Médecine de précision cardiovasculaire,

recherche clinique et science des données

Jean-Claude Tardif CM, MD, FRCPC, FCCS, FACC, FAHA, FESC, FCAHS

Directeur, Centre de Recherche de l’ICM

Chaire de Recherche du Canada en médecine personnalisée

Chaire Pfizer de recherche en athérosclérose de l’UdeM

Professeur de médecine

Institut de Cardiologie de Montréal

Université de Montréal

Mars 2017

Applications of AI in precision medicine

• Drug development

– Optimized clinical trials

– Drug repurposing

– Target discovery

• Cardiovascular disease risk stratification

and risk management

• Medical and molecular imaging

• Patient empowerment and partnership

The 10 Leading Causes of

Death Worldwide (2012)

Cardiovascular diseases are the leading

global cause of death

CVD includes ischemic heart disease and stroke. World Health Organization. Cause-specific Mortality. Accessed at:

http://www.who.int/healthinfo/global_burden_disease/estimates/en/index1.html.

Top 5 Global Causes of Death in 2012

Curing atherosclerosis through precision

medicine and artificial intelligence

• Multifaceted approach, multiple therapeutic targets

• Precision medicine, personalized therapies

- Genetic markers, plasma biomarkers

- Molecular imaging

- Big data (artificial intelligence)

PROJECT 1:Targeting LDL

1.1 PCSK9i

1.2 AZ cohorts

1.3 Biobank discovery projects

PROJECT 2: Targeting HDL

2.1 Biologics

2.2 CAIN3

2.3 DalCor

PROJECT 3: Targeting vascular inflammation

3.1 GevoPET

3.2 COLPET

3.3 COLCOT

3.4 THR-184

PROJECT 4: Targeting heart rate

reduction

4.1 Post-MODIFY biomarkers

ARTERIA 2014-2019 (36M$) IN FPQIS OF

GOVERNMENT OF QUEBEC

CK algorithm validated1 trial completed

8 publications2 new patents

3 deliverables in 1.3

1 ongoing trial (COLCOT)Regulatory approval postQ20 (COLCOT)

6 publications

HDL phenotypingValidation of biomarkers

Mechanisms of dal PGx effects2 trials completed (phase 2b; CAIN3)

9 publications1 patent

Discovery and/or validation of biomarkers

2 publications

ENTIRE ARTERIA PROGRAM

9 trials completed > 10 scientific deliverables

> 25 publications 5 patents

Multi-faceted approach to cardiovascular disease

NEJM 2012;367:2089-2099

Leadership of landmark clinical trials

Main dal-Outcomes Trial Results

NEJM 2012;367:2089-2099

Discovery GWAS results indal-Outcomes

8

Cox proportional hazards model for CV events adjusted for sex and 5 principal componentsNote: Chr 23 is the non-pseudoautosomal region of the X chr and 25 is for the pseudoautosomal regions

ADCY9

Q-Q plot

Manhattan plot of 5,543,264 SNPs with MAF ≥ 0.05 in the dalcetrapib arm

P= 2.4 x 10 -8

8Tardif et al. Circulation Cardiovasc Genet. 2015;8:372-382

Treatment effect by genotypes

9

Tested for main study primary outcome orunanticipated coronary revascularization (Primary PGx endpoint)

Tardif et al. Circulation Cardiovasc Genet. 2015;8:372-382

Treatment effect by genotypes:A different picture emerges!

Events:

main study primary outcome or unanticipated coronary revascularization

N at risk/days 0 200 400 600 800 1000 1200

Dalcetrapib 933 870 820 778 604 329 74

Placebo 956 898 867 831 649 339 75

0 200 400 600 800 1000 1200

1313 1242 1189 1159 937 504 120

1342 1253 1211 1170 946 504 119

0 200 400 600 800 1000 1200

462 452 435 426 355 200 51

452 437 416 402 331 186 33

ADCY9 rs1967309

GG AG AA

Tardif et al. Circulation Cardiovasc Genet. 2015;8:372-382

P= 2.4 x 10 -8

Lindpaintner K. Circulation Cardiovascular Genetics 2015

dal-PLAQUE-2: Change in global cholesterol

efflux from baseline to 12 months

12

P=0.93

P=0.001

P=0.005

Tardif JC et al. Circ Cardiovasc Genetics 2016;9:340-348

dal-OUTCOMES : Placebo-adjusted GM percent change in hs-CRP

13

-10

-5

0

5

10

15

20

25

3 months(n= 5211)

24 months(n= 1701)

36 months(n= 2424)

End of trial(n= 5243)

Pla

ceb

o-a

dju

ste

d

GM

% c

han

ge in

hs-

CR

PPercent change in hs-CRP (dal-OUTCOMES)

GG AG AA

****

**

**

****

** P< 0.001

* P< 0.05NS P> 0.05

NS

NS NS

NS

Tardif JC et al. Circ Cardiovasc Genetics 2016;9:340-348

0

2

4

6

8

10

Adcy9 inactivation protects from atherosclerosis in mice infected with AAV8-Pcsk9_D377Y fed a high-cholesterol diet

WT Adcy9Gt/Gt

Ao

rtic

lesi

on

(%

of

the

su

rfac

e o

f th

e in

tim

a)

WT Adcy9Gt/Gt

**

** P<0.01

DalCor Pharma licenses a late-stage investigational cardiovascular drug following major scientific discoveryJun 08, 2015, 10:05 ET from DalCor Pharmaceuticals

DalCor Pharmaceuticals Sets Sights on Drug Reboot

http://investingnews.com/category/daily/life-science-investing/genetics-investing/

As the Wall Street Journal outlines, “The trial raises the provocative possibility that other

failed drugs might be revived based on genetic variations that affect how patients

respond.”

Traditional mendelian randomization:

Identifying or validating drug targets

Mendelian Randomization + AI:

Identifying drug targets and responders

AI handling complexity

Taking into account:

- Multiple SNPs/genes

- Environmental factors

- Complex interactions

Recent ACS

Visits ~ every 6 months until

endpoint target reached

dalcetrapib

placebo

Consent

and

genotyping

Dal-GenE Phase 3 Study

Primary Objective: To prospectively evaluate the potential of dalcetrapib to reduce cardiovascular morbidity and mortality in patients with a documented recent ACS and the AA genotype at rs1967309 in ADCY9 gene

N=33,000n=5,000

Full-Service Academic CRO

Study Program &

ProtocolDevelopment

DataCollection

Data Management

DataAnalysis

StudyReport

Sponsor Approval

On-site or Electronic Monitoring of Sites

Core Laboratories/ Pharmacogenomics

CEC, DSMB/Audits

Power Calculation Feasibility Assessment

Site Management/ Safety Surveillance

SAP /Analyses

Report ApprovalPublications

Study Design & Management

Cost-effective, Operational efficiency, Quality Assurance, Network of 3500 clinical sites in >30 countries

Cardiovascular & Metabolic Studies

Trial #sites #patients #countries

AF-CHF 131 1 450 12

CTAF-2 46 320 1

LOYAL 16 200 1

EARTH 30 360 3

VICTORY 10 280 2

REFINE 15 155 4

AFFORD 20 332 1

BRAIN-AF 60 1 500 1

CAIN 45 2 000 1

AMI-ONTIME 12 2 400 1

COLCOT 300 4500 12

Trial #sites #patients #countries

BEAUTIFUL 660 9 650 31

SHIFT 315 6 500 35

CART-2 25 2 000 1

dalOUTCOMES 900 15 600 41

SIGNIFY 900 19 000 42

ALECARDIO 720 7 226 26

dal-PLAQUE 2 100 906 5

SELECT-ACS 66 544 4

SELECT-CABG 40 384 2

MODIFY 110 500 18

Dal-GenE 1000 5000 32

Academic research Contractual research

Pharmacogenomics Centre

Genotyping – Sequencing

21

Genotyping: Sequenom/Agena MassArray (CS-pro certification)

Illumina Beadstation (Infinium)

LightCycler LC480 real-time PCR

Sequencing: Illumina HiSeq 2500

Illumina miSeq

Custom panels

Diagnostic panels

High throughput

GWAS and NGS

The André and France Desmarais MHI

Hospital Cohort 2006-2016

30,000 patient cohort and biobank in development (n=22,000 currently)

- Collection of DNA and plasma

- Complete medical and familial history

- Investigation of cardiovascular, inflammatory and other diseases

- Longitudinal follow-up throughout patient’s life

- Creation of a resource for present and future

Competitive advantages- High-quality samples, extensive characterization

- Pre-consented samples for retrospective and prospective biomarker validation studies

- Savings in time/funds for patient recruitment

ImagingGLP

Integrative

Biology

R&D GLP

Metabolomics

Integration

Synergistic platforms

Integrated strategy in innovating clinical research

and personalized medicine (including PGx and biomarkers)

Basic research

Clinical research

MHICC

CEPMedCohorts

MHI, RAMQPGx

Centre

Innovation

ecosystem

in Mtl

CAIN, MITNEC

Human

genetics

“Big data”

AI

Integration of the different components of

precision medicine for risk stratification

Epigenomics Metabol-omics

MicrobiomicsMeta-

genomics

Environmental Factors

Genomics

Transcript-omics

Integration with AI approaches – Deep learning

Patient =partner

Imaging

Applications of AI in precision medicine

• Drug development

– Optimized clinical trials

– Drug repurposing

– Target discovery

• Cardiovascular disease risk stratification

and risk management

• Medical and molecular imaging

• Patient empowerment and partnership