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

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

Townsend, Emru, Contributing Writer has reference to this Academic Journal, PHwiki organized this Journal 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 in addition to invention Source: Burrill & Company; US Food in addition to Drug Administration. Note: NMEs do not include BLAs R&D Productivity Gap

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The realities of having the best pipeline Lehman Brothers PharmaPipelines (Sept 2007) Pharma Replacement Power – NPV LB Method: [NPV of recent launches (06-07) + NPV of pipeline opportunities from ‘08-’13] / NPV of products marketed be as long as e 2006. GlaxoSmithKline Merck Bristol Myers Squibb Novartis Johnson & Johnson Sanofi-Aventis AstraZeneca Pfizer Wyeth Eli Lilly Roche Abbott Labs Schering Plough AVERAGE R&D as long as a New Medicine: 10+ years, $1 bn+ Sources: Drug Discovery in addition to Development: Underst in addition to ing the R&D Process, www.innovation.org; CBO, Research in addition to Development in the Pharmaceutical Industry, 2006 Indefinite Drug Discovery Preclinical Clinical Trials Regulatory Review Scale-Up to Manufacture Post-Marketing Surveillance 1 Approved New Medicine 0.5 – 2 Years 6 – 7 Years 3 – 6 Years Number Of Patients / Subjects Phase I Phase II Phase III 5 250 ~ 5,000 – 10,000 Compounds Pre-Discovery 20 – 100 100 – 500 1,000 – 5,000 IND Submitted NDA Submitted a big challenge as long as addressing both developed in addition to developing world diseases Reintroduce Scientific Judgement

Evolution From Monolith Virtualization of Drug Discovery External Internal Pharma Centralized Control/Management De-Centralized Control/Management The Market Source: Pharma Pipelines – Strategic Analysis in addition to Conclusions 2006 – Lehman Brothers The Lehman Brothers analysis of predicted global sales as long as 2006 does not include generic drugs in addition to estimates that their database captures 80% of br in addition to ed drug sales. Diabetes, cancer in addition to 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 Diabetes Cancer Inflammation Dermatology Metabolism/Endocrinology Drugs Genito-Urinary Haematology Sexual Dysfunction Immune System Ophthalmic Drugs CNS Respiratory Global Sales $m Separately, composite median lead project interval duration times by phase of development as long as CV&M are as follows Source: CMR International, 2006 Global R&D Per as long as mance Metrics Programme Report, May 2006

R&D as long as a New Medicine: 10+ years, $1 bn+ Sources: Drug Discovery in addition to Development: Underst in addition to ing the R&D Process, www.innovation.org; CBO, Research in addition to Development in the Pharmaceutical Industry, 2006 Indefinite Drug Discovery Preclinical Clinical Trials Regulatory Review Scale-Up to Manufacture Post-Marketing Surveillance 1 Approved New Medicine 0.5 – 2 Years 6 – 7 Years 3 – 6 Years Number Of Patients / Subjects Phase I Phase II Phase III 5 250 ~ 5,000 – 10,000 Compounds Pre-Discovery 20 – 100 100 – 500 1,000 – 5,000 IND Submitted NDA Submitted a big challenge as long as addressing both developed in addition to developing world diseases Role of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) in Atherosclerosis in addition to its Potential as a Therapeutic Target Elevated Lp-PLA2 is Consistently Associated with Increased Risk as long as Cardiovascular Disease 0.5 4.5 1 1.5 2 2.5 3 3.5 4 Corson et al. 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) Darapladib HL/DM Porcine Study: Plasma Lp-PLA2 Activity Induction Treatment Diabetes + Hypercholesterolemia

Direct inhibition in plaque with an Lp-PLA2 inhibitor Pre-surgical dosing (14 days) in patients undergoing carotid endarterectomy 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 in addition to 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

R&D as long as a New Medicine: 10+ years, $1 bn+ Sources: Drug Discovery in addition to Development: Underst in addition to ing the R&D Process, www.innovation.org; CBO, Research in addition to Development in the Pharmaceutical Industry, 2006 Indefinite Drug Discovery Preclinical Clinical Trials Regulatory Review Scale-Up to Manufacture Post-Marketing Surveillance 1 Approved New Medicine 0.5 – 2 Years 6 – 7 Years 3 – 6 Years Number Of Patients / Subjects Phase I Phase II Phase III 5 250 ~ 5,000 – 10,000 Compounds Pre-Discovery 20 – 100 100 – 500 1,000 – 5,000 IND Submitted NDA Submitted a big challenge as long as addressing both developed in addition to developing world diseases Scientific Opportunity Patient need Market size How should we choose where to invest discovery ef as long as t External Internal Pipeline strength Organisational structure

Scientific publications in biomedicine A disconnect between discovery in addition to invention The opportunity has never been greater

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