The Horizons of Predictive Medicine

1SIMG Florence 4.12.99.ppt

The Horizons of Predictive Medicine

The Horizons of Predictive Medicine

Dr Ian GilhamWorldwide Director, Predictive

MedicineGlaxo Wellcome Research and

Development


What is a diagnostic?What is a diagnostic?

“A device or service that provides specific information on the current health status of an individual”


However………...However………...

Newer technologies can be used to determine

Predisposition to future change in health status

Monitoring of health statusSuitability for specific medicines

A better description would be…...


Predictive MedicinePredictive Medicine

“A device or service that can predict a change in the health status of an individual, either towards the onset of disease or towards the likely response to a therapeutic intervention.”


PrognosticsSurrogates

What is Predictive Medicine?

What is Predictive Medicine?

Diagnostics


20th Century20th Century

SYMPTOMS OF DISEASE

DIAGNOSTICS(IVD, IMAGING)

OUTCOME

THERAPEUTICINTERVENTION


21st Century21st Century

DIAGNOSTICS(IVD, IMAGING)

PREDISPOSITION PROFILING(GENETICS, FUNCTIONAL GENOMICS)

THERAPEUTICINTERVENTION

MONITORING AND PREVENTION(BEHAVIOUR MODIFICATION, SURROGATES, VACCINES ETC)

TREATMENT SELECTION (PHARMACOGENETICS)

TREATMENT MONITORING(THERAPEUTIC RESPONSE, SURROGATES, COMPLIANCE)


PATIENT-TARGETEDTHERAPIES

INNOVATIVEMEDICINES

PREDICTIVEMEDICINE

Right Medicine

Right Patient

Right Disease

Right Time

Right Dose

Right Response


The drivers and enablers of Predictive

Medicine

The drivers and enablers of Predictive

Medicine-- Today -- -- Tomorrow --

Diagnosis

Treatment

Prediction

Prevention

Dri

vers

• Payer pressures (governments/insurance firms): more prevention, more effective cures

• Regulator pressure to try to eliminate adverse events

• Demand for better healthcare from the patient• Demand for more accurate healthcare predictions for

the patient• Shareholder expectation of growth - getting better

medicines to the market faster

En

able

rs

• Development of Genetics and Functional Genomics knowledge

• New technologies (e.g. genechips, bioinformatics, molecular diagnostics, etc.)

• New regulation on Intellectual Property Rights, genomic ethics, data protection & consent


Genetics Diagnostics

TherapeuticsDisease

Management

Health Outcomes

MolecularDiagnostics

In Vitro Diagnostics

Imaging

Monitoring Devices

Predisposition Profiling

Gene Therapy

Population Stratification

VaccinesProteins

Small Molecules

Pharmacoeconomics

Compliance

Therapeutic Intervention

Non-Therapeutic Intervention

Potential areas of interest

Potential areas of interest


Application of Predictive Medicine

Application of Predictive Medicine

Disease Detection

Disease Intervention


Susceptibility Gene Strategy

Susceptibility Gene Strategy

Alzheimer Disease


Human GeneticsHuman Genetics

Over the past two decades, disease genes have been identified for hundreds of rare, inherited diseases that are seen in families

Susceptibility genes underlie common diseases (e.g. diabetes, heart disease, asthma)

To date, only one susceptibility gene linked to a common, polygenic disease (APOE, Alzheimer)

Over the past two decades, disease genes have been identified for hundreds of rare, inherited diseases that are seen in families

Susceptibility genes underlie common diseases (e.g. diabetes, heart disease, asthma)

To date, only one susceptibility gene linked to a common, polygenic disease (APOE, Alzheimer)


Glaxo Wellcome Genetics Strategy

Glaxo Wellcome Genetics Strategy

To identify susceptibility genes To identify susceptibility genes contributing to the risk and age of onset contributing to the risk and age of onset of common diseases with high unmet of common diseases with high unmet needneed

Identify the 20-30 most relevant genes Identify the 20-30 most relevant genes for specific diseases, using genetics and for specific diseases, using genetics and genomic tools. genomic tools.

Focusing to find specific susceptibility Focusing to find specific susceptibility genes is the artgenes is the art


Genetics Research - Outcomes

Genetics Research - Outcomes

DiseaseSegmentation

Definition ofunderlyingDisease

MechanismsRight

medicinesto RightPatient

Gene Analysis

Gene ExpressionAnalysis

Development of “mechanism-based”medicines

Development of Diagnosticsto detect Disease segment


Changing technology will accelerate susceptibility gene

discovery

Changing technology will accelerate susceptibility gene

discovery

Database of wellcharacterised

patients &their DNA

Database of geneticpolymorphism and

high capacity resequencing technology

(in development)

Geneticepidemiology

Gene - Diseaseassociations

Current genomic screening technology (today)


Alzheimer costs a lot today…...

Alzheimer costs a lot today…...

2.3 million Alzheimer cases in the US4% of 75 year olds8.5% of 80 year olds28.5% of 90 year olds

360,000 new US cases each yearUS costs estimated at $90bn annually

Source: Reuters 1998


Alzheimer will cost more tomorrow….

Alzheimer will cost more tomorrow….

1992 - 7.0% of population over 75 years old

2051 - 13.6% of population over 75 years old

Estimated 7.5m to 14.3m Alzheimer sufferers in the US by 2050

Source: Prevention of Alzheimer Disease JAMA (262): p251


APOE in Alzheimer disease - a

susceptibility Gene

APOE in Alzheimer disease - a

susceptibility Gene

60 65 70 75 80 85 90

1.0

0.8

0.6

0.4

0.2

0

Pro

port

ion

of

each

g

en

oty

pe

un

aff

ect

ed

Age at onset

2/3

2/43/3

3/4

4/4

Mean age of onset of Alzheimer disease as a function of the inheritance of the five common APOE genotypes


Significance of APOESignificance of APOE

Predictive Medicine

Drug Discovery

21SIMG Florence 4.12.99.pptSource: Reiman et al NEJM 334 p752

Symptomatic Alzheimer Disease

22SIMG Florence 4.12.99.pptSource: Reiman et al NEJM 334 p752

APOE4 Homozygotes


APOE as a Predictive Medicine Tool in

Alzheimer Disease

APOE as a Predictive Medicine Tool in

Alzheimer Disease

Value in assigning more accurate diagnoses, not simply whether a patient is APOE4 “positive” or APOE4 “negative”

If a patient is cognitively impaired, and fits the current clinical diagnosis of possible AD, the diagnostic accuracy goes from 60-70% to >95% if the patient carries an APOE4 allele

Value in assigning more accurate diagnoses, not simply whether a patient is APOE4 “positive” or APOE4 “negative”

If a patient is cognitively impaired, and fits the current clinical diagnosis of possible AD, the diagnostic accuracy goes from 60-70% to >95% if the patient carries an APOE4 allele


APOE as a potential diagnostic

Considerations

APOE as a potential diagnostic

ConsiderationsRigorous test validation Role of APOE in other neurological

conditionsValue of a diagnostic in the

absence of an effective therapyOutcomes analysisRegulatory considerations


Significance of APOESignificance of APOE

Predictive Medicine

Drug Discovery


Disease Mechanism and Target Identification

Strategy

Disease Mechanism and Target Identification

StrategyCreate a transgenic animal with the

only difference being the human polymorphism isoform associated with disease

Determing differences in appropriate organsDifferential Gene ExpressionProteomicsOthers


APOE GeneCalling Study


APOE knock out (KO) mouse = normal

ID “rescue” genes in APOE KO mouse (compensate for APOE loss)

VS.

NORMALAPOE KO

AD “Rescue” Genes

GeneCalling




APOE3 form = normalID mechanism whereby APOE4

AD

VS.

APOE4APOE3

Other AD Genes

GeneCalling


APOE in Alzheimer Disease

APOE in Alzheimer Disease

True ValueIn Treating

Disease

TherapyPredictive

Testing


SummarySummary

Today

Diagnosis

Treatment

Prediction

Prevention

Tomorrow


What are the consequences to the Global Healthcare?

What are the consequences to the Global Healthcare?

How will the Healthcare look in the 21st Century?

The gate keeping role of patient-specific information

Selection of intervention method and timing

An integrated health management approach


SummarySummary

Clear trends in Genetics and Predictive Medicine will lead to broader options in therapeutic interventions

Traditional healthcare paradigm will be impacted by new technologies and ever-expanding disease knowledge

An integrated approach could be a key feature of 21st Century Healthcare

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The Horizons of Predictive Medicine

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