PGFI 2009 Franklin FitzGerald

© 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” !


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


A Crisis in Drug Development


Lex, FT April 9th 2008

Prescription Drugs: $286.5Bn – 10% of 2007 Healthcare Budget


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


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


Hold on a Moment!!Hold on a Moment!!


The Challenges of PersonalizationThe Challenges of Personalization

• Medical and technical• Social and Political• Economic and Regulatory


Expensive Introspection for the Worried WellExpensive Introspection for the Worried Well


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


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


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?


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Variability in the response to Vioxx and Celebrex

Attained COX-2 selectivity


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


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CYP2C9*3 +/+

CYP2C9*3 +/-

Genetic contribution to interindividual variability


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?


Yes, but is this actually leading anywhere?Yes, but is this actually leading anywhere?

Education

PGFI 2009 Franklin FitzGerald