Disclosures - Biosimilars Nederland

Prof.WojciechJurczakMD,PhD

Disclosures

PROF.WOJCIECHJURCZAK,M.D.,PH.D.

ADVISORYBOARDS:SANDOZNOVARTIS,ROCHE,JANSSEN,ACERTA,ABBVIE,TGTHERAPEUTICS,TEVA,TAKEDA,SPECTRUM,NOVONORDISK,MUNDIPHARMA,RESEARCHFUNDING:CELGENE,ABBVIE,GILEAD,TGTHERAPEUTICS,JANSSEN,ACERTA,,MERCK,BEGENE,PHARMACYCLICS,PFIZER,ROCHE,SANDOZ–NOVARTIS,TAKEDA,TEVA,SERVUIER,EISAI.

DISCLAIMER:Thesenon-promo,onalslidesareintendedtobeusedaseduca,onalmaterialonly.Thedouble-dagger(‡)symbolindicatesthattheseslidesmaycontaininforma,onthatisnotwithinEMAorFDAapprovedproductlabelingandhasnototherwisebeenapprovedbytheEMAorFDA.Informa,onwithinthisslidedeckisrelatedtoinves,ga,onalagentsthatarenotapprovedbytheEMAorFDAandhavenotyetbeendeterminedtobesafeorefficaciousinhumans


Biosimilar-trialswithRituximab:be6eracceptancethroughbe6erunderstanding

Prof.WojciechJurczak,M.D.,Ph.D.DptofHematology,[email protected],(+48602338290)


MoAbinNHL:EverythingStartedWithRituximab

Development and registration

of original particle (Roche)

Subcutaneous Rituximab (Roche)

Rituximab biosimilars: •  CT-P10 (Celltrion)

•  GP2013 (Sandoz Novartis)

Coiffier,Czuczman,Sales,Marcus,Hiddemann

Davies

Coiffier,Jurczak


RituximabremainsastandardofcareinIlineBcellNHL

WithnewMoAbandsmallparGcles,Rituximabroleinrelapsing/refractoryNHLmaybedisputable

LymphomaSubtype IlineinducGon Ilinemaintenance

AggresiveLymphomas yes NoMCL yes yesIndolentlymphomas yes ?CLL yes yes


First-LineDLBCLTreatment

60%cure,40%relapsed/refractory

Intensive eligible (70%)

High-risk intensive eligible

(10%)

Intensive ineligible

(20%)

R-CHOP

R-DAEPOCH

R–miniCHOPR-Nodoxorubicin-chemotherapy

R-CHOP:Rituximab+cyclophosphamide,doxorubicin,vincrisdne,prednisone;DA-EPOCH-R:etoposide,vincrisdne,doxorubicin,cyclophosphamide,prednisone,rituximab.Basedon:NCCNguidelines.hfps://www.nccn.org/about/nhl.pdf.Accessed22June2017.


RituximabIs“AGreatEqualiser”ofChemotherapyRegimens

CALGB/Alliance 50303 trialArm N Events 5Y(95%CI)

R-CHOP 233 44 0.80(0.74-0.85)

DA-EPOCH-R 232 50 0.76(0.70-0.71)

Years from Study Entry

OS

Pro

babi

lity

0 1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

R-CHOP DA-EPOCH-R

WilsonWH,etal.:ASH2016

CHOEP

CHOP-14

DA-EPOCH

Prof.WojciechJurczakMD,PhDVitoloetal.:2016

ChemotherapyMayBe“AGreatEqualiser”ofMonoclonalAnGbodies MOR208

?

RituximabObinutuzumab

OSinpreviouslyuntreatedDLBCLpaGents(GOYAtrial)


LenalidomideandIbruGnibinABC-DLBCL:Phase3TrialsAreUnderway(‡)

ABC:acdvatedB-celllike.Figure:1.ShafferAL3rdetal.AnnRevImmunol.2012;30:565-610.

Chronic Active BCR signalling Constitutive

MYD88 signalling

Autocrine cytokine signalling

Akt/mTOR pathway

NF-κB pathway

Interferon pathway

STAT1 STAT3 P P

P P

P P

IFN-β IL-6/IL-10

MYD88 TIR domain

mutation

CARD11 CC domain

mutation

CD79A/B ITAM

mutation SYK

SFK

PI93)K

BTK

PKCβ

A20 loss A20

Survival

CARD11 MALT1 BCL10

IgL

IgH

CD

79A

CD

79B

TYK2 JAK1 MYD88 IRAK4 IRAK1

TRAF6

Lenalidomide downregulates NF-κB and upregulates the

IFN-β pathway 2.ClinicalTrials.govIdendfier:NCT01855750;3.ClinicalTrials.govIdendfier:NCT02285062.


First-LineMCLTreatment

DreylingMetal.ESMO,MCLguidelines.2017.Inpress.

Young Patients (<65) Elderly Patients (>65) “Compromised”Dose-intensified (R-CHOP

+ R-HAD à ASCT)

+ Rituximab Maintenance

Conventional Immunochemotherapy (eg, R-CHOP, VR-CAP,

BR)

+ Rituximab maintenance

Best supportive care R-Chlorambucil, R-CVP,

BR (dose reduced)

+ Rituximab maintenance


MCL-LYMAtrialin“youngerpaGents”

LEGOUILLetal.:ASH2013/2014/2015/2016


IndollentLymphomas

R-B

R-CHOP

R-CVP

R


CD20therapies:improvingoutcomesin1LFLoverthelastdecadePFS

Treatment management optimisation

R-chemo‡ + R-maintenance#

G-chemo‡ + G-maintenance#

PRIMA3

HR, 0.55 p<0.0001

GALLIUM4

HR, 0.66 p=0.0012

0 Chemo*/R-chemo*,+ R-chemo† +

R-maintenance$ R-chemo† + observation$

Maintenance

GLSG’001

M390212

Time

Impr

ovin

g p

atie

nt o

utco

mes

aCD20 optimisation

Induction + maintenance Induction

Chemo *

R-Chemo *

1.HiddemannW,etal.Blood2005;106:3725–322.MarcusR,etal.Blood2005;105:1417–233.SallesG,etal.Lancet2010;377:42–514.MarcusR,etal.NEnglJMed2017;377:1331–44

Prof.WojciechJurczakMD,PhD13

Marcusetal.:2016

Chemotherapymaybe“AGreatEqualiser”ofMonoclonalAnGbodies

MOR208?


OSinpreviouslyuntreatedFLpaGents(GALLIUMtrial)


14

Geodeetal.:2014

ChemotherapyMayBe“AGreatEqualiser”ofMonoclonalAnGbodies

MOR208?


OSinpreviouslyuntreatedelderlyCLLpaGents(CLL-11trial)

OS

StratyfikowanyHR0,7795%CI0,57–1,05p=0,0932

GClbRClb

Czas[miesiące]

ClbAlone

(n=118)

RClb

(n=233) O-Clb

(n=238)

ORR 32% 65% 78% CR 0 7% 21% MedianPFS

11months

16months

27months

Unlessitischlorambucil?


IsmaintenanceRituximabsGllthestandardofcareiniNHL?

RituximabMaintenance

•  DoesnotprolongOS

•  MoreAE(infecGons,secondaryneoplasms)

•  EfficacyofRituximabretreatment

•  Costefficacy?


BiosimilarsApprovedbyEMA

Omnitrope (Somatotropin)

Biograstim

Ratiograstim Tevagrastim

(all – filgrastim)

Zarzio Filgrastim

Hexal® (all –

filgrastim)

Nivestim (filgrastim)

Inflectra (infliximab) Remsima (Infliximab) Grastofil (filrastim) Ovaleap

(follitropin)

In clinical use

Bemfola (follitropin) Accofil

(filgrastim) Abasaglar

(insulin)

Solymbic (adalimumab)

Lusduna (insulin)

Truxima Rixathon

(Rituximab)

Benepali (etanercept)

Flixabi (infliximab)

Inhixa (enoxaparin)

Movymia (terparatide)

1

5 3 2 1

4 3 4 3

2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

In development

Bevacizumab, Trastuzumab, Etanercept, Cetuximab,

Pegfilgrastim, Insulin,

Adalimumab

Binocrit®

Epoetin Alpha

Hexal® Abseamed®

Retacrit® Silapo®

(all – epoetin)

EPO

G-CSF Rituximab

G-CSF:Granulocyte-colonysdmuladngfactor;EMA:EuropeanMedicinesAgency;EPO:epoedn.EMAwebsite.hfp://www.ema.europa.eu/ema/.Accessed7June2017


BiosymilarswhichmaybepotenGallydevelopedinthenext10years


OncebiosymilarisapprovedithassubstanGalfinancialimpact

“Biosymilars– symilarbutnotiden@cal”


AherintruducingG-CSFbiosymilarit’susagedoubled

WalshK.:BiosimilarMedicines11thEGAInternadonalSymposium,2013


Analydcal

Preclinical

PK/PD

Clinical

Majorgoalistodeterminetheclinicaleffect

Referencemedicine

Clinical

PK/PD

Preclinical

Analydcal

Majorgoalistodeterminesimilarity;establishmentofthesciendficbridge

totheclinicalexperienceoftheoriginator

Biosimilar

Differentfocusbetweenoriginator&biosimilardevelopment

Intheend,bothapproachesprovidethesamelevelofconfidencewithregardtosafetyandefficacyofthemedicine


KeyconsideraGonsforPhaseIIItrialdesigns

Originator Biosimilar

Padentpopuladon Any Sensidveandhomogeneous

Clinicaldesign Superiorityversusstandardofcare

ComparaGveversusinnovator(therapeudcequivalencestudies)

Studyendpoints Clinicaloutcomesdata(OS&PFS)oraccepted/establishedsurrogates

PharmacokineGcandPharmacodynamicmarkers;objecdveresponserate(RR)

Safety Acceptablerisk/benefitprofileversusstandardofcare Similarsafetyprofiletoinnovator

Immunogenicity Acceptablerisk/benefitprofileversusstandardofcare

Similarimmunogenicityprofiletoinnovator

Extrapoladon Notallowed Possibleifjusdfied

prIME Podcast Series 2013: A Focus on Biosimilar Antibodies, Reference Slidk [online]. Available at: https://www.youtube.com/watch?v=VwNWUzyuJuw [Accessed 2016 March 22].


Shihsinqualitya6ributesofRituxan®/Mabthera®betweendifferentbatches

ShieldsetalJBiolChem.2002


RituximabBiosimilars

GP2013BeingassessedbyEMA

CT-P10RegisteredbyEMA


GP2013developmentprogram

PK/PD

Pre-clinical

Biological characterization

Physicochemical characterization

Clinical trials

Binding (target binding, receptor binding) Mode-of-action (programmed cell death, CDC, ADCC)

Primary structure, higher order structure, size, heterogeneity (C-and N-terminal),post-translational modifications (variants glycosylation, glycation, oxidation, deamidation). Purity, Aggregates

PK/PD (single dose in monkeys); toxicity (repeat dose in monkeys); Efficacy (xenograft tumor models in SCID mice); Local tolerance (rabbits); Tissue cross reactivity, ADCC (in vitro)

Efficacy and safety from two indications: RA & FL

PK/PD from two indications: RA & FL

ADCC,andbody-dependentcellularcytotoxicity;CDC,complement-dependentcytotoxicity;FL,follicularlymphoma;PD,pharmacodynamics;PK,pharmacokinedcs;RA,rheumatoidarthrids;SCID,severecombinedimmunodeficiency

Non-clinicaldevelop-ment

Clinicaldevelopment


§  Potencybioassaysdesignedtogivequandtadveresults

FuncGonalcharacterizaGon:Rituximabbiosimilarbioassays

Targetbinding(n=59/11)

ADCC(n=62/11)

CDC(n=42/11)

Apoptosis(n=7/5)

GP2013 97–108% 86–105% 99–111% 88–97%

Referencerange 96–110% 70–132% 95–127% 88–102%

P-values* <0.0001 <0.0001 <0.0001 <0.0001*Assessedusingthetwo-sidedtestprocedure(TOST)withbioequivalencelimitsof0.8–1.25

Figure adapted from Taylor RP et al. Nat Clin Pract Rheumatol 2007;3:86–95.

CDC complement dependent cytotoxicity

Effector cell (NK cells)

Target cell

Membrane attack complex

FcγRIIa ADCC Antibody dependent cellular cytotoxicity

PCD

ADCC,andbody-dependentcellularcytotoxicity;CDC,complement-dependentcytotoxicity;NK,naturalkiller;PCD,programmedcelldeathTargetbindingwasassessedbyFACS

Visseretal.BioDrugs2013;27:495–507.


Pre-clinicalinvitrocomparability:ADCCassayswithNKcells

Further cell lines tested: Raji, Z138

ADCC comparable to EU-sourced reference rituximab

Daudi cell line & fresh effector cells SU-DHL4 & fresh effector cells

EU-rituximab GP2013

80

-3

70

60

50

40

30

20

10

0 -2 -1 0 1 2 3 4

Log[Abs] (ng/ml)

Spec

ific

lysi

s (%

)

EU-rituximab GP2013

80

-3

70 60 50 40 30 20 10

0 -10

-2 -1 0 1 2 3 4 Log[Abs] (ng/ml)

Spec

ific

lysi

s (%

)

da Silva et al. Leuk Lymphoma 2014;55:1609–17.


Pre-clinicalinvivocomparability(tumorgrowthmodels)

Efficacy is similar

SU-DHL-4 model Jeko-1 model

2000

0

1750

1500

1250

1000

750

500

250

0 7 14 21 28

Time (days)

Tum

or v

olum

e (m

m3 )

IgG-Control (30 mg/kg) GP2013 (3 mg/kg) GP2013 (30 mg/kg) EU-rituximab (3 mg/kg) EU-rituximab (30 mg/kg)

20 25 35 40 Time (days)

30

2400

1600

1200

800

400

0

Tum

or v

olum

e (m

m3 )

2000

IgG-Control (1 mg/kg) GP2013(0.03mg/kg)GP2013 (0.1 mg/kg) GP2013 (0.3 mg/kg) GP2013 (1.0 mg/kg) EU-rituximab(0.03mg/kg)EU-rituximab(0.1 mg/kg) EU-rituximab(0.3 mg/kg) EU-rituximab(1.0 mg/kg)



Pre-clinicalinvivocomparability:PKfollowingIVadministraGonto

primates

PK: AUC and Cmax are similar


5 mg/kg 20 mg/kg, repeat dosing 100 mg/kg , repeat dosing

EU-rituximab

Time after administration (days)

Ritu

xim

ab c

once

ntra

tion

(µg/

mL)

180

0

160 140 120 100

80 60 40 20

0 2 4 6 8 10

450 400 350 300 250 200 150 100

50 0

0 2 4 6 8 10 12 14 16 Time after administration

(days)

2000 1800 1600 1400 1200 1000

800 600 400 200

0 0 2 4 6 8 10 12 14 16

Time after administration (days)

GP2013

Seconddose Seconddose


GP2013andCT-P10developmentprogram

PK/PD

Pre-clinical

Biological characterization

Physicochemical characterization

Clinical trials

Binding (target binding, receptor binding) Mode-of-action (programmed cell death, CDC, ADCC)

Primary structure, higher order structure, size, heterogeneity (C-and N-terminal),post-translational modifications (variants glycosylation, glycation, oxidation, deamidation). Purity, Aggregates

PK/PD (single dose in monkeys); toxicity (repeat dose in monkeys); Efficacy (xenograft tumor models in SCID mice); Local tolerance (rabbits); Tissue cross reactivity, ADCC (in vitro)

Efficacy and safety from two indications: RA & FL

PK/PD from two indications: RA & FL

ADCC,andbody-dependentcellularcytotoxicity;CDC,complement-dependentcytotoxicity;FL,follicularlymphoma;PD,pharmacodynamics;PK,pharmacokinedcs;RA,rheumatoidarthrids;SCID,severecombinedimmunodeficiency

Non-clinicaldevelop-ment

Clinicaldevelopment


ClinicaltrialassessingthesafetyandimmunogenicityoftransiGoningtoGP2013treatmentinpaGentswithRArefractoryorintolerantofstandardDMARDSandanG-TNFswhoreceivedatleastonepriordoseofrituximab1

•  N=107(planned)•  PrimaryobjecGve:AEs•  SecondaryobjecGves:IRRs,immunogenicity

ClinicaltrialassessingthesafetyandPKofGP2013incombinaGonwithMTXinpaGentswithRAwhofailedonatleasttwoanG-TNFs2,3

•  N=312(173EU-rituximab,139US-rituximab)•  PrimaryobjecGve:PK•  SecondaryobjecGves:DAS28atWeek24,PK/PD,safety

ConfirmatoryPhaseIIIclinicaltrialassessingtheefficacyandsafetyofrituximabbiosimilartreatmentinpaGentswithpreviouslyuntreated,

advanced-stageFL5,6•  N=629•  8cyclesofR-CVP,followedby2years’maintenance•  PrimaryobjecGve:ORRatWeek24•  SecondaryobjecGves:CR/PR,PFS,OS,PK/PD,safety

GP2013clinicaldevelopment

AE,adverseevent;CR,completeresponse;CVP,cyclophosphamide,vincrisdne,prednisolone;DAS,diseaseacdvityscore;FL,follicularlymphoma;IRR,infusion-relatedreacdon;JP,Japanesepadents;MTX,methotrexate;NHL,non-Hodgkin’slymphoma;ORR,overallresponserate;OS,overallsurvival;PD,pharmacodynamics;PFS,progression-freesurvival;PK,pharmacokinedcs;PR,pardalresponse;R,rituximab;RA,rheumatoidarthrids;TNF,tumornecrosisfactor1.Clinicaltrials.gov(NCT02514772);2.Clinicaltrials.gov(NCT01274182);3.Smolenetal.AnnRheumDis2017;76:1598–1602;4.Clinicaltrials.gov(NCT01933516);5.Clinicaltrials.gov(NCT01419665);6.JurczakW,etal.LancetHaematol2017Jul13[Epubaheadofprint]

ClinicaltrialassessingthesafetyandPKofGP2013weeklymonotherapyinJapanesepaGentswithindolentNHL4

•  N=6

GP13-201ASSIST-RA

GP13-301ASSIST-FL

GP13-302ASSIST-RT

GP13-101JP-trial

Oncologytrials

Totalsafetydata:c.1000paGents(500receivingGP2013),efficacydata:312(RA)+629(FL)paGents

RAtrials


CT-P10 Clinical Overall Program

Study Indication Primary Endpoint Sample size Status

1.1 1.3

(1.1 Extension Study)

RA PK equivalence Long term safety and efficacy

154 58 Completed

3.2 RA §  Part 1: PK equivalence §  Part 2: Therapeutic equivalence 372

Study Ongoing Week 48 results availab

le

3.3 AFL §  Part 1: PK equivalence §  Part 2: Therapeutic non-inferiority 140

Study Ongoing Week 24 results availab

le

3.4 LTBFL Therapeutic equivalence 174** Recruiting

Safety Data: 650 (325 in CT-P10), Efficacy data: 372 (RA)+ 140 (FL)


PharmacokineGcs-(AUC(0-inf))-(PAS)

Serumconcentradon-dmeprofilesforthetwotreatmentsweresimilaruptoweek24AUC(0-inf),Theareaundertheconcentradon-dmecurvefromdmezerotoinfinity;FAS,fullanalysisset;PK,pharmacokinedcs;SD,standarddeviadon*ThePKanalysissetwasasubsetoftheFASandconsistedofpadentswhodidnothaveanymajorprotocoldeviadons

ArithmeGcmean(SD)serumPKconcentraGon-Gmeprofileover24weeksbytreatment(PKanalysisset*)

SmolenJetal.,EULARcongress,8-11June,LondonUK:FRI0222


Pharmacodynamics-peripheralBcelldepleGonB-cellcoun

t(%)

Time(weeks)GP2013 Time(weeks)CT-P10

GeometricmeanraGoinAUEC0-14d1.019(95%CI:0.997,1.042)

GP2013

Referencerituximab

Median (±SE) B-cell Kinetics (cells/µL)

CT-P10 3.2 RA


CT-P10 3.2 RA

EfficacyDAS(DisesseAcGvityScore)


SafetyprofilesofGP2013andreferencerituximab

n(%) GP2013(n=86) Rituximabreference(n=87) Deaths 1(1.16) 0(0.0) Othernon-fatalSAEs 10(11.63) 14(16.09) Leadingtodiscondnuadon 2(2.33) 4(4.60)

AnyAE 56(65.1) 57(65.5) Leadingtostudydrugdiscondnuadon 2(2.33) 3(3.45)

AEsbymostfrequentSOCs Infecdonsandinfestadons 27(31.4) 31(35.6)

Musculoskeletal 16(18.6) 14(16.1)

Gastrointesdnaldisorders 13(15.1) 15(17.2)

Generaldisorders 12(14.0) 9(10.3)

Skinandsubcut.dssue 9(10.5) 11(12.6)

Injuryandpoisoning 9(10.5) 11(12.6)

Resp.,thoracic,mediasdnal 7(8.1) 12(13.8)

Vasculardisorders 7(8.1) 10(11.5)

Nervoussystemdisorders 7(8.1) 10(11.5)

Potendalinfusionrelatedreacdon 32(37.2) 37(42.5)


Events, n (%) CT-P10

(N=161) US-RTX (N=151)

EU-RTX (N=60)

RTX (N=211)

AE - Related

122 (75.8)

73 (45.3)

96 (63.6)

47 (31.1)

37 (61.7)

25 (41.7)

133 (63.0)

72 (34.1) SAE - Related

13 (8.1) 0

14 (9.3) 5 (3.3)

2 (3.3) 1 (1.7)

16 (7.6) 6 (2.8)

Infection - Related

61 (37.9)

27 (16.8)

53 (35.1)

25 (16.6)

17 (28.3)

6 (10.0)

70 (33.2)

31 (14.7)

IRR 33 (20.5) 12 (7.9) 13 (21.7) 25 (11.8)

Malignancy 0 2 (1.3) 1 (1.7) 3 (1.4) Discontinuation due to AEs - Related

3 (1.9)

2 (1.2)

7 (4.6)

5 (3.3)

2 (3.3)

1 (1.7)

9 (4.3)

6 (2.8)

CT-P10 3.2 RA SafetyprofilesofCTP-10andreferencerituximab


GP13-302clinicaltrialassessingAEinRApaGentstreatedpreviouslywithoriginatorRituximab

GP2013(N)

MabThera(N)

Total(N)

NooftreatedpaGents 53 54 107

AnaphylacGcReacGons 0 1 1

HypersensiGvityReacGons 5 6 11

Immunogenicity 0 1 1

Infusion-RelatedReacGons 6 10 16

SAE 0 4 4

AE 19 21 40

www.clinicaltrials.gov/ct2/show/results/NCT02514772


:studyraGonale

•  ASSIST-FLwasdesignedtoconfirmnon-inferiorclinicaleffecGvenessofGP2013ascomparedtooriginatorrituximabinasensidvepopuladon

•  Follicularlymphomawaschosenasthemostappropriateindicadonasthediseasehasamorehomogeneousnatureamongsttheapprovedoncologyindicadonsofrituximab

•  Further,thecombinadonR-CVPwasconsideredthemostsensiGvetreatmentopGon,asrituximabhadshownthelargestaddidvetreatmenteffecttoachemotherapybackbonetreatmentinthecombinadonwithCVP

•  ImmunochemotherapywithRituximabremainsthecurrentstandardofcareforpreviouslyuntreatedpadents,thecombinadonregimenincreasestheRRandprolongsbothPFSandOS

CT-P10 3.3 AFL

JurczakW,etal.Abstract1809presentedatthe58thASHSanDiego,USA,3–6December2016.CoiffierB,etalAbstract1807presentedatthe58thASH,SanDiego,USA,3–6December2016.


EquivalentEfficacyofaBiosimilarRituximabandReferenceRituximabinPreviouslyUntreatedAdvancedFollicular

Lymphoma:ExtendedResultsofASSIST-FL,aConfirmatoryPhaseIIIStudy

WojciechJurczak;IlidiaMoreira;KanakaSefyGovindbabu;EduardoMunhoz;Maria-AsuncionEcheveste;PratyushGiri;NelsonCastro;JulianaPereira;LuizaAkria;SergeyAlexeev;DzhalilOsmanov;PeijuanZhu;SiykaAlexandrova;AngelaZubel;OlofHarlin;JufaAmersdorffer

Jurczaketal,ESMO2017,LancetHematol2017


(GP13-301):629randomizedptsin22countries

India: 95 Japan: 29

Russia: 46

Colombia: 2

Brazil: 102

Ukraine: 21 Poland: 42

Germany: 2 Austria: 6 Netherlands: 17

UK: 1 Ireland: 2

France: 9

Spain: 37 Portugal: 33 Italy: 23

Greece: 9

South Africa: 28

Peru: 9

Argentina: 5

Bulgaria: 15 Romania: 13 Hungary: 14

Australia: 27

Malaysia: 30

Israel: 12



ASSIST-FL:AprospecGve,mulGcenter,randomized,double-blind,acGve-controlled,parallel-group,confirmatory,PhaseIIItrial

GP2013 375 mg/m2 + CVP (n=312‡) N=629

•  ≥18 years of age •  Treatment-naïve, advanced-stage, CD20-

positive, stage III/IV FL (Ann Arbor classification)

•  WHO histologic grade 1, 2 or 3a FL •  At least one measurable lesion •  ECOG performance status 0–2

Screening ≤28 days

GP2013 375 mg/m2 every 3 months*

Combination treatment period

Maintenance period (responders only)

2 years

Reference rituximab 375 mg/m2 + CVP (n=315)

24 weeks (8 cycles)

Reference rituximab 375 mg/m2 every 3 months*

R1:1 Stratification: FLIPI risk group and geographical region

‡2padentsweremis-randomized;*ExceptinItaly,wheremaintenancetherapywasadministeredevery2monthsCVP,cyclophosphamide,vincrisdne,prednisone;ECOG,EasternCooperadveOncologyGroup;FL,follicularlymphoma;FLIPI,FollicularLymphomaInternadonalPrognosdcIndex;WHO,WorldHealthOrganizadon



Studyassessments

Efficacy

•  Efficacyassessments:•  primaryendpoint:•  Overallresponserate(ORR)

•  Secondaryendpoints:•  Completeresponse(CR)•  Pardalresponse(PR)•  Progressionfreesurvival(PFS)•  Overallsurvival(OS)

Safety(secondaryendpoints)

•  Safetyassessments:AEs,SAEs,withtheirseverityandreladonshiptostudydrug,pregnancies,monitoringofhematology,bloodchemistryandurine,vitalsigns,performancestatus,ECG,andbodyweight

•  Immunogenicity:ADAformadon

PK/PD

(secondaryendpoints)

•  PK:Cmax,Ctrough,AUC(0-t),andAUCall

•  PD:peripheralCD19+Bcellcounts(absoluteandreladvetobaseline)andAUEC(0-21)inCycle1

CT-P10 3.3 AFL PK being the primary target, ORR the secondary target

JurczakW,etal.Abstract1809presentedatthe58thASHSanDiego,USA,3–6December2016.CoiffierB,etalAbstract1807presentedatthe58thASH,SanDiego,USA,3–6December2016.


ORRatWeek24–primaryefficacyendpoint

Theprimaryendpointwasmet,withequivalencedemonstratedinORRforGP2013andreferencerituximabwhencombinedwithCVPBoth95%and90%CIlayendrelywithinpredefinedmarginofequivalence(–12%to+12%)

*Centrally-assessedORRintheper-protocolpopuladon(allpadentswhoreceivedatleastone(pardalorcomplete)doseofinvesdgadonaltreatmentandwhodidnothaveanymajorprotocoldeviadons)CI,confidenceinterval;CR,completeresponse;CVP,cyclophosphamide,vincrisdne,prednisone;PR,pardalresponse;ORR,overallresponserate;R-CVP,rituximab-CVP

PR:72% PR:74%

CR:15% CR:13%

0

20

40

60

80

100

Overallrespon

sera

te(%)*

ORR:87% ORR:88%

Difference:–0.40%(95%CI:–5.94%,5.14%;90%CI:–5.10,4.30)

GP2013-CVP(n=311)

R-CVP(n=313)



PopulaGon GP2013-CVPn(%)

R-CVPn(%)

DifferenceinORR,%(95%CI)

Overall

Age<60years

Age≥60years

Male

Female

Asian

Caucasian

Other

Asia-Pacific

Europe

LaGnAmerica

Bulkydisease–yes

Bulkydisease–no

FLIPIscore0–2

FLIPIscore3–5

271(87.1)

136(83.4)

135(91.2)

113(86.3)

158(87.8)

61(85.9)

186(87.3)

24(88.9)

77(87.5)

143(86.1)

51(89.5)

38(86.4)

233(87.3)

111(82.8)

160(90.4)

274(87.5)

150(86.7)

124(88.6)

120(82.8)

154(91.7)

75(88.2)

178(86.8)

21(91.3)

82(89.1)

141(88.1)

51(83.6)

46(82.1)

228(88.7)

125(91.2)

149(84.7)

–0.4(–5.94,5.14)

–3.27(–11.49,4.95)

2.64(–5.02,10.31)

3.50(–5.74,12.75)

–3.89(–10.82,3.04)

–2.32(–14.21,9.57)

0.49(–6.42,7.41)

–2.42(–22.97,18.14)

–1.63(–12.13,8.87)

–1.98(–9.86,5.90)

5.87(–8.07,19.80)

4.22(–12.07,20.51)

–1.45(–7.40,4.50)

–8.41(–17.09,0.28)

5.74(–1.70,13.17)

-25 -20 -15 -10 -5 0 5 10 15 20 25

SubgroupanalysesofORR

CVP,cyclophosphamide,vincrisdne,prednisone;FLIPI,FollicularLymphomaInternadonalPrognosdcIndex;ORR,overallresponserate;R-CVP,rituximab-CVP

Equivalencemargin(±12%)*

FavorsGP2013Favorsreference

Difference(%)

*Thepredefinedequivalencemarginwaspoweredonlyfortheprimaryendpointofoverallresponserateinthefullpopuladon,andnotforsubgroupanalyses



PFS&OS–secondaryefficacyendpoints

•  ASSIST-FLwasnotpoweredtoevaluatecomparabilityintermsofPFSandOS–theseendpointsarenotintendedtobeusedtoconfirmbiosimilarity•  Dataarecurrentlyimmature,withahighproporGonofpaGentscensored(~70–90%)•  TheobservedhazardraGosforPFSandOSareinconsistent,suggesGngthatcurrentresultsarelikelyduetorandomvariaGonandnotactualtreatment

differences

Outcome†GP2013-CVPN=312,n(%)

R-CVPN=315,n(%)

HazardraGo(90%CI)*

PFS

Event,n(%) 94(30) 76(24) 1.31(1.02,1.69)

Censoredevents,n(%) 218(70) 239(76)

Kaplan-Meieresdmate,median Notreached Notreached

OS

Event,n(%) 23(7) 29(9) 0.77(0.49,1.22)

Censoredevents,n(%) 289(93) 286(91)

Kaplan-Meieresdmate,median Notreached Notreached



46

Patients with CD20+

confirmed FL

Randomization 1:1

(N=134)

Core Study Period

24 weeks

Maintenance Study Period

2 years (for responders; CR, CRu or PR)

Follow-up Period: Up to 3 years from the Day 1 of Cycle 1 of the last patient

EOT1

EOT2

CT-P10² + CVP1

(n=67)

Rituxan² + CVP (n=67)

Rituxan

CT-P10

1. CVP: Cyclophosphamide 750 mg/m2, Vincristine 1.4 mg/m2 [max 2mg], Prednisone or prednisolone 40 mg/m2 2. Rituximab: 375 mg/m2 (Core study: 3-weekly, Maintenance study: every 2 months)

Abbreviations: FL, Follicular Lymphoma; EOT, End of Treatment; FLIPI, Follicular Lymphoma International Prognostic Index

Stratification Factor §  Gender: Male vs. Female §  FLIPI score: 0-2 vs. 3-5 §  Country

StudydesignCT-P10 3.2 RA

CoiffierB,etalASH2017,LancetHematology2017


ITT Population

Response CT-P10 (N=70)

Rituxan (N=70)

Difference [lower bound of 95%

CI]

ORR1 67 (95.7%) 63 (90.0%) 5.7% [-3.41%]

CR 21 (30.0%) 15 (21.4%) -

CRu 6 (8.6%) 8 (11.4%) -

PR 40 (57.1%) 40 (57.1%) -

The difference between the groups lies on the positive side of -7%. lower bound of 95% CI of differences lies on the positive side of -7%.

Efficacyresults(ORR)–secondaryendpointCT-P10 3.2 RA

CoiffierB,etalASH2017,LancetHematology2017


ResearchonBiosimilars:pivotaltrialsandprinciplesWojciechJurczak,ArnoldGVulto,JufaAmersdorffer,WonSKim,BertrandCoiffierTheLancetHaematology,Vol.4,No.9,e409–e410Published:September,2017RituximabbiosimilarandreferencerituximabinpaGentswithpreviouslyuntreatedadvancedfollicularlymphoma(ASSIST-FL):primaryresultsfromaconfirmatoryphase3,double-blind,randomised,controlledstudyWojciechJurczak,IlídiaMoreira,GovindBabuKanakasefy,EduardoMunhoz,MariaAsunciónEcheveste,PratyushGiri,andothersTheLancetHaematology,Vol.4,No.8,e350–e361Published:July13,2017Rituximabbiosimilars:introducGonintoclinicalpracGceShinichiMakita,KenseiTobinaiTheLancetHaematology,Vol.4,No.8,e342–e343Published:July13,2017Efficacy,pharmacokineGcs,andsafetyofthebiosimilarCT-P10comparedwithrituximabinpaGentswithpreviouslyuntreatedadvanced-stagefollicularlymphoma:arandomised,double-blind,parallel-group,non-inferiorityphase3trialWonSeogKim,ChrisdanBuske,MichinoriOgura,WojciechJurczak,Juan-ManuelSancho,EdvardZhavrid,andothersTheLancetHaematology,Vol.4,No.8,e362–e373Published:July13,2017

July17wasamilestoneinRituximabbiosimilardeveloppment


:summary

ORR with GP2013 and CT-P10 equivalent to reference rituximab

PK (Cmax) of GP2013 and CT-P10 equivalent to reference rituximab

1 2

Medians not yet reached for PFS and OS 3 PD (B-cell depletion) with GP2013 and CT-P10 equivalent to reference rituximab 4 No clinical meaningful differences between GP2013 or CT-P10 and reference rituximab in safety, tolerability or immunogenicity 5

CT-P10 3.2 RA

No clinical meaningful differences between GP2013 or CT-P10 and reference rituximab in safety, tolerability or immunogenicity 5 Registered by EMA 6

Jurczaketal,ESMO2017,LancetHematol2017CoiffierB,etalASH2017,LancetHematology2017


ExtrapolaGonisbasedontheenGresimilarityexercise

Structural attributes (pre-clinical)

Biological functions (pre-clinical)

Human PK/PD (phase I or II trial)

Less sensitive indications

Sensitive indication (phase III trial)

Reference Biosimilar

M A T C H

JUSTIFIED

M A T C H

M A T C H

M A T C H

PD,pharmacodynamics;PK,pharmacokinedcsKurkiP,etal.JCrohnsColids2014;8:258;WeiseM,etal.Blood2014;124:3191–6;WeiseM,etal.Blood2012;120:5111–17;Sandoz-generated/ownedfigure(November182014).


RrituximabregistraGon&clinicalpracGce

•  FL•  IlineDLBCL•  CLL•  RA•  GPA(Wegener’sgranulomatosis)

andMPA(microscopicpolyangiids)

MabTheraisamedicineusedtotreatthefollowingbloodcancersandinflammatorycondidons: •  FL,MZL,LPL

•  IlineDLBCL,R/RDLBCL•  CLL•  MCL•  RA•  GPA(Wegener’sgranulomatosis)



RrituximabbiosimilarsregistraGon,extrapolaGonandclinicalpracGce

•  FL•  RA

Rituximabbiosimilarsregistradonwasbasedonclinicaltrialsin:

•  FL,MZL,LPL•  IlineDLBCL,R/RDLBCL•  CLL•  MCL•  RA•  GPA(Wegener’sgranulomatosis)


•  FL•  IlineDLBCL•  CLL•  RA•  GPA(Wegener’sgranulomatosis)


extrapolaGon


Conclusions:

•  RituximabbiosimilarsaregoodqualityMoAbwithasafetyandefficacyprofileidendcaltotheiroriginator

•  TheirsimilaritytoRituximabwasdeterminedbyextensivepre-clinicalanalyses,andfinallyconfirmedbyclinicaltrials,withnearly2000parGcipaGngpaGents

•  SubcutaneousRituximabistheonlycompedtortoRituximabbiosimilarsintheIlineBcellNHLtherapy

•  Chlorambucil+Obinutuzumabistheonlyprotocol,withnovelandCD20MoAb,befertoRituximabbasedIlineimmuno-chemotherapyregimens


Prof.WojciechJurczak,M.D.,Ph.D.DptofHematology,[email protected],(+48602338290)

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Disclosures - Biosimilars Nederland