PatientDisease

Diagnosis T t dPersonalizedmedecine

Diagnosis

Risk

Targetedtherapies

Biomarkerprediction

Theranostic:Diagnostic TreatmentTheranostic:EfficayToxicity

g Treatment

y

Biomarkers and PM are included in medical practices since the 19th Biomarkers and PM are included in medical practices since the 19th century but their development has accelerated in the last century but their development has accelerated in the last decadedecadey py p

Biomarker of diabetes: glycemia

Biomarker of diabetes: Hb A1c 

Biomarker of cancer:

Ovarian (CA 125) Prostatic (PSA)

Erbitux (Merck/Imclone) or Vectibix (Amgen) &  

KRAS test

« Omics » and start of the genome sequencing 

Couple Tysabri®/Stratify‐JCV antibody Elisa 

test (Biogen Idec/Quest)

1960

1848 1980Couple 

Selzentry/Trofile (Pfizer)

1986

Fi t f Couple1960 Amplichip Cyp450

(Roche/Affymetrix)Biomarker of myeloma: Ig chain (BJ) 

in 75% cases

1959 First use of Pharmacogenomic 

definition

Couple Xalkori®/Vysis® ALK Break Apart test (Pfizer/Abbott)

1998

20102000 2005 2007

2006

First use of Pharmacogenetic 

definition

Discovery of genetic polymorphism of TPMT (Weinshilboum & Sladek)

1997 2011 2012

Biomarkers of cancer : alpha‐foetoprotein &  CE 

antigenCouple 

Herceptin/Herceptest

(Roche Genentech/Dako)

Ig : immunoglobulin

BJ : protein of Bence‐Jones

1998 2006

Dasatinib (BMS) &  Philadelphia chromosome

Couple Zelboraf®/ Cobas® 4800 

BRAFV600E mutation test (Roche/Daiichi)

(Roche, Genentech/Dako)PSA : prostate specific antigen

TPMT :  thiopurine‐méthyltransférase

chromosome

Medical genomics: a disruptive changeMedical genomics: a disruptive change

Time Period Genomes Turn‐around time

FTEs Cost per genome

1990‐2003 1. NIH reference2. Celera reference

~5 years ~5,000 ~2‐3 billion USD

2003‐2009 10 additional ~6 months Dozens 300,000→38,000 USD

2010‐2014 103‐104 2‐4 weeks 3‐4* 3,800/19,500→1,000 USD

2015‐2020 Millions 15 minutes <<1 100‐250 USD

*Excluding bioinformatics analysts

Source : ATIH-PMSI MCO base 2009F. Calvo, INCa

The top 10 CDx biomarkers evaluated in phases II andThe top 10 CDx biomarkers evaluated in phases II andThe top 10 CDx biomarkers evaluated in phases II andThe top 10 CDx biomarkers evaluated in phases II andIII confirm the dominant position of biomarkers in III confirm the dominant position of biomarkers in oncologyoncology

Top 10 biomarkers evaluated in phase II Top 10   biomarkers evaluated in phase III

Chr. PhKRASEGFRHER‐2

EGFRHER‐2Cyp

AKTCyp

BRCA1/BRCA2VEGFRBRAFc‐KIT

BRCA1/BRCA2ELM4‐ALK

Chr. PhBRAFKRASc‐KIT

Number of phase II clinical trials

0 10 20 30 40 50 60 70 80

PTEN

0 2 4 6 8 10 12 14 16

ERBRCA1/BRCA2

Number of phase III clinical trials

Cyp: cytochromes P450, HER‐2: Human Epidermal Growth Factor Receptor‐2, EGFR: Epidermal Growth Factor Receptor, c‐KIT: v‐kit Hardy‐Zuckerman 4 feline sarcoma viral oncogene‐like protein, KRAS: V‐Ki‐ras2 Kirsten Rat Sarcoma viral oncogene homolog, BRAF: v‐Raf murine sarcoma viral oncogene homolog B1, Chr.ph: chromosome de Philadelpie, EML4‐ALK: Echinoderm Microtubule‐associatedprotein‐Like 4‐ Anaplastic Lymphoma Kinase, ER: Estrogen Receptor, BRCA: Breast Cancer gene, TTPA: activated partial thromboplastin time, Anti‐XA: anti‐activated factor X.

Source: http://clinicaltrials.gov/, LEEM

The involvement of the pharmaceutical The involvement of the pharmaceutical industryindustry

in the clinical development of companion in the clinical development of companion diagnostic testsdiagnostic tests

Top 10  pharmaceutical companies involved in phase II clinical trials with companion diagnostics

nical tria

lsNum

ber o

f clin

Top 10 pharmaceutical companies involved in phase III clinical trials with companion diagnostics

Roche/ Genentech

Novartis BMS GSK Merck &CoPfizer  AmgenAstraZeneca Sanofi/Genzyme

Eli Lilly

Top 0 pharmaceutical companies involved in phase III clinical trials with companion diagnostics

cal tria

lsNum

ber o

f clin

ic

Roche/ Genentech

Novartis BMSGSK Merck SeronoPfizer  AbbottAstraZenecaSanofi/Genzyme

Ipsen

Source: http://clinicaltrials.gov

bioMerieux Silliker

bioMerieux

Transgene ABL industry

Food AndWater SafetyIn vitro Immunotherapy Water Safety

Nutrition/HealthIn vitro

DiagnosticsImmunotherapy

Therapeutic VaccineOncolytic viruses

Biomarkers(ADNA program)(ADNA program)

8

PARTNERSHIPS BETWEEN PHARMAS / BIOTECHS AND DIAGNOSTIC COMPANIES: MUTUAL BENEFITS

Benefits for

AND DIAGNOSTIC COMPANIES: MUTUAL BENEFITS

Benefits for Pharma & Biotech companies

Benefits for Diagnostic Companies

DiagnosticPharmas

•Reduction of cost / Development duration

•Capture of added value on Pharmas products

BiotechsDiagnostic

duration

•Drug salvage

p(royalties, patents, …)

N b i •Drug safety and Efficacy

De elop “niche”

•New business model (Companion test), source of income

Some times« ambiguous »

•Develop “niche” busters

source of income (co-marketing)

g

9

The impact of companion diagnostic tests on the The impact of companion diagnostic tests on the future of the pharma industry business model ? future of the pharma industry business model ?

Pros:

Improved evaluation of a given therapyImproved evaluation of a given therapy Life cycle management : differentiation against biosimilars/new entrants without Companion pdiagnostic tests Patient stratification during clinical development allows the patenting of new drug use & application

Cons: restricted patient populations and market

potential Increased and novel regulatory constraintswhich payor – price for the diagnostic test ? obligations to partner with IVD/biotechSource: Analyse Bionest Partners, Nature Reviews march 2009, « Biomarkers : The expanding global market », Yonker 2006

obligations to partner with IVD/biotech royalties on biomarker

‘’cancer biomarkers’’

n = 11,639 

Kulasingam V and Diamandis EP (2008) Strategies for discovering novel cancer biomarkers through utilization of emerging technologies

Nat Clin Pract Oncol doi:10.1038/ncponc1187

What types of biomarkers do we have ?What types of biomarkers do we have ?

Di P i

Diagnostic PronosticScreening Follow-upPredictionof response

Disease Progression

gg ppto treatment

1. Screening (e.g. mammography, fecal occult blood)

2. Diagnostic (e.g. cardiac troponin)

3. Prognosis (e.g. cytokeratins, estrogen receptors)

4. Prediction of response to treatment (e.g. HER2)

5. Patient follow-up (e.g. PSA)

What Drives Successful Diagnostic Test (DX) Development?

DX regulatory approval drivers

Analytical Validity

Clinical Validity

1. Prototype2. RUO/LDT

Scientific HypothesisClinical Evidence1. Training, test set2. External validation-single site2. External validation single site3. External validation-multi-site

Clinical Utility

Health Economics

1. Demonstrate dx utility2. Demonstrate therapeutic

changes as SOC

1. Demonstrate quality of life impact

2. Demonstrate cost reduction

DX reimbursement drivers

For market success, developping a test represents a compelling investment for DX company…

Biomarker Research and Validation:A Long JourneyA Long Journey

Cli i l

Clinical utility & Health economicsPrototype

Final assay

Analytical validity

Clinical validity

Clinical utility Analytical validity

Product Development

15

Analytical and clinical validity drive regulatory approvalClinical utility and health economics benefits drive reimbursement

Product Development ProcessDrug-Diagnostic Co-Development Process:

Theranostic Theranostic

Cli i l D l tTherapyCommercial

LaunchNDA

SubmissionPhase IIIPhase IIPhase IPreclinicalDevelopment

Clinical DevelopmentTherapyCompound

OptimizationLead

Discovery

CE markedtest

Companion Diagnostic testPMA

A d T t

test

Phase 4Commer-

Phase 3Validation

Phase 2bVerification

Phase 2aDesign &

Phase 1Feasibility

Phase OBusiness

Diagnostic testBiomarker

Discovery & Validation of

Approved Test

Commer-cialization

ValidationVerificationDesign & Optimization

FeasibilityProposal

Design Controls

yClinical Utility

16

The steps of biomarker discovery and validation

Discovery Marker Marker y&

Technical feasibility

Leadgeneration

Lead confirmation

validation in a clinical

setting

Marker validated

(on 1platform)y platform)

Clinical studies

S l il bilit d litSample availability and quality

Quality insurance

Information management

Main challenges in biomarker discoveryMain challenges in biomarker discovery

Evidence‐based biomarker validation

+++++ long‐term randomized prospective study in the general population

++++  prospective study in a selected population

+++ retrospective study in a set of non representative+++ retrospective study in a set of non‐representative patients

t ti t d i t f t ti++  retrospective study in a set of representative patients

+  lab investigation taken from « Levels of evidence », BJU Int, vol. 101, 2008, p. 150

Personalised Medecine: Difficulties and challengesA novel model, based on data integration and validation of biomarkers:

-Technology: genomics proteomics metabolomics-Technology: genomics, proteomics, metabolomics

imaging etc..

-Clinical studiesDiff t ti b k dDifferent genetic background

Different environmental contexts (life style, nutrition…)

Clinical studies: quality, ethics etc..

- Public health

- Economics: Cost-benefit reimbursment etc- Economics: Cost-benefit, reimbursment etc..

Personalised Medecine: Difficulties and challenges

• A change of paradigm :

A novel model, based on data integration and validation

• A change of paradigm :- Shift from unique to mutiple, complex, biomarkers(multi-parameters = data intégration, bioinformatics,( p g , ,Computational biology, systems biology)

Intellectual property?- Intellectual property?.

- Management and transfer of information: physicians,

patients (cell phone etc )patients (cell phone, etc…).

Criteria for success Access to biobanks infrastructures clinical data . Access to biobanks infrastructures, clinical data, standardization (sampling procedures etc.)

A novel paradigm for industrial partners:M i t ll b ti i t d f i l tiMoving to collaboration instead of « isolation »Refining the intellectual property bases

• Academic environment: Project-driven

• Pharma-Diagnostics companies win-win interactions

• Simplified discussions with regulatory agenciesEarly discussions to define the requirements

Pharma Diagnostics companies win win interactions

Early discussions to define the requirementsReimbursements…

Public Private Partnerships:• Public-Private Partnerships:NCI biomarker networkFDA

‘’How long does it take to reach 10,000 cases in a cohort study with 500 000 people?”in a cohort study with 500,000 people?”

Paul Burton, UK BioBank Technical Report 2005 

Breast cancer 17 yrsColorectal cancer 22 yrsProstate cancer 22 yrsLung cancer 34 yrsStroke 18 yrsStroke 18 yrsMI and coronary death 8 yrsDiabetes mellitus 6 yrsyCOPD 13 yrsHip fracture 21 yrsAlzheimer’s disease 18 yrs

Parkinson’s disease 23 yrs

Disease Consortium Number     Subjectsof teams

• Parkinson GEO‐PD 18 10,000• Osteoporosis     GENOMOS      10 30,000• Preterm birth PREGENIA 10 20 000• Preterm birth    PREGENIA      10 20,000• Allergy/Asthma  GA2LEN         50 20,000• Breast, Lung…K EPIC 20 500,000

L h INTERLYMPH 15 20 000• Lymphoma INTERLYMPH   15 20,000• Lung K ILLCO 30 51,000• Head & Neck K  INHANCE 13 28,000• Melanoma GENOMEL 12 3,000• Pancreatic K     PACGENE         10 5,000

Thematic network of biobanks

Main challenges in biomarker discovery

Bi l i l l T l

Main challenges in biomarker discovery

Biological samples ToolsBlood : plasma, serum DNA Tissue ; CellsUrine ; Stools

mRNA, miRNAMetabolome

Saliva ; Exhaled breath… ProteomeGlycomeyMicrobiomeImagingg g

BasicTranslational research needs

Model

Basicscienceshigh quality specimens

systems

Annotated biological samples

Patients ‐OmicsHTSsamples HTS

BioinformaticsData basesData bases

BiomarkersDrug targetsKnowledge

Personalized medicineg gKnowledge

Biobanks => 2 different conceptsBiobanks => 2 different concepts……

S i P hi• Service

S l i i d

• Partnerships

S l d il d i f i Samples + minimum data set

One‐way service

Samples + detailed information + outcome of patients + …

One way service

MTA + cash

Bi‐directional information

Customer service:From nothing to optional

MTA, contract + IPR

Customer service:From nothing to optional Customer service:Full expertise and advices

How to select a biobank ?main bottlenecksmain bottlenecks

Quality of both biological samples and linked y g pannotations, based on international standards and guidelines

Scientific and medical background

Quality of management 

Well defined access policy

Expertise

Willingness and reactivity Willingness and reactivity

Ethical and regulatory issues

Inter- and Multidisciplinarity

Handling of data: knowledge managementBioinformatics, Systems Biology

« Big Science » and « curiosity-driven » science

BiomarkerInformationTechnologyF H lth

Public healthEthicsdiscoveryFor Health

« services »Business model

Ethics

Technologies: « omics »Research-Sequencing

- Epigenetic analysis- Proteomics

CohortsClinical studies

ResearchConsortia

AndNetworks

-MetabonomicsNetworks

Recherche académique-industrielleqLes « difficultés »

L i ibilité d l h h dé i La « visibilité » de la recherche académique pour l’industriel

La « frustration » générée par les choix de l’industrie (marketing…)industrie (marketing…)

R&D: le « D » plus que le « R »

Recherche sur projet, management

Recherche académique-industrielleRecherche académique-industrielleLes « besoins»

Un partage très précoce des objectifs et une définition précise de ces objectifs

Une absence « d’à priori »:U té li t- Une communauté: lieu, temps

- Des équipes « mixtes »

- Formation précoce des étudiants

Excellence-based TechnologicalTransfert

science

« curiosity-

TranslationalMedecine

« curiositydriven » Valorisation:

EconomicalProject-driven

MedicalSocial

Early phases of innovation: proof of concept

Education, training

Centres of excellence, innovation clusters

BIOASTER A j t ll th A project well on the go

What is at the base?  Key figures Where do we stand?2 Co‐leaders :

• Lyonbiopôle• Institut Pasteur • 585 M€ budget over 9 years

• 180 M€ public funding

• Project set up team since May 2011

• Scientific Cooperation Foundation created (April 17, 2012)

3 Major industrial companies : • Sanofi Pasteur• Institut Mérieux• Danone Research

• 180 M€ public funding

• 40 projects at the 3 year mark

• 700 + scientists over 9 years

• Global Funding agreement signed with French National Research Agency (July 5, 2012)

• 1st BIOASTER board (July 6 2012)

3 Academic research institutions : • INSERM• CNRS

• ±35 000 m² new infrastructures• 300 + contributors involved in setting up the BIOASTER project

• 1st BIOASTER board (July 6, 2012)• BIOASTER scientific strategy released (28 Aug 2012)

• 1st wave of projects selected• CEA

2   Sites• Lyon : Gerland• Paris : Institut Pasteur

g p p j 1st wave of projects selected          End of 2012 ‐ 6 projects launched 

• Operational team  in place               End of Jan 2013 ‐ 20  people on board  

• Paris : Institut Pasteur

1  Cluster of 50+  SME’s • Rhône‐Alpes &  Ile‐de‐France 

• Technology centers & Core facilities  End of Feb 2013 ‐ 300m2 in Lyon &  600m2 in Paris 

33Confidential 

BIOASTER A change of scale in the infectious disease

fi ldfield•A new approach for infectious disease research : create a new operator to boost technological R&D and speed up the time to market of new products and services

– BIOASTER will constitute a strong link in the infectious disease innovation chain and will be the favored place to co-invest and share risks between industrials, intermediate size companies (ISC), SMEs and academic organizationsBIOASTER will speed up the time to market of innovative products and – BIOASTER will speed up the time to market of innovative products and services by changing knowledge and assets (patents, prototypes, licenses….) produced by interdisciplinary, collaborative public / private research, through short, medium and long-term projects meeting the market and industrial partners needs market and industrial partners needs

3434Confidential 

BIOASTER will be structured around four main pillars

Technological Technological Internal and Internal and Technological Centers

Technological Centers Cooperative

R&D projectsCooperative R&D projects

Effective translational

research

Effective translational

research

Human resources

and Training

Human resources

and Traininggg

35

BIOASTERR&D programs performed through the technology centers & with partners

Program 1New

Therapies and Vaccines

Program 2Towards a real-time diagnosis

Program 3Microbiota, an indicator and health- New

therapeutic and Vaccines diagnosis care product therapeutic, preventive

and diagnostic products products

New

TC1A hub for the collection and

characterization f bi l i l

TC2Innovative

diagnostic and analytical

TC3Product

deorphaning, improvement

d

TC4Novel and

more efficient tools for

TC5Preclinical and

ealy clinical d l t

TC6Information technology,

data analysis d

New technologies and services

with high added valueof biological

resourcesanalytical

technologies and combination

tools for bioproduction development and

managementadded value

36Confidential 

BIOASTERFirst round lab and office space – Paris & First round lab and office space – Paris &

Lyon Institut PasteurP t I tit t L bi l I f ti di François Jacob Center (BIME)Pasteur Institute Lyonbiopole – Infection disease

Center (CI)• 600 m2 available   • 300 m2  available 

– 250 m2 P1&P2 labs for core facilities– 150 m2 offices and meeting rooms– 100 m2 of labs for project teams

– 200 m2 P2, P2+  labs for core facilities– 100 m2 offices and meeting rooms

• Upcoming 500 m2 lab space

37

BIOASTER « One » Facilities in Lyon (Q4 2014)

38

Market drivers in PMarket drivers in Personalised Medicineersonalised Medicine

Regulatory agencies & official bodies (EC)

PayorsP t f fbodies (EC)

Global improvement  of healthcare, innovationGreater integration of Rx /Dx for more efficient and safer clinical trials

Payment for performancePayors/PBM are pushing for Rx‐Dx integrationespecially diagnostics that reduce healthcareexpenditures ‐ Ex: Medco Research Institute 

L d hi l i H lth I tiIncreased vigilance on drug approvals and increased approval of genetic tests that influence safety and efficacy of drugs

Leadership role in Healthcare Innovation Establish clinical utility and cost effectiveness

Pharma companies Potential for higher price due to betterefficacy

Patients & Clinicians

yMore effective clinical trials – reduced  groups  with better resultsDx facilitates better Rx sales by enabling better market penetration differentiation

Increasing influence of patientadvocacy groupsPersonalized medicine reducesunnecessary therapies, leading

f d ffbetter market penetration, differentiation and expansion.

CDX: Life Cycle management tool, defence strategy against biosimilars threat  Diagnostic Industry

Research progress in biomarker discovery

to fewer side effects

Research progress in biomarker discoverytranslating into more Dx testsNew emerging companies focusing on Dx

The European ChallengeThe European Challengegg

EPEMED White paper: Market access challenges in the EU for high medical value diagnostic testsIain Miller†1 2 Joanna Ashton Chess1 3 Herman Spolders1 4 Vincent Fert1 5 Joseph Ferrara6 Werner Kroll1 7 Jon Askaa8 PatrickIain Miller†1,2, Joanna Ashton-Chess1,3, Herman Spolders1,4, Vincent Fert1,5, Joseph Ferrara6, Werner Kroll1,7, Jon Askaa8, Patrick Larcier3, Patrick F Terry1,9, Anne Bruinvels10 & Alain Huriez1,3 Ref: Personalized Medicine (2011) 8(2), 137–148

EPEMED is an independent, broad and inclusive not-for-profit organisation founded in 2009 and bringing together forces in personalised medicine in the EU.

Key Value EPEMED’s Value PropositionEPEMED’s Value Proposition

p

Points for Members

•Forum to share best practices•Publications, white papers, conferences, education & promotion on promotion on Personalised Medicine subjects•Privileged access Privileged access to European decision makers•Input to policy makers on relevant legislation

Thank you for your attention

For more information or to download recent study reports, white paper or y p , p p

webinars, please visit www.epemed.orgp g

Contact: contact@epemed.org@ p g