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