enhancing the drug discovery pipeline – a perspective on cv drugs
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Enhancing the drug discovery pipeline – a perspective on CV drugs
Patrick VallanceHead 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
1721
31
18 1814
$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
$55
New Drug Approvals (NMEs) PhRMA Member R&D Spending
New
Dru
g Ap
prov
als (N
MEs
)
Phar
ma R
&D
($ b
illio
ns)
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 SquibbNovartis
Johnson & JohnsonSanofi-Aventis
AstraZenecaPfizerWyeth
Eli LillyRoche
Abbott LabsSchering 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 RegulatoryRegulatory
ReviewReviewScale-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
18,8
08
43,9
28
15,3
37
11,5
49
65,2
75
17,7
93
76,8
50
26,8
75
19,4
81 39,9
10
0
10,000
20,000
30,000
40,000
50,000
60,000
70,000
80,000
90,000
Diabete
s
Cance
r
Inflammati
on
Dermato
logy
Metabolis
m/Endocrinology D
rugs
Genito
-Urin
ary
Haemato
logy
Sexual
Dysfuncti
on
Immune S
ystem
Ophthalmic
DrugsCNS
Respira
tory
2005 - 2010 Market Growth p.a.
0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
Diabete
s
Cance
r
Inflammati
on
Dermato
logy
Metabolis
m/Endocrinology D
rugs
Genito
-Urin
ary
Haemato
logy
Sexual
Dysfuncti
on
Immune S
ystem
Ophthalmic
DrugsCNS
Hormone C
ontrol
Cardiova
scular
Respira
tory
Gastro
intestin
al
Anti-Infec
tives
Hormone C
ontrol
Cardiova
scular
Gastro
intestin
al
Anti-Infec
tives
Glo
bal S
ales
$m
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 RegulatoryRegulatory
ReviewReviewScale-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
Month0 1 2 3 4 5 6 7
Plas
ma
Lp-P
LA2 a
ctiv
ity
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
Plaq
ue L
p-PL
A 2 A
ctiv
ity
(nm
ol/m
in/m
g pr
otei
n)
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
OBJECTIVEReduction 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-PLA2 oxLDLLp-PLA2 oxLDLLp-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 RegulatoryRegulatory
ReviewReviewScale-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
Patient need
Market 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
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