Enhancing the drug discovery pipeline – a perspective on CV drugs

Patrick Vallance

Head of Drug Discovery, GSK

Scientific publications in biomedicine

A disconnect between discovery and invention?

New Medicines

Source: Burrill & Company; US Food and Drug Administration.Note: NMEs do not include BLAs

26 2522

28

53

39

30

35

2724

17

21

31

18 18

14

$12 $13 $13$15

$17$19

$21$23

$26

$30$32 $33

$39 $39

$43

$54

0

10

20

30

40

50

60

0

5

10

15

20

25

30

35

40

45

50

$55

New Drug Approvals (NMEs) PhRMA Member R&D Spending

New

Dru

g App

rova

ls (N

MEs)

Pha

rma

R&

D ($

billi

ons)

92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07

R&D Productivity Gap

The realities of having the best pipeline

0.0x 0.1x 0.2x 0.3x 0.4x 0.5x 0.6x 0.7x

Lehman Brothers PharmaPipelines (Sept 2007)Pharma Replacement Power – NPV

Pipeline renews 60% of sales

LB Method: [NPV of recent launches (06-07) + NPV of pipeline opportunities from ‘08-’13] / NPV of products marketed before 2006.

GlaxoSmithKlineMerck

Bristol Myers Squibb

Novartis

Johnson & Johnson

Sanofi-Aventis

AstraZeneca

Pfizer

Wyeth

Eli Lilly

Roche

Abbott Labs

Schering Plough

AVERAGE

R&D for a New Medicine: 10+ years, $1 bn+

Sources: Drug Discovery and Development: Understanding the R&D Process, www.innovation.org; CBO, Research and Development in the Pharmaceutical Industry, 2006

IndefiniteIndefinite

Drug Drug DiscoveryDiscovery PreclinicalPreclinical Clinical TrialsClinical Trials

RegulatoryRegulatoryReviewReview

Scale-Up to Scale-Up to ManufactureManufacture

Post-Post-MarketingMarketing

SurveillanceSurveillance

1Approved

NewMedicine

0.5 – 2 0.5 – 2 YearsYears6 – 7 Years6 – 7 Years3 – 6 Years3 – 6 Years

Number Of Patients / Subjects

PhasePhaseII

PhasePhaseIIII

PhasePhaseIIIIII

55250250~ 5,000 – ~ 5,000 – 10,00010,000

CompoundsCompounds

Pre

-Dis

cove

ryP

re-D

isco

very

20 – 100

100 – 500 1,000 – 5,000

IND

Sub

mitt

ed

ND

A S

ubm

itted

… … a big challenge for addressing both developed and developing world diseasesa big challenge for addressing both developed and developing world diseases

Reintroduce Scientific Judgement

CEEDD

Evolution From Monolith

Virtualization of Drug

Discovery

External

Internal

CEDD/DPUs

Pharma

CentralizedControl/Management

De-CentralizedControl/Management

The Market

Source: Pharma Pipelines – Strategic Analysis and Conclusions 2006 – Lehman Brothers

The Lehman Brothers analysis of predicted global sales for 2006 does not include generic drugs and estimates that their database captures 80% of branded drug sales.

Diabetes, cancer and inflammation projected to be the biggest growth opportunities

2006 Estimated Global Sales

18,

808

43,

928

15,

337

11,

549

65,

275

17,

793

76,

850

26,

875

19,

481

39,

910

0

10,000

20,000

30,000

40,000

50,000

60,000

70,000

80,000

90,000

Diabet

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Cance

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Derm

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Met

abolis

m/E

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Sexual

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mic

Dru

gs

CNS

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tory

2005 - 2010 Market Growth p.a.

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

Diabet

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r

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Separately, composite median lead project interval duration times by phase of development for CV&M are as follows

1.5

2.0

1.1

1.2

1.2

0.8

1.9

2.2

0.8

2.2

2.0

1.3

2.3

4.4

1.6

1.8

1.7

1.5

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0

CV

Cardiac therapy

Lipid lowering

Metabolics

Diabetes

Obesity

Median Project Interval Duration Times in Years, 2001-2005

Phase 1 Phase 2 Phase 3

Source: CMR International, 2006 Global R&D Performance MetricsProgramme Report, May 2006

R&D for a New Medicine: 10+ years, $1 bn+

Sources: Drug Discovery and Development: Understanding the R&D Process, www.innovation.org; CBO, Research and Development in the Pharmaceutical Industry, 2006

IndefiniteIndefinite

Drug Drug DiscoveryDiscovery PreclinicalPreclinical Clinical TrialsClinical Trials

RegulatoryRegulatoryReviewReview

Scale-Up to Scale-Up to ManufactureManufacture

Post-Post-MarketingMarketing

SurveillanceSurveillance

1Approved

NewMedicine

0.5 – 2 0.5 – 2 YearsYears6 – 7 Years6 – 7 Years3 – 6 Years3 – 6 Years

Number Of Patients / Subjects

PhasePhaseII

PhasePhaseIIII

PhasePhaseIIIIII

55250250~ 5,000 – ~ 5,000 – 10,00010,000

CompoundsCompounds

Pre

-Dis

cove

ryP

re-D

isco

very

20 – 100

100 – 500 1,000 – 5,000

IND

Sub

mitt

ed

ND

A S

ubm

itted

… … a big challenge for addressing both developed and developing world diseasesa big challenge for addressing both developed and developing world diseases

11

Role of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) in

Atherosclerosis and its Potential as a Therapeutic Target

Elevated Lp-PLA2 is Consistently Associated with Increased Risk for Cardiovascular Disease

Packard (WOSCOPS) – CAD2000

Blake (WHS) – CAD 2001Blankenberg (AtheroGENE) – CAD 2003Ballantyne (ARIC) – CHD (LDL < 130) 2004Winkler – CAD 2004Oei (ROTTERDAM) – CAD 2005Brilakis (Mayo Heart) – CAD 2005Ballantyne (ARIC) – Stroke 2005Oei (ROTTERDAM) – Stroke 2005Winkler (LURIC) – CAD 2005Khuseyinova (HELICOR) – CAD 2005Koenig (KAROLA) – CVD 2005May (Intermountain Heart) – CAD 2006Caslake (PROSPER) – CVD 2006Jenny (CHS) – MI 2006Daniels (Rancho Bernardo) – CAD 2006Elkind (NOMAS) – Stroke 2006O’Donoghue (PROVE IT) - CVD 2006Corsetti (THROMBO) - CAD 2006Gerber (Olmsted Cty) – Death post MI 2006Oldren (GUSTO/FRISK) – ACS 2007Sabatine (PEACE) – CVD 2007Persson (Malmo) – CVD 2007Möckel (NOBIS-II) – CVD 2007Hatoum (NHS) – CVD 2007

0.5 4.51 1.5 2 2.5 3 3.5 4CorsonCorson et al. et al. Am J Cardiol. 2008;101(suppl):41F-50F.Am J Cardiol. 2008;101(suppl):41F-50F.

Kolodgie et al Arterioscler Thromb Vasc Biol. 2006:26:2523

Lp-PLA2 is greatly up-regulated in high risk coronary artery lesions

Lp-PLA2

IHC

H&E

staining

B. Two animals from Darapladib-treated

A. Two animals from Control group

Two worst proximal LAD Lesions

Darapladib Reduced Complexity of Coronary Lesions in DM/HC Swine

NC NC

▪ No/little necrotic core▪ Smaller lesions▪ Intact media▪ Reduced macrophages

▪ Large necrotic core (NC)▪ Medial destruction (arrow)

15

Darapladib HL/DM Porcine Study: Plasma Lp-PLA2 Activity

Month

0 1 2 3 4 5 6 7

Pla

sm

a L

p-P

LA

2 a

cti

vit

y

0

20

40

60

80

100

120

Control (n=17)

SB480848 (n=20)

Induction Treatment Diabetes +Hypercholesterolemia

16

Direct inhibition in plaque with an Lp-PLA2 inhibitor

Pre-surgical dosing (14 days) in patients undergoing carotid endarterectomy

placebo low dose high dose

Pla

qu

e L

p-P

LA

2 A

cti

vit

y

(nm

ol/m

in/m

g p

rote

in)

0

0.2

0.4

0.6

0.8

1A. Lp-PLA2

n=30 n=29n=30

*

*

Baseline

Follow-up

3.59 mm2, 54%0.56 mm2,

9%

1.94 mm2, 30%

0.42 mm2,7%

5.18 mm2, 68%

1.74 mm2, 23%

0.56 mm2, 7%

0.16 mm2, 2%

Placebo: Necrotic Core Progression

Lp-PLA2 : The current evidence

PRECLINICAL: reduces coronary atherosclerosis (DM/HC pig)

HUMAN ATHEROMA:

downregulates plaque Lp-PLA2 activity

SYSTEMIC EFFECTS:sustained inhibition of Lp-PLA2

activity on background of intensive statin therapy

FUNCTIONAL:higher plasma Lp-PLA2 levels coronary endo dysfunction

PATHOLOGY:

upregulation of Lp-PLA2 in TCFA and ruptured VP

EPIDEMIOLOGY: higher plasma levels predict CV events

OBJECTIVE

Reduction in CV events with an Lp-PLA2

inhibitor

CORONARY IMAGING:

IBIS-2

Association studies

OUTCOMES TRIALS:

High risk 2o prevention population

Intervention with darapladib

oxLDLLp-PLA2oxLDLLp-PLA2oxLDLLp-PLA2

R&D for a New Medicine: 10+ years, $1 bn+

Sources: Drug Discovery and Development: Understanding the R&D Process, www.innovation.org; CBO, Research and Development in the Pharmaceutical Industry, 2006

IndefiniteIndefinite

Drug Drug DiscoveryDiscovery PreclinicalPreclinical Clinical TrialsClinical Trials

RegulatoryRegulatoryReviewReview

Scale-Up to Scale-Up to ManufactureManufacture

Post-Post-MarketingMarketing

SurveillanceSurveillance

1Approved

NewMedicine

0.5 – 2 0.5 – 2 YearsYears6 – 7 Years6 – 7 Years3 – 6 Years3 – 6 Years

Number Of Patients / Subjects

PhasePhaseII

PhasePhaseIIII

PhasePhaseIIIIII

55250250~ 5,000 – ~ 5,000 – 10,00010,000

CompoundsCompounds

Pre

-Dis

cove

ryP

re-D

isco

very

20 – 100

100 – 500 1,000 – 5,000

IND

Sub

mitt

ed

ND

A S

ubm

itted

… … a big challenge for addressing both developed and developing world diseasesa big challenge for addressing both developed and developing world diseases

ScientificOpportunity

ScientificOpportunity

Patient needPatient need

Market sizeMarket size

How should we choose where to invest discovery effort?

External Internal

Pipeline strength

Organisationalstructure

Scientific publications in biomedicine

A disconnect between discovery and invention?

New Medicines

The opportunity has never been greater