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John L. LaMattina, Ph.D.President, Worldwide Research

Pfizer Global Research and Development

John L. LaMattina, Ph.D.President, Worldwide Research

Pfizer Global Research and Development

Leveraging the Genome

Fact, Fiction, and Ethical Implications

Leveraging the Genome

Fact, Fiction, and Ethical Implications

WPI 3/2002

The Global R&D ChallengeThe 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

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

WPI 3/2002

Lipid-Lowering Hypertension/Angina

Arthritis

Depression/Anxiety

Antibiotic

Erectile Dysfunction

Seizure Disorders

Antifungal

Hypertension/BPH

Alzheimer’s Disease

Allergy

Cardiovascular

Lipid-Lowering Hypertension/Angina

Arthritis

Depression/Anxiety

Antibiotic

Erectile Dysfunction

Seizure Disorders

Antifungal

Hypertension/BPH

Alzheimer’s Disease

Allergy

Cardiovascular

ProductsProducts CategoryCategory

NeurontinNeurontin

Accupril/AccureticAccupril/Accuretic

Major Internally Discovered ProductsMajor Internally Discovered Products

Broad Portfolio - Number 1 or 2 Broad Portfolio - Number 1 or 2

WPI 3/2002

A Research-Based Health Care Company

CompanyCompany

2000 Total R&D Spending($ Billions)

2000 Total R&D Spending($ Billions)

Aventis

Johnson & Johnson

Schering-Plough

4.4

3.8

2.9

3.2

Pfizer

Glaxo/SmithKline

1.3

Novartis

AstraZeneca

Roche

Merck

Bristol-Myers Squibb

Eli Lilly

American Home Products

2.7

2.6

2.4

2.3

2.0

2.0

1.7

WPI 3/2002

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

Pharmaceutical R & D - A Multi-Disciplinary Team

Over 100Over 100

DifferentDifferent

DisciplinesDisciplines

Working TogetherWorking Together

WPI 3/2002

Development Process Starts with Many Hypotheses

Attenuate Neuro-inflammationAttenuate Neuro-inflammation

Stop Programmed Cell DeathStop Programmed Cell Death

Prevent Amyloid Plaques Prevent Amyloid Plaques

Block Glutamate NeurotoxicityBlock Glutamate Neurotoxicity

Stabilize Neuronal Infrastructure Stabilize Neuronal Infrastructure

Alzheimer’s DiseaseAlzheimer’s Disease

WPI 3/2002

DiscoveryDiscovery

Exploratory DevelopmentExploratory Development

Full Full DevelopmentDevelopment

RegistrationRegistration

Large Amounts ofCandidate Medicine

Synthesized

Project Teamand Plans

Synthesisof Compounds

EarlySafety

Studies

CandidateFormulations

Developed

ExtensiveSafety

Studies

Screening

Studies in HealthyVolunteers Phase I

Candidate Medicine Tested in3-10,000 Patients (Phase III)

Studies in 100-300Patients (Phase II)

Clinical DataAnalysis

The Long Road to a New Medicine

WPI 3/2002

High Risk Process: 11-15 Years, $800MM+

Preclinical Pharmacology

Preclinical Safety

Millions ofCompounds Screened

IdeaIdea DrugDrug11 - 15 Years

1 - 2 1 - 2 ProductsProducts

DiscoveryDiscovery Exploratory DevelopmentExploratory Development Full DevelopmentFull Development

Phase I Phase II Phase III

00 151555 1010

Clinical Pharmacology& Safety

~100 Discovery Approaches~100 Discovery Approaches~100 Discovery Approaches~100 Discovery Approaches

WPI 3/2002

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 Most

Compounds Compounds

Do Not BecomeDo Not Become

MedicinesMedicines

WPI 3/2002

Opportunity to Do Much MoreOpportunity to Do Much More

WPI 3/2002

Molecular Insights into Disease

Cell Chromosomes

DNA

GeneSwitch

Nucleotide Base Pairs

Protein

Receptors

HormonesEnzymes

Nucleus

WPI 3/2002

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

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

WPI 3/2002

Implications of the Genome: Insulin Signaling - 1977

WPI 3/2002

Glucose transport and storage Signaling pathways - 2000Glucose transport and storage Signaling pathways - 2000

WPI 3/2002

Myths about Genomic InformationMyths 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

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

WPI 3/2002

Ethical Issues of Genomic InformationEthical 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

Who owns the data?

Government?

Individuals?

Companies?

Who Collects the data? Who pays?

How will the data be used?

Insurance issues

Privacy issues

Discrimination

WPI 3/2002

Ethical Issues: PatentsEthical 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

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

WPI 3/2002

Example of Ethical Issues: SNP’sExample 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

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

WPI 3/2002

Example of Ethical Issues: SNP’sExample 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?

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?

WPI 3/2002

Some ThoughtsSome 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

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

WPI 3/2002

Final ThoughtsFinal 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

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

WPI 3/2002

Extending our Web of AlliancesExtending our Web of Alliances

X-RayX-Ray

UTHSUTHS

Trans-Trans-genicsgenics HumAbHumAb

ChipChipTechnologyTechnology

MolecularMolecularModelingModeling

GeneGeneTherapyTherapy

GenomicsGenomicsChemicalChemicalDiversityDiversity

Combina-Combina-torialtorial

LibrariesLibraries

Mass. Mass. GeneralGeneral CornellCornell

Univ.Univ.

HarvardHarvard

YaleYale

MITMIT

Washington Washington Univ.Univ.

RockefellerRockefellerUniv.Univ.

Univ. ofUniv. ofWashingtonWashington

RigeRigell

IBISIBIS

NeurogenNeurogen

CeleraCelera

EvotecEvotec IncyteIncyte

XenonXenon

ArQuleArQule

AuroraAurora

AbgenixAbgenix

JohnsJohns HopkinsHopkins

WPI 3/2002

SummarySummary

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

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