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Personalized Medicine in the ICU Asim Siddiqui Sirius Genomics 13th September 2007 VANBUG

Personalized Medicine in the ICU Asim Siddiqui Sirius Genomics 13th September 2007 VANBUG. Developing and commercializing rapid, DNA-based diagnostic (Dx) and pharmacogenetic (PGx) tests that will revolutionize critical care medicine. Why genetics? Heredity in infectious diseases (1).

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Personalized Medicine in the ICU Asim Siddiqui Sirius Genomics 13th September 2007 VANBUG

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  1. Personalized Medicine in the ICU Asim Siddiqui Sirius Genomics 13th September 2007 VANBUG

  2. Developing and commercializing rapid, DNA-based diagnostic (Dx) and pharmacogenetic (PGx) tests that will revolutionize critical care medicine.

  3. Why genetics? Heredity in infectious diseases(1) Parents Relative Risk of Death (Death of a Biologic Parent < 50 yr) of Adoptee from the same cause Cancer 1.2 Infectious Disease 5.8 1. Sorensen TI et al. NEJM 1988; 318: 727

  4. APC (Activated Protein C)Xigris® • Severe sepsis, high risk of death • Uptake: 5% of target population • Concern re: efficacy • Concern re: safety • Physicians have difficulty determining who gets the drug

  5. Pathways for APC Activity PAI-1 Mosnier LO, et al. Blood. 2006 Nov 16

  6. APC Product:Analytical Approach 3. Additional Validation VASST Cohort N= 423 1. Derivation Cohort (Sirius) N = 1024 Xigris-treated and Controls Risk of Death Analysis IRP Analysis 2. Validation Cohort (Sirius and Partner) PROWESS Cohort (Lilly) (APACHE II ≥ 25) N = 752 Protein C 4. Biological Plausibility PAI-1 5. SAE Analysis Improved Response Polymorphism (IRP) Genotype

  7. IRP Definition • rs2069912 ‘C’ allele efficacious response • rs7242 ‘T’ allele efficacious response • 1 or more copy of each ‘+/+’ • 1 or more copy of only one ‘+/-’ • Zero copies of each ‘-/-’

  8. Absolute Risk Reduction (ARR)Across Three Cohorts Improved Response Polymorphism (IRP) Genotype

  9. Serious Adverse Events by IRP genotype PROWESS APACHE II 25 *Chi-square or Fisher exact test

  10. Efficacy, Biology, SAEs +/+ +/- -/- +/+ +/- -/- +/+ +/- -/- +/+ +/- -/- +/+ +/- -/- +/+ +/- -/- Improved Response Polymorphism (IRP) Genotype

  11. IRP Combination GenotypePROWESS APACHE II ≥ 25 IRP: Prediction of Improved Response to Xigris Prediction of Adverse Response to Xigris 37% 53% 10% % of Pop.

  12. That’s where the science ends but….

  13. Platform & Regulatory Process • Identify a suitable platform • 45 mins from blood sample to genotype • Fully automated • CLIA-waived • Hospital lab or point-of-care • FDA approval for test • Further studies

  14. Acknowledgements • Jim Russell • Keith Walley • Tony Gordon • Karen Mooder • Hugh Wellman • Marissa LeBlanc • Xuekui Zhang • Bill Macias • Mark Williamson • Sandra Kirkwood • Nicholas Lewin-Koh • Lee O’Brian

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