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Page 1: Recent in COPD
Page 2: Recent in COPD

Recent in COPD

Gamal Rabie Agmy, MD,FCCP Professor of Chest Diseases, Assiut university

Presentation1.lnk

Page 3: Recent in COPD

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

Page 4: Recent in 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

Page 5: Recent in COPD
Page 6: Recent in COPD

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

Page 7: Recent in COPD

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

Page 8: Recent in COPD

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

Page 9: Recent in COPD

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

Page 10: Recent in COPD

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

Page 11: Recent in COPD

Dr.Sarma@works 11

CLINICAL FEATURES

Page 12: Recent in COPD

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.

Page 13: Recent in COPD

Dr.Sarma@works 13

CHRONIC BRONCHITIS EMPHYSEMA

BLUE BLOTTER PINK PUFFER

Page 14: Recent in COPD

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 ↓

Page 15: Recent in COPD

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

Page 16: Recent in COPD

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

Page 17: Recent in COPD
Page 18: Recent in COPD
Page 19: Recent in COPD
Page 20: Recent in COPD
Page 21: Recent in COPD

Bronchiolitis

obliterans

Page 22: Recent in COPD

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.

Page 23: Recent in COPD

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.

Page 24: Recent in COPD

Bronchodilators

Indacterol Glycopyrronium bromide

Olodaterol Aclidinium bromide

Vilanterol

Xanthines

Page 25: Recent in COPD

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

Page 26: Recent in COPD

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.

Page 27: Recent in COPD

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.

Page 28: Recent in COPD

28

COPDforum is

supported by

Inflammatory Cells in Stable COPD

Gamal Agmy 2-5-2014

Inflammation in COPD

Page 29: Recent 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

Page 30: Recent 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

Page 31: Recent 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

Page 32: Recent 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

Page 33: Recent 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

Page 34: Recent 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

Page 35: Recent 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

Page 36: Recent 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

Page 37: Recent in COPD

37

COPDforum is

supported by

Modulation of Inflammation by Histone Deacetylase (HDAC)

Inflammation in COPD

Gamal Agmy 2-5-2014

Page 38: Recent in COPD

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

Page 39: Recent 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

Page 40: Recent 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

Page 41: Recent 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

Page 42: Recent 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

Page 43: Recent 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

Page 44: Recent 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

Page 45: Recent 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 .

Page 46: Recent in 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

Page 47: Recent in COPD

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

Page 48: Recent in COPD

Influencing The Cellular Components

Of Inflammation

Adenosine receptors A2a Agonists

CGS21680; ATL146e; UK371,104; GW328267X;

regadenoson (CVT-3146); 2-(cyclohexylethylthio)-AMP

Page 49: Recent in COPD

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

Page 50: Recent 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

Page 51: Recent in COPD

Influencing The Inflammatory mediators

1-TNF-a

2-Chemokines

3-NF-kB

4-p38 MAPK and MK2

5-PI3K

6-LTB4

7-PPAR

Page 52: Recent in COPD

Targeting protease activity at the

enzymatic level

Page 53: Recent in COPD

Drugs that may have indirect anti-

inflammatory actions

Reversing glucocorticoid resistance :

Activation of HDAC2: theophylline;

curcumin; resveratrol

Inhibition of P-glycoprotein

Inhibition of MIF

Page 54: Recent in COPD

THE PRIMARY PHYSIOLOGIC IMPAIRMENT IN COPD IS

Rabe K et al. PATS 2006;3:270–5.

AIRFLOW LIMITATION

Page 55: Recent in COPD

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

Page 56: Recent in COPD

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)

Page 57: Recent in COPD

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

Page 58: Recent in COPD

Air trapping and associated hyperinflation provide a mechanistic link between the physiological impairment and the characteristic symptoms of COPD

Page 59: Recent in 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

Page 60: Recent in COPD

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

Page 61: Recent in COPD

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

Page 62: Recent in COPD

Bronchodilators address airflow limitation by targeting bronchoconstriction and reducing air trapping

GOLD 2014

Page 63: Recent in COPD

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

Page 64: Recent in COPD

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

Page 65: Recent in COPD

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.

Page 66: Recent in COPD

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

Page 67: Recent in COPD

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

Page 68: Recent in COPD

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

Page 69: Recent in COPD

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

Page 70: Recent in COPD

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

Page 71: Recent in COPD

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.

Page 72: Recent in COPD

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

Page 73: Recent in COPD

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

Page 74: Recent in COPD

*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

Page 75: Recent in COPD

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.

Page 76: Recent in COPD

Jones PW et al, Respir Med 2011; 105 (6): 892-9.

Indacaterol 300 μg dose was superior compared to the twice-daily β2-agonists

Page 77: Recent in COPD

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.

Page 78: Recent in COPD

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.

Page 79: Recent in COPD

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

Page 80: Recent in COPD

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

Page 81: Recent in COPD

RESULTS

Page 82: Recent in COPD

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

Page 83: Recent in COPD

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

Page 84: Recent in COPD

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

Page 85: Recent in COPD

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.

Page 86: Recent in COPD

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.

Page 87: Recent in COPD

Breezhaler®: Easy-to-use device for effective drug delivery

Page 88: Recent in COPD

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)

Page 89: Recent in COPD

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

Page 90: Recent in 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.

Page 91: Recent in COPD

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.

Page 92: Recent in COPD

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

Page 93: Recent in COPD

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

Page 94: Recent in COPD

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

Page 95: Recent in COPD