Adapted f rom Barnes PJ. J COPD. 2004;1:59-70. Copyright © 2004 f rom "Alveolar Macrophages as Orchestrators of COPD" by
Barnes. Reproduced by permission of Taylor & Francis Group, LLC., www.taylorandfrancis.com
Emphysema
Severe emphysema
Images courtesy of R Buhl.
Numbers
Secretion
Inflammation in COPD
34 34
Inflammatory Mediators in COPD – Summary
Cell
Neutrophils
Macrophages
T-cell
Epithelial cell
IL-8, TGF- 1, IP-10, Mig, I-TAC, LTB4, GRO- , MCP-1, MMP-9
Granzyme B, perforins, IFN-, TNF-
IL-8, IL-6, TGF-1 TGF-, IP-10, Mig, I-TAC, LTB4, GRO-, MCP-1, ROS, MMP-9
Serine proteases, TNF-, ROS, IL-8, MPO, LTB4
Selected Mediators
Barnes PJ, et al. Eur Respir J. 2003;22:672-888.
Inflammation in COPD
35 35
Examples of Chemotactic Factors in COPD
Barnes PJ. Curr Opin Pharmacol. 2004;4:263-272.
Hill AT, et al. Am J Respir Crit Care Med. 1999;160: 893-898.
Montuschi P, et al. Thorax. 2003;58:585-588.
MCP-1
GRO-
Elastin
fragments
LTB4
IL-8
GRO-
Elastin
fragments
IP-10
Mig
I-TAC
Neutrophil Monocyte T-cell
Inflammation in COPD
36 36
TNF- Has Pro-inflammatory
Actions in COPD
Mukhopadhyay S, et al. Respir Res. 2006;7:125. Reproduced with permission f rom Biomed Central.
Oxidative stress
Activation of NF-B and AP-1
Activation of proinflammatory molecules e.g. VCAM-1, ICAM-1 and RAGE
Subcellular ROS production
TNF-
Antioxidants
e.g. GSH, Catalase
Scavenge free radicals,
detoxify cellular hydrogen peroxide and inhibit ROS generation
Proinflammation
+
+ +
+
+
+
+
-
-
Inflammation in COPD
37
COPDforum is
supported by
Modulation of Inflammation by Histone Deacetylase (HDAC)
Inflammation in COPD
Gamal Agmy 2-5-2014
38 38
Decreased HDAC Expression May Promote
Inflammation and Decrease Response to
ICS in COPD
Normal
Histone acetylation
Stimuli
Steroid sensitive
Histone hyperacetylation
nitration ubiquitination
oxidation
↑TNF
↑IL-8
↑GM-CSF
Stimuli
Steroid resistant
HAT
TF
HAT
TF
TNF IL-8 GM-CSF
Glucocorticoid
receptor
COPD
HDAC2
HDAC2
Glucocorticoid
peroxynitrite
Reproduced f rom Pharmacol Ther, Vol 116, Ito et al, “Impact of protein acetylation in inf lammatory lung diseases,” pp249-265.
Copyright © 2007, with permission f rom Elsevier.
Inflammation in COPD
39 39
Pulmonary HDAC Levels Decrease
With COPD Severity
Adapted f rom Ito K, et al. N Engl J Med. 2005;352:1967-1976.
S = COPD Stage
0
.5
1.0
1.5
2.0
Non-
smoker
N=11
P<0.001
HD
AC
2 e
xp
ressio
n (vs. la
min
A/C
)
P=0.04
P<0.001
P<0.001
S4
N=6
S0
N=9
S1
N=10 S2
N=10
■ ■
■
■
■
Inflammation in COPD
40 40
Inflammation Leads to Small
Airway Narrowing
Acute and chronic inflammation suspected to contribute to COPD-related small airway narrowing
Airway narrowing leads to airway obstruction
Narrowing results from several factors:
– Collagen deposition and increased lymphoid follicles in outer airway wall
– Mucosal thickening of airway lumen
– Inflammatory exudate in airway lumen
Barnes PJ, et al. Eur Respir J. 2003;22: 672-688.
Inflammation in COPD
41 41
Inflammation and Airway Destruction
Normal COPD
Reproduced f rom The Lancet, Vol 364, Hogg JC. "Pathophysiology of airf low limitation in chronic obstructive pulmonary
disease," pp709-721. Copyright © 2004, with permission f rom Elsevier.
Inflammation in COPD
42 42
Exacerbations of Chronic Bronchitis
and Inflammatory Cell Types
Saetta M, et al. Am J Respir Crit Care Med. 1994;150:1646-1652.
Maestrelli P, et al. Am J Respir Crit Care Med. 1995;152:1926-1931.
Barnes PJ. N Engl J Med. 2000;343:269-280.
COPD Exacerbation
Eosinophils
Eosinophils
T-Cells
Neutrophils
Cells Predominant in:
Induced sputum
Biopsy
Neutrophils
Inflammation in
COPD
43 43
Clinical Impact of Inflammation in COPD
Tsoumakidou M, et al. Respir Res. 2006;7:80. Reproduced with permission f rom Biomed Central.
Increased Airway Inflammation
Increased mucous production
Airway wall thickening
Airway wall oedema
Bronchoconstriction
Airway narrowing
V’/Q’ Mismatching Hyperinflation
Worsening of gas exchange
Increased work of breathing
Increased oxygen consumption –
Decreased mixed venous oxygen
Cough, sputum, dyspnoea, Respiratory failure
Inflammation in COPD
44 44
Inflammation:
Clinical Consequences
Systemic
Nutritional abnormalities and weight loss
Hypoxaemia
Skeletal muscle dysfunction
Cardiovascular disease
Depression
Osteoporosis
Anaemia
Agusti AG, et al. Eur Respir J. 2003;21:347-360.
Agusti AG. Proc Am Thorac. 2006;3:478-483.
Barnes PJ, Cell BR. Eur Respir J. 2009;33:1165-1185.
Pulmonary
Dyspnoea
Cough
Sputum production
Exacerbations
Inflammation in COPD
Influencing The Cellular Components
Of Inflammation
Phosphodiesterase Inhibitors
The PDE4 isoenzyme is a major therapeutic target
because it is the predominant isoenzyme in the majority
of inflammatory cells, including neutrophils, which are
implicated in the pathogenesis of COPD. Inhibition of
PDE4 in inflammatory cells influences various specific
responses, such as the production and/or release of pro-
inflammatory mediators including cytokines and active
oxygen species , with a well-documented efficacy in
animal models of COPD .
Influencing The Cellular Components
Of Inflammation
Phosphodiesterase Inhibitors
Oral PDE4 inhibitors: roflumilast; GRC-3886;
ELB353; GRC 4039; MEM1414; oglemilast;
OX914; ASP3258; TAS-203; Zl-n-91; NIS-
62949; tetomilast
Inhaled PDE4 inhibitors; GSK256066;
SCH900182; Compound 1; tofimilast;
AWD12-281; UK500001
PDE3/4 inhibitors: RPL554
PDE4/7 inhibitors: TPI 1100
Influencing The Cellular Components
Of Inflammation
Adenosine receptors Agonist
Some evidence suggests the involvement of adenosine
receptors in inflammation. Four subtypes (A1, A2A, A2B, A3) of
adenosine receptors have been characterized. The anti-
inflammatory effect of adenosine is due to a short-term
activation of A2A receptor that elevates cAMP and,
consequently, modulates key pro-inflammatory neutrophil
functions such as superoxide generation, degranulation and
adhesion. Furthermore, adenosine A2A receptor activation
induces a shift in the profile of lipid mediator production from
leukotrienes to prostaglandin E2.This shift may contribute to
prevent the subsequent neutrophil-elicited inflammatory
events
Influencing The Cellular Components
Of Inflammation
Adenosine receptors A2a Agonists
CGS21680; ATL146e; UK371,104; GW328267X;
regadenoson (CVT-3146); 2-(cyclohexylethylthio)-AMP
Influencing The Cellular Components
Of Inflammation
Adhesion molecules Inflammatory processes in COPD are coupled to an increased
recruitment of neutrophils to the lung in response to a release of IL-8
and leukotriene B4 (LTB4) by activated epithelial cells and
macrophages . Migration of inflammatory cells from the vascular
compartment to the surrounding tissue is partly regulated by
selectins (L-, P- and E-selectin) . Selectins mediate transient adhesive
interactions pertinent to inflammation through the recognition of the
carbohydrate epitope, sialyl Lewisx (sLex), expressed on circulating
leukocytes. The rapid turnover of selectin--ligand bonds mediates the
cell tethering and rolling in shear flow. Several studies suggest that
selectins are involved in the inflammatory processes of COPD .
Therefore, targeting these molecules might reduce the inflammation
in COPD
Influencing The Cellular Components
Of Inflammation Drugs that interfere with adhesion molecules
Carbohydrate-based inhibitors: sLex antagonists
(bimosiamose); heparins and heparinoids (PGX-
100, PGX-200); synthetic glycomimetic molecule
(GMI-1070) mAb inhibitors: EL246
Influencing The Inflammatory mediators
1-TNF-a
2-Chemokines
3-NF-kB
4-p38 MAPK and MK2
5-PI3K
6-LTB4
7-PPAR
Targeting protease activity at the
enzymatic level
Drugs that may have indirect anti-
inflammatory actions
Reversing glucocorticoid resistance :
Activation of HDAC2: theophylline;
curcumin; resveratrol
Inhibition of P-glycoprotein
Inhibition of MIF
THE PRIMARY PHYSIOLOGIC IMPAIRMENT IN COPD IS
Rabe K et al. PATS 2006;3:270–5.
AIRFLOW LIMITATION
COPD is caused by inhaled noxious agents, with lung damage leading to airflow
limitation
Inhaled noxious agents (e.g. cigarette smoking, pollutants)
Obstruction and airflow limitation
Lung damage
Small airway disease: Airway narrowing
and fibrosis
Mucus
hypersecretion (chronic
bronchitis)
Parenchymal
destruction: Loss of alveolar
attachments, decrease
in elastic recoil
(emphysema)
GOLD 2014
Eur Respir Rev 2006; 15: 99, 37–41
The physiological hallmark of COPD is expiratory flow limitation.
Expiratory flow limitation in patients with COPD
Air trapping
Dyspnea (breathlessness)
Exercise intolerance
Hyperinflation
Reduced health-related quality of
life (HRQoL)
Obstruction and airflow limitation lead to dyspnea and exercise intolerance
Narrowing of peripheral airways
Decreased FEV1
Progressive Air Trapping and Hyperinflation Inspiratory capacity
reduced
Dyspnea and Limitation of Exercise capacity
1. GOLD 2014; 2. Rabe. PATS 2006
Air trapping and associated hyperinflation provide a mechanistic link between the physiological impairment and the characteristic symptoms of COPD
Air Trapping and Hyperinflation
• Air trapping and associated hyperinflation provide a mechanistic link between the physiological impairment and the characteristic symptoms of COPD, such as :
1. Dyspnea (breathlessness)
2. Exercise intolerance
3. Reduced health-related quality of life
Proc Am Thorac Soc Vol 3. pp 185–189, 2006
Relationship between static lung volumes and disease severity.
• Gas trapping and lung hyperinflation were shown to occur even in the earliest stages of COPD and increased exponentially with severity of airway obstruction
Expert Rev. Respir. Med. 6(6), 651–662 (2012)
RV: Residual volume
Improve exercise
tolerance
GOLD guidelines state that effective management should aim to:
The GOLD guideline recommends long-acting bronchodilators as first-line maintenance
treatment in COPD.
Eur Respir Rev 2006; 15: 99, 37–41
Relieve symptoms (dyspnea) 1 2 Improve
HRQoL 3
Bronchodilators address airflow limitation by targeting bronchoconstriction and reducing air trapping
GOLD 2014
Bronchodilators improves airflow limitation by targeting bronchoconstriction and
reducing air trapping
Bronchodilators Bronchodilators
Smooth muscle relaxation
Increased
mucociliary
clearance
Reduced
hyperinflation Improved respiratory muscle function
Improve emptying of the lungs
GOLD 2014
Chest 2001;120;258-270
V
BD
Air flow Deflation
Improvement in flow – FEV1
Improvement in volumes – FVC and IC
Bronchodilator therapy deflates the lung
BD = bronchodilator; V = ventilation; FEV1= forced expiratory volume in 1 second;
FVC= forced vital capacity; IC = inspiratory capacity
Bronchodilators work by:
Eur Respir Rev 2006; 15: 99, 37–41
Relieve dyspnea by deflating the lungs
Allowing improved lung emptying with each breath
Improvement in exercise tolerance
Reduces the elastic load on the inspiratory muscles.
The GOLD guidelines recommend bronchodilators
• The GOLD guidelines recommend bronchodilators, such as β2-agonists, anticholinergic agents and methyl xanthines, for first line symptom control, and long-acting bronchodilators for first-line maintenance treatment in COPD
Proc Am Thorac Soc Vol 3. pp 185–189, 2006
Bronchodilators are the cornerstone of COPD treatment
• Target air flow limitation, bronchodilating by altering airway smooth muscle tone
• Improve emptying of the lung
• Reduce hyperinflation at rest and during exercise
GOLD 2014
Indacaterol once daily β2-agonist
Indacaterol demonstrates fast onset of bronchodilator effect at 5 minutes post-dose.1 and sustained bronchodilation over 24 hours.2
1-Balint, et al. Int J COPD 2010;5:311–8.
2- Vogelmeier et al. Respiratory Research 2010, 11:135
1.2
1.3
1.4
1.5
1.6
Placebo
(n=88)
Salmeterol/
fluticasone (n=88)
Salbutamol
(n=86)
Indacaterol
150 µg (n=85)
Indacaterol
300 µg (n=87)
LS
me
an
of
FE
V1 (
L)
Data are least squares mean (LSM) with standard errors of the mean at 5 minutes post-dose
**
*** *** ***
Balint, et al. Int J COPD 2010;5:311–8.
Indacaterol demonstrates fast onset of bronchodilator effect at 5 minutes
post-dose
INSURE: INdacaterol: Starting qUickly and Remaining Effective in COPD
***p<0.001,
**p<0.01 versus placebo
N= 89 patients
Data are LSM±SE.
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Indacaterol 150 µg
Indacaterol 300 µg
Tiotropium
Placebo
1.65
1.60
1.55
1.50
1.45
1.40
1.35
1.30
†
†
† †
†
† †
†
Time post-dose
(hours)
FE
V1 (
L)
Vogelmeier et al. Respiratory Research 2010, 11:135
Indacaterol provided sustained bronchodilation over 24 hours
INTIME: INdacaterol & TIotropium: Measuring Efficacy
p<0.001 for indacaterol (150 and 300 µg) vs placebo at each timepoint, p<0.001 for indacaterol 150 µg vs
tiotropium at 5 and 15 minutes, †p<0.05 for indacaterol 300 µg vs tiotropium, p<0.05 for tiotropium vs placebo at each timepoint
n= 153 patients
Renard D, et al. 2011 Respir Res; 12:54
• Pooled analysis of 11 placebo-controlled studies
• Aim: determine Optimal Indacaterol dosage
• Primary endpoint: trough FEV1 with a duration of at least 14 days.
• n=7,476 COPD patients
• Patients received Indacaterol 18.75-600 µg o.d.
Indacaterol 300 μg provide optimal bronchodilation, particularly in patients
with severe disease.
Renard D, et al. 2011 Respir Res; 12:54
Ranking of efficacy by dose
1.31 1.31 1.28
1.43
1.38
1.32
1.45 1.48
1.43
1.15
1.2
1.25
1.3
1.35
1.4
1.45
1.5
After 1 day Week 12 Week 52
†††
***
†††
***
†
***
***
***
*
Tro
ug
h F
EV
1 (
L)
Placebo (n=364) Formoterol 12 μg b.i.d. (n=373)
Indacaterol 300 μg o.d. (n=383)
Indacaterol 300 µg provides significant improvement in trough FEV1 over 52 weeks,
superior to Formoterol
*p<0.05, ***p<0.001 vs placebo; †p<0.05, †††p<0.001 vs Formoterol
Dahl et al. Thorax 2010;65:473–9.
100 ml 110 ml 20 ml
*p<0.05, ***p<0.001 vs placebo; †††p<0.001 for difference vs tiotropium; ‡p=0.008 for difference vs
indacaterol 150 μg
Once Daily Indacaterol Pooled Analysis Clinical efficacy in COPD-Patients with severe
dyspnoea (mMRC>2)
Mahler et al. ERS Annual Congress 2012
Indacaterol reduces breathlessness as indicated by improvements in TDI score
at all assessments points
Data are LSM and 95% confidence intervals
***p<0.001 versus placebo, †p<0.05, †††p<0.001 versus tiotropium
n= 326 360 355 363 309 349 343 353 342 372 367 367 324 353 348 360
***
***
***
*** ***
***
***
***
*** ††† ††† ***
*** †
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Week 4 Week 8 Week 12 Week 26
TD
I to
tal s
co
re
Placebo Tiotropium 18 µg o.d. Indacaterol 150 µg o.d. Indacaterol 300 µg o.d.
TDI = transition dyspnea index
Donohue JF et al. Am J Respir Crit Care Med 2010;182:155–62.
Jones PW et al, Respir Med 2011; 105 (6): 892-9.
Indacaterol 300 μg dose was superior compared to the twice-daily β2-agonists
Indacaterol 300 μg dose was superior compared to the twice-daily β2-agonists
Jones PW et al, Respir Med 2011; 105 (6): 892-9.
Differences between active and placebo treatments in TDI total score after 6 months (pooled data). 1
Patient numbers were 602 (Indacaterol 150 μg QD), 651 (Indacaterol 300 μg QD ), 317 (formoterol 12 μg BID), 320 (tiotropium 18 μg QD ), 279 (salmeterol 50 μg BID) and 823 (placebo). 1
Data are least square means and 95% CI.1
Dotted line indicates the MCID (minimum clinically important difference) vs. placebo.
Indacaterol 300 µg increases % of days without rescue medication use over 52 weeks, compared
with placebo and Formoterol
***p<0.001 vs placebo; ††p=0.007 vs formoterol
***
68% improvement
Over 52 weeks
Da
ys
wit
h n
o r
es
cu
e u
se
(%
)
70
60
50
40
30
20
10
0
34.8%
52.1% 58.3%
Placebo (n=364) Formoterol 12 μg b.i.d. (n=373)
Indacaterol 300 μg o.d. (n=383)
***
††
Dahl et al. Thorax 2010;65:473–9.
Effect of Indacaterol on exercise endurance and lung hyperinflation in COPD
INABLE 1: Indacaterol: endurance, exercise-based, and lung evaluation 1.
Respiratory Medicine (2011) 105, 1030-1036
Exercise endurance study INABLE-1 study design
Indacaterol 300 μg o.d. Indacaterol 300 μg o.d.
Placebo Placebo
Screening Treatment 1 Washout Treatment 2
3 weeks 3 weeks 3 weeks
• Double-blind, placebo-controlled, two-period
crossover study
• 90 patients randomized
• The primary efficacy variable was exercise endurance time after 3 weeks
of treatment, measured through constant-load cycle ergometry testing
performed at 75% of the peak work rate in a screening incremental exercise
test.
Respiratory Medicine (2011) 105, 1030-1036
RESULTS
Indacaterol improves exercise endurance time (in mins)
5
8
10
11
12
Day 1 Week 3
Data are LSM and standard errors
*p=0.011, ***p<0.001
Ex
erc
ise
en
du
ran
ce
tim
e (m
ins
)
Indacaterol 300 µg Placebo
8.07
9.75
Δ 1.68 ***
7.92
9.77
Δ 1.85 *
9
7
6
Respiratory Medicine (2011) 105, 1030-1036
Indacaterol improves inspiratory capacity
1.5
2.1
2.5
Day 1 Week 3
Data are LSM and standard errors
*p=0.04, **p=0.002
En
d-e
xerc
ise
ins
pir
ato
ry c
ap
ac
ity (
L)
Indacaterol 300 µg Placebo
1.98
2.17
Δ 190 mL *
1.94
2.22
Δ 280 mL **
2.3
1.9
1.7
Respiratory Medicine (2011) 105, 1030-1036
Indacaterol improves bronchodilation
1.4
1.7
1.9
Day 1 –
75 min post-dose
Week 3 –
60 min pre-dose
Resting FEV1 was a secondary endpoint
Data are LSM and standard errors
***p<0.001
Re
sti
ng
FE
V1 (L
)
Indacaterol 300 µg Placebo
1.56
1.79
Δ 0.23 ***
1.53
1.73
Δ 0.20 ***
1.8
1.6
1.5
1.59
1.84
Δ 0.25 ***
Week 3 –
75 min post-dose
Respiratory Medicine (2011) 105, 1030-1036
Indacaterol has a good overall safety & tolerability profile
• In terms of safety, Indacaterol 300 μg demonstrated good overall safety and tolerability profile.
• The overall rate of adverse events (AEs) was comparable between Indacaterol and placebo, with nearly all AEs reported being mild or moderate in severity.
Laforce C et al, Pulm Pharmacol Ther 2011; 24 (1): 162-8.
Indacaterol has a good overall safety & tolerability profile
• In a 52-week study that compared Indacaterol 300 and 600 μg once daily with Formoterol and placebo, Indacaterol was also well tolerated, with a safety profile that indicated minimal impact on QTc interval and systemic β2-mediated events.
Laforce C et al, Pulm Pharmacol Ther 2011; 24 (1): 162-8.
Breezhaler®: Easy-to-use device for effective drug delivery
Breezhaler® has lower airflow resistance than other inhalers
0
20
40
60
80
100
120
0 2 4 6 8 10
Inspiratory effort (kPa)
Flo
w r
ate
(L
/min
)
Breezhaler 2.2 10-2 kPa1/2 L-1 min
Diskus 2.7 10-2 kPa1/2 L-1 min
Turbuhaler 3.4 10-2 kPa1/2 L-1 min
Handihaler 5.1 10-2 kPa1/2 L-1 min
Singh D et al. ATS 2010 (poster)
Conclusion
• COPD is caused by inhaled noxious agents, with lung damage leading to airflow limitation
• Air trapping and associated hyperinflation provide a mechanistic link between the physiological impairment and the characteristic symptoms of COPD
Conclusion
• The GOLD guideline recommends long-acting bronchodilators as first-line maintenance treatment in COPD.
• Bronchodilators address airflow limitation by targeting bronchoconstriction and reducing air trapping.
Conclusion
• LABAs – Improve lung function.
– Improve health status related quality of life.
– Reduce exacerbations in symptomatic patients with moderate-to-severe COPD.
– Provide a significant relief from exercise and Dyspnea.
• There is a need for novel once-daily LABA with fast onset of action and superior efficacy over existing bronchodilators.
Conclusion
• Indacaterol demonstrates fast onset of
bronchodilator effect at 5 minutes post-dose and sustained bronchodilation over 24 hours.
• Indacaterol 300 μg provide optimal bronchodilation, particularly in patients with severe disease.
• Indacaterol 300 µg provides significant improvement in trough FEV1 over 52 weeks
Conclusion
• Indacaterol reduces breathlessness as indicated by improvements in TDI score at all assessments points
• Indacaterol 300 μg dose was superior compared to the twice-daily β2-agonists
• Indacaterol 300 µg increases % of days without rescue medication use over 52 weeks
Conclusion
• Indacaterol improves exercise endurance time
• Indacaterol improves inspiratory capacity
• Indacaterol improves bronchodilation
• Indacaterol has a good overall safety & tolerability profile
• Breezhaler® is an Easy-to-use device for effective drug delivery