Leveraging the Genome
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Leveraging the Genome Fact, Fiction, and Ethical Implications. John L. LaMattina, Ph.D. President, Worldwide Research Pfizer Global Research and Development. The Global R&D Challenge. One Pill Must Be Globally Safe and Efficacious Across Racial and Ethnic Groups

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

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John l lamattina ph d president worldwide research pfizer global research and development

Leveraging the GenomeFact, Fiction, and Ethical Implications

John L. LaMattina, Ph.D.

President, Worldwide Research

Pfizer Global Research and Development


The global r d challenge

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


  • Broad portfolio number 1 or 2

    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


    A research based health care company

    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


    John l lamattina ph d president worldwide research pfizer global research and development

    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


    John l lamattina ph d president worldwide research pfizer global research and development

    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


    John l lamattina ph d president worldwide research pfizer global research and development

    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


    John l lamattina ph d president worldwide research pfizer global research and development

    ~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


    John l lamattina ph d president worldwide research pfizer global research and development

    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


    Opportunity to do much more

    Opportunity to Do Much More


    John l lamattina ph d president worldwide research pfizer global research and development

    Molecular Insights into Disease

    Nucleus

    Cell

    Chromosomes

    Nucleotide Base Pairs

    DNA

    Gene

    Switch

    Protein

    Hormones

    Enzymes

    Receptors


    What are practical implications of human genome for drug development

    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


    John l lamattina ph d president worldwide research pfizer global research and development

    Implications of the Genome: Insulin Signaling - 1977


    Glucose transport and storage signaling pathways 2000

    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


    Myths about genomic information

    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


    Ethical issues of genomic information

    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


    Ethical issues patents

    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


    Example of ethical issues snp s

    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


    Example of ethical issues snp s1

    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?


    Some thoughts

    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


    Final thoughts

    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


    Extending our web of alliances

    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


    Summary

    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


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