DEFINITION OF COPD IS A DISEASE STATE CHARACTERIZED BY AIRFLOW LIMITATION THAT IS NOT FULLY REVERSIBLE.

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2 DEFINITION OF COPD CHRONIC OBSTRUCTIVE PULMONARY DISEASE(COPD) IS A DISEASE STATE CHARACTERIZED BY AIRFLOW LIMITATION THAT IS NOT FULLY REVERSIBLE. THE AIRFLOW LIMITATION IS USUALLY BOTH PROGRESSIVE AND ASSOCIATED WITH AN ABNORMAL INFLAMMATORY RESPONSE OF THE LUNGS TO NOXIOUS PARTICLES OR GASES.

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4 Lung Function NATURAL HISTORY OF COPD Never smoked Exacerbation Exacerbation Smoker Exacerbation Time (Years) Fletcher C. BMJ 1977;1:

5 Chronic Inflammation plays a central role in COPD Smoke Inflammation Pollutants e.g. bacteria & viruses Key inflammatory cells Neutrophils CD8 + T-lymphocytes Macrophages Chronic inflammation Structural changes Systemic inflammation Bronchoconstriction, oedema, mucus, emphysema Acute exacerbations Airflow limitation Barnes PJ. From: Stockley RA, Rennard SI, Rabe K, et al. (Editors). Chronic Obstructive Pulmonary Disease. Oxford, England: Blackwell Publishing; 2007:860.

6 Airways with measurable cells (%) Airway Inflammation occurs from COPD onset and increases with disease severity GOLD Stage I 100 P<0.001 P<0.001 GOLD Stage II and III P=0.038 GOLD Stage IV Neutrophils Macrophages CD8 + cells Adapted from Hogg JC et al. Thorax 2006;61:96-97.

7 Frequent Exacerbators are found at All stages of COPD severity Base-line therapy GOLD stage % Patients on long-acting bronchodilators % Patients on inhaled corticosteroids Exacerbation rate in year 1 (number/ patient) % of patients who were Frequent exacerbators II III IV Adapted from Hurst JR et al. N Engl J Med 2010;363:

8 Half of Exacerbations are Not reported by patients Adapted from Seemungal TAR, Donaldson GC, Paul EA, et al. Am J Respir Crit Care Med 1998;157:

9 Probability of survival Exacerbation Frequency and Severity both increase Mortality Risk Patients with no acute exacerbations p < p = p< Patients with 1 2 acute exacerbations requiring hospital management 0.2 Patients with 3 acute exacerbations Time (months) Soler-Cataluna JJ et al. Thorax 2005;60:

10 COPD is caused by inhalation of noxious substances 53% of men in China smoke and 2 million people will die by 2020 if the trends continues 2 1. Salvi SS, Barnes PJ. Lancet 2009;374; Global Initiative for Chronic Obstructive Lung Disease Boschetto P et al. J Occup Med Toxic 2006;1: Campaign for tobacco free kids c. 5. Baris E et al KES08_Mongolia_Indoor%20Air%20Pollution%20in%2 0Cold%20Climates.pdf

11 COPD has pulmonary and systemic components Inhaled substances + Genetic susceptibility Airway inflammation Mucociliary dysfunction Structural changes Systemic inflammation Airway limitation Breathlessness Bronchitis: coughing, sputum production Emphysema: hyperinflation, wheezing Weight changes Co-morbidities (e.g. diabetes, cardiovascular disease) Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) Available from

12 Vicious Circle of FREQUENT Exacerbations Tobacco smoke Noxious agents Chronic Inflammation Oxidative stress Mucociliary malfunction Epithelial injury Impaired lung defence Chronic colonisation Increased susceptibility respiratory viruses new strains of bacteria environmental irritants Further acute on top of chronic inflammation 1. Wedzicha JA & Seemungal TAR. Lancet 2007; 370: Bhowmik A et al. Thorax 2000;55: Perera W et al. Eur Respir J 2007;29: Wedzicha JA &Hurst JR. Proc Am Thorac Soc 2007;4: Sethi S & Murphy TF. NEJM 2008;359: Soler-Cataluna JJ & Rodriguez-Roisin R. J COPD 2010;7: Increased disease progression Decreased health status

13 Guideline goals for successful COPD management Relieve symptoms Current control Improve exercise tolerance Improve health status Prevent disease progression Future risk Prevent and treat complications Prevent and treat exacerbations Reduce mortality GOLD Report 2010 Global Initiative for Chronic Obstructive Lung Disease 2010 Available at:

14 GOLD 2011 management objectives divided into two categories of equal importance Relieve symptoms Improve exercise tolerance Improve health status REDUCE SYMPTOMS and Prevent disease progression Prevent and treat exacerbations Reduce mortality REDUCE RISK Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) Available from

15 The new GOLD COPD strategy Symptoms, Spirometry and Future risk Risk GOLD classification of airflow limitation C A D B Risk Exacerbation history mmrc < 2 CAT < 10 mmrc 2 CAT 10 Symptoms mmrc or CAT score GOLD,

16 GOLD 2013 Recommendations Pharmacologic Therapy for Stable COPD* Patient group A B C D Recommended First Choice SABA prn or SAMA prn LABA or LAMA ICS/LABA or LAMA ICS/LABA and/or LAMA Alternative Choice LABA or LAMA or SABA/SAMA LABA/LAMA LAMA/LABA or LAMA/PDE4i or LABA/PDE4i ICS/LABA/LAMA or ICS/LABA/PDE4i or LAMA/LABA or LAMA/PDE4i Other Possible Treatments** Theophylline SABA and/or SAMA SABA and/or SAMA or Theophylline Carbocysteine or SABA and/or SAMA or Theophylline *Medications in each box are mentioned in alphabetical order and therefore not necessarily in order of preference. **Medications in this column can be used alone or in combination with other options in the First and Alternative Choice columns. Glossary: SABA: short-acting beta2 agonist SAMA: short-acting anticholinergic LABA: long-acting beta2 agonist LAMA: long-acting anticholinergic ICS: inhaled corticosteroid PDE4i: phosphodiesterase-4 inhibitor prn: when necessary

17 PDE4 INHIBITORS RATIONALE AND CLINICAL DEVELOPMENT

18 Inflammation in COPD is different from asthma COPD Noxious agent Triggers Asthma Sensitising agent Neutrophils CD8 + T-lymphocytes Macrophages Inflammatory cells Eosinophils CD4 + T-lymphocytes Mast cells Not fully reversible Airflow limitation Reversible Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) Available from

19 PDE4 Plays an important role in Inflammation PDE4 inhibition P P P PDE4 P Adapted from Rabe KF. Expert Rev Resp Med 2010;4:

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21 The PDE4 enzyme is expressed in key Inflammatory Cells involved in COPD LEUKOCYTE PDE ISOFORM STRUCTURAL CELLS PDE ISOFORM Mast cells 4, 7 Airway smooth muscle 1, 2, 3, 4, 5, 7 Eosinophils 4, 7 Epithelial cells 1, 2, 3, 4, 5, 7, 8 Neutrophils 4, 7 Endothelial cells 2, 3, 4, 5 Monocytes 1, 3, 4, 7 Macrophages 1, 3, 4, 5, 7 T-cells (CD4 + and CD8 + ) 3, 4, 7 Sensory nerve 1, 3, 4 Cholinergic nerves 1, 3, 4 Adapted from: Giembycz MA. Monaldi Arch Chest Dis 2002;57:48-64.

22 Phosphodiesterase 4 inhibition Roflumilast in COPD New oral once-daily antiinflammatory therapy Potent, selective PDE 4 inhibitor chemically and pharmacologically distinct from other COPD therapies Targets keyunderlying the pathogenesis of COPD and associated exacerbations pro-inflammatory mediators

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24 Roflumilast is metabolised in humans by hepatic cytochrome P450 (CYP)3A4 or CYP1A2 to form a pharmacodynamically active metabolite, roflumilast N-oxide. The pharmacokinetic properties of roflumilast are based on the activity of both forms of the drug. Roflumilast N-oxide has a long half-life, which enables once-daily dosing of DAXAS.

25 Plasma concentration (nm) The long terminal half-life of Roflumilast N-oxide enables once-daily dosing Roflumilast N-oxide Roflumilast Time (h) Hatzelmann A et al. Pulmonary Pharm Therapeutics 2010;23:

26 Other PDE4 inhibitors and Theophylline Have lower potency than Roflumilast PDE4 inhibition (IC 50 nm) Dosage for COPD Roflumilast mg once daily Cilomilast mg twice daily Rolipram Theophylline >10, mg daily Adapted from: Wang D, Cui X. Int J COPD 2006;1:

27 The Anti-inflammatory effects of Roflumilast were evaluated in a 4-Week crossover study 2 weeks Run-in 4 weeks 4-6 weeks 4 weeks Wash-out Roflumilast 500µg OD Placebo Placebo Placebo Placebo Roflumilast 500µg OD Sputum collection Lung function Sputum collection Lung function Sputum collection Lung function Grootendorst DC et al. Thorax 2007;62;

28 Roflumilast reduced levels of Inflammatory Markers in sputum samples Total leukocyte count IL-8 Neutrophil elastase Grootendorst DC et al. Thorax 2007;62; Placebo Roflumilast

29 Roflumilast improved Pre- and Post-bronchodilator FEV 1 levels Pre-bronchodilator FEV 1 Post-bronchodilator FEV 1 Placebo Roflumilast Grootendorst DC et al. Thorax 2007;62;

30 EFFICACY OF ROFLUMILAST IN CLINICAL STUDIES

31 The Roflumilast Clinical Study Programs Early phase III studies 1,2 M2-111 (n=1173) M2-112 (n=1513) Pivotal studies 3 M2-124 (n=1523) M2-125 (n=1568) Supplementary 6-month studies 4 M2-127 add on to LABA (n=933) M2-128 add on to LAMA (n=743) 1. Calverley PMA et al. Am J Respir Crit Care Med 2007;176: Rennard SI et al. Respiratory Research 2011,12: Calverley PMA et al. Lancet 2009;374: Fabbri LM et al. Lancet 2009;374: LABA = Long-acting β 2 -agonist LAMA = Long-acting muscarinic antagonist

32 Design of Early Phase III Studies M2-111 & M2-112 Placebo o.d. Roflumilast 500µg o.d. Followup 30 days Visit 0 Baseline 4 weeks R Treatment 52 weeks VE Followup Placebo o.d. Allowed concomitant medication: ICSs ( 2000µg BDP or equivalent) Approximately 60% of all patients were on ICS treatment Calverley PMA et al. Am J Respir Crit Care Med 2007;176: R = randomization ICS = Inhaled corticosteroids VE = Visit end BDP = Beclomethasone dipropionate o.d. = once daily

33 Pooled analysis revealed Lower Exacerbation Rates with Roflumilast Study M2-111 Study M2-112 Pooled analysis post-hoc Rennard SI et al. Respiratory Research 2011;12:18. *Moderate or severe exacerbations treated with systemic steroids or leading to hospitalization or death

34 Pre- and Post-bronchodilator FEV 1 (M2-111 & M2-112 Pooled Data) Pre-bronchodilator FEV 1 Post-bronchodilator FEV 1 Rennard SI et al. Respiratory Research 2011;12:18. FEV 1 = Forced expiratory volume in 1 second

35 Roflumilast reduced Exacerbation Rate when added to ICS M2-111 and M2-112 pooled post hoc analysis Rennard SI et al. Respiratory Research 2011;12:18. ICS = Inhaled corticosteroids

36 Roflumilast reduced Exacerbation Rate when added to ICS M2-111 and M2-112 pooled post hoc analysis of sub-group with chronic bronchitis +/- ICS Rennard SI et al. Respiratory Research 2011;12:18. ICS = Inhaled corticosteroids

37 The Effect of Roflumilast on exacerbations was Greatest in patients with Chronic Cough and Sputum Patients with chronic bronchitis ± emphysema Rennard SI et al. Respiratory Research 2011;12:18.

38 The Roflumilast Clinical Study Programme Early phase III studies 1,2 M2-111 (n=1173) M2-112 (n=1513) Pivotal studies 3 M2-124 (n=1523) M2-125 (n=1568) Supplementary 6-month studies 4 M2-127 add on to LABA (n=933) M2-128 add on to LAMA (n=743) 1. Calverley PMA et al. Am J Respir Crit Care Med 2007;176: Rennard SI et al. Respiratory Research 2011,12: Calverley PMA et al. Lancet 2009;374: Fabbri LM et al. Lancet 2009;374: LABA = Long-acting β 2 -agonist LAMA = Long-acting muscarinic antagonist

39 Design of pivotal studies M2-124 & M2-125 Single-blind Double-blind, randomized, parallel group Follow-up 4 weeks Run-in 4 weeks Roflumilast 500µg o.d. Visit 0 R Treatment 52 weeks VE Followup Placebo o.d. Concomitant medication: LABA or short-acting anticholinergics Targeting a proportion of ~ 50% of all patients on LABA Calverley PMA et al. Lancet 2009;374: R = randomization VE = Visit end o.d. = Once daily LABA = Long-acting β 2 -agonist

40 Roflumilast significantly reduced the Rate of Moderate/Severe Exacerbations Co-primary endpoint: Exacerbation rate Calverley PMA et al. Lancet 2009;374:

41 Roflumilast significantly improved Lung Function in 12-month clinical studies Calverley PMA et al. Lancet 2009;374:

42 Lung Function improved in roflumilast-treated patients after 4 weeks of treatment Adapted from Calverley PMA et al. Lancet 2009;374: *Statistically significant difference from baseline FEV 1 : Forced expiratory volume in 1 second

43 Greatest benefits of Roflumilast were observed in patients with a history of Frequent Exacerbations M2-124 and M2-125 pooled post hoc analysis Bateman ED et al. Eur Respir J 2011;38:

44 Roflumilast significantly reduced Exacerbations when added to LABA Pre-specified analysis of exacerbation rate in LABA subgroup Absolute Rate Reduction = 0.32 NNT = 3 Bateman ED, Rabe KF, Calverley PMA, et al. Eur Respir J 2011;38: LABA = Long-acting β 2 -agonist

45 NNTs for reducing COPD exacerbations Treatment % reduction NNT ICS/LABA vs LABA 1 9 (ns) NA ICS/LABA vs LABA 2 12 (p=0.002) 8.3 Roflumilast vs placebo 3, (p<0.001) 4.3 Roflumilast/LABA vs placebo/laba3, (p=0.001) Calverley, et al. Lancet Calverley, et al. NEJM Calverley, et al. Lancet Fabbri, et al. Lancet 2009 Woolf AH. JAMA :

46 Roflumilast significantly improved lung function when added to LABA Calverley PMA et al. Lancet 2009;374: LABA = Long-acting β 2 -agonist FEV 1 = Forced expiratory volume in one second

47 The Roflumilast Clinical Study Programme Early phase III studies 1,2 M2-111 (n=1173) M2-112 (n=1513) Pivotal studies 3 M2-124 (n=1523) M2-125 (n=1568) Supplementary 6-month studies 4 M2-127 add on to LABA (n=933) M2-128 add on to LAMA (n=743) 1. Calverley PMA et al. Am J Respir Crit Care Med 2007;176: Rennard SI et al. Respiratory Research 2011,12: Calverley PMA et al. Lancet 2009;374: Fabbri LM et al. Lancet 2009;374: LABA = Long-acting β 2 -agonist LAMA = Long-acting muscarinic antagonist

48 Design of 6-month Roflumilast Study M2-127 Single-blind Run-in 4 weeks Double-blind, randomized, parallel group Salmeterol 50µg b.i.d. + roflumilast 500µg o.d. Follow-up 4 weeks Visit 0 R Treatment 24 weeks VE Follow-up Salmeterol 50µg b.i.d. + placebo o.d. Fabbri LM et al. Lancet 2009;374: R = randomization VE = Visit end b.i.d. = twice daily o.d. = Once daily

49 Design of 6-month Roflumilast Study M2-128 Single-blind Run-in 4 weeks Double-blind, randomized, parallel group Tiotropium 18µg + roflumilast 500µg o.d. Follow-up 4 weeks Visit 0 R Treatment 24 weeks VE Follow-up Tiotropium 18µg + placebo o.d. Fabbri LM et al. Lancet 2009;374: R = randomization VE = Visit end o.d.: Once daily

50 Fabbri LM et al. Lancet 2009;374: Roflumilast significantly improved Lung Function when added to Tiotropium

51 Roflumilast significantly improved Lung Function when added to Tiotropium Rabe KF. Br J Pharm 2011;163: LABA = Long-acting β 2 -agonist SAMA = Short-acting muscarinic antagonist

52 Roflumilast reduced Exacerbations when added to Bronchodilators Rabe KF. Br J Pharm 2011;163: LABA = Long-acting β 2 -agonist SAMA = Short-acting muscarinic antagonist

53 Improvement of lung function with Roflumilast 80 Δ FEV1 (ml, pre-bd) ml + 48 ml + 46 ml + 50 ml + 49 ml + 80 ml OPUS & RATIO Pooled data LABA users No LABAs Salmeterol Tiotropium AURA & HERMES Rabe, et al. Lancet 2005 Calverley, et al. Lancet 2009 Fabbri, et al. Lancet 2009 Calverley, et al. COPD 7, 2010

54 Reduction of exacerbations by Roflumilast Defining different subsets of COPD patients Pooled analysis 2,686 COPD patients Reduction of exacerbations Roflumilast 500 µg / day Placebo year -20 Exacerbations -30 All patients Chronic bronchitis Cough Sputum ICS use Rennard, et al. Respir Res 2011

55 Clinical characteristics of the pooled COPD population: Trials M2-124 (n = 1,523) & M2-125 (n = 1,568) Characteristic Pooled COPD population (n=3,091) Number of exacerbations in the previous year before inclusion Infrequent exacerbator (1) Frequent exacerbator ( 2) (n=2,261, 73%) (n=830, 27%) Roflumilast Placebo Roflumilast Placebo Roflumilast Placebo Subjects, n Age, years ± SD 63.7± ± ± ± ± ±9.3 Male, n (%) 1,150 (75) 1,186 (76) 853 (76) 877 (77) 297 (72) 309 (74) COPD severity, n (%) Severe(GOLD 3) Very severe (GOLD 4) 943 (61.4) 463 (30.1) 989 (63.6) 440 (28.3) 697 (62.0) 336 (29.9) 750 (66.0) 289 (25.4) 246 (59.6) 127 (30.8) 239 (57.3) 151 (36.2) SD, standard deviation CHEST. November 1, 2012 doi: /chest

56 No. of patients (%) Frequent exacerbator subgroup AT BASELINE: One-year treatment with roflumilast significantly reduced the risk of remaining a frequent exacerbator Pooled M2-124 and M2-125 Infrequent Exacerbators after 1 year of treatment Frequent Exacerbators after 1 year of treatment 60-20% RR 0.799; p= % Placebo % Roflumilast No. of exacerbations during the study CHEST. NOVEMBER 1, 2012 DOI: /CHEST RR, risk ratio; CI, confidence interval

57 No. of patients (%) Infrequent exacerbator subgroup AT BASELINE : One-year treatment with roflumilast significantly reduced the risk of becoming a frequent exacerbator Pooled M2-124 and M Infrequent Exacerbators after 1 year of treatment Frequent Exacerbators after 1 year of treatment 40-23% RR 0.768; p= Placebo % 17.5% Roflumilast No. of exacerbations during the study CHEST. NOVEMBER 1, 2012 DOI: /CHEST RR, risk ratio; CI, confidence interval

58 Annual rate of severe exacerbations per patient Reduction on rate of Hospitalizations resulting from severe exacerbations (Pooled Trials M2-124 and M2-125) In the overall population, Roflumilast decreased the rate of hospitalizations resulting from severe exacerbations vs. placebo by 21.6% = -21.6% Rate ratio= % CI 0.619, P= Eur Respir J 2012 ;40: Suppl. 56, 374s(P2109) Placebo n= 1,554 Roflumilast n= 1,537

59 Annual rate of moderate/severe exacerbations per patient Eur Respir J 2012; 40: Suppl. 56, 122s(P742) Effects of Roflumilast on exacerbations added to Tiotropium in symptomatic patients A post-hoc subgroup analysis on patients with baseline mmrc grade 2, Study M2-128 = -23.2% Rate ratio= % CI 0.515, P=0.196 = -45.5% Rate ratio= % CI 0.311, P=0.0338

60 SUMMARY Roflumilast can help to shift patients from the frequent exacerbator phenotype to the more stable infrequent exacerbator phenotype This effect was independent of concomitant LABA use or previous treatment with ICS, and was applicable for both moderate/severe exacerbations and for severe exacerbations alone These data suggest the anti-inflammatory effects of roflumilast in reducing exacerbations could have a stabilizing effect on the disease

61 Percent with Condition COPD as an independent risk factor for CV morbidity Adapted from Finkelstein J, et al. Int J Chron Obstruct Pulmon Dis. 2009;4:

62 Percent of Patients CV risk is particularly High in GOLD groups B and D Mortality from CVD was significantly higher in group B compared with group A (P<0.001) and in Group D vs Group C (P=0.008) Adapted from Lange P, et al. Am J Respir Crit Care Med 2012;186:

63 Study Designs and Patients Retrospective assessment of CV events pooled from the entire clinical database of placebo-controlled roflumilast COPD trials of 12 weeks or longer Patient level evaluation was performed by an expert committee blinded to treatment group and unaware of any study results at the time of the assessment The focus of the analysis was on the incidence of major CV events (MACE) with roflumilast and its placebo comparator MACE include: Non-fatal myocardial infarction Non-fatal stroke CV death White WB et al. Chest Feb 14. doi: /chest [Epub ahead of print]

64 Study Trials Included for Analysis Roflumilast Dose (µg/day) Comparator Duration of Trial (weeks) Sample Size (N) a FK , 500 placebo FK1 103 b 500 placebo M , 500 placebo M placebo M placebo M placebo M placebo M placebo M placebo M placebo M placebo M salmeterol placebo + salmeterol M tiotropium placebo + tiotropium IN , 500 placebo a 1 patient each in studies M2-124 and FK1 103 was randomized twice. b Evaluated withdrawal of roflumilast after 12 weeks of treatment vs continued treatment for 24 weeks. The switch arm of the study (patients who received roflumilast for 12 weeks then placebo for 12 weeks) was not included in this pooled analysis. White WB et al. Chest Feb 14. doi: /chest [Epub ahead of print]]

65 Probability of experiencing a MACE composite event Time to event for major cardiovascular events on Roflumilast and placebo Probability of experiencing the composite of major adverse cardiovascular events (MACE*) roflumilast placebo HR 0.65; p= CHEST doi: /chest Days *MACE : non-fatal MI, non-fatal stroke, cardiovascular death

66 SAFETY OF ROFLUMILAST IN CLINICAL STUDIES

67 Incidence of AEs ( 2.5%)* Independent of investigator causality assessments (1/2) M2-124 M2-125 Roflumilast 500 µg (n=769) Placebo (n=755) Roflumilast 500 µg (n=778) Placebo (n=790) COPD 9.1 % 10.9 % 11.2 % 15.4 % Diarrhoea 8.2 % 3.4 % 8.6 % 2.9 % Weight decrease 12.0 % 3.2 % 8.4 % 2.5 % Nasopharyngitis 7.4 % 6.6 % 4.5 % 5.9 % Upper Respiratory Tract Infection 2.1 % 2.8 % 4.2 % 4.8 % Headache 3.4 % 2.3 % 3.2 % 1.0 % Pneumonia 2.2 % 2.0 % 3.2 % 2.0 % *descending order of M2-125 Calverley et al., Lancet 2009;374:

68 Incidence of AEs ( 2.5%)* Independent of investigator causality assessments (2/2) M2-124 M2-125 Roflumilast 500 µg (n=769) Placebo (n=755) Roflumilast 500 µg (n=778) Placebo (n=790) Back Pain 3.5 % 2.9 % 3.0 % 1.6 % Bronchitis 4.6 % 5.3 % 2.7 % 3.0 % Nausea 5.3 % 2.0 % 2.7 % 1.9 % Hypertension 2.6 % 3.7 % 2.3 % 2.5 % Insomnia 2.5 % 1.1 % 2.3 % 1.5 % Decreased Appetite 2.7 % 0.3 % 1.9 % 0.6 % Influenza 3.5 % 2.4 % 1.5 % 2.5 % *descending order of M2-125 Calverley et al., Lancet 2009;374:

69 Roflumilast was generally Well Tolerated in clinical studies Data were pooled from four 1-year placebo-controlled trials and four 6-month trials for evaluation of adverse reactions Adverse reactions that occurred with a frequency >2% of patients tested Adverse reaction Roflumilast (N=4438) Placebo (N=4192) Diarrhoea 9.5% (420) 2.7% (113) Weight loss 7.5% (331) 2.1% (89) Nausea 4.7% (209) 1.4% (60) Back pain 3.2% (142) 2.2% (92) Influenza 2.8% (124) 2.7% (112) Insomnia 2.4% (105) 1.0% (41) Decreased appetite 2.1% (91) 0.4% (15) Michalski JM et al. Clin Pharm Ther 2012;91:

70 The majority of GI-related adverse events Resolved within 4 weeks Diarrhoea Nausea 69% resolved 74% resolved Roflumilast Placebo Adapted from Gross N et al. Chest. 2010;138:466A (Abstract+ Poster). GI=Gastrointestinal

71 Weight Decrease associated with Roflumilast occurred mainly in the first 6 months of treatment Calverley PMA et al. Lancet 2009;374:

72 The Largest weight decrease was observed in Obese Patients Calverley PMA et al. Lancet 2009;374: (supplementary webappendix).

73 Weight decrease associated with Roflumilast was primarily Fat Mass Wouters EFM et al. Am J Respir Crit Care Med 2010;181:A4473. FFMI = Fat Free Mass Index BMI = Body Mass Index

74 Mean change in body weight [kg] M2-124 / M2-125 Body weight (patients with follow-up data) Double blind treatment period Follow-up period n Time (weeks) Roflumilast = Placebo =

75 A new perspective on optimal care for patients with COPD PATIENT CHARACTERISTICS BEST CURRENT CONTROL FUTURE RISK REDUCTION ADD ROFLUMILAST TO REDUCE EXACERBATIONS MANAGEMENT PLAN Postma, et al. Prim Care Respir J 2011; 20: GOLD,

76 Exacerbations per year Where does Daxas fit in the current GOLD 2011 treatment recommendations? GOLD 4 GOLD 3 C ICS + LABA or LAMA + ICS + LABA or LAMA + D > 2 GOLD 2 GOLD 1 A SAMA prn or SABA prn LABA or LAMA B 0 1 mmrc 0-1 CAT < 10 mmrc > 2 CAT > 10 Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) Available from

77 DAXAS FILM-COATED TABLETS 500 MCG 迪開舒膜衣錠 500 微克 許可證字號 : 衛署藥輸字第 號 適應症 : Daxas 適用於重度慢性阻塞性肺疾 (chronic obstructive pulmonary disease COPD)( 使用支氣管擴張劑後 FEV1 低於預期數值的 50%), 並伴隨頻繁惡化病史的成年慢性支氣管炎患者, 作為附加於支氣管擴張劑的維持治療 給藥劑量 : 建議劑量為一錠 500 微克 roflumilast, 每日 1 次 給藥方法 : 口服 錠劑應隨水吞服, 在每天的同一時間服用 錠劑可隨膳食或不隨膳食服用 禁忌症 : 對 roflumilast 或對任何賦形劑過敏的患者 中度或重度肝功能不全者 (Child-Pugh 分級 B 或 C) 配伍禁忌 : 無 副作用 : 報告最多的不良反應為腹瀉 (5.9%), 體重下降 (3.4%), 噁心 (2.9%), 腹痛 (1.9%), 和頭痛 (1.7%) 多數這些不良反應為輕度或中度 這些不良反應主要出現在治療第一週, 多數在後續治療期間緩解