Christian CONFAVREUXChristian CONFAVREUX

Hospices Civils de LyonHospices Civils de LyonUniversitUniversitéé

Claude Bernard Lyon 1Claude Bernard Lyon 1Fondation EugFondation Eugèène ne DevicDevic

EDMUSEDMUS

London, EMA, July 25London, EMA, July 25--26, 201126, 2011

FromFrom

NATALIZUMAB and EDMUSNATALIZUMAB and EDMUS

to TYSEDMUSto TYSEDMUS

and OFSEPand OFSEPTysabriTysabri®®

in French EDMUS Databasesin French EDMUS Databases

Observatoire FranObservatoire Franççais de la Sclais de la Scléérose En Plaquesrose En Plaques

EuropeanEuropean

DatabaseDatabase

for Multiple for Multiple SclerosisSclerosis

Natalizumab

(Tysabri®)

Marketing Approval

in France

Agence Française de Sécurité

SAnitaire

des Produits de Santé(AFSSAPS) & Risk

Management Plan

20072007

Polman et al. NEJM 2006; 354: 899Polman et al. NEJM 2006; 354: 899--910910

EFFICACYEFFICACY

as as comparedcompared

to placebo, to placebo, atat

2 2 yearsyearsAccumulation of Accumulation of DisabilityDisability

42 % 42 % Relapse Rate Relapse Rate 68 % 68 % MRI MRI ActivityActivity

92 % 92 %

TOLERANCETOLERANCE

SAFETYSAFETY

20062006

The Care of MS in France (1)

63 63 CentresCentres

28 28 UniversityUniversity

HospitalHospital

ReferralReferral

MS CentresMS Centres

18 18 City and City and HospitalHospital

HealthHealth

RegionalRegional

NetworksNetworks

The EDMUS NetworkThe EDMUS Network

The EDMUS SoftwareThe EDMUS Software

The Care of MS in France (2)

●● BIOMEDBIOMED

●● BIOMEDBIOMED1st 1st EuropeanEuropean

22ndnd EuropeanEuropeanConcertedConcerted

ConcertedConcertedActionAction

ActionAction

19571957

19761976

19801980

19901990

19921992

19931993

●● OnsetOnset

●● NaturalNatural

●● NaturalNatural

●● EDMUSEDMUSLyonLyon

HistoryHistory

HistoryHistory

JNNPJNNPMS MS CohortCohort

ThesisThesis

BrainBrain

●● EDMUS Software V1EDMUS Software V1

●● EDMUSEDMUSFoundationFoundation

●● MultiMulti--

●● ARS RhôneARS Rhône--AlpesAlpes

●● PHRCPHRCSponsorshipSponsorship

RRééseau RASEPseau RASEP

NOMADMUSNOMADMUS

●● OFSEPOFSEPPharmaceutical Pharmaceutical ●● PHRC PHRC ●● PHRC PHRC ●● AFSSAPS AFSSAPS ●● BiogenBiogen IdecIdec

InvestissementsInvestissementsIndustryIndustry

IRMUSIRMUS

POPARTMUSPOPARTMUS

TYSEDMUSTYSEDMUS

TYSEDMUSTYSEDMUS

dd’’Avenir ANRAvenir ANR

19981998

20002000

20012001

20042004

20052005

20072007

20102010

20112011

●● PRIMSPRIMS

●● NaturalNatural

●● VACCIMUSVACCIMUS

●● KIDMUSKIDMUSNEJMNEJM

HistoryHistory

NEJMNEJM

NEJMNEJMNEJMNEJM

Mai 2011Mai 2011

285 Centres285 Centres40 Countries40 Countries

DiffusionDiffusionof EDMUSof EDMUSWorldwideWorldwide

Use of EDMUS in France

Electronic

Medical

Record

Fully

Integrated

in Daily Medical

Practice

Directly

Indirectly

"Subcontracted"

A A CohortCohort

The Care of MS in France (3)

>32.000 >32.000 PwMSPwMS

Pregnancy

Natural HistoryVaccinationsChildhood

Onset

TYSEDMUS

Observational prospective phase IV Observational prospective phase IV pharmacopharmaco--epidemiological followepidemiological follow--up study up study of patients with MS and treated with of patients with MS and treated with natalizumabnatalizumab

in France in France based on the French network of neurologists using EDMUSbased on the French network of neurologists using EDMUS

SponsorSponsor

AFSSAPSAFSSAPS

SupportsSupports

FondationFondation

EugEugèènene

DevicDevic

EDMUSEDMUSHospices Hospices CivilsCivils

de Lyonde LyonSociSociééttéé

FranFranççaiseaise

de de NeurologieNeurologie

(SFN)(SFN)FFééddéérationration

FranFranççaiseaise

de de NeurologieNeurologie

(FFN)(FFN)BiogenBiogen

Idec France (Unconditional Grant)Idec France (Unconditional Grant)

Coordination Coordination LYON EDMUS LYON EDMUS CoordinatingCoordinating

CentreCentrewww.edmus.org www.edmus.org tysedmus@edmus.orgtysedmus@edmus.org

ScientificScientific

CommitteeCommitteePr. Christian CONFAVREUXPr. Christian CONFAVREUX

Pr. Michel CLANETPr. Michel CLANETDr. Anne CASTOT (AFSSAPS)Dr. Anne CASTOT (AFSSAPS)

Dr. Fanny ROCHER (CRPV)Dr. Fanny ROCHER (CRPV)Dr. Eric VAN GANSEDr. Eric VAN GANSEPr. Sandra VUKUSICPr. Sandra VUKUSIC

CoordinatingCoordinating

CentreCentreNadine PASSANTE (CRA)Nadine PASSANTE (CRA)Julie BORGETTO (CRA)Julie BORGETTO (CRA)

Marion DUFOUR (Statistician)Marion DUFOUR (Statistician)Bernard FRANGOULIS (EngineerBernard FRANGOULIS (Engineer)

InvestigatorsInvestigators

Dr AL KHEDR Dr AL KHEDR AbdullatifAbdullatif, Dr ANDRODIAS G, Dr ANDRODIAS Gééraldine, Dr ANNE Olivier, raldine, Dr ANNE Olivier, Dr AUFAUVRE Dominique, Dr BERGER Eric, Dr BERROIR StDr AUFAUVRE Dominique, Dr BERGER Eric, Dr BERROIR Stééphane, phane,

Dr BESSON GDr BESSON Géérard, Dr BOUILLAGUET Sophie, rard, Dr BOUILLAGUET Sophie, Pr BRASSAT David, Pr BROCHET Bruno, Dr CABRE Philippe, Pr BRASSAT David, Pr BROCHET Bruno, Dr CABRE Philippe,

Dr CAMDESSANCHE JeanDr CAMDESSANCHE Jean--Philippe, Pr CAMU William, Dr CASEZ Philippe, Pr CAMU William, Dr CASEZ Olivier, Dr CASTELNOVO Giovanni, Pr CLANET Michel, Olivier, Dr CASTELNOVO Giovanni, Pr CLANET Michel,

Pr CLAVELOU Pierre, Dr CLERC Christine, Pr CONFAVREUX Christian,Pr CLAVELOU Pierre, Dr CLERC Christine, Pr CONFAVREUX Christian,

Pr CREANGE Alain, Dr CREISSON Eric, Dr DE MARCO Olivier, Pr CREANGE Alain, Dr CREISSON Eric, Dr DE MARCO Olivier, Pr DE SEZE JPr DE SEZE Jéérôme, Pr DEBOUVERIE Marc, Pr DEFER Gilles, rôme, Pr DEBOUVERIE Marc, Pr DEFER Gilles,

Dr DOUBRERE JeanDr DOUBRERE Jean--FranFranççois, Dr DURANDois, Dr DURAND--DUBIEF FranDUBIEF Franççoise, oise, Pr EDAN Gilles, Dr EVRARD Serge, Pr GODEFROY Olivier, Pr EDAN Gilles, Dr EVRARD Serge, Pr GODEFROY Olivier,

Dr GRIMAUD JDr GRIMAUD Jéérôme, Dr GUENNOC Annerôme, Dr GUENNOC Anne--Marie, Dr HABAMarie, Dr HABA--RUBIO RUBIO JosJoséé, Pr HANNEQUIN Didier, Pr HAUTECOEUR Patrick, Dr HEINZLEF , Pr HANNEQUIN Didier, Pr HAUTECOEUR Patrick, Dr HEINZLEF

Olivier, Pr LABAUGE Pierre, Dr LAPLAUD DavidOlivier, Pr LABAUGE Pierre, Dr LAPLAUD David--Axel, Dr LEBRUNAxel, Dr LEBRUN--

FRENAY Christine, Mme LEFRERE Fabienne, Pr LUBETZKI Catherine, FRENAY Christine, Mme LEFRERE Fabienne, Pr LUBETZKI Catherine, Pr MAGY Laurent, Dr MARIGNIER Romain, Pr MOREAU Thibault, Pr MAGY Laurent, Dr MARIGNIER Romain, Pr MOREAU Thibault,

Pr NEAU JeanPr NEAU Jean--Philippe, Dr OUALLET JeanPhilippe, Dr OUALLET Jean--Christophe, Dr OUBARY Christophe, Dr OUBARY Paul, Dr PAPEIX Caroline, Pr PELLETIER Jean, Dr RICO Audrey, Paul, Dr PAPEIX Caroline, Pr PELLETIER Jean, Dr RICO Audrey, Dr RUGGIERI IrDr RUGGIERI Irèène, Pr RUMBACH Lucien, Dr SLESARI ne, Pr RUMBACH Lucien, Dr SLESARI IulianaIuliana, ,

Dr STANKOFF Bruno, Dr FrDr STANKOFF Bruno, Dr Frééddééric TAITHE, Dr Eric THOUVENOT, ric TAITHE, Dr Eric THOUVENOT, Pr TOURBAH Pr TOURBAH AymanAyman, Dr VENTRE Jean, Dr VENTRE Jean--Jacques, Pr VERMERSCH Jacques, Pr VERMERSCH Patrick, Dr VIALLET FranPatrick, Dr VIALLET Franççois, Pr VIGHETTO Alain, Pr VUKUSIC ois, Pr VIGHETTO Alain, Pr VUKUSIC

Sandra, Dr WIERTLEWSKI Sandrine, Dr ZIEGLER FranSandra, Dr WIERTLEWSKI Sandrine, Dr ZIEGLER Franççois, ois, and all the and all the neurologistsneurologists

involvedinvolved

in the in the regionalregional

citycity--hospitalhospital

MS MS networks.networks.

ParticipantsParticipants

PrimaryPrimary

Establish the

Safety ProfileSafety Profile

of NTZ (short to long term) in real life settingsDetermine the

Incidence of Adverse EventsIncidence of Adverse Events, notably, notablyinfusion-related events, hypersensitivity reactions, development of anti-NTZ antibodies,infections: serious, opportunistic,pregnancies and pregnancy outcomes, malignancies

ObjectivesObjectives

SecondarySecondary

Describe the

Evolution

of patients treated with NTZ (relapses, EDSS, MRI)Determine the

Conditions of UseConditions of Use

of NTZ in real life settingsCompare the incidence of serious and/or opportunistic infections

and malignancies, between a

Non-Exposed Population

and the NTZ-exposed one

InclusionsInclusions

395039203800

3500

32503100

2900

25502350

2100

1700

1325

970

575

187

2141

229131

16771575

1071

284

14001481

1420

1859

23082251

2180

12961163

1012

751531

471

28552855

881610

28602800

17001670

363

3351

1376

36983698

3351

930

1767

3134

743

0

500

1000

1500

2000

2500

3000

3500

4000

Apr-07 Oct-07 May-08 Nov-08 Jun-09 Dec-09 Jul-10 Jan-11

Cumulat

ive

no o

f pa

tien

ts

No of treated

patients (France)

Effective inclusions

Promised

inclusions (Incl. Effective)

±± 40004000

BiogenBiogen

CharacteristicsCharacteristics

atat

InclusionInclusion

Age (mean

± SD)

37.7 ± 9.8 yrFemale : Male Ratio

3 : 1

Disease Duration (mean

± SD)

9.1 ± 6.7 yrDisease Course (% patients with RRMS)

96 %Prior Disease-Modifying Treatments (% patients)

Immunomodulators

88 % Immunosuppressants

22 %None

10 %

Nb Relapses in the Previous

12 Months

(mean

± SD)

1.9 ± 1,2EDSS score (mean

± SD)

3.6 ± 1,8Brain MRI with Gad+ Lesions

55 %

425 (16%) patients definitively stopped 425 (16%) patients definitively stopped natalizumabnatalizumab487 treatment discontinuations487 treatment discontinuations

••

32 % = Adverse Events, Allergy, Persisting Neutralizing Antibodi32 % = Adverse Events, Allergy, Persisting Neutralizing Antibodies, es, ……••

23 % = Lack of Efficacy (Relapses, Secondary progression)23 % = Lack of Efficacy (Relapses, Secondary progression)••

45 % = Pregnancy, Convenience, 45 % = Pregnancy, Convenience, ……

Follow-up

Duration Duration MMeanean

±± SDSD

20.1 20.1 ±± 13.9 months13.9 monthsMedian [Range]Median [Range]

19.5 [0 19.5 [0 ––

57] months57] months

SeveritySeverity DescriptionDescription InfusionInfusionNoNo

NTZ NTZ StoppedStopped

DeathDeath

PMLPML 1818 --Acute Acute LeukoencephalopathyLeukoencephalopathy

((mycoplasmamycoplasma)) 1919 --CardiacCardiac

arrestarrest 1414 --CardiacCardiac

arrestarrest 22 --CompletedCompleted

suicide by suicide by defenestrationdefenestration 1414 --CompletedCompleted

suicide by suicide by drugdrug

overdoseoverdose 1818 --

Persistent or Persistent or significantsignificant

disabilitydisability CarotidCarotid

ArteryArtery

Dissection, Dissection, SylvianSylvian

InfarctionInfarction 2121 NONO

LifeLife--threateningthreatening

PMLPML 3232 YESYESEncephalitisEncephalitis

due to herpes simplexdue to herpes simplex 2323 YESYESUrticariaUrticaria, , extendedextended 22 YESYES

Suicide Suicide attemptattempt

by by drugdrug

overdose & overdose & cuttingcutting

femoralfemoral

veinvein 1717 UnknownUnknown

Suicide Suicide attemptattempt

by by drugdrug

overdoseoverdose 1818 NONO

Suicide Suicide attemptattempt 1111 NONO

CardioCardio--respiratoryrespiratory

arrestarrest

due to due to drowningdrowning 1010 NONO

Safety

164 Serious Adverse Events among 128 patients (4.5%)164 Serious Adverse Events among 128 patients (4.5%)

SeveritySeverity

DescriptionDescription

InfusionInfusion

NTZNTZNoNo

StoppedStopped

PMLPML

1919

YESYESPMLPML

3939

YESYESPMLPML

3434

YESYESPMLPML

UnknownUnknown

YESYESPMLPML

UnknownUnknown

YESYESPMLPML

UnknownUnknown

YESYES

BB--cellcell

lymphomalymphoma,,

3333

YESYESSmall Small cellcell

lunglung

cancercancer

2727

YESYESRectum cancerRectum cancer

77

YESYESHospitalisationHospitalisation

BreastBreast

CancerCancer

UnknownUnknown

YESYESBreastBreast

cancercancer

4343

NONOUterusUterus

cancercancer

2626

NONOSkin cancer Skin cancer 3030

NONO

AnaphylacticAnaphylactic

shockshock

22

YESYES14 14 AllergicAllergic

reactionsreactions

22x9,x9,

33x2x2,,

55x2,x2,

66x1x1

YESYES

Acute Acute retinalretinal

necrosisnecrosis

due to VZVdue to VZV

2121

YESYESMeningitisMeningitis

due to due to EnterovirusEnterovirus

11

YESYESHerpes Herpes ZosterZoster

shinglesshingles

33

NONOTuberculosisTuberculosis

((MycobacteriumMycobacterium

aviumavium))

2929

UnknownUnknown

CytolyticCytolytic

hepatitishepatitis

3434

YESYES

Efficacy

AtAt

StartingStarting

YearYear

11

YearYear

22

YearYear

33NTZNTZ

NTZNTZ

NTZNTZ

NTZNTZ

RelapsesRelapses((MeanMean

AnnualizedAnnualized

Relapse Rate)Relapse Rate)

EDSS Score EDSS Score ((MeanMean

±± SD)SD)

3.7 3.7 ±± 1.81.8

3.3 3.3 ±± 1.91.9

3.4 3.4 ±± 1.91.9

3.5 3.5 ±± 2.02.0

The Observatoire FranThe Observatoire Franççais de la SEPais de la SEP(OFSEP)(OFSEP)

10.341.968 10.341.968 €€

over 10 over 10 yearsyears

A A ""LargeLargeEpidemiologicEpidemiologic

ToolTool""

FOR WHOM ? FOR WHOM ? PhysiciansPhysicians, , ResearchersResearchers,,

HealthHealth

AuthoritiesAuthorities,,IndustryIndustry

WHERE ?WHERE ?France and ROWFrance and ROW

FOR WHAT ?FOR WHAT ?PromotePromote

ResearchResearch

…………

ClinicalClinical,,TranslationalTranslational,,

BasicBasic

TheTheNationalNational

MS MS CohortCohort

IncreaseIncreaseEnrichEnrich

DiversifyDiversify

SupplementarySupplementary

NestsNestsInaugural EpisodesInaugural Episodes

CancersCancersGeneticGenetic

EpidemiologyEpidemiology

PharmacoPharmaco--EpidemiologyEpidemiologySafetySafety, , ToleranceTolerance, ,

Conditions of PrescriptionConditions of PrescriptionAFSSAPSAFSSAPS

PharmacoPharmaco--EconomyEconomyCostCost

/ / EfficacyEfficacyCNAMTS, RSI, MSACNAMTS, RSI, MSA

PharmacologyPharmacologyEfficacyEfficacyHAS, CTHAS, CT

Perma

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ulti-D

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-Epid

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Survei

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Syste

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for M

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Scler

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Perma

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Perma

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Drug P

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demiolo

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Epidem

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for M

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