2 Double Bronchodilatation in COPD Bartolome R. Celli, M.D.Brigham and Women’s HospitalProfessor of MedicineHarvard 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 Deaths from COPD Worldwide Territories are sized in proportion to the absolute number of people who died from chronic obstructive pulmonary disease in one year.
6 Objective COPD progresses over a long period of time Reasoning for BD Patients respond to therapyBronchodilatorsNew agents
7 Objective COPD progresses over a long period of time Reasoning for BD Patients respond to therapyBronchodilatorsNew agents
8 The Natural History of Chronic Bronchitis and Emphysema LHSPOETTORCHUPLIFTFletcher and Peto BMJ 1976
9 Objective COPD progresses over a long period of time Reasoning for BD Patients respond to therapyBronchodilatorsNew agents
10 Mechanism of action of β2-agonists Extracellularβ2Rβ2RGsGsACAirway smooth muscleIntracellularcAMPATPPKA (active)PK (inactive)ReferenceTashkin DP, Fabbri LM. Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents. Respir Res 2010; 11: 149.RelaxationStimulation of β2-adrenoreceptors results in activation of adenylate cyclase, increased intracellular cAMP and subsequent airway smooth muscle relaxationAC, adenylyl cyclase; ATP, adenosine triphosphate; β2R, β2 receptor; cAMP, cyclic AMP; Gs, stimulatory G protein; PKA, protein kinase ATashkin DP, Fabbri LM, Respir Res. 2010;11:149.
11 Mechanism of action of muscarinic antagonists Preganglionic nerveParasympathetic ganglionPostganglionic nerveM2M3M1Airway smooth muscleAChMAMuscarinic antagonists block M1 and M3 receptors, thus preventing binding of acetylcholine and inhibiting airway smooth muscle contractionReferenceTashkin DP, Fabbri LM. Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents. Respir Res 2010; 11: 149.ACh, acetylcholine; Mx, muscarinic receptor; MA, muscarinic antagonistTashkin DP, Fabbri LM, Respir Res. 2010;11:149.
12 Objective COPD progresses over a long period of time Patients respond to therapyAnti-inflammatoriesBronchodilatorsNew agents
13 Benefits of maximal bronchodilation on clinical outcomes Correlation between change in FEV1 and outcomes54321-1-500-250250500TDIFEV1 (mL)P<0.0001, r2=8.2%5P<0.0001, r2=10%P<0.002, r2=5.6%2Number of exacerbations per yearSGRQ-51-10ReferenceJones PW, Donahue JF, Nedelman J, Pascoe S, Pinault G, Lassen C. Correlating changes in lung function with patient outcomes in chronic obstructive pulmonary disease: a pooled analysis. Respir Res 2011; 12: 151.-500-250250500-500-250250500FEV1 (mL)FEV1 (mL)ICS severeNo ICS severeICS moderateNo ICS moderateCorrelation analysis of pooled data from three indacaterol studies (N=3313)Jones PW et al, Respir Res 2011;12:161.
14 Objective COPD progresses over a long period of time Reasoning for BD Patients respond to therapyBronchodilatorsNew agents
18 FEV1 over 24 Hours Following Single Dosing of Olodaterol FEV1 (L)1.2524Time (h)1.151.050.950.85232221151296320.51Olodaterol 20 µgOlodaterol 10 µgOlodaterol 5 µgOlodaterol 2 µgPlacebo18Key point: Olodaterol provided significantly greater bronchodilation than placebo over 24 hoursA single-centre, double-blind, placebo-controlled, 5-way crossover study including 24-h spirometry following dosing of olodaterol 2, 5, 10 and 20 µg was conductedPrimary endpoint of the study was the 24 h post-dosing FEV1The FEV1 time-response curves measured over 24 h after single dosing of four olodaterol doses (ranging from 2 to 20 µg) or placebo are shownAll doses of olodaterol provided significantly greater bronchodilation compared with placebo in 24-h FEV1 post-dose (P<0.001)A clear dose-response relationship was observed, with values ranging from 70 mL for olodaterol 2 µg to 119 mL for olodaterol 20 µgVan Noord JA, Smeets JJ, Drenth BM et al. 24-hour bronchodilation following a single dose of the novel ß2-agonist olodaterol in COPD. Pulm Pharmacol Ther. 2011;24(6):van Noord JA et al. Pulm Pharmacol Ther. 2011;24)6):18
19 Long term efficacy and safety of Indacaterol N = FEV1 = 1.5 L DB,R, PC weeks Two doses versus placeboNo important adverse side effectsDecreased exacerbations by 14%USA FDA approved 75 mcgChapman K et al CHEST 2011;140:68
20 Indacaterol versus Tiotropium FEV1 = 1.5 l12 weeksIndacaterol 150 mcgTiotropium 18 mcgOutcomesspirometrySGRQTDIBuhl et al Eur Respir J 2011: 28:797
21 Efficacy and safety of Aclidinium The ATTAIN Study N = FEV1 = 1.5 L DB,R, PC weeks 2 doses versus placeboNo difference in side effects versus placeboTDI was also improvedJones P et al Eur Respir J 2012 e published March 22
22 Aclidinium BID versus Tiotropium and Placebo N = FEV1 = 1.7 L R, PC days 2 medications versus placeboFurh R et al CHEST 2012;141:745
23 Efficacy of Glycopirronium : GLOW study Patients = 657Glycopirronium = 327Tiotropium = 328Duration = 12 weeksOutcomes:FEV1AUCChapman K et al BMC Pulm Med 2014;14:4
24 Conclusions I Bronchodilators do bronchodilate. The Ultra-LABA and LAMA increase FEV1 between 120 and 200 mlThe improve Qol and dyspneaDecrease exacerbations. All better than placebo
25 Bronchodilator response Distribution in UPLIFT 53%n= 5881FEV1 = 1.1 LTashkin e al ERJ 2008
26 UPLIFT: FEV1 versus FVC response FEV1, but notFVC responseFVC, but notFEV1 responseStage IIStage IIIStage IVStage IIStage IIIStage IV≥15%≥12% + ≥200 mL≥15%≥12% + ≥200 mLTashkin e al ERJ 2008
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 bidT+ F qdTF bidVan Noord J et al ERJ 2005;26:214
29 Indacaterol plus tiotropium vs tiotropium plus placebo FEV1 at Week 12 (The INTRUST Studies) Study 1Study 220406080100120140160180123234567824Study drug inhalationTime (h)FEV1 treatment difference (mL)FEV1, forced expiratory volume in 1 secondMahler et al. Thorax. 2012;67:
30 Reliever medication use Reliever medication use LAMA/LABA (tiotropium/salmeterol): Improvement in dyspnea and reliever medication useTDI focal scoreReliever medication use220.127.116.11*3.0*2.52.52.02.0Reliever medication use(puffs/24 hours)TDI focal score**1.51.5MCID1.01.00.50.50.00.0TiotropiumSalmeterol bidTiotropium + salmeterol qdTiotropium + salmeterol bid*P<0.001 compared to either single agent alonevan Noord JA et al. Respir Med 2010;104:995.
31 Δ rest to isotime inspiratory capacity (L) LAMA/LABA (tiotropium / formoterol): Improvement in constant work rate exercise toleranceΔ rest to isotime inspiratory capacity (L)% CWR exercise time1400.21200.0P=<0.05100-0.280-0.4Δ rest to isotime inspiratory capacity (L)% CWR exercise time60-0.640-0.820-1.0P=<0.050.0-1.2Formoterol bidTiotropium qd + formoterol bidCrossover study of 33 COPD subjects; FEV1=47%predBerton et al. Respir Med 2010; 104:1288.
32 Umeclidinium + Salmeterol versus S, Tiotropium or Placebo N = 47 FEV1 = 1.5 L R,PC,Crossover 1 weekmcg + Smcg + STioSPlaceboBeier J et al Intl J COPD 2012;7:153
33 LAMA + LABA (tiotropium + olodaterol) 4 week, crossover studies (n=232) 1.251.301.75-1.006.00TimeFEV1 (L) at 4 weeks1.351.401.451.501.551.601.651.700.001.002.003.004.005.00+Tiotropium 5 μg*+Tiotropium 2.5 μg*+Tiotropium 1.25 μg*Olodaterol 5 μgOlodaterol 10 μg~0.34 L~0.36 Lmean baselineData for Day 29.Addition of tiotropium to olodaterol significantly improved FEV1 versus olodaterol alone* via Respimat SMIAalbers et al. Eur Resp J 2012;40(Suppl 56): 525s (P2882).
34 LABA + LAMA Combined in one dispenser CompaniesProductsFDALABA + LAMA Combined in one dispenser
35 Overview of inhaled LABA/LAMA in development Drug combinationsFrequencyDevelopment stageCompanyFormoterol/ aclidiniumTwice dailyPhase III*Almirall/ForestFormoterol/ glycopyrrolatePhase IIPearl TherapeuticsOlodaterol/ tiotropiumOnce a dayPhase IIIBIUmeclidinium/ vilanterolTheravance/GSKIndacaterol/ glycopyrronium (QVA149)Novartis*Detailed data have not been presented publicly35
36 LAMA / LABA Effect on lung function (SHINE study) 1.001.051.101.18.104.22.1681.351.401.451.501.551.605m1h2h4h8h12h16h22h23h 45mLeast Square Mean of FEV1 (L)QVA149 (n=59)Indacaterol (n=55)Glycopyrronium (n=63)Tiotropium (n=66)Placebo (n=27)This slide shows that, despite differences in FEV1 favouring QVA149 vs placebo and QVA149 vs tiotropium, results from the SHINE study show that glycopyrronium and tiotropium have very similar 24-hour profiles.ReferenceBateman E, et al. Benefits of dual bronchodilation with QVA149 once daily versus placebo, indacaterol, NVA237 and tiotropium in patients with COPD: The SHINE study. Poster presented at ERS 2012; P2810.Serial spirometry substudyQVA110/50μg, indacaterol 150 μg, glycopyrronium 50 μg, and tiotropium 18 μg, all administered once daily
37 LAMA / LABA Effect on lung function (SHINE study) 0.08***0.09***0.07***Trough FEV1 at Week 26 (L)Open-label tiotropium 18 μg qdGlyco-pyrronium 50 μg qdIndacaterol 150 μg qdQVA /50 μg qdReferenceBateman ED, Ferguson GT, Barnes N et al. Dual bronchodilation with once-daily QVA149 versus single bronchodilator therapy: the SHINE study. Eur Resp J 2013; In press.Placebo0.13***0.12******P<0.001 QVA149, glycopyrronium plus indacaterol0.13***0.20***26-week randomized, controlled SHINE study in patients with moderate-to-severe COPD (n=2144)Bateman et al, Eur Resp J 2013 [Epub ahead of print]
38 Umeclidinium/ Vilanterol vs. each one FEV1Celli et al CHEST 2014
39 Open-label tiotropium 18 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∆=0.84, P<0.001∆=0.89, P<0.001∆=0.58; P<0.05At Week 26, TDI focal score was significantly improved with QVA149 compared with placebo (Least-squares mean difference 1.09 [95% CI: 0.61, 1.57]; p<0.001) and open-label tiotropium (Least-squares mean difference 0.51 [95% CI: 0.14, 0.88]; p=0.007).Values are least-squares mean± standard errorPlaceboOpen-label tiotropium 18 μg qdGlyco-pyrronium 50 μg qdIndacaterol 150 μg qdQVA /50 μg qdBateman et al, Eur Resp J 2013 [Epub ahead of print]
40 Open-label tiotropium 18 μg q.d. QVA149 improves SGRQ total score versus placebo and open-label tiotropium at Week 26∆=–3.01, P<0.01∆=–1.92, P=0.065∆=–1.83, P=0.078∆=–0.88, P=ns∆=–2.13, P=0.01∆=–1.18; P=ns∆=–1.09; P=nsSGRQ total scoreAt Week 26, SGRQ total score was significantly improved with QVA149 compared with placebo and open-label tiotropium with LSM treatment differences of –3.01 (95% CI: –5.05, –0.97; p=0.002) and –2.13 (95% CI: –3.72, –0.54; p=0.009), respectively. There were no significant improvements with any of the other active treatments compared with placebo.PlaceboOpen-label tiotropium 18 μg q.d.Glycopyrronium 50 μg q.d.Indacaterol 150 μg q.d.QVA /50 μg q.d.Bateman et al, Eur Resp J 2013 [Epub ahead of print]
41 Open-label tiotropium 18 μg qd QVA149 significantly reduces the rate of moderate or severe COPD exacerbations versus glycopyrronium12% reduction, P=0.03810% reduction, P=0.096The rate of all moderate or severe exacerbations was significantly reduced by 12% with QVA149 compared with glycopyrronium. The rate of moderate or severe exacerbations with QVA149 treatment compared with open-label tiotropium was not significantly different (10% reduction; p=0.096)Glycopyrronium50 μg qdOpen-label tiotropium 18 μg qdQVA /50 μg qdWedzicha J. et al, Lancet Respir Med 2013;1(3):
42 FEV1 over 12 hours postdose at wk 26 Improved lung function with FDC glycopyrronium / indacaterol qd versus monotherapy and SFCQVA /50 μg qdSFC 50/500 μg bidTrough FEV1 at Week 26 (L)0.1****Trough FEV1FEV1 over 12 hours postdose at wk 261.851.80SFC 50/500 μg bidQVA /50 μg qd1.751.701.65FEV1 at Week 26 (L)1.601.551.50ReferenceVogelmeier CF, Bateman ED, Pallante J et al. Efficacy and safety of once daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Respiratory Medicine 2012; 1:1.451.40124812Time postdose (hours)26-week randomized, controlled ILLUMINATE study in patients with moderate-to-severe COPD (n=523)****P<0.0001; P< at each time point over 12 hoursVogelmeier et al, Lancet Respir Med 2013;1(1):51-60
43 Improvement of mean SGRQ-C total score ReferenceVogelmeier CF, Bateman ED, Pallante J, Alagappan VKT, D’Andrea P, Chen H, Banerji D. Randomised investigation of the efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol/fluticasone in patients with COPD: the ILLUMINATE study. Lancet Resp Med. 2012Data 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 group12 months2485 patients Age = 63FEV1 = 0.98 LTio + F + SOver 18 weeks d/c SOutcome:ExacerbationsFEV1QoLMagnussen H et al NEJM 2014;371:1285
45 Withdrawal of ICS and Exacerbations of COPD Magnussen H et al NEJM 2014;371:1285
51 ConclusionsSeveral long acting bronchodilators are reaching the market.Combinations are already here, of which LAMA+LABA are attractiveTwo BD are more effective than one in lung function, mild exacerbations and QoLHead to head comparisons are neededMABA coming?????