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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)
ParentsParents Relative Risk of DeathRelative Risk of Death(Death of a Biologic Parent < 50 yr)(Death of a Biologic Parent < 50 yr) of Adoptee from of Adoptee from
the same causethe same cause
CancerCancer 1.2 1.2
Infectious DiseaseInfectious Disease 5.8 5.8
1.1.Sorensen TI et al. NEJM 1988; 318: 727Sorensen TI et al. NEJM 1988; 318: 727
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
Mosnier LO, et al. Blood. 2006 Nov 16
PAI-1
Pathways for APC Activity
APC Product:Analytical Approach
5. SAE Analysis
2. Validation Cohort (Sirius
and Partner)
PROWESS Cohort (Lilly)
(APACHE II ≥ 25)
N = 752
1. Derivation Cohort (Sirius)
N = 1024
Xigris-treated and Controls
Risk of Death Analysis
IRP Analysis
3. Additional Validation VASST Cohort
N= 423
4. Biological Plausibility
Protein C
PAI-1
Improved Response Polymorphism (IRP) Genotype
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 ‘-/-’
Absolute Risk Reduction (ARR)Across Three Cohorts
-20
0
20
40
ARR (%)
+/+
+/-
-/-
SPH
-20
0
20
40
ARR (%)
+/+
+/-
-/-
PROWESS
-20
0
20
40
ARR (%)+/+
+/-
-/-
VASST
Improved Response Polymorphism (IRP) Genotype
Serious Adverse Events by IRP genotype PROWESS APACHE II 25
IRP +/+ IRP +/- IRP -/-Within
treatment p-value*
Placebo 18.1% 12.9% 2.6% 0.04
APC 11.3% 14.2% 21.2% 0.33
Within genotype p-value*
0.17 0.83 0.02
Interaction p-value
0.01 0.05 Base
*Chi-square or Fisher exact test
Efficacy, Biology, SAEs
0
10
20
30
40
50
60
Placebo rhAPC
PAI-1 / Protein C .0
10
20
30
40
50
60
Placebo rhAPC
Mortality rate (%) .
0
10
20
30
40
Placebo rhAPCSerious Adverse Events (%) .
+/+ +/- -/- +/+ +/- -/- +/+ +/- -/- +/+ +/- -/- +/+ +/- -/- +/+ +/- -/-
Improved Response Polymorphism (IRP) Genotype
IRP Combination GenotypePROWESS APACHE II ≥ 25
IRP: Prediction of Improved Response
to Xigris
Prediction of Adverse Response
to Xigris
23%
9%
-2%
-5%
0%
5%
10%
15%
20%
25%
+/+ +/- -/-
Survival
% of Pop. 37% 53% 10%
1%
18%
-7%
-10%
-5%
0%
5%
10%
15%
20%
+/+ +/- -/-
Serious Adverse Events
That’s where the science ends but….
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
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