1. 1 Paradigm A University of Michigan non-profit company to facilitate next generation clinical sequencing and clinical trials October 24, 2012 Robert Penny M.D. Ph.D. CEO, Paradigm David Mallery J.D., MBA President, Paradigm Joe Paulauskis Ph.D. COO, Paradigm

2. 2 Mission: Revolutionize the treatment and prevention of cancer and complex diseases by rigorously developing and applying post-genome science to advances in human health  Expression Project for Oncology  Building the research foundation  The Molecular Profiling Institute  Target Now  TCGA  Biospecimen acquisition, banking and management for the largest cancer research project to date  (65 million in NUH contracts)

3. 3 TCGA, expO, TBAC databases and biorepositories TCGA, expO, Clinical Trials PCDx & Target Now Tissue Banking & Analysis Center TBAC PCDx & Target Now Paradigm & Molecular Profiling Institute Paradigm & Molecular Profiling Institute Patient Care Theranostics TCGA expO,TBAC Database Characterization Clinical Application PCDx & Target Now TBAC Research Discover TGen, Harvard, Stanford, GSK, BMS, Wyeth, Research Research

4. 4 Public Data Pharma Members IRB-approved Proprietary Protocols (as necessary) Open Competition IRB-approved Protocols (as necessary) Expression Array Data Clinical Annotation Data GenotypingHaplotyping Methylation Proteomics CGH Specimen RepositoryBenefitsBenefits New Treatments Diagnostic tests Prognostic tools Patents Publications Medical & Scientific presentations Public release of evolving database New Proprietary IP New Treatments Diagnostic tests Prognostic tools Patents Publications Medical & Scientific presentations Public release of evolving database New Proprietary IP Improved clinical management of cancer patients expO TCGA

5. 5 IGC’s Tissue Network Scottsdale HealthCare, AZ Inova Fairfax, VASt. Francis Tulsa, OK Community Hospitals of Indianapolis, IN IGC Headquarters St. Vincent Hospital, IN St. Francis Hospital, IN U of A Tucson, AZ Trinity MFH Tyler, TX Texas Health Dallas, TX U TN Cancer Inst., TN Virginia Piper Cancer Institute, MN Rex Hospital, NC Trinity, MI Lee Memorial, FL 7 ExpO / TCGA Sites 4 TCGA Sites 3 Low Volume - Withdrew

6. 6 TCGA Biospecimen Core Resource Full Project TCGA Tissue Source Site Network Full Project TCGA Biospecimen Core Resource Pilot Project

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8. 8 The Cancer Genome Atlas (TCGA) Sponsored by the National Cancer Institute and the National Human Genome Research Institute, the National Institutes of Health Human Cancer Biospecimen Core Resource The major requirement for The Cancer Genome Atlas Pilot Project is the development of a Single, Centralized Human Cancer Biospecimen Core Resource (BCR). The BCR will oversee the acquisition of appropriately consented, standardized and rigorously collected biospecimens (patient cancer samples etc…), transport and preservation of samples and patient information to the BCR. An independent categorization and quality assurance check on these samples will occur prior to the isolation of analytes (DNA and RNA) to be distributed to the Sequencing and Characterization Centers. Samples will be de-identified with removal of patient private information. Data Management, Bioinformatics and Computational Analysis The information that is generated by The Cancer Genome Atlas network will be centrally managed and entered into public databases as it becomes available, allowing scientists to access the information during the course of this project. Genome Sequencing Centers Building on the technologies that were used to complete the Human Genome Project, high-throughput genome sequencing centers will identify the mutations in DNA associated with specific types of cancer. Cancer Genome Characterization Centers Several characterization technologies will be used to analyze the copy number, methylation, miRNA and expression changes associated with cancer. Scientists will analyze the complete set of genetic and clinical data produced by The Cancer Genome Atlas network to develop a comprehensive Web-based resource which will be available to the scientific community. This resource will describe the genetic “fingerprints” of specific cancer types and will be known as The Cancer Genome Atlas. Researchers will evaluate the information contained in The Cancer Genome Atlas to determine how it can be used to speed up advances in cancer diagnosis, treatment, and prevention. Established Tissue Banks TSS Networks IGC Medical Centers

9. 9 EGFRERBB2 PI-3K Class I PDGFRAMET mutation, amplification in 45% mutation in 7% amplification In 13% amplification in 4% RAS NF-1 AKT FOXO PTEN Proliferation Survival Translation Activated oncogenes MDM4 TP53 MDM2 CDKN2A (ARF) CDKN2A (ARF) RB1 RTK/RAS/PI-3K signaling network 86% RTK/RAS/PI-3K signaling network 86% P53 signaling 86% SenescenceApoptosis CDK4 CDKN2A (P16/INK4A) CDKN2A (P16/INK4A) CDKN2B CDKN2C G1/S progression homozygous deletion in 51% RB signaling 77% RB signaling 77% homozygous deletion in 47% homozygous deletion in 2% homozygous deletion in 49% amplification in 14% amplification in 6% mutation, homozygous deletion in 35% amplification in 17% homozygous deletion, mutation in 11% mutation in 2% amplification in 2% mutation in 2%mutation in 15% mutation, homozygous deletion in 17% mutation, homozygous deletion in 36% CDK6 CCND2 amplificatio n in 1% amplification in 2% Pathway Analysis in GBM

10. 10 Cancer’s road map is now being formed

11. 11 Late Stage Cancer Patients Profile Patients for Potential Rx Targets Prospective Trial: Complete DNA microarray Immunohistochemistry Sequencing FISH Other Target Now

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13. 13 PDGFR (Platelet derived growth factor receptor) elevated Rx Inhibitor molecules  Gleevec  SU112248  BAY43-9006 Vitamin D receptor elevated, Rx Calcitriol

14. 14 106 Patients PFS ratio of ≥1.3 Deteriorating health of the patients was a significant cause of drop out from the trial Ratios for patient’s tumor type ≥ 1.3 PFS included: colorectal 4/11 (36%), breast 8/18 (44%), ovarian 1/5 (20%), mostly rare tumor types 5/32 (16%). Conclusion: When using an endpoint of patient as their own control, use of molecular profiling can provide clinical benefit in 26% of patients who are treated according to MP results. Results of the Prospective Trial in Late Stage Cancer Diagnosis 1st recurrence 2nd recurrence MP bx Outcome

15. 15 CEO Robert Penny, M.D., Ph.D. Founded 6 successful medical diagnostic companies Secured over $65 million in NIH contracts over 5 years Developed the leading revenue genomics test in Oncology today Built one of the first clinically annotated gene expression databases Leadership role The Cancer Genome Atlas project President David Mallery, J.D., M.B.A. Venture capital and medical diagnostic company Experienced scientist Co-founded 3 biotech companies Leadership TCGA COO Joe Paulauskis, Ph.D. Pfizer Global Head of Pharmacogenomics Leadership TCGA

16. 16 Specimen analysis, coupled with pathology expertise, state-of-the-art bioinformatics interpretation and personalized customer service that: Benefits patients by providing the most advanced information available for cancer treatment Benefits clinicians by providing accurate, validated diagnostic, prognostic and therapeutic information Benefits UMHS by – establishing UMHS as a national leader in personalized medicine – attracting additional patients – enhancing UMHS ability to conduct clinical trials – creating a new revenue source for UMHS

17. 17 CRO’s Patient Advocacy Groups Cooperative Groups Academic Institutions Physician Networks Life Sciences Companies Reference Laboratories Pharmaceutical Companies

18. 18 Sequencing Pathologist & Oncologist Reviewed Patient Delivery Analysis 1)Clinical Trial Eligible 2)Actionable Results Informed Consent Tumor Biopsy (FFPE) 3–4 Day Turnaround Laser Cryo Enrichment & Or oncologist ordered

19. 19 Tens of thousands of articles identified Thousands of articles evaluated Thousands of articles reviewed and graded Thousands of rules developed Hundreds of articles cited Division of dedicated professional staff Real-time evidence report with weekly updates Bench Bedside Test ID and development Millions of papers interrogated

20. 20 ServicesClients Diagnostic Panels: ~500 targets/cancer pathways providing the associated therapies and supporting evidence Additional proprietary panels + analysis based on targeted sequencing for clinical trials, actionable Rx, R & D UMHS Clinical Systems Physicians and oncology groups Patients/Advocacy Groups Pharma/industry Payors Industry Services: Biobanking support & consulting Standard protocol development Clinical trial design and planning Companion molecular diagnostics Sequencing, IHC, FISH, SNP, Tissue Microarray, Laser Cryo Enrichment Payor consulting and contracting Clinical evidence database Pharma-sponsored clinical trials Clinical research organizations Advocacy Groups Payors Academic Investigators

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