Pharmaceutical Products R

1
Leveraging the GenomeFact, Fiction, and Ethical
Implications
John L. LaMattina, Ph.D. President, Worldwide
Research Pfizer Global Research and Development
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The Global RD 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
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 RD Spending( Billions)
Eli Lilly
2.0
American Home Products
1.7
Schering-Plough
1.3
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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
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Development Process Starts with Many Hypotheses
Prevent Amyloid Plaques
Block Glutamate Neurotoxicity
Attenuate Neuro-inflammation
Stabilize Neuronal Infrastructure
Stop Programmed Cell Death
Alzheimers Disease
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The Long Road to a New Medicine
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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
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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
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Consolidation Trends
Shrinking Ranks - 1988 PMA Members
Still Independent
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Opportunity to Do Much More
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Molecular Insights into Disease
Nucleus
Cell
Chromosomes
Nucleotide Base Pairs
DNA
Gene
Switch
Protein
Hormones
Enzymes
Receptors
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What Are Practical Implications of Human Genome
for Drug Development?

• Increase in targets from 450 to gt 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

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Implications of the Genome Insulin Signaling -
1977
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Glucose transport and storage Signaling pathways
- 2000
IR
Glucose
PI3P
PI3K
Muscle Contraction
IRS-P
PTP-1B
PTEN
PDK-1
?
SHIP
?
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
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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

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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

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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

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Example of Ethical Issues SNPs

• Single nucleotide polymorphisms (SNPs)
• 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

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Example of Ethical Issues SNPs

• 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? (Huntingtons, e.g.).
• What about artificial selection?

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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

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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 Cant Do it Alone

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Extending our Web of Alliances
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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 RD more critical than ever
• Price controls in the US would devastate
  innovation
• Good public health is expensive, and worth it