1. 1 SIMG Florence 4.12.99.ppt The Horizons of Predictive Medicine Dr Ian Gilham Worldwide Director, Predictive Medicine Glaxo Wellcome Research and Development

2. 2 SIMG Florence 4.12.99.ppt What is a diagnostic? “A device or service that provides specific information on the current health status of an individual”

3. 3 SIMG Florence 4.12.99.ppt However………... Newer technologies can be used to determine Predisposition to future change in health status Monitoring of health status Suitability for specific medicines A better description would be…...

4. 4 SIMG Florence 4.12.99.ppt Predictive 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.”

5. 5 SIMG Florence 4.12.99.ppt Prognostics Surrogates What is Predictive Medicine? Diagnostics

6. 6 SIMG Florence 4.12.99.ppt 20th Century SYMPTOMS OF DISEASE DIAGNOSTICS (IVD, IMAGING) OUTCOME THERAPEUTIC INTERVENTION

7. 7 SIMG Florence 4.12.99.ppt 21st Century DIAGNOSTICS (IVD, IMAGING) PREDISPOSITION PROFILING (GENETICS, FUNCTIONAL GENOMICS) THERAPEUTIC INTERVENTION MONITORING AND PREVENTION (BEHAVIOUR MODIFICATION, SURROGATES, VACCINES ETC) TREATMENT SELECTION (PHARMACOGENETICS) TREATMENT MONITORING (THERAPEUTIC RESPONSE, SURROGATES, COMPLIANCE)

8. 8 SIMG Florence 4.12.99.ppt PATIENT-TARGETED THERAPIES INNOVATIVE MEDICINES PREDICTIVE MEDICINE Right Medicine Right Patient Right Disease Right Time Right Dose Right Response

9. 9 SIMG Florence 4.12.99.ppt The drivers and enablers of Predictive Medicine -- Today ---- Tomorrow -- Diagnosis Treatment Prediction Prevention Drivers 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 Enablers 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

10. 10 SIMG Florence 4.12.99.ppt GeneticsDiagnostics Therapeutics Disease Management Health Outcomes Molecular Diagnostics In Vitro Diagnostics Imaging Monitoring Devices Predisposition Profiling Gene Therapy Population Stratification Vaccines Proteins Small Molecules Pharmacoeconomics Compliance Therapeutic Intervention Non-Therapeutic Intervention Potential areas of interest

11. 11 SIMG Florence 4.12.99.ppt Application of Predictive Medicine Disease Detection Disease Intervention

12. 12 SIMG Florence 4.12.99.ppt Susceptibility Gene Strategy Alzheimer Disease

13. 13 SIMG Florence 4.12.99.ppt Human 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)

14. 14 SIMG Florence 4.12.99.ppt Glaxo Wellcome Genetics Strategy To identify susceptibility genes contributing to the risk and age of onset of common diseases with high unmet need To identify susceptibility genes contributing to the risk and age of onset of common diseases with high unmet need Identify the 20-30 most relevant genes for specific diseases, using genetics and genomic tools. Identify the 20-30 most relevant genes for specific diseases, using genetics and genomic tools. Focusing to find specific susceptibility genes is the art Focusing to find specific susceptibility genes is the art

15. 15 SIMG Florence 4.12.99.ppt Genetics Research - Outcomes Disease Segmentation Definition of underlying Disease Mechanisms Right medicines to Right Patient Gene Analysis Gene Expression Analysis Development of “mechanism-based” medicines Development of Diagnostics to detect Disease segment

16. 16 SIMG Florence 4.12.99.ppt Changing technology will accelerate susceptibility gene discovery Database of well characterised patients & their DNA Database of genetic polymorphism and high capacity resequencing technology (in development) Genetic epidemiology Gene - Disease associations Current genomic screening technology (today)

17. 17 SIMG Florence 4.12.99.ppt Alzheimer costs a lot today…... 2.3 million Alzheimer cases in the US 4% of 75 year olds 8.5% of 80 year olds 28.5% of 90 year olds 360,000 new US cases each year US costs estimated at $90bn annually Source: Reuters 1998

18. 18 SIMG Florence 4.12.99.ppt 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

19. 19 SIMG Florence 4.12.99.ppt 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 Proportion of each genotype unaffected Age at onset 2/3 2/4 3/3 3/4 4/4 Mean age of onset of Alzheimer disease as a function of the inheritance of the five common APOE genotypes

20. 20 SIMG Florence 4.12.99.ppt Significance of APOE Predictive Medicine Drug Discovery

21. 21 SIMG Florence 4.12.99.ppt Source: Reiman et al NEJM 334 p752 Symptomatic Alzheimer Disease

22. 22 SIMG Florence 4.12.99.ppt Source: Reiman et al NEJM 334 p752 APOE4 Homozygotes

23. 23 SIMG Florence 4.12.99.ppt 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

24. 24 SIMG Florence 4.12.99.ppt APOE as a potential diagnostic Considerations Rigorous test validation Role of APOE in other neurological conditions Value of a diagnostic in the absence of an effective therapy Outcomes analysis Regulatory considerations

25. 25 SIMG Florence 4.12.99.ppt Significance of APOE Predictive Medicine Drug Discovery

26. 26 SIMG Florence 4.12.99.ppt Disease Mechanism and Target Identification Strategy Create a transgenic animal with the only difference being the human polymorphism isoform associated with disease Determing differences in appropriate organs Differential Gene Expression Proteomics Others

27. 27 SIMG Florence 4.12.99.ppt 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

28. 28 SIMG Florence 4.12.99.ppt APOE GeneCalling Study APOE3 form = normal ID mechanism whereby APOE4  AD VS. APOE4APOE3 Other AD Genes GeneCalling

29. 29 SIMG Florence 4.12.99.ppt APOE in Alzheimer Disease True Value In Treating Disease Therapy Predictive Testing

30. 30 SIMG Florence 4.12.99.ppt Summary Today Diagnosis Treatment Prediction Prevention Tomorrow

31. 31 SIMG Florence 4.12.99.ppt 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

32. 32 SIMG Florence 4.12.99.ppt Summary 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