pgfi 2009 franklin fitzgerald
TRANSCRIPT
© 2007 Trustees of the University of Pennsylvania
How They Treat UsHow They Treat Us
• Medicine determines drug benefit and risk from large average effects in clinical trials
• Law determines drug benefit and risk at the individual level; “personalized legal medicine” !
© 2007 Trustees of the University of Pennsylvania
The Promise of PersonalizationThe Promise of Personalization
• This drug is likely to work for you ( Gleevec and Herceptin)• This drug is unlikely to do harm to you ( Warfarin, Statins, Plavix and genotyping)• Your genome suggests you should take this
drug even though you are well• Your genome and these markers suggest that
you should now start this drug although you seem well
© 2007 Trustees of the University of Pennsylvania
Lex, FT April 9th 2008
Prescription Drugs: $286.5Bn – 10% of 2007 Healthcare Budget
© 2007 Trustees of the University of Pennsylvania
Pfizer – Wyeth (Wyzer) Pfizer – Wyeth (Wyzer) “a great fit that made the deal creditworthy”* “a great fit that made the deal creditworthy”*
• Pfizer has “so much cash” – deal doesn’t have to be highly leveraged
• Enough overlap..to consolidate operations and cut costs [ fire people]
• Parts – animal health – of a combined operation can be spun off to make money
*Erik Gordon, Univ of Michigan Business School quoted in NYT
1/25/09
© 2007 Trustees of the University of Pennsylvania
Tancredi in The Leopard
"If we want things to stay as they are, things will have to change.""If we want things to stay as they are, things will have to change."
The Stuttering Path towards Personalization of Medicine
© 2007 Trustees of the University of Pennsylvania
The Challenges of PersonalizationThe Challenges of Personalization
• Medical and technical• Social and Political• Economic and Regulatory
© 2007 Trustees of the University of Pennsylvania
Expensive Introspection for the Worried WellExpensive Introspection for the Worried Well
© 2007 Trustees of the University of Pennsylvania
Gene Discovery and Drug DevelopmentGene Discovery and Drug Development
• GWAS discovers new gene – disease associations
• Are they important?• If they are, can we
target them?• If we can, will the
drug work and work safely?
deCode Genetics
Dow
© 2007 Trustees of the University of Pennsylvania
An Inconvenient (off –label ) TruthAn Inconvenient (off –label ) Truth
• Bextra, Celebrex and Vioxx alleviate pain and inflammation
• They all suppress a fat that protects against blood clots and hardening of the arteries in mice
© 2007 Trustees of the University of Pennsylvania
The Problems of PersonalizationThe Problems of Personalization
• Celebrex causes heart disease/stroke in ~2% of patients.
• This relates to dose and prior history of heart disease
• Can we identify patients predisposed to risk or developing risk during treatment?
• Can we identify patients predisposed to benefit?
© 2007 Trustees of the University of Pennsylvania
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Fries, Grosser, FitzGerald, Gastroenterology, 130(1):55-64. 2006
Placebo
n=50
celecoxib (200 mg)
n=50
rofecoxib(25 mg)
n=50
Variability in the response to Vioxx and Celebrex
Attained COX-2 selectivity
© 2007 Trustees of the University of Pennsylvania
Genes and the EnvironmentGenes and the Environment
• All the genetic variation accounted for ~30% of the variability in drug response
• Most of the environmental variables of relevance are unknown
• Need to combine quantitative measures of drug response – biased and unbiased – with genetic information and relate to clinical outcome
© 2007 Trustees of the University of Pennsylvania
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Time after last dose (hrs)
CYP2C9*3 +/+
CYP2C9*3 +/-
Genetic contribution to interindividual variability
© 2007 Trustees of the University of Pennsylvania
The Long Haul towards PersonalizationThe Long Haul towards Personalization
• Do (i) blood levels of the drug or (ii) the suppression of heart protective fats or (iii) a rise in blood pressure predict problems on Celebrex?
• Do unbiased analyses of genes, proteins or fats suggest some “off target” effect is relevant?
• Does this information provide tests to detect evolving risk on Celebrex?
• Can using these tests reduce risk?