10/08/2012

ALAT Montevideo 2012

New Drugs for COPD Klaus F. Rabe

Krankenhaus Grosshansdorf & CAU Kiel

Hansel TT, Lancet 2009

Bronchitis Bronchiolitis

ALAT Montevideo 2012

New Drugs for COPD

4

Nutrition

Infections

Socio-economic status

Aging Populations

ALAT Montevideo 2012

New Drugs for COPD

Pauwels RA and Rabe KF, Lancet 2004;364:613-620

Adapted from GOLD

ALAT Montevideo 2012

New Drugs for COPD: Why?

Wissam M. et al., Proc Am Thorac Soc 2008;5:549-555

What do Patients with COPD die from?

Author

Mannino et al Hansell et al Camilli et al Huiart et al Anthonisen et al Zielinski et al Waterhouse et al Keistinen et al Vilkman et al Celli et al

Reported causes of mortality in patients with COPD (%)

Site

USA

England Tucson Canada

USA Europe Europe Europe Europe

USA, Spain, Venezuela

Patients with COPD Dying

1.1 million

312,000 86

2,000 149 215 103 973

1,070 162

Cause: COPD (%)

43 60 23 14

<15 38 49 22 30 61

Cause: Cardiovasc (%)

26 26 42 38 25 27 22 37 37 14

Cause: Malign (%)

8 8 9 -

60 7

21 21 20 12

Cause: Other Respiratory (%)

- 4

26 - -

21 - 4 - -

GOLD 2011/2012

Hansel TT, Lancet 2009

ALAT Montevideo 2012

New Drugs for COPD

Innovations for the Teatment of COPD…?

Others

18 month approval assumption for all products. Competitive products could be approved within one review cycle (10 months) resulting in an eight month earlier launch. Flutiform will initially launch with asthma indication

Indacaterol QD LABA

07/10

Aclidinium Br 09/12

LAMA 06/13

QD Advair LABA+ICS

04/14 QD LABA

11/13

Generic Advair BID LABA+ICS

2012

QD Triple

QMF149 QD LABA+ICS

07/14

T+1744 & 1744 Mono LAMA+LABA

01/13

QD LAMA & LAMA+LABA

02/14

Novel Anti-Inflammatory

Agents

1st QD LABA

1st QD LABA+ICS

QD Triple

QD Triple

QVA149 QD LABA+LAMA

06/13

2012 2013 2014 2009 2010 2011 2015 2005-2008

LAMA+ICS LAMA+LABA 06/14

Symbicort First Patent Expires

LABA+ICS 09/2012

Spiriva Patent Expires (1/18)

LABA+ICS

Source: Business Intelligence

Symbicort COPD LABA+ICS (AZ), 02/09

Flutiform (asthma) LABA+ICS

(ABBOTT), 2010

Daxas Oral PDE-IV (QD)

(Nycomed) 2010

QVA 149 -Pharmacotherapy of COPD V3.0

Hansel TT, Lancet 2009

New Drugs for COPD: Role of Exacerbations

Hurst JR et al. N Engl J Med 2010;363:1128-1138

ASSOCIATION OF DISEASE SEVERITY WITH THE FREQUENCY

AND SEVERITY OF EXACERBATIONS

Hurst JR et al. N Engl J Med 2010;363:1128-1138

Vogelmeier C et al. N Engl J Med 2011;364:1093-1103

MACROLIDE (AZITHROMYCIN) STUDY PROPORTION OF PARTICIPANTS FREE OF ACUTE EXACERBATIONS OF COPD

Albert RK et al. N Engl J Med 2011;365:689-698.

Fabbri LM, Rabe KF. Eur Respir J 2008;31:204-212

ALAT Montevideo 2012

New Drugs for COPD

Statin Therapy and Mortality: Peripheral Arterial Disease With Associated COPD

Van Gestel YRBM et al., Am J Cardiol 2008;102:192-196

50

75

100

25

0 0 2 4 6 8 10

No COPD / Statins

No COPD / no Statins

COPD / Statins

COPD / no Statins

Surv

ival

(%)

Follow-up (years) Number at risk No COPD Mild COPD Moderate COPD Severe COPD

1545 476 961 327

1223 348 667 208

1018 224 505 107

824 154 345 60

610 106 229 39

433 55 145 18

Abdominal Obesity and CVD risk

Atherogenic Dyslipidemia Triglycerides HDL cholesterol

Cholesterol/HDL cholesterol ratio "Normal" LDL cholesterol but apo B

Small, dense LDL and HDL Postprandial hyperlipidemia

Insulin Resistance Insulin resistance Hyperinsulinemia

Hyperglycemia Type 2 diabetes

Thrombotic State PAI-1

Fibrinogen

Inflammatory State Leptin CRP

Cytokines Abdominal Obesity Metabolic Risk Factors

Inflammation

Thin fibrous cap

Lipid Core

Coronary Atherosclerosis Unstable Plaque

Adapted from Després JP, et al. Progress in Obesity Research: 9; 2003:29-35.

Risk of Acute Coronary Syndrome

Young RP et al., Eur Respir J 2007;30:616-622

0

2

4

6

8

Odd

s ra

tio

>100 80 - 100 65 - 79 <65

FEV1 % pred

0

10

20

30

40

50

60

70

80

Mor

talit

y ra

te %

<50 50 - 70 70 - 90 90 - 110 >100

FEV1 height adjusted

current smoker ex-smoker never smoker

heavy smoker moderate smoker ex- smoker non-smoker

CV mortality Overall mortality

ALAT Montevideo 2012

New Drugs for COPD

Time to Onset of First Major Adverse CV Event:

Effect of PDE4 Inhibition Roflumilast 500 mcg, od, p.o. + Roflumilast 250 mcg, od p.o.

placebo, od, p.o.

Prob

abili

ty o

f eve

nt

0.00

0.02

0.04

0 30 60 90 120 150 180 210 240 270 300 330 360 390

Days post-randomisation

0.01

0.03

*MACE : CV death, non-fatal MI, non-fatal stroke White WB, et al. submitted

Weight Decrease In Obese Patients with COPD

Percent weight change from baseline to end of treatment by BMI at baseline: pivotal COPD studies pool (SAF)

Calverley PMA, Rabe KF, Goehring UM, et al. Lancet 2009;374:685–694. (supplementary webappendix).

Roflumilast and Glucose Homeostasis in Diabetes

Wouters et al, Endocrinology 2012

Roflumilast and Glucose Homeostasis in Diabetes

Wouters et al, Endocrinology 2012

10/08/2012

Safety and tolerability of NVA237, a Once Daily Long-acting Muscarinic Antagonist, in Patients with COPD

Placebo (n=91) NVA237 100 μg (n=92) NVA237 200 μg (n=98)

Peak FEV1 defined as the maximum value up to 5 hours post-dose Data are presented as least squares mean + SE; *p<0.05 vs placebo

Pea

k FE

V1 (

L) * * * *

1,2

1,4

1,6

1,8

Day 1 Day 28

Stan

dard

ized

AU

C o

f FE

V1

(L)

(5

min

–5

h p

ost-

dose

)

* * * *

1,2

1,4

1,6

1,8

Day 1 Day 28