Biomarker Based PGx Strategies Rick Hockett, MD Chief Medical Officer Affymetrix

2 Affymetrix Confidential One size fits all Goal Goal : Improve individual patient outcomes and health outcome predictability through tailoring drug, dose, timing of treatment, and relevant information assess spectrum of patient response to therapy; stratify patient populations; optimize benefit/risk. Providing meaningful improved health outcomes for patients by delivering the right drug at the right dose at the right time. Tailoring ( e.g. oncology products comprising drug and companion diagnostic) Targeted Therapy Tailoring is Broader Than Pharmacogenomics Measure something in a patient to learn how to prescribe medicine Why Are Biomarkers So Important?

3 Affymetrix Confidential Increased Benefit:Risk Scenarios Providing meaningful improved health outcomes for patients by improving diagnosis, prognosis, or therapy choice. Can apply one or more scenarios to each Lilly compound. Scenarios can often be interdependent. Accommodate info for patient diversity, questions specific to payors or providers, or provide tools to meet needs of customers Tailoring Information/ Tools Tailoring Information/ Tools Identifying Patient Identifying Patient Diagnosis Diagnosis Prognosis Prognosis Therapy Therapy Diagnosing patients with particular traits Identifying responders for targeted therapies (essentially highly tailored therapies) Identifying who have an alternate prognosis (perhaps needing additional therapy) Optimize dosing regimen for patient subpopulation(s) to achieve optimal benefit/risk Tailoring Dose Tailoring Dose Identify time to intervene during disease progression, time to complete therapy, or time to alter treatment regimen Tailoring Time Tailoring Time

4 Affymetrix Confidential Why do we think genetics will play?

5 Affymetrix Confidential Pinpoint the right biomarker DNA ----ACGTGGGCAGTAGACTCAT TGCACCCGTCATCTGAGTA---- Protein ----Thr Trp Ala Val Asp Ser ---- RNA ----ACGUGGGCAGUAGACUCAU---- Large Scale Fishing Whole Genome Scan Medium Scale Confirmation Many Different Groups Small Scale Validated Clinical Trial Support Large Scale Fishing DNA – 100K to 2x10 6 SNPs Chip Based Electrophoresis RNA – 30K+ Chip Based -oligos Slide Based - cDNAs Protein – 1K upward Mass Spec Med. Scale Confirm. DNA –2K to 30K Chip Based Electrophoresis PCR Based RNA – 30 to 1K Chip Based -oligos Slide Based – cDNAs RT-PCR Based Protein – 50 to 500 Mass Spec Luminex Type Small Scale Valid. DNA – 1 to 25 PCR Based Electrophoresis RNA – 1 to 25 RT-PCR Based Protein – 1 to 30 ImmunoAssay

Clinically Utilized PGx Tests Shrinking Clinical PGx Funnel Hercept Test Philly Chromosome Variation Y Response N Y N Variation Y Response N Y N vs. 3 Predictive Situation Specific Onc vs. Neuroscience c-kit TPMT HLA Disease vs. Response Interesting Genetic Associations Prospective Clinical Proof Genetic Polymorph With Rel. Risk Genetic Variant Freq Genetic Polymorph With Good Sens. & Spec Apo E, CETP 5 - LO Variants in Growth Genes DMET NeedsExamples OncotypeDx UGT1A1 EGFr CYP2C9/VKORC1 Tissue of Origin

7 Affymetrix Confidential Hurdles to applying -omics to medicine Strategic Gearing the infrastructure Obtaining the talent Technologic Information overload Lack of biologic understanding Platform challenges Regulatory Understand how to apply technology Implementation Clinician education, understanding, and acceptance X ??

DMET Plus Drug Metabolism Enzymes & Transporters An Example of Applying New Technologies to the Clinical Marketplace

9 Affymetrix Confidential The Genesis of DMET: March of 2004: Collaboration initiated between Lilly, ParAllele, and Affymetrix The goal for Eli Lilly was to develop a clinical solution for better understanding the genetic components behind metabolism and transport: Better ability to understand PK outliers in early phase trials Build a database for selective recruitment of healthy volunteers with a defined genotype Work with the FDA in an attempt to decrease the number of biopharm (DDI) trials needed for future NDAs June 2006 was the inception of a working assay for clinical trials Dec 2007 first NDA was submitted the FDA

10 Affymetrix Confidential Pinpoint the right biomarker Large Scale Fishing Whole Genome Scan Medium Scale Confirmation Many Different Groups Small Scale Validated Clinical Trial Support Large Scale Fishing DNA – 100K to 2x10 6 SNPs Chip Based Electrophoresis RNA – 30K+ Chip Based -oligos Slide Based - cDNAs Protein – 1K upward Mass Spec Med. Scale Confirm. DNA –2K to 30K MIP Based True Materials RNA – 30 to 1K Panomics Expression Protein – 50 to 500 Mass Spec Luminex Type Small Scale Valid. DNA – 1 to 25 MIP Based True Materials RNA – 1 to 25 Panomics Expression Protein – 1 to 30 ImmunoAssay Using existing Affymetrix technology

11 Affymetrix Confidential Setting the stage for adoption of genetic analysis tools for use in personalized medicine Risks associated with taking popular heart disease medication Plavix (Clopidogrel) Paper published in New England Journal of Medicine Conclusion: Patients taking Clopidogrel and who were carriers of a certain gene variation had higher rates of heart attack, death and other cardiac-related events Two additional independent studies recently published in NEJM and Lancet show similar PGx associations.

12 Affymetrix Confidential No Relationship between Genetics and PK/PD for Prasugrel, Significant Effect for Clopidogrel Pharmacokinetics Integrated Genetic Analyses in Healthy Subjects Pharmacodynamics

13 Affymetrix Confidential PGx associated clinical outcomes of 1459 acute coronary syndrome patients treated with clopidogrel were significant 1477 Patients were randomly assigned Plavix treatment with 98.8% being genotyped CYP2C19 variant allele (1) frequency in treated population was 27.1%. Primary efficacy outcome: composite of death from cardiovascular causes, MI and stroke. 395 variant carrier patients had a 1.5 fold higher risk of death vs non-carriers Rx patients had stents implanted with a secondary endpoint of stent thrombosis C19 variant patients had a 3 fold increase in risk of thrombosis. Two additional independent studies recently published in NEJM and Lancet show similar PGx associations.

14 Affymetrix Confidential Identification of potential biomarker or drug target DNA marker RNA expression level Protein DNA or RNA Samples Plasma or Serum Samples Use of marker in prospective clinical trials Patient Stratification Literature Cell Lines Retrospective confirmation on clinical samples Tissues A. B. C. D. Pharmacogenomics in drug development Development of a biomarker Patient Samples are the Key Biomarker: A physiological response or laboratory test that occurs in association with a pathological process and that has putative diagnostic and/or prognostic utility

15 Affymetrix Confidential What we Must Do to Enable -omics Impact Align focus on what can be done and where genetics is likely to work Analyze, Integrate and Learn from data Enable the field of Molecular Epidemiology Enhance our biologic understanding of genetic influence of complex traits and produce more examples Develop and validate technologies for clinical use IT Infrastructure Standards & Controls Educate the medical infrastructure Engage patients and third party payers

16 Affymetrix Confidential How Do We Enable -omics Uptake? We cannot maintain silos We must enable certain, common functions Sample banking Clinical trials We must look to the regulators for direction Standards Controls Critical Path Initiative FDA Industry Academics Labs Diagnostic Companies

17 Affymetrix Confidential The Biotech/Genomics Revolution: Increase the Benefit:Risk Ratio Develop clinical aids for: Diagnosis Prognosis Dosing Therapy Decisions