Professor Paul Jones MD, PhD, FERS

• Emeritus Professor of Respiratory Medicine; St George’s, University of London

• Global Medical Expert; GSK*

Disease progression in COPD:• What is it?

• How should it be measured?

• Can it be modified?

* Financial conflict of interest

755025Age (years)

25

0

50

75

100

Disability

Death

Smoked

regularly and

susceptible to

its effects

FE

V1

(% o

f valu

e a

t ag

e 2

5)

Never smoked

or not

susceptible

to smoke

Stopped

at 45

Stopped at 65

Disease progression – as measured

by FEV1

Fletcher et al, 1976.

1 2 3

1.25

76 ml

1.35

1.40

1.45

1.50

0 3 2 4 6

50 ml/year

59 ml/year

FEV1

(litre)

1.30

1.20

Months

p=0.16

Fluticasone propionate*

Placebo

Burge et al BMJ 2000; 320:1297

* Not licensed for COPD

Rate of decline of FEV1: the ISOLDE trial

TORCH: Exacerbation rate and FEV1 decline

n=1306n=1862n=1735

Adjusted for smoking status, gender, baseline FEV1, region, BMI, prior exacerbations,

treatment, time, time by treatment and covariate by time

Rate

of

decli

ne i

n F

EV

1(m

L/y

r)

Celli et al AJRCCM 2008; 178: 332

65% faster

Exacerbations per year

37% faster

P<0.001

Exacerbations and worsening in health status over 3 years

Exacerbation Category

0

0.5

1.0

1.5

2.0

2.5

3.0

None

in 3 years

Infrequent

<1.65/yr

Frequent

>1.65/yr

ANOVA p<0.0003

SGRQ slope

(units/yr)Getting

worse

faster

Spencer et al. Eur Respir J 2004;23:1-5.

Change in steps per day over 3 years

Washki et al Am J Resp Crit Care Med 2015; 192: 295-30

SE

Daily activity is lower after 3 years with all degrees of severity

FEV1 and SGRQ changes

SGRQ, St George’s Respiratory QuestionnaireFive-year study of male outpatients with stable COPD (n=137)

Oga et al; Respir Med; 2007; 101; 146-153

48

40

1.5

FEV1 (% predicted)

52

51

50

49

48

47

46

45

44

43

42

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

Time (years)

42

SGRQ total score

50

46

44

38

36

34

32

30

0 0.5 1.0 2.0 2.5 3.0 3.5 4.0 4.5 5.0

Time (years)

ECLIPSE: Post-bronchodilator FEV1 rate of decline over 3-years

38

31

23

8

0

5

10

15

20

25

30

35

40

Fast decline>40ml

Slow decline 20-40ml

No change +/-20ml

Improvement>20ml

% patients

Vestbo et al; NEJM 2011; 365:1184-92.

Normal or no decline

Half of people with COPD (as determined by FEV1) do

not appear to have abnormal rates of FEV1 decline

FEV1 decline in early COPD cohort1

TR3 = 53 ml/yr (47% of COPD population)

TR4 = 27 ml/yr (53% of COPD population)

Reference: 1.Adapted from Lange P et.al. NEJM 2015 Vol 373 : 111-122 2. supplementary appendix

At time of diagnosis –

no knowledge of how the

patient reached this point

Long-term trial issues

TORCH: Early study withdrawal on placebo: FEV1

rate of decline

Placebo patients with 3-years of data annual decline = 54 ml/year 2

“Healthy survivor issue”

Annual decline in last 6-months leading to withdrawal >100ml/year

1. Adapted from Vestbo J et al Clin. Respir J (2011) 5. 44-49

2. Celli B et al Am J Respir Crit Care Med (2008) 178. 332–338

Early withdrawal patients annual decline = 76 ml/year 2

Clinically Important Deterioration (CID) - Rationale

A composite approach to assess short-

term worsening in COPD

Naya I et al. Thorax. 2015; 70(3): A34 (S57)

Measurable deterioration

Loss of lung function Deterioration in health

statusOccurrence of first

exacerbation

Clinically Important Deteriorations (CID) in COPD

•Decrease of ≥100 mL from baseline in trough FEV1

and/or

•Deterioration in SGRQ ≥4 units

and/or

•Moderate/severe COPD exacerbation

Long term risk based on composite

CID status (+) or (-) at 6-months

(TORCH post hoc analysis):

At 6 months CID+ (n=2870 [54%])

Placebo n=1524

Salmeterol n=1521

Fluticasone n=1534

FP/ SAL combination n=1533

Reason for CID+ status

Exacerbation = 33%

FEV1 = 23%

SGRQ = 17%

2 or more causes = 27%

Naya I et al. Thorax. 2015; 70(3): A34 (S57)

Naya et al; European Respiratory Society Congress 2016 (PA304)

TORCH: 3-year outcome on FEV1 & SGRQ based on composite CID status at 6-months

Naya I et al. Thorax. 2015; 70(3): A34 (S57), DOF: RF/CPD/0041/16

-150

-100

-50

0

50

100

150

-40 10 60 110 160

FE

V1 M

ean

ch

an

ge (

95%

CI)

Time after day 182 (weeks)

FEV1 (mL) deterioration over time

Patients CID -

Patients CID +

SGRQ total score deterioration over time

-10

-8

-6

-4

-2

0

2

4

6

-40 10 60 110 160

SG

RQ

mean

ch

an

ge (

95%

CI)

Time after day 182 (weeks)

Patients CID +

Patients CID -

- 117 ml

p<0.001

+ 6.4

units

p<0.001

TORCH: 3-year risk assessments based on

composite CID status at 6-months

All treatment groups combined in TORCH. At 6-Mo. 2870 [54%] patients were CID (CID+) and 2422 [46%] were (CID-).

Naya et al; European Respiratory Society Congress 2016 (PA304)

Su

bje

cts

wit

h ≥

1 e

xacerb

ati

on

(%

)

Time after day 182 (weeks)

Patients CID+ [73%]

Patients CID- [60%]

Future risk of exacerbations

on treatment

CID+ patients had a 61% increased

risk of an exacerbation (p<0.001)

Median time to event

520 days [CID-] vs. 265 days [CID+]

Time after day 182 (weeks)

All c

au

se d

eath

(%

su

bje

cts

)

Future risk of all cause mortality

on treatment

Patients CID-

[6.6%]

Patients CID+ [8.3%]

CID+ patients

had a 41% increased risk of

all-cause death (p<0.001)

CID in short-term trials

Time to first clinically important

deterioration: Relative Risk (RR) reduction

RR: 43%

(95% CI 31, 53; p<0.001)

UMEC/VI 55/22mcg TIO 18mcg

Singh et al. Int J COPD; 2016; 11; 1413

Post-hoc analysis of ZEP117115: Maleki-Yazdi M et al. Respir Med 2014; 108:1752–1760

All components of the composite endpoint were

significantly better with UMEC/VI vs. tiotropium

RR: 43%

(p<0.001)

RR: 47%

(p=0.044)

RR: 26%

p=0.025

RR: 53%

(p<0.001)

UMEC/VI 55/22mcg TIO 18mcg

*RR = Relative Risk reduction

Singh et al. Am J Respir Crit Care Med 2015:191; A5760 (poster presentation)

Post-hoc analysis of ZEP117115: Maleki-Yazdi M et al. Respir Med 2014; 108:1752–1760

Proportion of patients with a first clinically important deterioration event

Pro

po

rtio

n o

f p

ati

en

ts (

%)

Composite Exacerbations SGRQ≥4 units FEV ≥100 ml decline

Preventing short-term worsening: comparison

between dual and mono bronchodilator therapy

Post hoc analysis of time to a first composite CID

21

(A) Dual bronchodilator therapy

(UMEC/VI) vs. tiotropium

Tiotopium n=869

UMEC/VI n=878

HR 0.62 (0.54, 0.71)

P<0.001

41%

56%

Singh et al ERS abstract PA1487

(C) Open triple therapy

(ICS/LABA + UMEC)

vs.ICS/LABA + placebo

ICS/LABA + PBO n=818

ICS/LABA + UMEC n=819

HR 0.52 (0.45, 0.59)

P<0.001

46%

68%

Singh et al ERS abstract PA1487

(B) Dual bronchodilator therapy

(UMEC/VI) vs. placebo

Placebo n=280

UMEC/VI n=413

HR 0.37 (0.30, 0.45)

P<0.001

44%

75%

0 50 100 150

Time to event (days)

Malaki-Yazdi et al ERS abstract PA1001

• All components contribute to CID worsening

• CID distinguishes between treatments in the short-term

• Short term worsening measured over 6 months may predict long-term outcome

• Prevention of short-term worsening looks a promising therapeutic target

• As a surrogate for long term trials

• To identify potential disease modifying treatments more quickly

Summary