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1. Double Bronchodilatation in COPD Bartolome R. Celli, M.D. Brigham and Women’s Hospital Professor of Medicine Harvard Medical School.

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Presentation on theme: "1. Double Bronchodilatation in COPD Bartolome R. Celli, M.D. Brigham and Women’s Hospital Professor of Medicine Harvard Medical School."— Presentation transcript:

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2 Double Bronchodilatation in COPD Bartolome R. Celli, M.D. Brigham and Women’s Hospital Professor of Medicine Harvard Medical School

3 50 years Trend in Smoking Related Mortality US Thun M et al NEJM 2013;368:351

4 Global Burden of Disease Murray and Lopez NEJM 2013;369:448

5 Territories are sized in proportion to the absolute number of people who died from chronic obstructive pulmonary disease in one year. Deaths from COPD Worldwide

6 Objective COPD progresses over a long period of time Reasoning for BD Patients respond to therapy Bronchodilators New agents

7 Objective COPD progresses over a long period of time Reasoning for BD Patients respond to therapy Bronchodilators New agents

8 The Natural History of Chronic Bronchitis and Emphysema Fletcher and Peto BMJ 1976 LHS TORCH UPLIFT POET

9 Objective COPD progresses over a long period of time Reasoning for BD Patients respond to therapy Bronchodilators New agents

10 β2Rβ2R GsGs GsGs AC β2Rβ2R β 2 -agonist Extracellular Intracellular cAMPATP PKA (active) PK (inactive) Relaxation Mechanism of action of β 2 -agonists Stimulation of β 2 -adrenoreceptors results in activation of adenylate cyclase, increased intracellular cAMP and subsequent airway smooth muscle relaxation Airway smooth muscle AC, adenylyl cyclase; ATP, adenosine triphosphate; β 2 R, β 2 receptor; cAMP, cyclic AMP; Gs, stimulatory G protein; PKA, protein kinase A Tashkin DP, Fabbri LM, Respir Res. 2010;11:149.

11 Mechanism of action of muscarinic antagonists Muscarinic antagonists block M 1 and M 3 receptors, thus preventing binding of acetylcholine and inhibiting airway smooth muscle contraction Preganglionic nerve Parasympathetic ganglion Postganglionic nerve M2M2 M3M3 M1M1 Airway smooth muscle ACh MA ACh ACh, acetylcholine; M x, muscarinic receptor; MA, muscarinic antagonist Tashkin DP, Fabbri LM, Respir Res. 2010;11:149.

12 Objective

13 2 1 0 5 0 -5 -10 0 Benefits of maximal bronchodilation on clinical outcomes Jones PW et al, Respir Res 2011;12:161. 5 4 3 2 1 0 -500-2500250500 TDI  FEV 1 (mL) P<0.0001, r 2 =8.2% -500-2500250500 Number of exacerbations per year  FEV 1 (mL) P<0.002, r 2 =5.6% -500-2500250500  SGRQ  FEV 1 (mL) P<0.0001, r 2 =10% Correlation between change in FEV 1 and outcomes ICS severe No ICS severe ICS moderate No ICS moderate Correlation analysis of pooled data from three indacaterol studies (N=3313)

14 Objective COPD progresses over a long period of time Reasoning for BD Patients respond to therapy Bronchodilators New agents

15 Ultra LABA

16

17 LAMA’s Tiotropium Umeclidinium Aclidinium Glycopirronium

18 van Noord JA et al. Pulm Pharmacol Ther. 2011;24)6):666-672. FEV 1 over 24 Hours Following Single Dosing of Olodaterol FEV 1 (L) 1.25 24 Time (h) 1.15 1.05 0.95 0.85 232221 15 12 9 6 3 20.51 Olodaterol 20 µg Olodaterol 10 µg Olodaterol 5 µg Olodaterol 2 µg Placebo 18

19 Long term efficacy and safety of Indacaterol Chapman K et al CHEST 2011;140:68 No important adverse side effects Decreased exacerbations by 14% USA FDA approved 75 mcg N = 412 FEV1 = 1.5 L DB,R, PC. 26 weeks Two doses versus placebo

20 Indacaterol versus Tiotropium Buhl et al Eur Respir J 2011: 28:797 n = 1600 FEV1 = 1.5 l 12 weeks Indacaterol 150 mcg Tiotropium 18 mcg Outcomes spirometry SGRQ TDI

21 Efficacy and safety of Aclidinium The ATTAIN Study N = 824 FEV1 = 1.5 L DB,R, PC. 24 weeks 2 doses versus placebo No difference in side effects versus placebo TDI was also improved Jones P et al Eur Respir J 2012 e published March 22

22 Aclidinium BID versus Tiotropium and Placebo N = 30 FEV1 = 1.7 L R, PC. 15 days 2 medications versus placebo Furh R et al CHEST 2012;141:745

23 Patients = 657 Glycopirronium = 327 Tiotropium = 328 Duration = 12 weeks Outcomes: FEV 1 AUC Efficacy of Glycopirronium : GLOW study Chapman K et al BMC Pulm Med 2014;14:4

24 Conclusions I Bronchodilators do bronchodilate. The Ultra-LABA and LAMA increase FEV 1 between 120 and 200 ml The improve Qol and dyspnea Decrease exacerbations. All better than placebo

25 Bronchodilator response Distribution in UPLIFT 53% n= 5881 FEV 1 = 1.1 L Tashkin e al ERJ 2008

26 UPLIFT: FEV 1 versus FVC response Stage IIStage IIIStage IV Stage IIStage IIIStage IV ≥15%≥12% + ≥200 mL ≥15%≥12% + ≥200 mL FVC, but not FEV 1 response FEV 1, but not FVC response Tashkin e al ERJ 2008

27 Are 2 better than 1?

28 Comparison T versus F bid and both combined qd n = 71 FEV1=1.04L Cross-over 3 X 6 weeks periods T, T+ F qd and F bid F bid T+ F qd T Van Noord J et al ERJ 2005;26:214

29 Indacaterol plus tiotropium vs tiotropium plus placebo FEV 1 at Week 12 (The INTRUST Studies) Mahler et al. Thorax. 2012;67:781-788. Study 1Study 2 FEV 1, forced expiratory volume in 1 second

30 * * ** van Noord JA et al. Respir Med 2010;104:995. 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 TDI focal score MCID 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Reliever medication use (puffs/24 hours) Reliever medication use Tiotropium Salmeterol bid Tiotropium + salmeterol qd Tiotropium + salmeterol bid LAMA/LABA (tiotropium/salmeterol): Improvement in dyspnea and reliever medication use *P<0.001 compared to either single agent alone

31 P=<0.05 Berton et al. Respir Med 2010; 104:1288. 0.0 20 40 60 80 100 120 140 %  CWR exercise time Formoterol bid -1.2 -0.8 -0.6 -0.4 -0.2 0.0 0.2 Δ rest to isotime inspiratory capacity (L) Tiotropium qd + formoterol bid LAMA/LABA (tiotropium / formoterol): Improvement in constant work rate exercise tolerance Crossover study of 33 COPD subjects; FEV 1 =47%pred P=<0.05

32 Umeclidinium + Salmeterol versus S, Tiotropium or Placebo N = 47 FEV1 = 1.5 L R,PC,Crossover 1 week 705 50 mcg + S 705 20 mcg + S Tio S Placebo Beier J et al Intl J COPD 2012;7:153

33 LAMA + LABA (tiotropium + olodaterol) 4 week, crossover studies (n=232) Aalbers et al. Eur Resp J 2012;40(Suppl 56): 525s (P2882). Addition of tiotropium to olodaterol significantly improved FEV 1 versus olodaterol alone * via Respimat SMI

34 LABA + LAMA Combined in one dispenser Products Companies FDA

35 Drug combinations FrequencyDevelopment stageCompany Formoterol/ aclidinium Twice dailyPhase III*Almirall/Forest Formoterol/ glycopyrrolate Twice dailyPhase II Pearl Therapeutics Olodaterol/ tiotropium Once a dayPhase IIIBI Umeclidinium/ vilanterol Once a dayPhase III*Theravance/GSK Indacaterol/ glycopyrronium (QVA149) Once a dayPhase IIINovartis Overview of inhaled LABA/LAMA in development *Detailed data have not been presented publicly

36 LAMA / LABA Effect on lung function (SHINE study) Bateman E. et al. Eur Respir J. 2013 Epub ahead of print Serial spirometry substudy QVA110/50μg, indacaterol 150 μg, glycopyrronium 50 μg, and tiotropium 18 μg, all administered once daily QVA149 (n=59) Indacaterol (n=55) Glycopyrronium (n=63) Tiotropium (n=66) Placebo (n=27)

37 26-week randomized, controlled SHINE study in patients with moderate-to-severe COPD (n=2144) ***P<0.001 QVA149, glycopyrronium plus indacaterol Bateman et al, Eur Resp J 2013 [Epub ahead of print] 0.07*** 0.09*** 0.08*** 0.13*** 0.12*** 0.13*** 0.20*** Trough FEV 1 at Week 26 (L) Glyco- pyrronium 50 μg qd QVA149 110/50 μg qd Indacaterol 150 μg qd Open-label tiotropium 18 μg qd Placebo LAMA / LABA Effect on lung function (SHINE study)

38 Umeclidinium/ Vilanterol vs. each one Celli et al CHEST 2014 FEV 1

39 Glyco- pyrronium 50 μg qd QVA149 improves TDI focal score versus placebo and tiotropium at Week 26 ∆=1.09, P<0.001 ∆=0.51, P<0.01 ∆=0.21,P=ns ∆=0.26, P=ns ∆=0.58; P<0.05 ∆=0.89, P<0.001 ∆=0.84, P<0.001 QVA149 110/50 μg qd Indacaterol 150 μg qd Values are least- squares mean± standard error Open-label tiotropium 18 μg qd Placebo Bateman et al, Eur Resp J 2013 [Epub ahead of print]

40 QVA149 improves SGRQ total score versus placebo and open-label tiotropium at Week 26 ∆=–3.01, P<0.01 ∆=–2.13, P=0.01 ∆=–1.18; P=ns ∆=–1.09; P=ns ∆=–0.88, P=ns ∆=–1.83, P=0.078 ∆=–1.92, P=0.065 Open-label tiotropium 18 μg q.d. QVA149 110/50 μg q.d. Glycopyrronium 50 μg q.d. Indacaterol 150 μg q.d. Placebo SGRQ total score Bateman et al, Eur Resp J 2013 [Epub ahead of print]

41 QVA149 significantly reduces the rate of moderate or severe COPD exacerbations versus glycopyrronium 12% reduction, P=0.038 10% reduction, P=0.096 Open-label tiotropium 18 μg qd QVA149 110/50 μg qd Wedzicha J. et al, Lancet Respir Med 2013;1(3):199-209 Glycopyrronium 50 μg qd

42 Improved lung function with FDC glycopyrronium / indacaterol qd versus monotherapy and SFC Vogelmeier et al, Lancet Respir Med 2013;1(1):51-60 FEV 1 at Week 26 (L) QVA149 110/50 μg qd SFC 50/500 μg bid Trough FEV 1 at Week 26 (L) 0.1**** Trough FEV 1 FEV 1 over 12 hours postdose at wk 26 26-week randomized, controlled ILLUMINATE study in patients with moderate-to-severe COPD (n=523) 0 1.40 1.45 1.50 1.55 1.60 1.65 1.70 1.75 1.80 1.85 0124812 Time postdose (hours) SFC 50/500 μg bid QVA149 110/50 μg qd ****P<0.0001; P<0.0001 at each time point over 12 hours

43 Improvement of mean SGRQ-C total score Improvement Data are LSM (SE); Mean difference in SGRQ-C total score for QVA149 versus SFC at Week 26 was –1·24 (P=0·245) Vogelmeier et al, Lancet Respir Med 2013;1(1):51-60

44 Withdrawal of ICS and Exacerbations of COPD DB, Parallel group 12 months 2485 patients Age = 63 FEV 1 = 0.98 L Tio + F + S Over 18 weeks d/c S Outcome: Exacerbations FEV1 QoL Magnussen H et al NEJM 2014;371:1285

45 Withdrawal of ICS and Exacerbations of COPD

46 Are 3 better than 2?

47 Tiotropium + (Placebo, Salmeterol, or S/F) in COPD Aaron S et al Ann Intern Med 2007;146:545 p = 0.049 n = 449 1 year FEV1 = 1.02 L Primary Outcome Exacerbations

48 Tiotropium vs Tio/Bud/Formoterol Welte et al AJRCCM 2009;180:741 n = 660 12 weeks FEV1 = 1.1 L Outcome lung function QoL Exacerbations T + B/F T + Placebo 62%

49 Objective COPD progresses over a long period of time Reasoning for BD Patients respond to therapy Bronchodilators New agents

50 MABA M uscarinic-receptor A ntagonists B eta(2)- A drenergic receptor agonists

51 Conclusions Several long acting bronchodilators are reaching the market. Combinations are already here, of which LAMA+LABA are attractive Two BD are more effective than one in lung function, mild exacerbations and QoL Head to head comparisons are needed MABA coming?????

52 Occurring as we speak


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