October, 13, 2010

1. iSAEC Overview, Results, and Future Directions Cerner Healthcare Conference October, 13, 2010

2. Speakers • Arthur Holden • Founder, Chairman, and CEO • International Serious Adverse Events Consortium, Ltd. • Mark Hoffman, Ph.D. • Vice President Cerner Research Solutions

4. … A Novel Pathway to the Podium… • Hospital Administrator • BC/BSA National Fellow • Medical Products Executive • Biotech Entrepreneur (2) • “Mapper” of the Genome • Social Entrepreneur  Personalized Medicine  Drug Safety

5. iSAEC Overview • Our Focus & Public Mission • Phase 1 Results Summary • Phase 2 Launch and Research Focus • Cerner Collaboration • Q & A

6. iSAEC’s Websitehttp://www.saeconsortium.org

7. iSAECOur Mission & Scientific Focus

8. “The iSAEC will identify and validate DNA-variants useful in predicting the risk of drug induced serious adverse events.” iSAEC’s Mission

9. ADR  “a response to a drug which is noxious and unintended, and which occurs at doses normally used in humans..." 1 SAE  a response to a drug [at normal dosing] which is severely debilitating or life threatening and typically requires the cessation of the drug ADR vs SAE 1. WHO

10. Industrial Biomedical Consortium“Generic Model” Skilled External Partners Industrial Members Clear Project/ Unifying Goal(s)/ Finite Timeframe Private Foundations/ Governmental Bodies Organized by Professional Management & Supported by Quality Processes

11. Fill a research gap, not being effectively filled by existing players Gain greater efficiency/effectiveness (scale) via pooling of talents and resources across industry Establish common “research platforms” (risky) which help all researchers (pre-competitive) Reduce legal/IP barriers Why Industrial Biomedical Consortia [IBCs]?

12. Disease susceptibility Drug response or how patients are likely to respond to treatment  efficacy and safety Development of new drugs (vs just new targets) How Human Genomic Data can Apply to Medicine Maybe the “easiest” of the three areas!

13. Studying Genetic Differences • 99.9% of our DNA is identical in unrelated individuals • Differences in 0.1% contribute to our individual differences in: • Physical characteristics • Personality • Susceptibility to disease • Response to medicines

14. What is a SNP? …most common type of DNA variation …G GT A A C T G... …G GC A A C T G... Some people have a different base at a given location - Single Nucleotide Polymorphism (SNP)

15. “The good news is we have the human genome. The bad news is the computer alphabetized it.”

16. Pharmacogenetics Section of Genome/ SNP profile Patients without a side effect Patients with a side effect Predictive of no side effect Predictive of a side effect

17. Impact of rare, drug-related SAEs on patient health, healthcare costs and pharmaceutical development productivity is significant Safety research is difficult due to scale and collaboration challenges Current SAE research channels (academic investigator networks) are disjointed, variable, and poorly funded. Broadening the sources of “cases”, the “collaborative models” utilized, and the application of EHR data will likely expedite PGx drug safety research and personalized medicine Some Conclusions … beginning with the end in mind

18. iSAEC Origins & Rationale • Origins: • FDA and industry biomedical collaboration  consortium model • Private 501 c 3 entity formed to do research in the public good • 2006-07 -- Formation • 2007-2009 – Phase 1 • 2010-2013 – Phase 2 • Rationale: • Public health need • Scale • Pooled risk • Global orientation • Improved pace of the science > research productivity > personalized medicine • Support of the FDA’s “Critical Path” effort

19. iSAEC – Scientific Focus/Core Goals Supporting the development of existing and newinternational networks to obtain well phenotyped cases and controls for PGx research on important drug-induced SAEs Developing effective whole genome genotyping and sequencing methods for SAE research Supporting the development of the computational methods necessary for effective genetic analysis Creating a timely and publicly available scientific database (raw data and genetic markers) associated with key drug-induced SAEs Managing the intellectual property related to genetic markers associated with SAEs, to ensure broad and open access to all users in all settings

20. iSAEC’s Phase 1 Membership/Collaborators Members/Directors Spanish DILI EUDRAGENE DILI & SSRs External Collaborators/Contributors

21. iSAECPhase 1 Focus and Results Summary

22. Phase 1 Execution DACC development SSR characterization & analysis DILI network expansion DILI GWAS characterization & analysis Data release[s] iSAEC Phase 1 Operational Perspective Core Investments SSR GWAS, Paper & DR1 DILI GWAS, Papers (3) & DRs 2 & 3 Dividends! TdP GWAS, Paper (1) & DRs 4 A-E GWAS, Paper (1) & DRs 5 DILI , CIA, TdP Sequencing Pilots EHR SAE Case Sourcing Pilots (2) 09/07-12/09 SAE GWAS Cohorts Member (3)

23. MHC

24. Augmentin GWAS results201 cases, 532 POPRES controls • DR2 association is confirmed, however… • DQB1*0602has a larger effect in Spanish than nw-EU • DQB1*0402 is strongly associated only in nw-Eu and perhaps stronger in hepatocellular cases • rs2523822 within class I is a novel association, significant in both sub-populations, however… • In nw-EU it is a near-perfect tag of A*0201 • In Spanish it is a poor tag of A*0201 MHC

25. iSAEC’s Phase 1 Experience • GWAS analysis of SAEs • Demonstrated common variants, with a significant impact on the risk of an SAE, can be identified in small case sample sizes (<50) • Most genetic risk factors are drug specific • Important role for the MHC in the pathology of DILI • Significant influence of genetic variants in immune response & ADME genes • Common risk alleles are shared across drugs and/or SAEs are emerging (e.g. HLA-B*5701, HLA-DRB1*1501, UGT1A1*28) that will provide insights into “SAE mechanisms” • Common genetic risk factors (alone) do not accurately predict patient risk for rare SAEs ? • Drug specificity: Which subsets of drugs share genetic risk factors and why • Population specificity: Insufficient access to patients from different racial/ethnic groups to draw conclusions about population-specific effects • Rare variants: Current experience is limited to common variants (>5%) ; influence of rare variants unknown • Biological mechanisms: We don’t fully understand the mechanisms underlying the genetic associations and how they may interact with other risk factors

26. Importance of MHC variants in SAEs Emerging Sample Set: • HLA-DRB1*1501 DILI with Augmentin & Lumiracoxib • HLA-DRB1*0701  DILI with GSK Oncology drug & Ximelagatran • HLA-B*5701  DILI & AHSS Flucloxacillin & Abacavir TNXB Genetic Risk Alleles for SAEs/ADRs

27. Common Risk Alleles are Beginning to Emerge

28. Acknowledgments – Phase 1 Board Members • Brian Spear (Abbott) • Rick Scheyer (Daiichi Sankyo) • Vincent Mooser (GSK) • Nadine Cohen (J&J) • Joanne Meyer (Novartis) • Aidan Power (Pfizer) • Klaus Lindpaintner (Roche) • Robert Dix (Sanofi-Aventis) • Leonardo Sahelijo (Takeda) • Michael Burczynski (Wyeth) • Janet Woodcock (FDA) • ShaAvhree Buckman (FDA) • Michael Dunn (Wellcome Trust) • iSAEC Collaborating Researchers • Ann Daly & Diligen(Newcastle) • Mariam Molokhia & EUDRAGENE (London) • Maribel Lucena and Camille Stephens (Malaga) • John Dillon (Scotland) • Elijah Behr (SGUL) & Dan Roden (Vanderbilt/LeDucq) • DILIN • Paul Watkins (Hamner) • Bob Fontana (Michigan) Scientific Management Committee • Co-chairs: Matt Nelson (GSK) & Sally John (Pfizer) • Anahita Bahthena(Abbott) • Steve Lewitzky (Novartis) • Joe Walker (Daiichi Sankyo) • Klaus Lindpaintner(Roche) • Leonardo Sahelijo (Takeda) • Nadine Cohen, Quingqin Serena Li (J&J) • Steven Kovacs (Sanofi-Aventis) • Ted Burczynski & Maha Karnoub (Wyeth) • John Senior & Jan Johannessen (FDA) • Scientific Advisors • Mark Daly (Harvard/Broad) • David Goldstein (Duke) • Munir Pirmohamed (Liverpool) • Data Analysis & Coordinating Center (Columbia U.) • Yufeng Shen • Itsik Pe’er • Aris Floratos • Paola Niccoletti • Andrea Califano

29. iSAECPhase 2 Focus and Objectives

30. iSAEC Phase 2 Objectives (2010-2013) • Enhanced Efforts • Further characterize the genetics of “drug induced immunologic SAEs” (SSR, AHSS, & DILI) associated with specific drugs and ethnicities • Develop novel, international SAE research channels (HMORN, EHR vendors partnerships (Cerner) etc. vital to drug-specific SAE research. • Continued Efforts • Develop optimal genotyping and sequencing approaches for SAE genetics research • Develop a publicly available database of PGx markers predictive of key SAEs/across drugs • Manage IP relating to PGx markers useful in predicting SAEs to ensure broad and open access

31. iSAEC Phase 2 Objectives Balanced Investment Mix Case Recruitment Discovery Research Academic networks iDILIC – Liver Injury ITCH – Hypersensitivity GWAS Common risk factors Sequencing Rare risk factors Existing collections Pharmacos Partners Mechanistic studies Pathways and context New channels EMR-based Integrated healthcare systems “Developing new SAE research opportunities”

32. Pathways to SAE Case Cohorts Genetic Markers Discovery &Validation Pharmaco Safety Cohorts IHS research (via EMRs) LS EMR Provider databases Academic Networks • IDILIC • ITCH • Global, Cross Industry • Key SAEs  Existing & New • HMO Research Network (HMORN) • European Mkts (Scotland/Nordic/ Finland) • SAEC (Cerner) Phase 2 Project • US large hospital SAE Research network iSAEC Phase 2 Case Ascertainment Pilots Scalability & Specificity of Safety PGx Research

33. International DILI Consortium (iDILIC)Phase 2 Academic Network DILIN NIDDK SAEC Genomics Core Web Based Clinical Network Expression Analysis & Seq. Partnerships Spanish Network Ann Daly & Guru Aithal Newcastle Coordinating Hub EUDRAGENE 300+ Cases & Canadian Network SAEC DACC Cerner 2b Other EMR Vendors Columbia, Sanger & Select Analysis Partnerships DILI Investigator Network [8] – Bjornsson, Takikawa, Gee, & Larrey, etc. Japanese NIHR HMORN SAEC Members /Pharmacos DNA Repository SAEC Members /Pharmacos Int. TB Study Menzies et al (Montreal) Newcastle

34. International Consortium on Hypersensitivity (ITCH)Phase 2 Academic Network SAEC Genomics Core Web Based Clinical Network Expression Analysis & Seq. Partnerships European PGx Network ITCH Network Pirmohamed et al 400 Cases Eudragene & SAEC DACC Columbia & Select Analysis Partnerships Cerner 2b Other EMR Vendors Canadian Network HSS Investigator Network [6] – Spielberg (US), Shear (Canada), Day, Shiohara (Japan) etc HMORN SAEC Members /Pharmacos SAEC Members /Pharmacos SSR Investigator Network [5] – GATC, Italy, & Singapore DNA Repository Liverpool

35. Web-based Enrollment via Cerner’s Discovereplatform iSAEC Phase 2 – SAE Phenotype & IT Focus • DILI (expansion) • SSR (expansion) • AHSS (new) EMR Identification & Enrollment From IHN & EHR Vendors

36. IDILIC & ITCH Clinical Registries

37. HMO SAE Research Network

38. Cerner iSAEC Hospital Research Network • Cerner/iSAEC collaboration is focused on two studies • International Consortium on Drug Hypersensitivity (ITCH) • International Drug-Induced Liver Injury Consortium (IDILIC) • Cerner is committed to provide technology to sites interested in participating in either study • Technology to help sites determine study feasibility • Technology to help sites identify potential candidates • Projects are an example of the research required to enable genetically informed medicine

39. IDILIC Phase 2 Collection Targets Yes Yes Yes Yes TBD Yes

40. ITCH Phase 2 Collection Targets Yes Yes Yes ? Yes Yes Yes

41. Benefits to Participating Institutions • Personalized Medicine Exposure  PGx and very select disease risk profiling (e.g. cancer) will be the first steps (MGH example) • Innovative Translational Research Involvement  medical staff development • Scale  faster, better SAE research results via with larger, more diverse cohorts & integrated genomic support with the best centers in the world • iSAEC Support for network development, IT infrastructure, web-based enrollment, WGAS/Sequencing, data analysis & management

42. Academic collaborators Networking partners Members [companies, government & foundations] Research partners [large hospitals] …. The iSAEC would not be possible without it’s current and additional …. Arthur HoldenChairman, iSAEC8770 W. Bryn Mawr Avenue, Suite 1300, Chicago, IL 606311-773-867-8595aholden@earthlink.netwww.saeconsortium.org

43. iSAEC Phase 2 -- “Membership” Drug induced immunologic SAEs Regulatory Participants

44. How can Cerner clients get involved? • Contact Cerner to learn more about the studies and how Cerner can help • Cole Erdmann, cole.erdmann@cerner.com, 816-201-8602

45. For more information or to continue the dialogue after this session, visit the Academic Healthcare Community group on uCern. You may also be interested in joining these other groups related to Pediatric Care. • Personalized Medicine • Clinical Transformation Get access to all 2010 CHC education sessions and other Cerner educational content for your organization through Cerner’s new uLearn program. To learn more, visit the booth by registration in the 2300 lobby or contact a representative atuLearn@cerner.com.

46. Q & As