Organ Specific Proteomics as Presented by Paul Kearney, PhD; CSO, Integrated Diagnostics at the 2010 Personalized Health Care National Conference at Ohio State.

1. Realizing P4 Medicine: First Steps Paul Kearney, Ph.D. President, CSO and Founder Integrated Diagnostics October 14, 2010 1

2. Integrated Diagnostics Spin out from the Institute for Systems Biology and based in Seattle. Founded September 2009 raising $30M in venture capital from InterWest, Wellcome Trust and BioTechCube. Focus is on the development of early diagnostics for lung cancer and Alzheimer’s. Founding concepts include large scale system measurements and organ-specific proteins. 2

3. The Power of Vision: The First Step 3 enables The value of visionary ideas, such as P4 medicine, is that they compel us (researchers, policy makers, entrepreneurs, etc.) to innovate and take those important first steps to realizing the vision. Advances in technology, policy, knowledge Visionary Idea compels/directs

6. cell phone location apps

9. monitor thousands of markers

10. from a drop of blood.?$ Today The first step is tactical: What can we do tomorrow with today’s innovations?

13. Working within the existing environment

15. Acquiring high value content markers

16. Regulatory hurdlesP4 Commercial Clinical What has Integrated Diagnostics done to address these challenges?

17. Challenge #1: Finding the Right Application 7 Determine if a lung cancer lesion detected by imaging is benign or malignant. Patrick Nana-Sinkham, MD The Ohio State University School of Medicine

18. What Makes This Application Ideal? estimated 2.7 million lung lesions are seen by imaging every year in the US current protocol is ‘watchful waiting’ if the lesion grows (operate – ~30% error rate) or if the lesion does not grow after 2 years then do nothing (97% of cases; 4-5 CT scans per patient on average) hard to biopsy (blood-based Dx test is ideal) market research indicates that this is the #1 diagnostic need in lung cancer among pulmonologists (the end-users) High unmet need drives adoption of new ideas, technologies and solutions. 8

19. Challenge #2: Intelligently Selecting Markers to Monitor 1. Lung-specific proteins (expressed only by the lung) * Sentinels of system health and disease of the lung only Lung-specific proteins are highly modulated by lung disease (statistical disease association analysis across GEO database) 2. Lung cancer tumor-specific cell surface markers ** Proteins expressed on the cell-surface of tumor cells but not healthy cells Likely to be found in blood. 3. Lung cancer tumor-specific secreted proteins ** Proteins secreted by tumor cells but not by normal cells Likely to be found in blood. 9 Total: ~750 proteins * licensed from the Institute for Systems Biology ** licensed from Caprion Proteomics

20. Challenge #3: Massively Parallel System Measurements Diagnosing/monitoring/treating complex diseases in a complex system (humans) with high population variability requires broad sampling across organs, pathways, biological functions, etc. One gene or one protein is not enough for a high resolution picture of an individual’s state of health. Massively parallel biological system queries are going to be the norm for P4 medicine 10

21. Challenge #3:The Power of Massively Parallel System Measurements 11 As the number of random blood analytes profiled increases, segregation of healthy and disease type occurs.

22. Challenge #3:Select a Technology that can Assay 750 Proteins MRM (Multiple Reaction Monitoring) is targeted, hypothesis driven mass spectrometry Focusing resources of the MS on a small number of proteins, not on sample surveys Emerging clinical tool pioneered at Institute for Systems Biology Largest lung cancer assay ever created (750 proteins) 12

23. Challenge #4: Avoid ‘Loss in Translation’ ‘Loss in Translation’ occurs when discovery results cannot be translated into clinical tools. discovery technology platforms (e.g. mass spectrometry) differ from commercial platforms (e.g. Luminex assays) technologies vary greatly in performance and in what they can detect and measure reliably often large panels of discovery-stage markers cannot be translated onto a commercially viable platform because of cost or multiplexing limitations Solution: Use the same platform technology (mass spec) discovery  validation  commercialization 13

24. Tactical First Step Solutions 14 Market Research Discovery Studies MRM Assay Development Validation Studies Commercial- ization 1 2 3 4 Select an indication of large market size and of high clinical unmet need. Validate with front line clinicians (end-users). License large systems-based discovery data sets. Select a highly multiplexed technology platform (MRM) that enables massively parallel system measurements. Select a technology platform (MRM) that avoids ‘loss in translation’. 100+ of the 750 MRM assays developed to date (completed in 6 months) 76% success rate in assay development ~ $2000 per MRM assay to develop high correlation between discovery data and assay verification data

25. Other Challenges … Regulation of IVDMIA Dx tests Developing a market channel to end users (e.g. pulmonologists) New use of MRM in the clinic (previously only used for single analyte monitoring such as vitamin D levels). Working within the existing environment. Who saves and who gains with each P4 innovation? 15

26. Concluding Remarks What are the first steps for the P4 vision? What are the demonstration projects? What are the emerging technologies that can be leveraged? What are the performance measures for P4 Medicine? What are the challenges that must be overcome in these demonstration projects? 16