ToreK.KvienDeptofRheumatologyDiakonhjemmetHospital

Oslo,Norway

Sharingclinicalexperience:TheNOR-SWITCHtrial

ToreK.Kvien–disclosuresHonorarium Institutional support

NOR-DMARD

Presentation Advice Previous Current

AbbVie X X X

BMS X X X X

MSD X X X

Pfizer/Wyeth X X X

Roche X X X

UCB X X X

Hospira X X

Epirus X

Orion X X

Merck Serono X

Mundipharma X

Celltrion X X

Sandoz X

Editor-in-ChiefAnnalsoftheRheumaFcDiseases

PutrikP,etal.AnnRheumDis2014;73:198-206.

InequiFesinAccesstoBiologicandSyntheFcDMARDsAcross46EuropeanCountries

PutrikP,etal.AnnRheumDis2014;73:198-206.

WhyBiosimilars?

•  Similartotheoriginatorproduct– Notbe[er– Notworse

– Butcheaper!

CouldimproveaccessibilitytogoodtherapiesformorepeoplewithRMDs

GenericsandBiosimilars

Aspirin(chemical)180daltons

Generic

mAb~150,000daltons

2ndgeneraBonbiosimilar

Insulin5,700daltons

1stgeneraBonbiosimilar

ComparisonofRegulatoryRequirements•  Theaimofabiosimilardevelopmentprogramistoestablish“biosimilarity”b

asedupontotalityofevidence.

1.  Guidelineonsimilarbiologicalmedicinalproducts.EuropeanMedicinesAgency23rdOctober2014.2.  h[p://www.ema.europa.eu/docs/en_GB/document_library/ScienFfic_guideline/2014/10/WC500176768.pdf(AccessedOctober2016).

TwoMainQuesFons

•  PrescripFonofbiosimilarwhentostartnewtherapyortochangetherapyformedicalreasons?– Notcontroversial(?)

YooDH,etal.AnnRheumDis2013;72:1613-1620.ParkW,etal.AnnRheumDis2013;72:1605-1612.

CT-P13Phase1PharmacokineFcEquivalenceTrialinAS:StudySchemaFc

Randomiseddouble-blindstudyinpaBentswithAS

*Dosesatweeks0,2and6by2-hrIVinfusion.**Dosesevery8weeksupto54weeksby2-hrIVinfusion.

EMA/CHMP/589422/2013;CT-P13AssessmentReport.

CT-P135mg/kg[monotherapy]

(N=125)N=250

MaintenancePhase**Dose-loadingPhase*

CT-P135mg/kg

Switch

Long-termExtensionStudy**

ROriginatorINX

5mg/kg[monotherapy](N=125)

Wk0 Wk6 Wk30 Wk54

CT-P13PKStudyinAS:PKAnalysis

Dose5(Week22)

Parameter Treatment NGeometricMean

RaBo(%)ofGeometricMeans

90%CIofRaBo(%)

AUCτ(μg*h/mL)

CT-P13(5mg/kg)OriginatorINX(5mg/kg)

111110

32,765.5131,475.68 104.10 (93.93–115.36)

Cmax,ss(μg/mL)

CT-P13(5mg/kg)OriginatorINX(5mg/kg)

112110

146.94144.81 101.47 (94.57–108.86)

ThePKprofilesofCT-P13andtheoriginatorINXareequivalentintermsofAUCTandCmax,ss

Pre-definedbioequivalenceacceptancerange:80%–125%

Source:EMAInflectraEPAR,June2013.

PLANETRA

•  Standarddesignandinclusioncriteriaforphase3trialinptsbeingIAresponderstoMTX

•  PrimaryendpointACR20week30

•  Equivalenceofefficacyifthe95%CIfortreatmentdifferencewaswithin+15%

Phase3TherapeuFcEquivalenceTrialinRA:StudySchemaFcRandomiseddouble-blindstudyinpaBentswithRA

*Dosesatweeks0,2and6by2-hrIVinfusion.**Dosesevery8weeksupto54weeksby2-hrIVinfusion.

EMA/CHMP/589422/2013;CT-P13AssessmentReport

CT-P133mg/kg[combinaFontherapy]

(N=302)N=606

MaintenancePhase**Dose-loadingPhase*

CT-P133mg/kg+MTX

Switch

Long-termExtensionStudy**

R

OriginatorINX3mg/kg[combinaFontherapy](N=304)

Wk0 Wk6 Wk30 Wk54

CT-P13StudyinRA:ACR20ResponseACRresponseatWeeks14,30and54

EsBmateoftreatmentdifference(95%CI)

Source:EMAInflectraEPAR,June2013

%paB

entsachievingACR

20

ACR20Week14010203040

6050

8070

90100

CT-P13

OriginatorINX

0.07(-0.01,0.15)

180/248 164/25

72.665.3

Primaryendpoint: Equivalencemargin

ACRatWeek30: CT-P13result

ACRatWeek54: CT-P13result

0.04(-0.04,0.12)

182/248 175/25

73.4 69.7

0.06(-0.02,0.15)

168/246 155/250

68.362.0

ACR20Week30 ACR20Week54

PerProtocolPopulaFon

+15

+12

+15

-15

-4

-2

TwomainquesFons

•  PrescripFonofbiosimilarwhentostartnewtherapyortochangetherapyformedicalreasons?–  Notcontroversial(?)

•  CanpaFentsonstabletreatmentwithanoriginatordrugbeswitchedtoacheaperbiosimilarofthisdrug?– Morecontroversial(concerningefficacy,safetyandimmunogenicity)

ParkW,etal.AnnRheumDis2016.[Epubbeforeprint].doi:10.1136/annrheumdis-2015-208783.

PLANETASExtensionStudy

ParkW,etal.AnnRheumDis2016.[Epubbeforeprint].doi:10.1136/annrheumdis-2015-208783.

TheNor-Switchstudy

Arandomized,double-blind,parallel-groupstudytoevaluatethesafetyandefficacyofswitchingfrominnovatorinfliximabtobiosimilarinfliximabcomparedwithmaintainedtreatmentwithinnovatorinfliximabinpaBentswithrheumatoidarthriBs,spondyloarthriBs,

psoriaBcarthriBs,ulceraBvecoliBs,Crohn’sdiseaseandchronicplaquepsoriasis

EudraCTNumber:2014-002056-40

AcknowledgementsThistrialwassupportedbyadirectgrantfromtheNorwegiangovernment,bytheMinistryofHealthandCareServices.Studycoordinators:KrisFnKJørgensen,GuroLøvikGoll,MereteLorentzenSta5s5cian:IngeCOlsenProjectgroup:JørgenJahnsen,CatoMørk,NilsBolstad,EspenAHaavardsholm,KnutEALundin,IngridPBerset,BjørgTSFevang,JonFlorholmen,SynøveKalstad,NilsJMørk,KrisFnRyggen,KåreSTveit,SigrunKSæther.Pa5entrepresenta5ves:BjørnGulbrandsen,JonHagfors,KennethWaksvikInvesFgators,nursesandparFcipaFngpaFentsateachstudysiteDatamonitoring:MarthaColban,NinaFlatner,TrondSmedsrud,BjørnSolvang,IngerHildeZahl,CecilieMoe,TrudeLangengandtheNorwegianClinicalResearchInfrastructureNetwork(NorCRIN)

StudyobjecBvesPrimary:•  ToassessifCT-P13isnon-inferiortoinnovatorinfliximab

(INX)withregardtodiseaseworseninginpaFentswhohavebeenonstableINXtreatmentforatleast6months

Secondary:•  ToassessthesafetyandimmunogenicityofCT-P13compared

toINXinpaFentswhohavebeenonstableINXtreatmentforatleast6months

•  TocomparetheefficacyofCT-P13toINXinpaFentswhohavebeenonstableINXtreatmentforatleast6monthsapplyinggenericanddisease-specificoutcomemeasures

MainInclusionCriteria

•  AclinicaldiagnosisofeitherrheumatoidarthriFs,spondyloarthriFs,psoriaFcarthriFs,ulceraFvecoliFs,Crohn’sdiseaseorchronicplaquepsoriasis

•  Maleornon-pregnant,non-nursingfemale•  >18yearsofageatscreening•  Stabletreatmentwithinnovatorinfliximab(Remicade®)duringthelast6months

•  Subjectcapableofunderstandingandsigninganinformedconsentform

•  Provisionofwri[eninformedconsent

NOR-SWITCHStudydesign

ScreeningStablepaFents(atleast6months)

RandomisaFon1:1

N=500

Remicade DiseaseworseningW52 Follow-upW78

Remsima DiseaseworseningW52 Follow-upW78

PrimaryendpointWeek52

Arandomized,double-blind,parallel-groupstudytoevaluatethesafetyandefficacyofswitchingfrominnovatorinfliximabtobiosimilarinfliximabcomparedwithconFnuedtreatmentwithinnovatorinfliximabinpaFentswithrheumatoidarthriFs,spondylarthriFs,psoriaFcarthriFs,ulceraFvecoliFs,Crohn’sdiseaseandchronicplaquepsoriasis

AssumpFon:30%worseningin52

weeksNon-inferioritymargin:15%

Switch

OpenLabelFollow-up

•  Exploringswitchingfornon-medicalreasons•  Primaryendpoint:EffecFveness(diseaseworsening)

N o n -inferiority Margin

1 0 % d i s e a s e worsening at 48 w

2 0 % d i s e a s e worsening at 48 w

3 0 % d i s e a s e worsening at 48 w

10% 248 504 660

15 % 126 224 294

20 % 72 126 166

Table2:ThenumbersinthecellsrepresentthetotalnumberofpaBentsneededintotal.AllcalculaBonsarebasedonapowerof90%andalpha2.5%.

Table1:ThenumbersinthecellsrepresentthetotalnumberofpaBentsneededintotal.AllcalculaBonsarebasedonapowerof80%andalpha2.5%

N o n -i n f e r i o r i t y Margin

10% disease worsening at 48 w

20% disease worsening at 48 w

30% disease worsening at 48 w

10% 380 674 884

15 % 170 300 394

20 % 96 170 222

Tromsø

Bodø

St.OlavÅlesund

Ahus

Ullevål

Tønsberg

SkienArendal

KrisBansand

Diakonhjemmet

RikshospitaletHaugesund

Lillehammer

Hamar

Gjøvik

Elverum

Bærum

National multicenter study n=40

19Gastro

16Rheuma

5Derma

Bergen

R G

R G

R G

G

R

R H

R G

G R G

G

G

RG

G H G

G R G

G G

GG

G H

Levanger R

Førde R

MarBnaHansen R

R

MoIRana R

H

R

Øssold

H

Kongsvinger R

Randomized patients 2014-2015

0

100

200

300

400

500

600

Oct Nov Dec Jan Feb March April May June

248Gastro

199Rheuma

35Derma

482intotal

Trialprofile

KvienT.NOR-SWITCHPrincipalInvesFgator.Unpublisheddata.

DiagnosisdistribuBonN=482

DemographicsandbaselinecharacterisBcsINX(n=241) CT-P13(n=240)

Age(years) 47·5(14·8) 48·2(14·9)

Female 99(41·1%) 87(36·2%)

DiseaseduraFon(years) 16·7(10·9) 17·5(10·5)

DuraFonofongoingINXtreatment(years) 6·7(3·6) 6·9(3·8)

PrevioustherapywithbiologicspriortoINX

TNFαinhibitors

none 188(78·0%) 188(78·3%)

one 43(17·8%) 40(16·7%)

two 10(4·1%) 9(3·8%)

threeormore 0(0%) 3(1·2%)

Otherbiologics 2(0·8%) 1(0·4%)

Concomitantimmunosuppressivetherapy* 113(46·9%) 129(53·8%)

*MXT,AZA,6-MP,SASAP,leflunomide

Results

PrimaryendpointINX

(n=202)CT-P13(n=206)

Ratedifference(95%CI)

Diseaseworsening* 53(26.2%) 61(29.6%) -4.4(-12.7–3.9)

*UC:increaseinp-Mayoscoreof≥3pointsandap-Mayoscoreof≥5points,CD:increaseinHBIof≥4pointsandaHBIscoreof≥7pointsRA/PsA:increaseinDAS28of≥1.2fromrandomizaFonandaDASscoreof≥3.2AS/SpA:increaseinASDASof≥1.1andASDASof≥2.1Psoriasis:increaseinPASIof≥3pointsfromrandomizaFonandaminimumPASIscoreof≥5IfapaFentdoesnotfulfilltheformaldefiniFon,butexperiencesaclinicallysignificantworseningaccordingtoboththeinvesFgatorandpaFentandwhichleadstoamajorchangeintreatmentthisshouldbeconsideredasadiseaseworseningbutrecordedseparatelyintheCRF

CRPandCalprotecBn

CRP CalprotecFn

Overall IBD

GlobalAssessmentofDiseaseAcBvity

PaFent Physician

-1

-.8

-.6

-.4

-.2

0

.2

.4

.6

.8

1

1.2

1.4

Δ H

arve

y-Br

adsh

aw in

dex

Baseline Week 8 Week 16 Week 24 Week 32 Week 40 Week 52

INXCT-P13

-.6-.5-.4-.3-.2-.1

0.1.2.3.4.5.6.7.8

Δ P

artia

l May

o Sc

ore

Baseline Week 8 Week 16 Week 24 Week 32 Week 40 Week 52

INXCT-P13

-.3

-.2

-.1

0

.1

.2

.3

.4

.5

Δ A

nkyl

osin

g Sp

ondy

litis

Dis

ease

Act

ivity

Sco

re

Baseline Week 8 Week 16 Week 24 Week 32 Week 40 Week 52

INXCT-P13

-2

-1.5

-1

-.5

0

.5

1

1.5

2

2.5

3

3.5

4

Δ C

linic

al D

isea

se A

ctiv

ity In

dex

Baseline Week 8 Week 16 Week 24 Week 32 Week 40 Week 52

INXCT-P13

-2

-1.5

-1

-.5

0

.5

1

1.5

2

2.5

3

3.5

4

Δ S

impl

ified

Dis

ease

Act

ivity

Inde

x

Baseline Week 8 Week 16 Week 24 Week 32 Week 40 Week 52

INXCT-P13

-2-1.8-1.6-1.4-1.2

-1-.8-.6-.4-.2

0.2.4.6.8

Δ P

soria

sis

Area

and

Sev

erity

Inde

x

Baseline Week 8 Week 16 Week 24 Week 32 Week 40 Week 52

INXCT-P13

-.4

-.2

0

.2

.4

.6

.8

1

Δ D

isea

se A

ctiv

ity S

core

28

join

ts

Baseline Week 8 Week 16 Week 24 Week 32 Week 40 Week 52

INXCT-P13

DiseaseAcBvity

HBI p-Mayoscore ASDAS DAS28

CDAI SDAI PASI

Drugtroughlevels

Overall

AnB-druganBbodies(ADAb)INX

(n=241)CT-P13(n=240)

ADAbobservedatanyFmepoint 26(10.8%) 30(12.5%)

IncidenceofADAb 17(7.1%) 19(7.9%)

Adverseevents–safetypopulaBon

Overview* INX(n=241)

CT-P13(n=240)

SUSAR 0 0

Seriousadverseevents(SAE) [32]24(10·0%) [27]21(8·8%)

Adverseevents(AE) [422]168(69·7%) [401]164(68·3%)

AdverseeventleadingtostudydrugdisconFnuaFon

[18]9(3·7%) [9]8(3·3%)

*[numberofevents]n(%)

•  Strengths•  Design-RCT•  ComprehensivedatacollecFon•  IncludedsufficientnumberofpaFentsaccordingtopowercalculaFons

•  PaFentrepresentaFvesinprojectgroup•  Financedbygovernment,monitoredwithinthehealthcaresystemandnoindustryinvolvement

•  Drugsprovidedthroughtheregularpaymentschedule•  LimitaFons

•  Notpoweredfornon-inferioritywithineachdiagnosFcgroup•  Blindingprocedures•  NodataonpaFentswhodeclinedparFcipaFon•  Non-inferioritymargintoolarge?•  ResultsrelevantalsoforotherboDMARDs/bsDMARDs?

MethodologicalconsideraBons

•  TheNOR-SWITCHtrialdemonstratedthatswitchfromINXtoCT-P13wasnotinferiortoconFnuedtreatmentwithINX.

•  TheresultssupportswitchingfromINXtoCT-P13fornon-medicalreasons.

InterpretaBon

Dörner T et al Ann Rheum Dis 2016