1

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

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

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

Fletcher and Peto BMJ 1976

LHS

TORCH

UPLIFT

POET

Objective

• COPD progresses over a long period of time

• Reasoning for BD

• Patients respond to therapy

• Bronchodilators

• New agents

β2R

Gs Gs

AC

β2R

β2-agonist

Extracellular

Intracellular

cAMP ATP

PKA(active)

PK(inactive)

Relaxation

Mechanism of action of β2-agonists

• Stimulation of β2-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; 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

• Muscarinic antagonists block M1 and M3 receptors, thus preventing binding of acetylcholine and inhibiting airway smooth muscle contraction

Preganglionicnerve

Parasympatheticganglion

Postganglionicnerve

M2

M3

M1

Airway smooth muscle

ACh

MA

MA

ACh

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 COPD progresses over a long period of timetime

• Patients respond to therapy

• Anti-inflammatoriesAnti-inflammatories

• BronchodilatorsBronchodilators

• New agentsNew agents

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

-1

-500 -250 0 250 500

TD

I

FEV1 (mL)

P<0.0001, r2=8.2%

-500 -250 0 250 500

Nu

mb

er

of

ex

ac

erb

ati

on

s p

er

ye

ar

FEV1 (mL)

P<0.002, r2=5.6%

-500 -250 0 250 500

SG

RQ

FEV1 (mL)

P<0.0001, r2=10%

Correlation between change in FEV1 and outcomes

ICS severe

No ICS severe

ICS moderate

No ICS moderate

Correlation analysis of pooled data from three indacaterol studies (N=3313)

Objective

• COPD progresses over a long period of time

• Reasoning for BD

• Patients respond to therapy

• Bronchodilators

• New agents

Ultra LABA

Ultra LABA

LAMA’s

Tiotropium

Umeclidinium

Aclidinium

Glycopirronium

van Noord JA et al. Pulm Pharmacol Ther. 2011;24)6):666-672.

FEV1 over 24 Hours Following Single Dosing of Olodaterol

FE

V1 (

L)

1.25

24

Time (h)

1.15

1.05

0.95

0.85

232221151296320.51

Olodaterol 20 µgOlodaterol 10 µgOlodaterol 5 µgOlodaterol 2 µgPlacebo

18

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

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

Efficacy and safety of AclidiniumThe 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 improvedJones 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

Patients = 657

Glycopirronium = 327

Tiotropium = 328

Duration = 12 weeks

Outcomes:FEV1

AUC

Efficacy of Glycopirronium : GLOW study

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

0

5

10

15

20

25

30

-300 -200 -100 0 100 200 300

FEV1 ml change

Per

cen

t o

f p

atie

nts

53%

n= 5881

FEV1 = 1.1 L

Tashkin e al ERJ 2008

UPLIFT: FEV1 versus FVC response

0

10

20

30

40

50

% o

f re

spo

nd

ers

0

10

20

30

40

50

% o

f re

spo

nd

ers

Stage II Stage III Stage IV Stage II Stage III Stage IV

≥15% ≥12% + ≥200 mL ≥15% ≥12% + ≥200 mL

FVC, but not FEV1 response

FEV1, but not FVC response

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

F bid

T+ F qd

T

Van Noord J et al ERJ 2005;26:214

Indacaterol plus tiotropium vs tiotropium plus placebo FEV1 at Week 12 (The INTRUST Studies)

Mahler et al. Thorax. 2012;67:781-788.

Study 1 Study 2

0

20

40

60

80

100

120

140

160

180

1 230 2 3 4 5 6 7 8 24

Study drug inhalation

Time (h)

FE

V1

trea

tmen

t d

iffe

ren

ce (

mL

)

FEV1, forced expiratory volume in 1 second

**

* *

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

TD

I fo

cal

sco

re

TDI focal score

MCID

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Rel

iev

er m

ed

icat

ion

us

e(p

uff

s/2

4 h

ou

rs)

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

P=<0.05

Berton et al. Respir Med 2010; 104:1288.

0.0

20

40

60

80

100

120

140

%

CW

R e

xerc

ise

time

% CWR exercise time

Formoterol bid

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2

Δ r

est

to is

otim

e in

spir

ato

ry c

apac

ity (

L)

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; FEV1=47%pred

P=<0.05

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)

Aalbers et al. Eur Resp J 2012;40(Suppl 56): 525s (P2882).

• Addition of tiotropium to olodaterol significantly improved FEV1 versus olodaterol alone

1.25

1.30

1.75

-1.00 6.00

Time

FE

V1

(L)

at

4 w

ee

ks

1.351.40

1.45

1.50

1.551.60

1.65

1.70

1.25

1.30

1.75

1.351.40

1.451.50

1.551.60

1.65

1.70

0.00 1.00 2.00 3.00 4.00 5.00 -1.00 6.00Time

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

+Tiotropium 5 μg*+Tiotropium 2.5 μg*+Tiotropium 1.25 μg*Olodaterol 10 μg

~0.34 L ~0.36 L

Olodaterol 5 μg Olodaterol 10 μg

mean baseline mean baseline

* via Respimat SMI

LABA + LAMACombined in one dispenser

Products

Companies

FDA

Drug combinations

Frequency Development stage Company

Formoterol/aclidinium

Twice daily Phase III* Almirall/Forest

Formoterol/glycopyrrolate

Twice daily Phase IIPearl

Therapeutics

Olodaterol/ tiotropium

Once a day Phase III BI

Umeclidinium/ vilanterol

Once a day Phase III* Theravance/GSK

Indacaterol/glycopyrronium (QVA149)

Once a day Phase III Novartis

Overview of inhaled LABA/LAMA

in development

*Detailed data have not been presented publicly

LAMA / LABAEffect on lung function (SHINE study)

Bateman E. et al. Eur Respir J. 2013 Epub ahead of printSerial spirometry substudyQVA110/50μg, indacaterol 150 μg, glycopyrronium 50 μg, and tiotropium 18 μg, all administered once daily

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

Leas

t Squ

are

Mea

n of

FE

V1 (L

)

QVA149 (n=59)

Indacaterol (n=55)

Glycopyrronium (n=63)

Tiotropium (n=66)

Placebo (n=27)

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***

Tro

ug

h F

EV

1 a

t W

eek

26 (

L)

Glyco-pyrronium

50 μg qd

QVA149110/50 μg qd

Indacaterol150 μg qd

Open-label tiotropium

18 μg qdPlacebo

LAMA / LABAEffect on lung function (SHINE study)

Umeclidinium/ Vilanterol vs. each one

Celli et al CHEST 2014

FEV1

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

QVA149110/50 μg qd

Indacaterol150 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]

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-labeltiotropium 18 μg q.d.

QVA149110/50 μg q.d.

Glycopyrronium 50 μg q.d.

Indacaterol150 μg q.d.

Placebo

SG

RQ

to

tal

sco

re

Bateman et al, Eur Resp J 2013 [Epub ahead of print]

QVA149 significantly reduces the rate of moderate or severe COPD exacerbations versus glycopyrronium

12% reduction, P=0.038

10% reduction, P=0.096

Open-labeltiotropium 18 μg qd

QVA149 110/50 μg qd

Wedzicha J. et al, Lancet Respir Med 2013;1(3):199-209

Glycopyrronium50 μg qd

Improved lung function with FDC glycopyrronium / indacaterol qd versus monotherapy and SFC

Vogelmeier et al, Lancet Respir Med 2013;1(1):51-60

FE

V1 a

t W

eek

26 (

L)

QVA149 110/50 μg qd

SFC 50/500 μg bid

Tro

ugh

FE

V1 a

t W

eek

26 (

L)

0.1****

Trough FEV1 FEV1 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

0 1 2 4 8 12Time 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

Improvement of mean SGRQ-C total score

Imp

rove

me

nt

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

Magnussen H et al NEJM 2014;371:1285

Withdrawal of ICS and Exacerbations of COPD

Are 3 better than 2?

Tiotropium + (Placebo, Salmeterol, or S/F) in COPD

1

1.05

1.1

1.15

1.2

0 4 20 36 52

Time weeks

Pre-

BD

FEV1

(L)

T + P

T + S

T + SF

Aaron S et al Ann Intern Med 2007;146:545

p = 0.049

n = 449

1 year

FEV1 = 1.02 L

Primary Outcome

Exacerbations

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%

Objective

• COPD progresses over a long period of time

• Reasoning for BD

• Patients respond to therapy

• Bronchodilators

• New agents

MABAMuscarinic-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