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

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

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

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.

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

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

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

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

Mechanism of action of β2-agonists Extracellular β2R β2R Gs Gs AC Airway smooth muscle Intracellular cAMP ATP PKA (active) PK (inactive) Reference Tashkin DP, Fabbri LM. Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents. Respir Res 2010; 11: 149. Relaxation Stimulation of β2-adrenoreceptors results in activation of adenylate cyclase, increased intracellular cAMP and subsequent airway smooth muscle relaxation AC, adenylyl cyclase; ATP, adenosine triphosphate; β2R, β2 receptor; cAMP, cyclic AMP; Gs, stimulatory G protein; PKA, protein kinase A Tashkin DP, Fabbri LM, Respir Res. 2010;11:149.

Mechanism of action of muscarinic antagonists Preganglionic nerve Parasympathetic ganglion Postganglionic nerve M2 M3 M1 Airway smooth muscle ACh MA Muscarinic antagonists block M1 and M3 receptors, thus preventing binding of acetylcholine and inhibiting airway smooth muscle contraction Reference Tashkin 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 antagonist Tashkin DP, Fabbri LM, Respir Res. 2010;11:149.

Objective COPD progresses over a long period of time Patients respond to therapy Anti-inflammatories Bronchodilators New agents

Benefits of maximal bronchodilation on clinical outcomes Correlation between change in FEV1 and outcomes 5 4 3 2 1 -1 -500 -250 250 500 TDI FEV1 (mL) P<0.0001, r2=8.2% 5 P<0.0001, r2=10% P<0.002, r2=5.6% 2 Number of exacerbations per year SGRQ -5 1 -10 Reference Jones 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 -250 250 500 -500 -250 250 500 FEV1 (mL) FEV1 (mL) ICS severe No ICS severe ICS moderate No ICS moderate Correlation analysis of pooled data from three indacaterol studies (N=3313) Jones PW et al, Respir Res 2011;12:161.

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

Ultra LABA

Ultra LABA

Aclidinium Tiotropium LAMA’s Umeclidinium Glycopirronium

FEV1 over 24 Hours Following Single Dosing of Olodaterol FEV1 (L) 1.25 24 Time (h) 1.15 1.05 0.95 0.85 23 22 21 15 12 9 6 3 2 0.51 Olodaterol 20 µg Olodaterol 10 µg Olodaterol 5 µg Olodaterol 2 µg Placebo 18 Key point: Olodaterol provided significantly greater bronchodilation than placebo over 24 hours A 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 conducted Primary endpoint of the study was the 24 h post-dosing FEV1 The FEV1 time-response curves measured over 24 h after single dosing of four olodaterol doses (ranging from 2 to 20 µg) or placebo are shown All 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 µg Van 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):666-672. van Noord JA et al. Pulm Pharmacol Ther. 2011;24)6):666-672. 18

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

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

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

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

Efficacy of Glycopirronium : GLOW study Patients = 657 Glycopirronium = 327 Tiotropium = 328 Duration = 12 weeks Outcomes: FEV1 AUC Chapman K et al BMC Pulm Med 2014;14:4

Conclusions I Bronchodilators do bronchodilate. The Ultra-LABA and LAMA increase FEV1 between 120 and 200 ml The improve Qol and dyspnea Decrease exacerbations. All better than placebo

Bronchodilator response Distribution in UPLIFT 53% n= 5881 FEV1 = 1.1 L Tashkin e al ERJ 2008

UPLIFT: FEV1 versus FVC response FEV1, but not FVC response FVC, but not FEV1 response Stage II Stage III Stage IV Stage II Stage III Stage IV ≥15% ≥12% + ≥200 mL ≥15% ≥12% + ≥200 mL Tashkin e al ERJ 2008

Are 2 better than 1?

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 T+ F qd T F bid Van Noord J et al ERJ 2005;26:214

Indacaterol plus tiotropium vs tiotropium plus placebo FEV1 at Week 12 (The INTRUST Studies) Study 1 Study 2 20 40 60 80 100 120 140 160 180 1 23 2 3 4 5 6 7 8 24 Study drug inhalation Time (h) FEV1 treatment difference (mL) FEV1, forced expiratory volume in 1 second Mahler et al. Thorax. 2012;67:781-788.

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

Δ rest to isotime inspiratory capacity (L) LAMA/LABA (tiotropium / formoterol): Improvement in constant work rate exercise tolerance Δ rest to isotime inspiratory capacity (L) % CWR exercise time 140 0.2 120 0.0 P=<0.05 100 -0.2 80 -0.4 Δ rest to isotime inspiratory capacity (L) % CWR exercise time 60 -0.6 40 -0.8 20 -1.0 P=<0.05 0.0 -1.2 Formoterol bid Tiotropium qd + formoterol bid Crossover study of 33 COPD subjects; FEV1=47%pred Berton et al. Respir Med 2010; 104:1288.

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

LAMA + LABA (tiotropium + olodaterol) 4 week, crossover studies (n=232) 1.25 1.30 1.75 -1.00 6.00 Time FEV1 (L) at 4 weeks 1.35 1.40 1.45 1.50 1.55 1.60 1.65 1.70 0.00 1.00 2.00 3.00 4.00 5.00 +Tiotropium 5 μg* +Tiotropium 2.5 μg* +Tiotropium 1.25 μg* Olodaterol 5 μg Olodaterol 10 μg ~0.34 L ~0.36 L mean baseline Data for Day 29. Addition of tiotropium to olodaterol significantly improved FEV1 versus olodaterol alone * via Respimat SMI Aalbers et al. Eur Resp J 2012;40(Suppl 56): 525s (P2882).

LABA + LAMA Combined in one dispenser Companies Products FDA LABA + LAMA Combined in one dispenser

Overview of inhaled LABA/LAMA in development Drug combinations Frequency Development stage Company Formoterol/ aclidinium Twice daily Phase III* Almirall/Forest Formoterol/ glycopyrrolate Phase II Pearl Therapeutics Olodaterol/ tiotropium Once a day Phase III BI Umeclidinium/ vilanterol Theravance/GSK Indacaterol/ glycopyrronium (QVA149) Novartis *Detailed data have not been presented publicly 35

LAMA / LABA Effect on lung function (SHINE study) 1.00 1.05 1.10 1.15 1.20 1.25 1.30 1.35 1.40 1.45 1.50 1.55 1.60 5m 1h 2h 4h 8h 12h 16h 22h 23h 45m Least 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. Reference Bateman 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 substudy QVA110/50μg, indacaterol 150 μg, glycopyrronium 50 μg, and tiotropium 18 μg, all administered once daily

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 qd Glyco-pyrronium 50 μg qd Indacaterol 150 μg qd QVA149 110/50 μg qd Reference Bateman 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. Placebo 0.13*** 0.12*** ***P<0.001 QVA149, glycopyrronium plus indacaterol 0.13*** 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]

Umeclidinium/ Vilanterol vs. each one FEV1 Celli et al CHEST 2014

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<0.05 At 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 error Placebo Open-label tiotropium 18 μg qd Glyco-pyrronium 50 μg qd Indacaterol 150 μg qd QVA149 110/50 μg qd Bateman et al, Eur Resp J 2013 [Epub ahead of print]

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=ns SGRQ total score At 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. Placebo Open-label tiotropium 18 μg q.d. Glycopyrronium 50 μg q.d. Indacaterol 150 μg q.d. QVA149 110/50 μg q.d. Bateman et al, Eur Resp J 2013 [Epub ahead of print]

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

FEV1 over 12 hours postdose at wk 26 Improved lung function with FDC glycopyrronium / indacaterol qd versus monotherapy and SFC QVA149 110/50 μg qd SFC 50/500 μg bid Trough FEV1 at Week 26 (L) 0.1**** Trough FEV1 FEV1 over 12 hours postdose at wk 26 1.85 1.80 SFC 50/500 μg bid QVA149 110/50 μg qd 1.75 1.70 1.65 FEV1 at Week 26 (L) 1.60 1.55 1.50 Reference Vogelmeier 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: 51-60. 1.45 1.40 1 2 4 8 12 Time postdose (hours) 26-week randomized, controlled ILLUMINATE study in patients with moderate-to-severe COPD (n=523) ****P<0.0001; P<0.0001 at each time point over 12 hours Vogelmeier et al, Lancet Respir Med 2013;1(1):51-60

Improvement of mean SGRQ-C total score Reference Vogelmeier 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. 2012 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

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

Withdrawal of ICS and Exacerbations of COPD Magnussen H et al NEJM 2014;371:1285

Are 3 better than 2?

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

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

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

MABA Muscarinic-receptor Antagonists Beta(2)-Adrenergic receptor agonists

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?????

Occurring as we speak