personalized medicine in the icu asim siddiqui sirius genomics 13th september 2007 vanbug
TRANSCRIPT
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