TRANSLATING GENOME WIDE ASSOCIATION

STUDIESTO PREVENTION,

DIAGNOSTICS, AND THERAPEUTICS

Alan E. Guttmacher, M.D.National Human Genome Research

Institute May 1, 2007

GWAS Improved Health?1. Use of genetic information regarding

common disease to individualize providers’ approach to patients and change patients’ behaviors in ways that lead to improved health (“Personalized Medicine”).

2. Use of genetic information regarding common disease to understand the biology of human disease to lead to improved diagnostic, therapeutic, and preventive approaches.

GWAS vs. Study of “Single Gene” Disorders

From large effects of single genes in rare, “single-gene” diseases to smaller effects of multiple genes in common, “complex” diseases

Genomic Medicine1. Heart disease (654,000 deaths in 2004) 2. Cancer (550,000) 3. Cerebrovascular diseases (150,000)4. Chronic lower respiratory dis. (124,000)5. Injury? (109,000)6. Diabetes (73,000) 7. Alzheimer disease (66,000)8. Pneumonia/Influenza (61,000)9. Kidney disease (43,000)10. Septicemia (33,000)

Genomic Medicine

• GWAS today, so new drug tomorrow?

• No. There are many steps between GWAS and improved health...

GWAS Prevention, Dx, and RxGWASGWAS

Replicate/validate

Identify gene(s)/gene product(s)

Define function

Identify drug target

Design candidate drug

Clinical trials

Obtain FDA approval

Develop Dx test

Show analytic validity, clinical validity and utility

Obtain third party payer coverage

Devise prevention/ non-drug therapeutic strategies

Validate via outcome studies

GWAS Prevention, Dx, and RxGWASGWAS

Replicate/validate

Identify gene(s)/gene product(s)

Define function

Identify drug target

Design candidate drug

Clinical trials

Obtain FDA approval

Develop Dx test

Show analytic validity, clinical validity and utility

Obtain third party payer coverage

Devise prevention/ non-drug therapeutic strategies

Validate via outcome studies

GWAS Prevention, Dx, and RxGWASGWAS

Replicate/validate

Identify gene(s)/gene product(s)

Define function

Identify drug target

Design candidate drug

Clinical trials

Obtain FDA approval

Develop Dx test

Show analytic validity, clinical validity and utility

Obtain third party payer coverage

Devise prevention/ non-drug therapeutic strategies

Validate via outcome studies

Identify gene(s)/gene product(s): Age-Related Macular Degeneration

This and later articles show that three genes appear to account for approximately74% of the attributable risk of AMD in older adults – and we did not even view this as a particularly “genetic” disorder…

GWAS Prevention, Dx, and RxGWASGWAS

Replicate/validate

Identify gene(s)/gene product(s)

Define function

Identify drug target

Design candidate drug

Clinical trials

Obtain FDA approval

Develop Dx test

Show analytic validity, clinical validity and utility

Obtain third party payer coverage

Devise prevention/ non-drug therapeutic strategies

Validate via outcome studies

Develop Diagnostic Test

• Test methodologies will vary

• To develop the test requires investment of resources, supported either by public or private sector

• A viable market is usually necessary if the test is to move from research use to clinical availability

GWAS Prevention, Dx, and RxGWASGWAS

Replicate/validate

Identify gene(s)/gene product(s)

Define function

Identify drug target

Design candidate drug

Clinical trials

Obtain FDA approval

Develop Dx test

Show analytic validity, clinical validity and utility

Obtain third party payer coverage

Devise prevention/ non-drug therapeutic strategies

Validate via outcome studies

Analytical Validity, Clinical Validity and Clinical Utility

• Analytical validity: The ability of a test to measure the characteristic that it was designed to measure.

• Clinical validity: The ability of a test to distinguish affected and unaffected populations, including a determination of the probability of being affected. The clinical sensitivity, specificity, and predictive value of a test.

• Clinical utility: The value of a test in diagnosing/ruling out a disease, in suggesting treatment or prevention strategies, and in evaluating risks and benefits associated with the test. (from CDC)

GWAS Prevention, Dx, and RxGWASGWAS

Replicate/validate

Identify gene(s)/gene product(s)

Define function

Identify drug target

Design candidate drug

Clinical trials

Obtain FDA approval

Develop Dx test

Show analytic validity, clinical validity and utility

Obtain third party payer coverage

Devise prevention/ non-drug therapeutic strategies

Validate via outcome studies

Third Party Coverage

• Without coverage for the lab component of the test, it will seldom be used

• Coverage for the health professional time involved is also desirable, but MAY not be as necessary

GWAS Prevention, Dx, and RxGWASGWAS

Replicate/validate

Identify gene(s)/gene product(s)

Define function

Identify drug target

Design candidate drug

Clinical trials

Obtain FDA approval

Develop Dx test

Show analytic validity, clinical validity and utility

Obtain third party payer coverage

Devise prevention/ non-drug therapeutic strategies

Validate via outcome studies

Define FunctionScientists Identify 7 New Diabetes Genes By Nicholas WadeApril 27, 2007, New York Times on-line“The importance of the new genes is that they point to previously unknown pathways involved in diabetes….Several of the new variant genes make the pancreatic beta cells produce less insulin, Dr. Altshuler said. That suggests that diabetes may start as a disease of too little insulin production, even though patients turn up in the doctor’s office making too much insulin, to which their tissues have become resistant.”

GWAS Prevention, Dx, and RxGWASGWAS

Replicate/validate

Identify gene(s)/gene product(s)

Define function

Identify drug target

Design candidate drug

Clinical trials

Obtain FDA approval

Develop Dx test

Show analytic validity, clinical validity and utility

Obtain third party payer coverage

Devise prevention/ non-drug therapeutic strategies

Validate via outcome studies

Identify Drug Target

Once gene/protein function is understood, established strategies can be used to develop a new drug.

But, support for development requires a market for the drug.

GWAS Prevention, Dx, and RxGWASGWAS

Replicate/validate

Identify gene(s)/gene product(s)

Define function

Identify drug target

Design candidate drug

Clinical trials

Obtain FDA approval

Develop Dx test

Show analytic validity, clinical validity and utility

Obtain third party payer coverage

Devise prevention/ non-drug therapeutic strategies

Validate via outcome studies

E.g., chemical genomics approach with quantitative high-throughput screen

Design Candidate Drug

GWAS Prevention, Dx, and RxGWASGWAS

Replicate/validate

Identify gene(s)/gene product(s)

Define function

Identify drug target

Design candidate drug

Clinical trials

Obtain FDA approval

Develop Dx test

Show analytic validity, clinical validity and utility

Obtain third party payer coverage

Devise prevention/ non-drug therapeutic strategies

Validate via outcome studies

Ba

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Bio

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NIH’s Molecular Libraries Initiative

Ph IV-V(Additional indications, Safety monitoring)

Dedicated Chem-Biol

Project Team formed

Target identification

Assay develop-ment Hit-to-

Probe

Screening (HTS or otherwise)

1 yr 1 yr 1 yr ~ 3 yrs 1 yr 2 yrs ~3 yrs

Ph III (Efficacy and safety in large populations)

Ph II (Dose finding, initial efficacy

in patient pop.)

Ph I (Safety)

Lead Development, Optimization

Indefinite Indefinite1.5 yrs

Regulatory review

Drug Development Phases

Compound accepted into

Clinical Development

GWAS Prevention, Dx, and RxGWASGWAS

Replicate/validate

Identify gene(s)/gene product(s)

Define function

Identify drug target

Design candidate drug

Clinical trials

Obtain FDA approval

Develop Dx test

Show analytic validity, clinical validity and utility

Obtain third party payer coverage

Devise prevention/ non-drug therapeutic strategies

Validate via outcome studies

Design Prevention Strategies“We believe it is premature at this time to consider genotyping individuals with various stages of AMD. Screening should consider (1) that genotyping of about 30 individuals with drusen/pigment changes would be required to identify 1 individual who is homozygous for the risk allele for both genes and (2) the observation that many but not all individuals with those genotypes will develop the disease. However, in the future, a risk profile that includes However, in the future, a risk profile that includes genetic and environmental factors, such as the one genetic and environmental factors, such as the one calculated herein, may ultimately lead to targeted calculated herein, may ultimately lead to targeted screening and closer monitoring of individuals who screening and closer monitoring of individuals who are at higher risk of visual loss due to AMD are at higher risk of visual loss due to AMD progression.progression.

- Seddon, et al. JAMA. 2007;297:1793-1800.

GWAS Prevention, Dx, and RxGWASGWAS

Replicate/validate

Identify gene(s)/gene product(s)

Define function

Identify drug target

Design candidate drug

Clinical trials

Obtain FDA approval

Develop Dx test

Show analytic validity, clinical validity and utility

Obtain third party payer coverage

Devise prevention/ non-drug therapeutic strategies

Validate via outcome studies

Genomic Medicine

But, even if we invent a better mouse trap…

will the world beat a path to genomic medicine’s door?

Genomic Medicine

• Will require– Informed, interested providers

– Informed, interested public

A Pathway to Informed, Interested Providers

URL: nchpeg.org

A Pathway to an Informed, Interested Public

URL: familyhistory.hhs.gov

The U.S. Surgeon General’s Family History Initiative

GWAS?

• While many of today’s standard medical practices have never been proven to improve health or to make sense economically, we should use rigorous outcome and cost-benefit studies to decide which genomic medicine practices to utilize.

Executive Summary

• Will GWAS actually lead to prevention, diagnostics, and therapeutics for common disease?

Executive Summary

“Our age may be known to history as the age of genetic medicine, a time when many of the most feared illnesses were overcome.”

     - President Bush April 10, 2002

Executive Summary

“It is now conceivable that our children’s children will know the term cancer only as a constellation of stars.”

- President Clinton

June 26, 2000