1. TRANSLATING GENOME WIDE ASSOCIATION STUDIES TO PREVENTION, DIAGNOSTICS, AND THERAPEUTICS Alan E. Guttmacher, M.D. National Human Genome Research Institute May 1, 2007

2. 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.

3. 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

5. Genomic Medicine 1. 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)

6. Genomic Medicine GWAS today, so new drug tomorrow? No. There are many steps between GWAS and improved health...

7. GWAS Prevention, Dx, and Rx GWAS 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

8. GWAS Prevention, Dx, and Rx GWAS 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

9. GWAS Prevention, Dx, and Rx GWAS 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

10. Identify gene(s)/gene product(s): Age-Related Macular Degeneration This and later articles show that three genes appear to account for approximately 74% of the attributable risk of AMD in older adults – and we did not even view this as a particularly “genetic” disorder…

11. GWAS Prevention, Dx, and Rx GWAS 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

12. 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

13. GWAS Prevention, Dx, and Rx GWAS 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

14. 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)

15. GWAS Prevention, Dx, and Rx GWAS 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

16. 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

17. GWAS Prevention, Dx, and Rx GWAS 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

18. Define Function Scientists Identify 7 New Diabetes Genes By Nicholas Wade April 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.”

19. GWAS Prevention, Dx, and Rx GWAS 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

20. 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.

21. GWAS Prevention, Dx, and Rx GWAS 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

22. E.g., chemical genomics approach with quantitative high-throughput screen Design Candidate Drug

23. GWAS Prevention, Dx, and Rx GWAS 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

24. Basic Biomedical Research 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 ~ 3 yrs1 yr2 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 1.5 yrs Regulatory review Drug Development Phases Compound accepted into Clinical Development

25. GWAS Prevention, Dx, and Rx GWAS 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

26. Design Prevention Strategies However, in the future, a risk profile that includes genetic and environmental factors, such as the one calculated herein, may ultimately lead to targeted screening and closer monitoring of individuals who are at higher risk of visual loss due to AMD progression. “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 genetic and environmental factors, such as the one calculated herein, may ultimately lead to targeted screening and closer monitoring of individuals who are at higher risk of visual loss due to AMD progression. - Seddon, et al. JAMA. 2007;297:1793-1800.

27. GWAS Prevention, Dx, and Rx GWAS 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

28. Genomic Medicine But, even if we invent a better mouse trap… will the world beat a path to genomic medicine’s door?

29. Genomic Medicine Will require –Informed, interested providers –Informed, interested public

30. A Pathway to Informed, Interested Providers URL: nchpeg.org

31. A Pathway to an Informed, Interested Public URL: familyhistory.hhs.gov The U.S. Surgeon General’s Family History Initiative

32. 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.

33. Executive Summary Will GWAS actually lead to prevention, diagnostics, and therapeutics for common disease?

34. 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

35. 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