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. 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 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
LHS
POET
TORCH
UPLIFT
Fletcher and Peto BMJ 1976

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

10. 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.

11. 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.

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

13. 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.

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

15. Ultra LABA

16. Ultra LABA

17. Aclidinium
Tiotropium
LAMA’s
Umeclidinium
Glycopirronium

18. 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):
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 placebo
No important adverse side effects
Decreased exacerbations by 14%
USA FDA approved 75 mcg
Chapman K et al CHEST 2011;140:68

20. 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

21. Efficacy and safety of Aclidinium The ATTAIN Study
N = FEV1 = 1.5 L DB,R, PC 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 = FEV1 = 1.7 L R, PC days 2 medications versus placebo
Furh R et al CHEST 2012;141:745

23. 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

24. 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

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

26. 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

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

29. 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:

30. 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.

31. 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.

32. Umeclidinium + Salmeterol versus S, Tiotropium or Placebo
N = 47 FEV1 = 1.5 L R,PC,Crossover 1 week
mcg + S
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)
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).

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

35. 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

36. 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

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 qd
Glyco-pyrronium 50 μg qd
Indacaterol 150 μg qd
QVA /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]

38. Umeclidinium/ Vilanterol vs. each one
FEV1
Celli 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<0.05
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
QVA /50 μg qd
Bateman 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=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.
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 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
QVA /50 μg qd
Wedzicha 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 SFC
QVA /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
QVA /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:
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< at each time point over 12 hours
Vogelmeier et al, Lancet Respir Med 2013;1(1):51-60

43. 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

44. 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

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

46. Are 3 better than 2?

47. 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

48. 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

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

50. MABA Muscarinic-receptor Antagonists
Beta(2)-Adrenergic 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