Integrating Time and Information

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Integrating Time and Information

• Peter N Goodfellow

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The four ages of a scientist

• Active experimentalist
• Professional fund raiser
• Philosopher
• Gardener

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Productivity and the problem facing the
pharmaceutical industry
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The success
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20th Century health achievements

• Vaccination
• Control of infectious diseases
• Decline in deaths from coronary heart disease and
  stroke
• Family planning
• Healthier mothers and babies
• Fluoridation of drinking water
• Safer and healthier foods
• Recognition of tobacco use as a health hazard
• Motor vehicle safety
• Safer workplaces
• Source CDC MMWR April 02, 1999 /
  48(12)241-243 http//www.cdc.gov/mmwr/preview/mm
  wrhtml/00056796.htm

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Dying of different diseases success in treating
major diseases
1900
1997
of all deaths, USA
of all deaths, USA
Then vs. Now - in the West
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Beating a modern plague...
AIDS prevalence and deaths, 1985-2001 (USA)
90
400
AIDS deaths
80
350
AIDS prevalence
70
300
60
250
50
Number of cases (in thousands)
Prevalence (in thousands)
200
40
150
30
100
20
50
10
0
0
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
Year of diagnosis or death
Source Center for Disease Control, USA
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The problem
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NIH funding history
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Declining output of medicines
240
220
RD expenditure
200
180
160
Indexed RD expenditure (1991 100)
140
120
100
80
Global NME output
60
40
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
Year
10
Source CMR Institute for Regulatory Science, 2002
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The challenges to RD

• Rapid escalation of the costs of RD The cost
  of new technology?
• Higher risks of failure associated with greater
  innovation The products of new technology?
• Global tightening of regulatory policy The fear
  of new technology?

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Drug DiscoveryFinding a Molecule that
Satisfies Multiple Criteria
1 Drug Molecule
manufacturable
patentable
non-mutagenic
non-teratogenic
durable
reversible
non-inducing
metabolically stable
permeable
soluble
physically stable
potent
10,000 Drug Candidates
selective
Valid Biomedical Hypothesis?
targeted
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Drug Development Finding a Drug That is Safe and
Effective
1 Drug Launch
Regulatory filing
Competitive profile
Cost-effective manufacturing
Carcinogenicity studies
Long-term safety
Efficacy
Side effect profile
Dosing ranges
Patient recruitment
Trial sites and investigators
Stability
Formulation
10 Drug Molecules
Safe and active in lab and animal models
All discovery criteria met
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The real problem..
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U.S. Cancer Statistics
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Scheme for making monoclonal antibody to EGF
receptor
Monoclonal
Mouse cells
Antibodies
Mouse human chromosome 7 (somatic cell hybrid)
A431
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GW 572016
Biochemical IC50 vs. Erb-B1 and Erb-B2 10.8 and
9.3 nM Cell Culture EC50 approx. 200 nM for
growth inhibition Efficacious in three
independent tumor xenograft models
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Study EGF20009

• To evaluate the response rate of two lapatinib
  dosing regimens as first-line treatment for
  patients with locally advanced or metastatic
  breast cancer and documented ErbB2 amplification
  by FISH

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Efficacy in All Patients
Two subjects considered to have a PR by
investigator had lt28 day confirmation scans.
One subject not evaluated due to death from
multiple injuries prior to tumor assessment. 1
subject by the investigator review and 4 subjects
by independent review had only one timepoint and
that timepoint did not meet the criteria for SD
per the protocol (8 weeks).
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Putting the data in perspective
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Brain Metastases Patient C
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The Timelines

• Linking EGF Receptor to cancer 1984
• Launch of Herceptin - 1998
• Launch of small molecule inhibitors 2002
  onwards
• From science to medicine 15-20 years

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The conflicting times lines

• Every 3 months companies report their earnings to
  the stock market and are judged
• Every 4 to 5 years politicians and governments
  are elected and judged
• Median tenure for CEO and Head of RD is 5 years
  then they are judged
• Cycle time for medicines 20 years in discovery
  and development 20 years on the market

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Drug DiscoveryFinding a Molecule that
Satisfies Multiple Criteria the really boring
stuff
1 Drug Molecule
manufacturable
patentable
non-mutagenic
non-teratogenic
durable
reversible
non-inducing
metabolically stable
permeable
soluble
physically stable
potent
10,000 Drug Candidates
selective
Valid Biomedical Hypothesis?
targeted
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Drug Development Finding a Drug That is Safe and
Effective more boring stuff!
1 Drug Launch
Regulatory filing
Competitive profile
Cost-effective manufacturing
Carcinogenicity studies
Long-term safety
Efficacy
Side effect profile
Dosing ranges
Patient recruitment
Trial sites and investigators
Stability
Formulation
10 Drug Molecules
Safe and active in lab and animal models
All discovery criteria met
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The Timelines

• Linking EGF Receptor to cancer 1984
• Launch of Herceptin - 1998
• Launch of small molecule inhibitors 2002
  onwards
• From science to medicine 15-20 years

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With thanks to

• My colleagues who did the experiments and
  provided the slides (including Shelagh Wilson,
  Alan Wise, Tom Rimele, Lisa Shewchuk, Chris
  Keefer, Tim Willson Karen Lackey, the Oncology
  Groups at GSK and many others)
• Peter Machin, John Reardon and Tom Meek plus many
  others, for teaching me how to make drugs
• SB and GSK for letting me play with a
  large chemistry set