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Enhancing the drug discovery pipeline – a perspective on CV drugs

Enhancing the drug discovery pipeline – a perspective on CV drugs. Patrick Vallance Head of Drug Discovery, GSK. New Medicines. A disconnect between discovery and invention?. Scientific publications in biomedicine. R&D Productivity Gap.

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Enhancing the drug discovery pipeline – a perspective on CV drugs

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  1. Enhancing the drug discovery pipeline – a perspective on CV drugs Patrick Vallance Head of Drug Discovery, GSK

  2. New Medicines A disconnect between discovery and invention? Scientific publications in biomedicine

  3. R&D Productivity Gap Source: Burrill & Company; US Food and Drug Administration. Note: NMEs do not include BLAs

  4. The realities of having the best pipeline Pipeline renews 60% of sales Lehman Brothers PharmaPipelines (Sept 2007) Pharma Replacement Power – NPV GlaxoSmithKline Merck Bristol Myers Squibb Novartis Johnson & Johnson Sanofi-Aventis AstraZeneca Pfizer Wyeth Eli Lilly Roche Abbott Labs Schering Plough AVERAGE LB Method: [NPV of recent launches (06-07) + NPV of pipeline opportunities from ‘08-’13] / NPV of products marketed before 2006.

  5. R&D for a New Medicine: 10+ years, $1 bn+ … a big challenge for addressing both developed and developing world diseases RegulatoryReview Drug Discovery Post-MarketingSurveillance Scale-Up to Manufacture Preclinical Clinical Trials PhaseIII PhaseI Phase II ~ 5,000 – 10,000 250 5 1Approved NewMedicine Compounds Pre-Discovery IND Submitted NDA Submitted Number Of Patients / Subjects 20 – 100 100 – 500 1,000 – 5,000 0.5 – 2 Years Indefinite 3 – 6 Years 6 – 7 Years Sources: Drug Discovery and Development: Understanding the R&D Process, www.innovation.org; CBO, Research and Development in the Pharmaceutical Industry, 2006

  6. Reintroduce Scientific Judgement

  7. Evolution From Monolith CEEDD CEDD/DPUs External Virtualization of Drug Discovery Pharma Internal Centralized Control/Management De-Centralized Control/Management

  8. The Market Anti-Infectives Cardiovascular Gastrointestinal Hormone Control 2005 - 2010 Market Growth p.a. 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% CNS Cancer Diabetes Respiratory Dermatology Inflammation Haematology Anti-Infectives Genito-Urinary Cardiovascular Immune System Gastrointestinal Hormone Control Ophthalmic Drugs Sexual Dysfunction Metabolism/Endocrinology Drugs 2006 Estimated Global Sales 90,000 80,000 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. 70,000 60,000 50,000 Global Sales $m 40,000 76,850 65,275 30,000 43,928 39,910 20,000 26,875 19,481 18,808 10,000 17,793 15,337 11,549 0 CNS Cancer Diabetes Respiratory Dermatology Inflammation Haematology Genito-Urinary Immune System Ophthalmic Drugs Sexual Dysfunction Metabolism/Endocrinology Drugs Diabetes, cancer and inflammation projected to be the biggest growth opportunities Source: Pharma Pipelines – Strategic Analysis and Conclusions 2006 – Lehman Brothers

  9. Separately, composite median lead project interval duration times by phase of development for CV&M are as follows Source: CMR International, 2006 Global R&D Performance Metrics Programme Report, May 2006

  10. R&D for a New Medicine: 10+ years, $1 bn+ … a big challenge for addressing both developed and developing world diseases RegulatoryReview Drug Discovery Post-MarketingSurveillance Scale-Up to Manufacture Preclinical Clinical Trials PhaseIII PhaseI Phase II ~ 5,000 – 10,000 250 5 1Approved NewMedicine Compounds Pre-Discovery IND Submitted NDA Submitted Number Of Patients / Subjects 20 – 100 100 – 500 1,000 – 5,000 0.5 – 2 Years Indefinite 3 – 6 Years 6 – 7 Years Sources: Drug Discovery and Development: Understanding the R&D Process, www.innovation.org; CBO, Research and Development in the Pharmaceutical Industry, 2006

  11. Role of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) in Atherosclerosis and its Potential as a Therapeutic Target

  12. Elevated Lp-PLA2 is Consistently Associated with Increased Risk for Cardiovascular Disease Corson et al.Am J Cardiol. 2008;101(suppl):41F-50F. 2 0.5 1 1.5 2.5 3 3.5 4 4.5

  13. Lp-PLA2 is greatly up-regulated in high risk coronary artery lesions H&E staining Lp-PLA2 IHC Kolodgie et al Arterioscler Thromb Vasc Biol. 2006:26:2523

  14. Darapladib Reduced Complexity of Coronary Lesions in DM/HC Swine A. Two animals from Control group • Large necrotic core (NC) • Medial destruction (arrow) NC NC B. Two animals from Darapladib-treated • No/little necrotic core • Smaller lesions • Intact media • Reduced macrophages Two worst proximal LAD Lesions

  15. Darapladib HL/DM Porcine Study: Plasma Lp-PLA2 Activity Induction Treatment Diabetes + Hypercholesterolemia

  16. Pre-surgical dosing (14 days) in patients undergoing carotid endarterectomy A. Lp-PLA2 * * n=30 n=30 n=29 Direct inhibition in plaque with an Lp-PLA2 inhibitor

  17. 0.16 mm2, 2% Baseline 0.56 mm2, 7% 1.74 mm2, 23% 5.18 mm2, 68% 0.42 mm2, 7% Follow-up 1.94 mm2, 30% 3.59 mm2, 54% 0.56 mm2, 9% Placebo: Necrotic Core Progression

  18. Lp-PLA2 : The current evidence Intervention with darapladib Association studies PRECLINICAL: reduces coronary atherosclerosis (DM/HC pig) EPIDEMIOLOGY: higher plasma levels predict CV events HUMAN ATHEROMA: downregulates plaque Lp-PLA2 activity PATHOLOGY: upregulation of Lp-PLA2 in TCFA and ruptured VP SYSTEMIC EFFECTS: sustained inhibition of Lp-PLA2 activity on background of intensive statin therapy OBJECTIVE Reduction in CV events with an Lp-PLA2 inhibitor FUNCTIONAL: higher plasma Lp-PLA2 levels  coronary endo dysfunction CORONARY IMAGING: IBIS-2 OUTCOMES TRIALS: High risk 2o prevention population

  19. R&D for a New Medicine: 10+ years, $1 bn+ … a big challenge for addressing both developed and developing world diseases RegulatoryReview Drug Discovery Post-MarketingSurveillance Scale-Up to Manufacture Preclinical Clinical Trials PhaseIII PhaseI Phase II ~ 5,000 – 10,000 250 5 1Approved NewMedicine Compounds Pre-Discovery IND Submitted NDA Submitted Number Of Patients / Subjects 20 – 100 100 – 500 1,000 – 5,000 0.5 – 2 Years Indefinite 3 – 6 Years 6 – 7 Years Sources: Drug Discovery and Development: Understanding the R&D Process, www.innovation.org; CBO, Research and Development in the Pharmaceutical Industry, 2006

  20. How should we choose where to invest discovery effort? External Internal Scientific Opportunity Market size Pipeline strength Organisational structure Patient need

  21. New Medicines A disconnect between discovery and invention? Scientific publications in biomedicine The opportunity has never been greater

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