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Better Prevention and Management of Chronic Disease are Critical to Improving Health Outcomes and Lowering Healthcare Costs

Source: DeVol, R, Bedroussian, A, et al. An Unhealthy America: The Economic Burden of Chronic Disease. The Milken Institute. October 2007.

An Unsustainable Path

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Our Leaders Agree

“In the future, when doctors can truly prescribe the right treatment, to

the right person, at the right time, we will have a new level of precision

and effectiveness that will provide the knowledge-driven power that is

necessary to achieve our highest goals in healthcare reform – including

more effective disease prevention and early disease detection.”

HHS Secretary Kathleen SebeliusSenate confirmation hearings, April 2, 2009

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IGNITE is a unique non-profit medical research institute in the national capital area aimed at alleviating human suffering and transforming the health care system using a new strategy:

Personalized Medicine

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Strategy

Chronic disease R&D focus – align program with market needs from outset

Deep molecular sub-classification of chronic disease (all heritable risk identified)

Identify at-risk individuals from across the population via “genetic risk factor testing”

Run distributed primary prevention trials facilitated by HIT network

Apply results rapidly back to at-risk individuals via a robust translational infrastructure – including a “captured” health care system

Integrate health information technology to allow heritable risk information to be incorporated into point-of-care with clinical decision support

Empower change across the personalized medicine ecosystem through policy, education, health economics, regulation

Outcome: Alleviate or delay the onset of chronic disease and decrease the time individuals are sick at the end of life and allow resources to care for more

CASE STUDY: ALZHEIMER’S

Alzheimer’s Disease

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How AD Contributes to the Crisis

In ‘Boomer’ Diseases, such as Alzheimer’s, Impact and Costs Will Escalate Dramatically Without New Interventions

2000 2010 2020 2030 2040 2050$0

$500

$1000

$1500

$2000

0

2

4

6

8

10

12

14

16

Baseline Estimate

Estim

ated N

um

ber o

f Peo

ple

With

AD

(in m

illion

s)

Delayed Onset & Slowed Progression (~6 yrs)

Adapted from The Lewin Group Report, June 2004, “Saving Lives. Saving Money: Dividends for Americans Investing in Alzheimer Research,” The Alzheimer’s Association (http://www.alz.org/Resources/FactSheets/Lewin_FullReport1.pdf)

DEEP MOLECULAR SUB-CLASSIFICATION

Molecular Scanning Technologies

– Chairman of NIH Microarray Consortium (15 NIH)– 10 years of experience with Affymetrix platform– 5 years experience with Illumina– >60,000 expression profiles run– >100,000 SNP arrays run (10k, 100k, 500k, 1M)– Data warehousing – First “Genomics Collaborators” , “Center of

Excellence”, and “TransMed” site of Affymetrix– NHLBI Programs in Genomic Applications– NEI intramural contract site– NIH Neuroscience Array Consortium– NCI funded ALL catalog– NIA funded Alzheimer’s disease catalog– ADNI Consortium hub– International Autism Genome Project Genotyping Site– TCGA Biospecimen repository– High throughput sequencing (Solexa, 454, ABI,

Pacific Biosiences)

The Shop

NIH Neuroscience Microarray Consortium

1650 registered users

455 proposals submitted from about 114 institutions around the country and from over 287 different investigators

Total Projects: 455455 (45,400 arrays)

POPULATION-WIDE SCREENING

Population-based Genetic Risk Factor Screening

David Agus, MD Dietrich Stephan, PhD

SAB:Isaac Kohane, MD PhDDavid Botstein, PhDSpencer Wells, PhD

Population-based Genetic Risk Factor Screening

David Agus, MD Dietrich Stephan, PhD

SAB:Isaac Kohane, MD PhDDavid Botstein, PhDSpencer Wells, PhD

Navigenics CONFIDENTIAL

Extract the Total Heritable Risk for Chronic Disease

Customer Acquisition Laboratory Bioinformatics

PersonalizedWeb Portal

OngoingService

1 52 3 4

ATACCGCTGGCCCTTTGGCATTACCTATGAAGATTGCTTCAGCCAGCGTCAGTTTCAACCTGTACGCTAGTGTGTTTCTACTCACGTGTCTCAGCATTGATCGATACCTGGCTATTGTTCACCCAATGAAGTCCC

FUTURE: Full genome sequencing, copy number analysis, methylation status leading to personalized exposure mitigation strategies and biomarker monitoring programs fully integrated into the established health care system.

Non-Invasive DNA Collection Kit

April 10, 2023

GMP-compliant, ISO-certified Array Manufacturing

Photolithography Chemistry

QUALITY

CLIA and stringent QC labCaptured perfectly Per SNP algorithm checksPer SNP concordanceH-W equilibrium checks

Navigenics CONFIDENTIAL

What we do

23 Navigenics CONFIDENTIAL

Review world class academic and clinical research published in leading peer-reviewed journals…

…and provide personalized, preventative, health and wellness information

Stringent Curation Criteria Replication in the same ethnic group

– Once for GWAS, twice for candidate gene studies

– >60% independent sample sets show same statistically significant effect with same allele (after trimming underpowered samples)

Study design - An effort was made to sample controls from the same source population as the cases, e.g. ethnicity, gender, age, or other risk factors.

Reasonable sample size to detect weak effects. OR <1.5 needs 250 cases/250 controls at least.

Significance level - Exact value depends on magnitude of the study (e.g. GWAS or candidate gene) Sound statistical design - correction for multiple testing, population

stratification, confounding Sound laboratory practice - independent genotyping platforms, replicated

samples Functional data and magnitude of effect are also taken into account, but

studies are not automatically excluded if functional data is unavailable or the effect estimate is small.

Finding the Relative Risk - see full details at navigenics.com

OR (RR)

(RN)

Prevalence

• We normally get genotypic odds ratios RR/NN, RN/NN

OR (RN)

Genotype Freq

• Using genotype frequencies and prevalence, we derive a set ofquadratic equations – the solution provides the relative risks.

(RN)?

?

Distribution of effect sizes for genetic and environmental risk factors

Risk factors determined from literature using strict curation guidelines

risk factor conditioneffect size

Ex-smoker T2D 1.15PPARG

genotypeT2D

1.53HDL<35mg/dl CHD 2.08

MHC genotype RA 5APOE genotype AD 18

BMI>35 T2D 42

Google, Microsoft, MDVIP, Cisco, etc…

Distribution of fold change in lifetime risk by individual patient

• Across the entire population:– 98% of patients showed at least condition with >1.2X increase in average lifetime risk

– 45% of patients showed at least condition with >3X increase in average lifetime risk

Fol

d A

LTR

Average lifetime risk for this condition = 0.06%Individual’s estimated lifetime risk = 0.37%Fold change in ALTR= 0.37/0.06 = 6.2

Orange (>1.2X)

Gray (<1.2X)

Individual Patient Number

Conditions with >3X ALTR risk by individual patient

Fol

d A

LTR

Individual Patient NumberAlzheimer’s diseaseCeliac diseaseCrohn’s diseaseGlaucomaGrave’s diseaseMacular degenerationMultiple sclerosis

Alzheimer’s Disease: Homozygous or Orange

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30% APOE4Heterozygous

3.3% APOE4Homozygous

Clinical Decision Support - Prevention

GUIDE PATIENTS TO PRIMARY PREVENTION TRIALS

fMRI in at-risk Individuals as a Surrogate for Clinical Efficacy (BAI)

• “push” loaded patients to BAI via Navigenics• baseline imaging performed• patients go on drug and placebo• periodic functional imaging• use imaging as surrogate measure of clinical efficacy

• PROS: • hundreds of patients vs. thousands• years vs. decades• millions vs. hundreds of millions• within patent life of compound

• CONS:• imagining not endpoint for approval• no biomarker associated with imaging

DELIVER GENOME AND CDS VIA HIT

Health Information Technology Accelerates Personalized Medicine

Embed the genome into the electronic medical record (EMR) Role-based access to genome data (insurance companies excluded) Connect to a consumer-facing portal (PCHR, patientslikeme,

Healthvault) Allow HIPAA-compliant messaging and interventional distributed trials Secure and authenticate transactions and data flow Undergird the clinical information system with a research database

that can connect to other regional HIT systems (MS Amalga) Build a flexible clinical decision support module that allows physicians

to understand molecularly-guided strategies Enable a “learning” CDS that constantly refines itself with the data

flows to optimize clinical care

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Summary of Solution – Alzheimer’s

Identify genes that classify the population into “high” and “low” risk Build a broad-based CLIA genetic testing infrastructure to classify

individuals across the world (Navigenics) Incorporate pointers to push “high” risk individuals into our clinical

trial at BAI Develop functional brain imaging strategy that can detect the earliest

brain changes associated with AD that can be used as a surrogate measure of clinical efficacy in slowing AD pathology

Run a series of small trials drawing on a national base and fMRI to develop primary prevention drugs for AD in the next decade

Work with the FDA so that fMRI and associated biomarkers are robust enough for approval of primary prevention therapies

Use HIT vehicle to disseminate approved therapies back to population

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Learning Health Care

System

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Results of Personalized Medicine in Chronic Disease

Genomic Profile / Predisposition / Environmental Risks

Personal Health / Wellness (Disease pre-emption)

Interaction with Health Care Provider (Early diagnosis if needed)

Interventions (Targeted treatment individualized to my molecular profile and that of my disease)

Post-Disease Management

Family Members’

Health Care

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What Does Success Look Like?

Americans living longer

without disease

American health care delivering

value at reduced cost

“Connected” information from

bench to bedside

Robust pipeline of diagnostics and targeted therapeutics

moving toward approval

Growing portfolio of emerging, innovative companies

$

$

TRANSFORMING THE HEALTH CARE SYSTEM THROUGH APPLIED RESEARCH IN THE NATIONAL

CAPITAL AREA

Inova Health SystemGeorge Mason University

George Washington University