Recent in COPD

2,215 views

Published on

Published in: Health & Medicine, Technology
1 Comment
16 Likes
Statistics
Notes
No Downloads
Views
Total views
2,215
On SlideShare
0
From Embeds
0
Number of Embeds
3
Actions
Shares
0
Downloads
330
Comments
1
Likes
16
Embeds 0
No embeds

No notes for slide

Recent in COPD

  1. 1. Recent in COPD Gamal Rabie Agmy, MD,FCCP Professor of Chest Diseases, Assiut university Presentation1.lnk
  2. 2. LUNG INFLAMMATION COPD PATHOLOGY Oxidative stress Proteinases Repair mechanisms Anti-proteinasesAnti-oxidants Host factors Amplifying mechanisms Cigarette smoke Biomass particles Particulates Source: Peter J. Barnes, MD Pathogenesis of COPD
  3. 3. 44 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-8Procasp-8 FADDBidtBid Bax Bak Cyt C ER stress DNAfragmentation 1 2 4 3 5 ? Fas COPD Pathogenesis
  4. 4. 66 Angiogenesis in COPD Reprinted from 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 from 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
  5. 5. 77 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
  6. 6. 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
  7. 7. 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
  8. 8. 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
  9. 9. Dr.Sarma@works 11 CLINICAL FEATURES
  10. 10. Dr.Sarma@works 12 CHRONIC BRONCHITISEMPHYSEMA 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 pulmonalecommon 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 pulmonalerare.
  11. 11. Dr.Sarma@works 13 CHRONIC BRONCHITISEMPHYSEMA BLUE BLOTTERPINK PUFFER
  12. 12. 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 ↓
  13. 13. 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
  14. 14. Patterns of Abnormality Upper AirwayObstruction 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
  15. 15. Bronchiolitis obliterans
  16. 16. 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.
  17. 17. 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.
  18. 18. Bronchodilators Indacterol Glycopyrronium bromide Olodaterol Aclidinium bromide Vilanterol Xanthines
  19. 19. 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
  20. 20. 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.
  21. 21. 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.
  22. 22. 28 COPDforum is supported by Inflammatory Cells in Stable COPD Gamal Agmy 2-5-2014 Inflammation in COPD
  23. 23. 2929 Neutrophils in COPD Mucoushypersecretion Serine proteases Neutrophil Elastase Cathepsin G Proteinase-3  O2 - MPO LTB4,IL-8, GRO- LTB4,IL-8 Adapted from Barnes PJ. N Engl J Med. 2000; 343: 269-280 Adapted from Barnes PJ, et al. Eur Respir J. 2003; 22: 672-688 Emphysema Severe emphysema Images courtesy R Buhl. Inflammation in COPD
  24. 24. 3030 Sputum Neutrophil Count Correlates With Declining Lung Function Reproduced with permission of Thorax from “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 NeutrophilsiniInducedsputum(%) 90 20 – 30 80 60 70 50 40 FEV1 decline (mL/year) P<0.01 Inflammation in COPD
  25. 25. 3131 Neutrophils Infiltrating Bronchial Glands in COPD Saetta M, et al. Am J Respir Crit Care Med. 1997;156:1633-1639. Reproduced with permission from American Thoracic Society. Copyright © 1997 Inflammation in COPD
  26. 26. 3232 Reduction in Neutrophil Apoptosis in COPD Adapted from Brown V, et al. Respir Res. 2009;10:24. Apoptotic neutrophils (arrows) *P<0.05 *P<0.01 MorphologyTunel NS HS COPD 60 50 40 30 20 10 0 Apoptotic neutrophils [%] Image courtesyof 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
  27. 27. 3333 Alveolar Macrophages in COPD  Phagocytosis Cigarette smoke Wood smoke Elastolysis MMP-9,MMP-12 Cathepsins K, L, S Emphysema Steroid resistance NO ROSONOO-  HDAC  Steroid response Monocytes MCP-1 GRO- Neutrophils LTB4 IL-8 GRO- CD8+ Cells IP-10 Mig I-TAC Adapted from Barnes PJ. J COPD. 2004;1:59-70. Copyright © 2004 from "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
  28. 28. 3434 Inflammatory Mediators in COPD – Summary Cell Neutrophils Macrophages T-cell Epithelialcell 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
  29. 29. 3535 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
  30. 30. 3636 TNF- Has Pro-inflammatory Actions in COPD Mukhopadhyay S, et al. Respir Res. 2006;7:125. Reproduced with permission from Biomed Central. Oxidative stress Activation of NF-B and AP-1 Activation of proinflammatorymolecules e.g.VCAM-1,ICAM-1 and RAGE SubcellularROS production TNF- Antioxidants e.g. GSH, Catalase Scavenge free radicals, detoxifycellular hydrogen peroxideand inhibit ROS generation Proinflammation + + + + + + + - - Inflammation in COPD
  31. 31. 37 COPDforum is supported by Modulation of Inflammation by Histone Deacetylase (HDAC) Inflammation in COPD Gamal Agmy 2-5-2014
  32. 32. 3838 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 from Pharmacol Ther, Vol 116, Ito et al, “Impact of protein acetylation in inflammatory lung diseases,” pp249-265. Copyright © 2007, with permission from Elsevier. Inflammation in COPD
  33. 33. 3939 Pulmonary HDAC Levels Decrease With COPD Severity Adapted from 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 HDAC2expression(vs.laminA/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
  34. 34. 4040 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
  35. 35. 4141 Inflammation and Airway Destruction Normal COPD Reproduced from The Lancet, Vol 364, Hogg JC. "Pathophysiology of airflow limitation in chronic obstructive pulmonary disease," pp709-721. Copyright © 2004, with permission from Elsevier. Inflammation in COPD
  36. 36. 4242 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
  37. 37. 4343 Clinical Impact of Inflammation in COPD Tsoumakidou M, et al. Respir Res. 2006;7:80. Reproduced with permission from Biomed Central. Increased Airway Inflammation Increased mucous production Airway wall thickening Airway wall oedema Bronchoconstriction Airway narrowing V’/Q’ MismatchingHyperinflation Worsening of gas exchange Increased work of breathing Increased oxygen consumption – Decreased mixed venous oxygen Cough, sputum, dyspnoea, Respiratory failure Inflammation in COPD
  38. 38. 4444 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
  39. 39. 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 .
  40. 40. 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
  41. 41. 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
  42. 42. Influencing The Cellular Components Of Inflammation Adenosine receptors A2a Agonists CGS21680; ATL146e; UK371,104; GW328267X; regadenoson (CVT-3146); 2-(cyclohexylethylthio)-AMP
  43. 43. Influencing The Cellular Components Of Inflammation Adhesion molecules Inflammatory processes in COPD are coupled to an increased recruitmentof neutrophilsto 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
  44. 44. 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
  45. 45. Influencing The Inflammatory mediators 1-TNF-a 2-Chemokines 3-NF-kB 4-p38 MAPK and MK2 5-PI3K 6-LTB4 7-PPAR
  46. 46. Targeting protease activity at the enzymatic level
  47. 47. Drugs that may have indirect anti- inflammatory actions Reversing glucocorticoid resistance : Activation of HDAC2: theophylline; curcumin; resveratrol Inhibition of P-glycoprotein Inhibition of MIF
  48. 48. THE PRIMARY PHYSIOLOGIC IMPAIRMENT IN COPD IS Rabe K et al. PATS 2006;3:270–5. AIRFLOW LIMITATION
  49. 49. 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
  50. 50. Eur Respir Rev 2006; 15: 99, 37–41 The physiological hallmark of COPD is expiratoryflow limitation. Expiratory flow limitation in patients with COPD Air trapping Dyspnea (breathlessness) Exercise intolerance Hyperinflation Reduced health- related quality of life (HRQoL)
  51. 51. Obstruction and airflow limitation lead to dyspnea and exercise intolerance Narrowingof 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
  52. 52. Air trapping and associated hyperinflation provide a mechanistic link between the physiological impairment and the characteristic symptoms of COPD
  53. 53. Air Trapping and Hyperinflation • Air trapping and associated hyperinflationprovide 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
  54. 54. 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
  55. 55. 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 HRQoL3
  56. 56. Bronchodilators address airflow limitation by targeting bronchoconstriction and reducing air trapping GOLD 2014
  57. 57. Bronchodilators improves airflow limitation by targeting bronchoconstriction and reducing air trapping BronchodilatorsBronchodilators Smooth muscle relaxation Increased mucociliary clearance Reduced hyperinflation Improved respiratory muscle function Improve emptying of the lungs GOLD 2014 Chest 2001;120;258-270
  58. 58. V BD  Air flowDeflation  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
  59. 59. Bronchodilators work by: Eur Respir Rev 2006; 15: 99, 37–41 Relievedyspnea by deflating the lungs Allowingimprovedlung emptying with each breath Improvementin exercise tolerance Reduces the elastic load on the inspiratory muscles.
  60. 60. The GOLD guidelinesrecommend 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 maintenancetreatment in COPD Proc Am Thorac Soc Vol 3. pp 185–189, 2006
  61. 61. Bronchodilators are the cornerstone of COPD treatment • Target air flow limitation, bronchodilatingby altering airway smooth muscle tone • Improve emptying of the lung • Reduce hyperinflation at rest and during exercise GOLD 2014
  62. 62. 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- Vogelmeieret al. Respiratory Research 2010, 11:135
  63. 63. 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) LSmeanofFEV1(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
  64. 64. 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) FEV1(L) Vogelmeieret 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
  65. 65. 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.
  66. 66. 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
  67. 67. 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 ††† *** ††† ***† *** *** *** * TroughFEV1(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 ml20 ml
  68. 68. *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
  69. 69. 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 353342 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 TDItotalscore 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.
  70. 70. Jones PW et al, Respir Med 2011; 105 (6): 892-9. Indacaterol 300 μg dose was superior compared to the twice-daily β2-agonists
  71. 71. 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 after6 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.
  72. 72. 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 Dayswithnorescueuse(%) 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.
  73. 73. 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
  74. 74. Exercise endurance study INABLE-1 study design Indacaterol 300 μg o.d. Indacaterol300 μg o.d. PlaceboPlacebo 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
  75. 75. RESULTS
  76. 76. 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 Exerciseendurancetime(mins) Indacaterol 300 µgPlacebo 8.07 9.75 Δ 1.68 *** 7.92 9.77 Δ 1.85 * 9 7 6 Respiratory Medicine (2011) 105, 1030-1036
  77. 77. 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 End-exerciseinspiratorycapacity(L) Indacaterol300 µgPlacebo 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
  78. 78. 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 RestingFEV1(L) Indacaterol 300 µgPlacebo 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
  79. 79. 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.
  80. 80. 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.
  81. 81. Breezhaler®: Easy-to-use device for effective drug delivery
  82. 82. Breezhaler® has lower airflow resistance than other inhalers 0 20 40 60 80 100 120 0 2 4 6 8 10 Inspiratory effort (kPa) Flowrate(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)
  83. 83. Conclusion • COPD is caused by inhaled noxious agents, with lung damage leading to airflow limitation • Air trapping and associated hyperinflationprovide a mechanistic link between the physiological impairment and the characteristic symptoms of COPD
  84. 84. Conclusion • The GOLD guideline recommends long-acting bronchodilators as first- line maintenance treatment in COPD. • Bronchodilatorsaddress airflow limitation by targeting bronchoconstriction and reducing air trapping.
  85. 85. Conclusion • LABAs – Improve lung function. – Improve health statusrelated quality of life. – Reduce exacerbations in symptomatic patients with moderate-to-severeCOPD. – 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.
  86. 86. 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
  87. 87. Conclusion • Indacaterolreduces 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
  88. 88. Conclusion • Indacaterolimproves exercise endurance time • Indacaterolimproves inspiratory capacity • Indacaterol improves bronchodilation • Indacaterolhas a good overall safety & tolerability profile • Breezhaler® is an Easy-to-use device for effective drug delivery

×