corus ™ cad overview corus cad intended use statement referenced at the end of this presentation

Corus™ CAD Overview

Corus CAD Intended Use Statement referenced at the end of this presentation

© 2010 CardioDx. Content is Confidential and ProprietaryLEN-090032 Rev.01

Patient population:• 397,954 stable patients with clinical

risk factors and/or symptoms of CAD (but no prior history of CAD) undergoing cardiac catheterization for evaluation

Study found: • 62% of patients who underwent

elective cardiac catheterization did not have significant CAD

• 40% of patients had minimal to no CADi

• Majority of patients (83.9%) received noninvasive diagnostic testsii prior to referral to catheterization

i Minimal to no CAD is defined as < 20% stenosisii Resting ECG, exercise or pharmacological stress, echocardiography, radionucleotide, CT scans, or other heart scans

38% obstructive coronary

arterydisease%

of

tota

l p

ati

en

ts

N=397,954 N=149,739

0

20

40

60

80

100

120

Pre-Coronary Angiography Post-Coronary Angiography

Better Diagnostic Methods are Needed to Stratify Patients for Elective Invasive Angiography8


The Challenge of Assessing CAD1-5

• Despite advances in imaging technology, non-invasive assessment of obstructive CAD continues to be subjective and challenging

• The complexity of CAD diagnosis lies not only in the variation of presenting symptoms, but also in the patient’s unique characteristics

• Implementation of standard of care involving non-invasive imaging assessment of CAD is highly variable regarding the type, number, and sequence of tests


Cardiac Imaging Procedures Deliver Significant Amounts of Ionizing Radiation6

Study reported:• MPI procedures contributed to

74.2% of cumulative effective radiation dose from overall cardiac imaging procedures

Estimates of Effective Doses for SelectedCardiac Imaging Procedures (in mSv)


MPI is the Largest Contributor of Radiation Overall6

Study design:• This is a subset of the NEJM

Fazel 2009 study, focused only on cardiac imaging procedures

Study reported:• MPI procedures contributed to

74.2% of cumulative effective radiation dose from overall cardiac imaging procedures

• Radiation dose and risk accumulates over a person’s lifetime

Contribution to Cumulative Effective Radiation Dose by Type of Cardiac Imaging Procedures (in mSv)


Women Receive Higher Radiation Dosing From Medical Imaging7

In 2009, the NEJM reported:• Cumulative effective doses of

radiation from imaging procedures were higher in women than in men• Computed tomography and

nuclear imaging accounted for 75.4% of the cumulative effective dose


Genomics: A New Era in Medicine

• Genomic testing has the power to inform about disease processes at the molecular and cellular level

• CardioDx delivers the first and only clinically validated gene expression test to turn the promise of genomic medicine into practice for assessing obstructive* coronary artery disease (CAD)

*Obstructive CAD is defined as at least one atherosclerotic plaque causing ≥50% luminal diameter stenosis in a major coronary artery (≥1.5mm lumen diameter) as determined by invasive quantitative coronary angiography (QCA).

The Human Genome Project has ushered in the era of genomic medicine and the promise of more individualized patient care


Genetic Testing VS Gene Expression Tests


About Corus™ CAD

• The first clinically validated gene expression test for assessing obstructive coronary artery disease (CAD) in non-diabetics

• Enables more informed decision-making and risk stratification

• Test has high sensitivity and negative predictive value

• Test score reflects the presence and extent of obstructive CAD

• Test improves classification of patient disease status

• A safe and convenient genomic test • Blood sample collection takes minutes, and test results are

delivered promptly to the clinician’s office


Clinically Validated Gene Expression Test for the Assessment of Obstructive CAD10,11

• Algorithm comprised of expression levels of 23 genes demonstrated to indicate obstructive CAD

• Molecular basis includes genes and pathways with known involvement in atherosclerosis and its progression

• Based on the detection of a reliable molecular signature for obstructive CAD

Delivers a biological view into a patient’s disease state


Rigorous Multi-Center Product Development and Validation


Corus™ CAD Gene Term Examples3-8


Corus™ CAD Algorithm Terms and Genes4

1) Neutrophil Activation - Apoptosis Innate Immunity (IL18RAP, TNFAIP6 CASP5) – (IL8RB TNFRSF10C, TLR4, KCNE3)

2) Neutrophil Activation/Lymphocytes Innate Immunity/Cell Necrosis (S100A8, S100A12, CLEC4E) - RPL28

3) NK Activation/T cells Innate Immunity SLAMF7, KLRC4 - TMC8, CD3D

4) B/T Ratio - Adaptive Immune Response SPIB, CD79B - TMC8, CD3D

5) AF2- TFCP2, HNRPF

6) TSPAN - TFCP2,HNRPF

1) Neutrophil Activation - Apoptosis Innate Immunity (IL18RAP, TNFAIP6 CASP5) – (IL8RB TNFRSF10C, TLR4, KCNE3)

2) Normalized Neutrophil Activation Innate Immunity/Cell Necrosis (S100A8, S100A12, CLEC4E) - (NCF4, AQP9)

3) NK Activation/T cells Innate Immunity SLAMF7, KLRC4 - TMC8, CD3D

4) B/T Ratio - Adaptive Immune Response SPIB, CD79B - TMC8, CD3D

5) AF2 - TFCP2,HNRPF

Males Females


Corus™ CAD is Multifactorial

Gene Expression Derived Cell Type Ratios

MOLECULAR & MOLECULAR & CELLULAR FACTORSCELLULAR FACTORS

Gene Expression Changes Within a Certain Cell Type

CELL TYPE-SPECIFIC CELL TYPE-SPECIFIC GENE EXPRESSIONGENE EXPRESSION

Gender-Specific, Age Dependent Coronary Disease Risk Functions

GENDER & AGE RISK GENDER & AGE RISK FUNCTIONSFUNCTIONS

U.S. Prevalence of Coronary Heart Disease by Age & Sex, NHANES


Clinical Validation Trials PREDICT TRIAL


Corus™ CAD Validation Data Published in Annals of Internal Medicine – October 201010

“Rosenberg and colleagues’ study lies at the vanguard of clinical genetics in cardiovascular care. ” -Excerpt from AIM editorial, Donna Arnett Ph.D., M.S.P.H.


PREDICT Summary9,10

• Prospective, multi-center, blinded* study• 1,343 nondiabetic patients enrolled to develop and validate

Corus™ CAD• 39 U.S. sites participated• Study PI: Eric Topol, MD, Scripps Research Institute• QCA Core Lab: Alexandra Lansky, MD, Columbia University/CRF• Enrolling sites and investigators included:

Vanderbilt Heart and Vascular Institute (TN) John McPherson, MD

Washington Hospital Center (DC) Ron Waksman, MD

Cleveland Clinic Foundation (OH) Steven Ellis, MD

Minneapolis Heart Institute (MN) Robert Schwartz, MD

Duke University Medical Center (NC) Bill Kraus, MD & Kristin Newby MD

Intermountain Medical Center (UT) Brent Muhlestein, MD

Piedmont Hospital Research Institute (GA) Szilard Voros, MD

Oklahoma Cardiovascular Research Group (OK) Naeem Tahirkheli, MD

Allegheny General Hospital (PA) Tony Farah, MD

*Data was analyzed in a blinded fashion


PREDICT Trial Design9,10

Personalized Risk Evaluation and Diagnosis In the Coronary Tree


Probability of CAD in Females and Males as Observed in PREDICT1,2


Corus™ CAD Score is Proportional to Disease Severity4


Clinical Validation Trials COMPASS TRIAL


COMPASS Study Overview

• Second validation study for Corus™ CAD in the intended use population• Will also evaluate MPI performance in the real-world clinical setting• Prospective, multi-center, blinded* study• 450 patients to be enrolled at 21 U.S. sites• QCA Core Lab: Cardiovascular Research Foundation• Study completion: Q4 2010• Steering committee: John McPherson, MD, Alexandra Lansky, MD, Greg

Thomas, MD, Szilard Voros, MD• Enrollees include patients referred for a clinically indicated MPI who meet

the following criteria**:

*Data to be analyzed in a blinded fashion **Complete inclusion and exclusion criteria may be found in protocol NCT01117506 at ClinicalTrials.gov.

i. Symptomatic (chest pain or anginal equivalent) who have been referred for MPI for the workup of suspected obstructive CAD

ii. Non-diabeticiii. No known obstructive CAD, prior myocardial infarction, or prior

revascularization procedure

© 2013 CardioDx. Content is Confidential and Proprietary23

COMPASS Trial Design

• All non-diabetic patients referred for clinically indicated MPI for chest pain or anginal equivalent symptoms without known obstructive CAD, MI or revascularization were enrolled.

• MPI positive patients received invasive angiography if clinically indicated.• MPI negative patients received CT angiography. If clinically indicated, patients went onto catheterization

for further evaluation.


On site interpretation

Core lab interpretation

CTAngiography

CTAngiography

MPIMPI



with QCA

QCA Core Lab:Cardiovascular Research Foundation

CTA Core Lab Readers:Szilard Voros, MDJames R Adams, MD

MPI Core Lab Reader:Timothy M Bateman, MD

InvasiveAngiography

InvasiveAngiography

Rigorous Data Analysis and Approach Undertaken in the COMPASS Trial


Corus CAD Site-read MPI P-value

Sensitivity 89% 27% p<0.001

NPV 96% 88% p<0.001

*Summary statistics at a pre-specified threshold of 15 Core-read MPI Sensitivity: 36% Core-read MPI NPV: 88%

• In the COMPASS trial, Corus CAD outperformed MPI in sensitivity and (89% vs. 27%, p<0.001) and negative predictive value (96% vs. 88%, p< 0.001) for ruling out obstructive coronary artery disease

Corus® CAD vs. MPI Performance


Corus™ CAD Decreases the Rate of False Positive Classifications From MPI4

Case/Total(case %)

MPIMPIPositive*Positive*

Corus CADOverall

76/223 (34%)

Corus CADLow

6/57 (11%)

Corus CADIntermediate

21/78 (27%)

Corus CADHigh

49/88 (56%)

LegendMPI Positive

76 cases/223 patients(34% case rate)

*MPIs were defined as positive if at least one reversible or fixed defect consistent with obstructive CAD was reported. Indeterminate or intermediate defects were considered negative. 60% of PREDICT validation cohort patients had MPI. Data from the PREDICT validation cohort, as determined by quantitative coronary angiography (QCA).

When Corus CAD and MPI disagreed, Corus CAD was correct* 89% of the time and MPI was correct 11% of the time


Potential New Paradigm of Care based on COMPASS Results

Thomas et al, Circ Cardiovasc Genetics 2 /15/2013; DOI: 10.1161/CIRCGENETICS.112.964015


Early Revascularization (within 1 month)

Late Revascularization and MACE

(between 1 and 6 months)

Corus CAD ≤15

(n=192)1 (0.5%) 0 (0%)

Corus CAD >15

(n=228)24 (11%) 3 (1.3%)

COMPASS Trial Follow-up: Patients with Low Corus® CAD Scores Showed Very Low Event Rates at 6 Months

COMPASS Trial6-month Follow-upn=420/431 (97%)

• Corus CAD had a sensitivity of 96% and NPV >99% for events and revascularizations at 6-month follow-up

• Significant correlation between increasing Corus CAD scores and increased event likelihood*

*p-value = 0.0015


Relationship Between Corus® CAD Score and Percent Coronary Artery Stenosis

• In patients with low Corus CAD scores ( ≤ 15), 96% of patients did not have obstructive CAD

• The higher the Corus CAD score, the higher the likelihood of obstructive (≥ 50% stenosis), minimal (1-24%) and moderate (25-49%) CAD, and the lower the likelihood of no disease


CORUS CAD PERFORMANCE

at threshold score of 15

COMPASS

(total N=431)

PREDICT-CTA*

(total N=216)

PREDICT

(total N=526)

Sensitivity 89% 83% 85%

Specificity 52% 45% 43%

NPV 96% 93% 83%

Prevalence 15% 16% 37%

*Core-lab CTA **AUC: Area under the curve, a method of measuring diagnostic accuracy***95% CI 0.73 - 0.84 **** 95% CI 0.54-0.63

• Corus CAD outperformed MPI in diagnostic accuracy in the assessment of obstructive CAD in symptomatic patients

• Corus CAD AUC** = 0.79*** and MPI AUC = 0.59****• Statistically significant with p < 0.001

Corus® CAD Demonstrates Consistent, Strong Performance in Three Independent Cohorts


Corus™ CAD Intended Patients

• With known prior myocardial infarction, or who have had a revascularization procedure

• Younger than 21 or older than 99 years of age• Who are asymptomatic and not considered at high risk for CAD

Corus CAD is NOT intended for patients:

Corus CAD is intended for use in the following non-diabetic patients that a clinician suspects may have coronary artery disease (CAD):

Asymptomatic High-Risk Patients

• Patients with a recent positive or inconclusive test result (ECG, ETT, Echo, MPI, CTA, Calcium Score)

and/or• Patients with 3 or more major risk factors for CAD (e.g., high cholesterol,

hypertension, family history, smoker, morbid obesity, known non-cardiac vascular disease, male > 50, female > 60)


Corus™ CAD Patient Sample Kit

• All-in-one solution: sample collection kit, sample shipper, self-contained cooling system

• PAXgene®-based sample collection means no processing, no spin-down at the clinic

• On-demand cooling system* means no dry-ice, no ice packs for sample shipment back to CardioDx

All-in-one solution in a convenient patient sample kit

*Evaporative, adsorption cooling system. Validated to maintain 4°C for 48 hours.For more information visit www.nanocool.com


Corus™ CAD Test Requisition Form

Billing Information

Comments

Patient Information

Ordering Clinician's Signature

Blood Draw Information

Account Information


Likelihood of Obstructive CAD: Derives from the patient score andis reported with a 95% confidenceinterval (CI). A 95% CI indicatesthere is a 95% chance that theactual likelihood is within thisrange.

Patient Score: Ranges between 1 and 40, with highervalues associated with higherlikelihood of obstructive CAD.

Graph: Depicts the relationship between test score and the likelihood of obstructiveCAD in the clinical validation study.

Corus™ CAD Patient Report


• The Corus CAD test is a quantitative in vitro diagnostic test performed in a single laboratory, using the gene expression profile of cells found in peripheral blood specimens to be used as an aid to identify patients who are likely to have coronary artery stenosis of at least 50%.

• The test should be performed on patients with a history of chest pain, with suspected anginal equivalent to chest pain, or with a high risk of coronary artery disease, but with no known prior myocardial infarction or revascularization procedures.

• The test is not intended for patients with acute myocardial infarction, high risk unstable angina, systemic infectious or systemic inflammatory conditions, diabetes, and/or who are currently taking steroids, immunosuppressive agents, or chemotherapeutic agents.

Corus™ CAD Intended Use (page 1 of 2)


Corus™ CAD Intended Use (page 2 of 2)

• The test is performed on a blood specimen obtained from the patient.

• The test incorporates the expression levels of multiple genes using an algorithm with weighted functions to generate a quantitative score.

• The results of the test should be used by clinicians in conjunction with other tests and clinical information in their assessment of a patient’s coronary artery disease.

• The Corus CAD test is for prescription use only.

• The test is not intended to be used to screen for stenosis among patients who are asymptomatic and not considered at high risk for coronary artery disease, to predict or detect response to therapy, or to help select the optimal therapy for patients.

corus ™ cad overview corus cad intended use statement referenced at the end of this presentation

Documents

significant cad

imaging technology

medical imaging

nuclear imaging

mpi procedures

proprietary len

corus cad overview corus

cad i majority of patients