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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

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Page 1: 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

Page 2: 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.

Page 3: Personalized Medicine in the ICU Asim Siddiqui Sirius Genomics 13th September 2007 VANBUG

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

Page 4: Personalized Medicine in the ICU Asim Siddiqui Sirius Genomics 13th September 2007 VANBUG

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

Page 5: Personalized Medicine in the ICU Asim Siddiqui Sirius Genomics 13th September 2007 VANBUG

Mosnier LO, et al. Blood. 2006 Nov 16

PAI-1

Pathways for APC Activity

Page 6: Personalized Medicine in the ICU Asim Siddiqui Sirius Genomics 13th September 2007 VANBUG

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

Page 7: Personalized Medicine in the ICU Asim Siddiqui Sirius Genomics 13th September 2007 VANBUG

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 ‘-/-’

Page 8: Personalized Medicine in the ICU Asim Siddiqui Sirius Genomics 13th September 2007 VANBUG

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

Page 9: Personalized Medicine in the ICU Asim Siddiqui Sirius Genomics 13th September 2007 VANBUG

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

Page 10: Personalized Medicine in the ICU Asim Siddiqui Sirius Genomics 13th September 2007 VANBUG

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

Page 11: Personalized Medicine in the ICU Asim Siddiqui Sirius Genomics 13th September 2007 VANBUG

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

Page 12: Personalized Medicine in the ICU Asim Siddiqui Sirius Genomics 13th September 2007 VANBUG

That’s where the science ends but….

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

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

Page 14: Personalized Medicine in the ICU Asim Siddiqui Sirius Genomics 13th September 2007 VANBUG

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