John L. LaMattina, Ph.D. President, Worldwide Research Pfizer Global Research and Development

1. Leveraging the GenomeFact, Fiction, and Ethical Implications John L. LaMattina, Ph.D. President, Worldwide Research Pfizer Global Research and Development

2. The Global R&D Challenge • One Pill Must Be Globally Safe and Efficacious • Across Racial and Ethnic Groups • Across Age, Weight, and Sex Differences • One Pill Must Appeal to Global Markets • Different Cultures, Healthcare systems, Distribution systems • One Pill to Pass Global Regulatory Review • MOST Regulated Industry in the World • Must meet regulatory requirements in EVERY country

3. Products Category Lipid-Lowering Hypertension/Angina Arthritis Depression/Anxiety Antibiotic Erectile Dysfunction Seizure Disorders Antifungal Hypertension/BPH Alzheimer’s Disease Allergy Cardiovascular Neurontin Accupril/Accuretic Broad Portfolio - Number 1 or 2 Major Internally Discovered Products

4. A Research-Based Health Care Company Company 4.4 Pfizer 3.8 Glaxo/SmithKline 3.2 Aventis 2.9 Johnson & Johnson 2.7 Novartis 2.6 AstraZeneca Roche 2.4 2.3 Merck Bristol-Myers Squibb 2.0 2000 Total R&D Spending($ Billions) Eli Lilly 2.0 American Home Products 1.7 Schering-Plough 1.3

5. Pharmaceutical R & D - A Multi-Disciplinary Team Administrative Support Analytical Chemistry Animal Health Anti-infective Disease Bacteriology Behavioral Sciences Biochemistry Biology Biometrics Cardiology Cardiovascular Science Clinical Research Communication Computer Science Cytogenetics Developmental Planning DNA Sequencing Diabetology Document Preparation Dosage Form Development Drug Absorption Drug Degradation Drug Delivery Electrical Engineering Electron Microscopy Electrophysiology Environmental Health & Safety Employee Resources Endocrinology Enzymology Facilities Maintenance Fermentation Finance Formulation Gastroenterology Graphic Design Histomorphology Intestinal Permeability Law Library Science Medical Services Mechanical Engineering Medicinal Chemistry Molecular Biology Molecular Genetics Molecular Models Natural Products Neurobiology Neurochemistry Neurology Neurophysiology Obesity Oncology Organic Chemistry Pathology Peptide Chemistry Pharmacokinetics Pharmacology Photochemistry Physical Chemistry Physiology Phytochemistry Planning Powder Flow Process Development Project Management Protein Chemistry Psychiatry Public Relations Pulmonary Physiology Radiochemistry Radiology Robotics Spectroscopy Statistics Sterile Manufacturing Tabletting Taxonomy Technical Information Toxicology Transdermal Drug Delivery Veterinary Science Virology X-ray Spectroscopy Over 100 Different Disciplines Working Together

6. Development Process Starts with Many Hypotheses Prevent Amyloid Plaques Block Glutamate Neurotoxicity Attenuate Neuro-inflammation Stabilize Neuronal Infrastructure Stop Programmed Cell Death Alzheimer’s Disease

7. Registration Clinical Data Analysis Full Development Studies in 100-300 Patients (Phase II) Candidate Medicine Tested in 3-10,000 Patients (Phase III) Large Amounts of Candidate Medicine Synthesized Extensive Safety Studies Candidate Studies in Healthy Volunteers Phase I Formulations Developed Exploratory Development Early Safety Studies Project Team and Plans Synthesis of Compounds Screening Discovery The Long Road to a New Medicine

8. ~100 Discovery Approaches High Risk Process: 11-15 Years, $800MM+ Millions of Compounds Screened Preclinical Pharmacology Preclinical Safety 1 - 2 Products Clinical Pharmacology & Safety Discovery Exploratory Development Full Development Phase I Phase II Phase III 0 15 10 5 Idea Drug 11 - 15 Years

9. Innovation Process Difficult • Complex Disease Targets • Too Long in Body • Adverse Reactions • Poor Absorption • Low Levels in Body • Not Effective Enough • Not Sufficiently Selective • Side Effects • Unsafe • Unstable • Competition • Impractical To Make Most Compounds Do Not Become Medicines

10. Opportunity to Do Much More

11. Molecular Insights into Disease Nucleus Cell Chromosomes Nucleotide Base Pairs DNA Gene Switch Protein Hormones Enzymes Receptors

12. What Are Practical Implications of Human Genome for Drug Development? • Increase in targets from ~ 450 to > 4000. • Can Focus on Human Receptors, Ligands. • Potentially develop more specific medicines. • However: • Exploring New Mechanisms takes time and $ • New Technologies are very expensive • No guarantee that they will lead to new medicines

13. Implications of the Genome: Insulin Signaling - 1977

14. Glucose transport and storage Signaling pathways - 2000 IR Glucose PI3P PI3K Muscle Contraction IRS-P PTP-1B PTEN SHIP ? PDK-1 ? Other Ser/Thr kinases ? ? AMPK NOS PKB PKC z, l [NO] GSK3 Guanylyl Cyclase GS [active] GS-PP [inactive] PP1 [cGMP] PDE Glycogenin Glycogen Synthesis

15. Myths about Genomic Information • It will lower the cost of drug development • Technology is expensive • Mechanisms poorly understood • More targets = More Cost • We can use it to develop “magic bullets” • Chronic disease complicated, multifaceted • Multiple genes frequently involved • Environment, behavior remain important • Sometimes determinative

16. Ethical Issues of Genomic Information • Who owns the data? • Government? • Individuals? • Companies? • Who Collects the data? Who pays? • How will the data be used? • Insurance issues • Privacy issues • Discrimination

17. Ethical Issues: Patents • Diamond v. Chakrabarty, 1980 • Biological organism can be patented • The Great Sequence Hunt • Positives - competition pushed sequencing • Negatives - what value was created? • Recent Ruling • Sequence not controlling, must have function

18. Example of Ethical Issues: SNP’s • Single nucleotide polymorphisms (SNP’s) • Can identify individual risk profile for various diseases • Could be used to screen patients for clinical trials - improve safety • Broad screening can provide important insights into population genetics • Each individual could have “tailored” drugs

19. Example of Ethical Issues: SNP’s • Who should pay for the screening? • Government? • Private companies? • Once you have broadly screened the population, what is societal obligation to treat? • Should you screen for diseases for which there is no cure? (Huntington’s, e.g.). • What about “artificial” selection?

20. Some Thoughts • New Area of Ethical Discussion • Need complete transparency • HIPPA rules promulgated, now to be implemented • Need “opt-in” system, not “opt-out” • Presumption of privacy should be preserved • Education is critical - complex issues with many facets - public good versus private rights • Different cultural contexts must be respected

21. Final Thoughts • Genomic Technologies show great promise but require enormous resources. • Ethical Issues Real • Transparent processes critical to public support • Support for Research Critical • Price Control Threats • We Can’t Do it Alone

22. IBIS Mass. General Cornell Univ. Aurora Neurogen Washington Univ. Trans- genics X-Ray HumAb Yale Abgenix UTHS Chip Technology Harvard Rigel Gene Therapy ArQule Rockefeller Univ. Molecular Modeling Xenon Combina- torial Libraries Celera Univ. of Washington Genomics MIT Chemical Diversity Johns Hopkins Incyte Evotec Extending our Web of Alliances

23. Summary • Genomics will play an important role in developing new medicines • Costs will increase, at least in the short term • Ethical issues daunting • Support for R&D more critical than ever • Price controls in the US would devastate innovation • Good public health is expensive, and worth it