TheScien)ficScenario:

Innova)veMedicinesinIBD&LatestNews

AlessandroArmuzzi

IBDUnit-ComplessoIntegratoColumbus

GemelliHospitalCatholicUniversityFounda@on-Rome

Medicinalproductsthathavebeenproducedbytheuseoflivingorganisms:

● Proteins

-Hormones(growthhormones,insulins,erythropoie@ns)-Enzymes-Monoclonalan(bodies

● Bloodproducts●  Immunologicalmedicinalproducts

-Sera-Vaccines-Allergens

● Advancedtechnologyproducts-Genetherapies-Celltherapies

Whatarebiologictherapies?

Biologicsarefarmorecomplexthanconven)onalmedicines

•  Biologicsdifferinsize,manufacturingcomplexity,andinthewaytheyinteractwithcellsandotherproteinsinthebody

•  Differentsystemsofapprovalarenecessaryforsmallmoleculegenericsandsubsequententrybiologics

Aspirin HumanGrowthHormone MonoclonalAn5body

Biologics

180DaltonsandZeroAminoAcids

22,125Daltonsand191AminoAcids

Non-GlycosylatedProtein

148,000Daltonsand1,330AminoAcids

availableathHp://www.healio.com/orthopedics/arthri5s/news/online/%7B7bfa55f8-fffe-4d03-bbe7-049421dbbdf9%7D/two-drugs-combined-beHer-for-ra-than-methotrexate-alone.AccessedOctober2015

Conven5onalMedicine(“small-molecule”)

4

ManufacturingofBiologicsInvolvesMul)pleStepsandIsInhererentlyComplex

FigureadaptedfromMellstedtetal.AnnOncol.2008;19:411.

ManyBiologicsHaveUndergoneMul)pleManufacturingChangesDuringTheirLifeCycle

Number of Manufacturing Changes for Biologics from Time of First Approval in Europe

DatafromtheEuropeanMedicinesAgency.www.ema.eu.Seenotesfordetailedreferences.AllfilesaccessedOctober12,2014.

0 10 20 30 40 50 60 70 80

Benlysta™(belimumab)

Ilaris™(canakinumab)

Cimzia™(certolizumabpegol)

RoActemra™[Actemra™](tocilizumab)

Orencia™(abatacept)

Humira™(adalimumab)

Enbrel™(etancercept)

Remicade™(infliximab)

MabThera™[Rituxan™](rituximab)

number of manufacturing changes

2/6/1998

13/8/1999

3/2/2000

8/9/2003

21/5/200716/1/20091/10/200923/10/200913/7/2011

EMA Guidelines

TheEMAUsesaComparabilityExercisetoEvaluateManufacturingChangestoApprovedBiologics1,2

1.  EMA Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1). 2014. 2.  http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp#Otherguidelinesrelevantforbiosimilars.

“The demonstration of comparability means that the quality attributes of the pre-change and post-change product are

highly similar and existing knowledge is sufficiently predictive to ensure that any differences in quality attributes have no

adverse impact upon safety or efficacy of the drug product”1

Comparability ≠ Identical

Source:IMSMIDAS,09/2012,IMSPatentfocus,AdaptedfromG.Morelli,IMSHealth*RaderRA,Biosimilarsmarkets.BioProcessInterna)onal2013;11(6)suppl:16-23

An)-TNFsontheTopofBiologicalSales

INN EUpatentexpdate

USpatentexpdate

Biosimilarsindevelopment*

Adalimumab 2018 2016 13

Etanercept 2015 2028 21

Infliximab 2014 2018 9

InsulinGlargine 2014 2014 5

Rituximab 2013 2016 30

Bevacizumab 2019 2017 14

InterferonB-1a Expired Expired N/A

Trastuzumab 2015 2015 N/A

InsulinAspart 2014 2019 N/A

Gla5rameracet 2017 2015 N/A

Pegfilgras5m 2015 2014 14

Ranibizumab 2016 2016 24

4.3

4.3

4.9

5

5

5.3

5.9

6.2

7.1

7.3

8.1

0 2 4 6 8 10

TotalUSD67billion

Globalsales,USDbillion

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

AccesstobiologicDMARDsinRAintheEUandGDPpercapita

Threemajordimensionsofaccesstomedicalcare

● WHOdefini5on:A“similarbiotherapeu5cproduct”isabiotherapeu5cproductthatissimilarintermsofquality,safety,andefficacytoanalreadylicensedbiotherapeu5cproduct1

●  EMAguidance:abiosimilarsponsoristo“generateevidencesubstan5a5ngthesimilarnature,intermsofquality,safetyandefficacy,ofthenewsimilarbiologicalmedicinalproductandthechosenreferencemedicinalproductauthorisedintheCommunity”2

●  USFDA(BPCIA)defini5on:afollow-onbiologicmeans:–  Thebiologicproductishighlysimilartothereferenceproduct,notwithstandingminor

differencesinclinicallyinac5vecomponents;and–  Noclinicallymeaningfuldifferencesexistbetweenthebiologicproductandthereference

productintermsofthesafety,purity,andpotency3

Whatarebiosimilars?

1.   hHp://www.who.int/biologicals/areas/biological_therapeu5cs/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdfAccessedOctober20152.   EMA:CHMPGuidelineonSimilarBiologicalMedicinalProducts(October2005)3.   FDADrakGuidances–QualityandScien5ficConsidera5onsinDemonstra5ngBiosimilaritytoaReferenceProteinProduct(Feb2012)–USGuidance)

BPCIA:BiologicsPriceCompe55onandInnova5onAct

Biosimilardevelopmentparadigmisdifferentfromtheorignatorpathway

Originaldevelopment

Proofofefficacy&safetyby

clinicalstudies

Benefit>risk

Biosimilardevelopment

Comparabilityexercise

Noclinicalevidence

Originaldevelopment

Proofofefficacyandsafety

Biosimilardevelopment

Proofofcomparability

Clinicalprogram=proof

PhaseI

Pre-clinical

Physical,Chemical&Manufacturingcontrols

Clinicalprogram=confirma5on

PhaseI

Pre-clinical

Physical,Chemical&Manufacturingcontrols

Time&effortspentTime&effortspentForreference:EMA,FDA,WHO,Biosimilarguidelines,EPARofCT-P13

Evalua)onofaBiosimilarAstepwise«comparabilityexercise»

1.  Physicochemicalcharacteris)cs

2.  Biologicalac)vity(comparisontotheRMP)

3.  Pharmacodynamicsandpharmacokine)csstudies

4.  Pre-clinicaltoxicologystudies

5.  Clinicaltrials

-Pharmacodynamicsandpharmacokine)cs

-Safetyandefficacystudies

GuidelineonSimilarBiologicalMedicinalProducts.CHMP/437/04Rev1.Guidelineonsimilarbiologicalmedicinalproductscontainingmonoclonalan)bodies–non-clinicalandclinicalissues.EMA/CHMP/BMWP/403543/2010.

ControlsofPhysicochemicalandBiologicalCharacteris)csofCT-P13

AdaptedfromEMA/CHMP/589317/2013AssessmentreportRemsimapp16-23

Biologicalcharacteris5cs Physicochemicalcharacteris5cs

CT-P13Clinicalstudies:PKequivalenceandclinicalefficacy

-50

0

50

100

150

200

0 4 8 12 16 20 24 28 32 36 40 44 48

Hour

Con

cent

ratio

n µ

g/m

L

600 400 1000 200 800

ParkW,etal.AnnRheumDis2013;72:1605–12YooDH,etal.AnnRheumDis2013;72:1613–20

60.973.4

58.669.7

0

20

40

60

80

100

ITTpopula)on PPpopula)onCT-P13 INX

Respon

sera

te(%

)

Treatmentdifference2%(95%CI:-6%,10%)

Treatmentdifference4%(95%CI:-4%,12%)

184/302 178/304 182/248 175/251

Clinical Pharmacokinetics

AS study: PK similar to RMP

Clinical efficacy

Primary Endpoint: ACR20 at Week 30 RA study: clinical efficacy similarto RMP

CT-P13 Phase 3 Study in RA Patients – Adverse Events (Source: 54 Week Data 8/12)

Drug-Related TEAEs occurring in >1% of overall safety population

AdverseEvent CT-P13(N=302) INX(N=300)

Nasopharyngi)s 24(7.9%) 17(5.7%) Latenttuberculosis 21(7.0%) 19(6.3%) UpperRespiratoryTractInfec)on 10(3.3%) 5(1.7%) InfusionRelatedReac)on 10(3.3%) 11(3.7%) ALTincreased 10(3.3%) 11(3.7%) UrinaryTractInfec)on 8(2.6%) 9(3.0%) Rheumatoidarthri)s 6(2.0%) 5(1.7%) Bronchi)s 6(2.0%) 7(2.3%) ASTincreased 5(1.7%) 7(2.3%) Hypertension 5(1.7%) 3(1.0%) Headache 5(1.7%) 7(2.3%) Pyrexia 1(0.3%) 6(2.0%) Drughypersensi)vity 6(2.0%) 11(3.7%) Hepa)cenzymeincreased 5(1.7%) 2(0.7%)

YooDH,etal.AnnRheumDis2013;72:1613–20

Whytoextrapolateinmedicine?

EuropeanMedicinesAgencyonextrapola5on

“Theprimaryra(onaleforextrapola(onistoavoidunnecessarystudiesinthetargetpopula@onforethicalreasons,forefficiency,andtoallocateresourcesto

areaswherestudiesarethemostneeded.“1

EMAConceptpaperonextrapola)onofefficacyandsafetyinmedicinedevelopment(Final).EMA/129698/2012,2013

KeyTopicsrelatedToInfliximabBiosimilarUptake

BiosimilarUptake

Extrapola5onAcross

Indica5ons

INNNaming&PrescribingGuidelines

Inter-changeability&Subs5tu5on

(automa5c,primary,secondary)

Pricing&Reimbursement

TenderPurchasing

IBDPhysicianPercep5on

EMA approved infliximab biosimilar for all

indications of originator (June 27, 2013)

EMA decided that infliximab biosimilar should share same INN* as originator

Countries determine whether to allow, based on presumed risk to patients, switching between

biosimilar & originator

Different Countries set different guidelines for

pricing & reimbursement

* INN: International Nonproprietary Name

?

LearnedSociety,Country

Date Limita5ons/addi5onalcomments

Efficacy Safety Extrapola5on Switchingandsubs5tu5on

BIRD,Belgium1

Jan,2015

Paediatrictrialsneeded TrialsneededinIBDpa)ents

TrialsneededinIBDpa)ents

Shouldnotextrapolate

Physician’sdecision

BSG,UK2 Aug,2015

Prescribebybrandnameonly

Efficacymaydiffer Registryforsafetydata

Nocomment Noswitching,datainIBDneeded

ANSM,France3

Sept,2013

NotspecificforIBD Trialsforspecificindica)ons

Pharmacovigilanceandtraceabilityneeded

Fulljus)fica)onneeded

Noswitchingbutsubs)tu)ononini)a)onallowed

DCCV,Germany4

Feb,2015

Prescribebybrandnameonly

Long-termcomparabilitydataneeded

AdverseeventsrecordedinIBDregistry

Nocomment Noswitching,long-termdatainIBDneeded

IG-IBD,Italy5 Aug,2014

Expectedcostreduc)on TrialsneededinIBDpa)ents

TrialsneededinIBDpa)ents

Shouldnotextrapolate

Noswitching,datainIBDneeded

SEPD,Spanish6

March,2013

Productlabelledasbiosimilar

Trialsneededinallphases

TrialsneededinIBDpa)ents

Shouldnotextrapolate

Subs)tu)onnotacceptedprac)ce

ESPGHAN,Europe7

Oct,2015

Concernsregardingpaediatricpopula)on

Post-marke)ngsurveillancemandatory&IBDtrials

Post-marke)ngsurveillancemandatory&IBDtrials

Withcau)onandscien)ficevidence

Noswitching,datainIBDneeded

FBG&GEDIIB,Brazil8

April,2015

Dis)nctnomenclatureneeded

Manufacturerstoprovideproofagainstreference

Pharmacovigilance(PV)shouldbemandatory

Withscien)ficproofofefficacyandsafety

Noautoma)csubs)tu)on

IBDnetSwitzerland1

Feb,2014

Paediatrictrialsneeded TrialsneededinIBDpa)ents

TrialsneededinIBDpa)ents

Shouldnotextrapolate

Physician’sdecision

Medicalsocietyposi)onstatementsforbiosimilarsinIBD

17 1. Vermeire et al. Acta Gastro-Enterol Belgica. 2015;78:26–29. 2. British Society of Gastroenterology biosimilar statement; 3. ANSM Les medicaments biosimilaires. Etat des lieux. 2013; 4. Positionspapier Biosimilars der DCCV e.V. 2015; 5. Annese & Vecchi. 2014. Digestive and Liver Disease;46:963–968. 6. Argüelles-Arias et al. Rev Esp Enferm Dig. 2013;105(1):37–43. 7. de Riddler et al. JPGN. 2015;61:503–508. 8. Azevedo et al. Autoimmunity Reviews. 2015;14:769–773

Nopolicyforsubs)tu)onofbiologicalsinplaceinEurope

Source:EGAInternalBiosimilarMapping,dataprovidedandupdatedbyEGANa)onalAssocia)onMembers,2014.*France:LOInr2013-1203du23décembre2013definancementdelasécuritésocialepour2013,Ar)cle47.

Nopolicyforsubs5tu5onofbiologicsinplaceinanycountry(EU-EEA)

FR:'Subs)tu)on'policyunderrestrictedcondi)onslegallyadopted,butNOTimplemented*

Subs5tu5onallowedforsamebiologicalproduct(differentbrandnames)

AuthorReference

CountryYear

CD UC SwitchCD/UC

Fail% LOR F-up(wks)

Stop% SAEs%

ADA%

KangHW28 Korea2014

8 9 3/5 12.5 11 8 6 6 ng

JungYS29 Korea2015

57 69 25/27 10.8 14 54 5.5 8 ng

GecseKB

Hungary2016

126 84 na 20.5 -- 14 7.5 171death

ng

ParkSH Korea2015 95 78 44/16 25.5 11 30 3 22 ng

SieczkowskaJ Poland2016 32 7 32/7 -- 18 12 2.5 2.5 ng

FarkasK Hungary2015 18 21 na 30 ng 8 ng ng ng

JahansenJ Norway2015 46 32 na 21 ng 14 6.5 7.5 ng

FarkasK CzechRep+Hungary2016

-- 63 na 17.5 ng 14 ng ng 11.8

HeilR CzechR2016 30 22 na 4.5 ng 14 ng 7.7 ng

GecseKGolovicsPALovaszB

Hungary2016

184 107 na 49 ng 30 ng 21.3 28

Be{eyM UK2016 134 134 1.5 0 16 1.5 41 ng

SmitsL Netherlands2016

57 24 57/24 6 0 16 6 7 8.6

KolarM CzechR2016 56 18 56/18 4 19 24 4 20.2 11.6

MurphyC

Ireland2015

14vs22IFX

-- 28.5 -- 24 28.5 ↑⬆Surg&Hosp

ng

9fullpapers7abstracts

2014-2016 1142 448 ±19%

±10%

8-54 ±7%

±15% ±11%

ThePROSIT-BIOcohort:APRospec)veObserva)onalStudyofpa)entswithInflammatoryboweldiseaseTreatedwithinfliximabBIOsimilar

•  333pa)entsreceivedRemsima®,214pa)entsreceivedInflectra®

•  Cumula)venumberof2061infusions

•  Meanfollow-upof4.3±2.8(median4months,IQR:2.0-6.6months).

547pa5entsenrolledin31referralCenters311pa5entswerenaïvetoan5-TNFα;139pa5entshadapreviousexposuretooneomorebiologics(31infliximab,105adalimumab,3golimumab)97pa5entsswitchedfromIFXoriginatortoCT-P13

57%50%

74%

55%43%

50%

26%

45%

0%10%20%30%40%50%60%70%80%

Overallcohort Naive Previouslyexposed

Switch

CD UC

Fiorino G, et al. Inflamm Bowel Dis 2016; in press

Efficacyofbiosimilars:treatmentpersistency Naïve Previouslyexposed Switched Overall 8weeks* 98.4% (95.0–99.5) 97.2% (89.3–99.3) 100.0% 98.9% (97.0–99.6) 16weeks* 91.3% (84.5–95.1) 91.5% (80.3–96.4) 98.7% (91.0–99.8) 93.5% (89.6–95.9) 24weeks* 82.2% (71.9–89.0) 70.9% (52.1–83.5) 92.1% (81.9–96.7) 83.4% (77.0–88.1)

* Assessed after week 8 in 399 patients who responded Fiorino G, et al. Inflamm Bowel Dis 2016; in press

Safety(Adverseeventsleadingtodiscon)nua)on)

4.8%2.3% 2.6%

18.0%

4.3%

13.7%

5.2%3.1% 2.1%

0,0%5,0%10,0%15,0%20,0%25,0%

AllAEs AEs(excl.Infusionreactions)

Infusionreactions

Naive Previouslyexposed Switched

AdverseEvents(excludinginfusionreac5ons)

Pvalue Infusionreac5ons Pvalue

Naivevs.previouslyexposed IRR,0.48(0.14–1.71) NS IRR:0.17(0.06–0.41) <0.001

Naivevs.switched IRR:1.10(0.25–6.58) NS IRR:1.88(0.37–18.2) NS

Previouslyexposedvs.switched IRR:2.31(0.49–14.3) NS IRR:11.0(2.65–97.3) <0.001

* *

Fiorino G, et al. Inflamm Bowel Dis 2016; in press

Posi)on’schange

Posi)on’schange

43.1

67.1

89.5

6.6 16.9

27.1

92.4

3.4 0

20

40

60

80

100

They can work differently from the originator

They can have a different

immunogenicity pattern than the

originator

They will be less expensive

than the originator

There will be more indications than for

the originator

Perc

ent (

%)

2013 (N=307) 2015 (N=118)

Comparison of responses in the 2013 and 2015 ECCO surveys to the multiple choice question “What could be issues or advantages of a mAb biosimilar?”. More than one was answer possible. 1. Danese S, et al. J Crohns Colitis 2014;8:1548-50. 2. Danese S, et al. J Crohns Colitis. April 2016. Manuscript Doi:10.1093/ecco-jcc/jjw090.

Advantages and issues with biosimilars

2015ECCOPhysicianSurvey1,2

66

84.8

5.9

22

72.3

35

89.8

44.4

27.4 39.9

0

20

40

60

80

100

Biosimilars should have different INN

Disagreement with automatic

substitution

They would switch a patient

on sustained remission

They would switch, but they would inform the

patient

They would not switch because of insufficient

data to support it

Perc

ent (

%)

2013 (N=307) 2015 (N=118)

1. Danese S, et al. J Crohns Colitis 2014;8:1548-50. 2. Danese S, et al. J Crohns Colitis. April 2016. Manuscript Doi:10.1093/ecco-jcc/jjw090.

Interchangeability and automatic substitution

2015ECCOPhysicianSurvey1,2

5 7.6

26.4 28.7

32.3 28.8

17.8

33.9

10.2 9.3

0

20

40

Totally confident

Very confident

Enough confident

A little confident

Not confident at all

Perc

ent (

%)

2013 (N=307) 2015 (N=118)

1. Danese S, et al. J Crohns Colitis 2014;8:1548-50. 2. Danese S, et al. J Crohns Colitis. April 2016. Manuscript Doi:10.1093/ecco-jcc/jjw090.

Confidence in biosimilars

2015ECCOPhysicianSurvey1,2

TheNOR-SWITCHStudyArandomized,double-blind,controlled,parallel-group,mul5center,phaseIV,non-inferioritycompara5vestudy

Popula5on:500pa)entsrandomised,100ineachindica)on(20%withdrawals)inpa)entswithrheumatoidarthri)s,spondyloarthri)s,psoria)carthri)s,ulcera)vecoli)s,Crohn’sdisease,andpsoriasis

Primaryendpoint:Percentageofpa)entsexperiencingdiseaseworsening

Controltreatment:•  Innovatorinfliximab:INX(Remicade)Inves5ga5onalMedicalProduct:•  Biosimilarinfliximab(Remsima®/Inflectra®):CT-P13

ScreeningStablepa5entsonINX(Remicade)

foratleast6months

Randomisa5on1:1

N=500

INX(Remicade)

DiseaseworseningW52 Follow-upW78

CT-P13 DiseaseworseningW52 Follow-upW78

PrimaryendpointWeek52

Switch

Assump5on:30%worseningin52weeksNon-inferioritymargin:15%

OpenLabelFollow-up

JørgensenK,etal.UEGW2016.Abstract#LB15.

PrimaryEndpoint:DiseaseWorseningAcrossIndica)ons

INX(N=202) CT-P13(N=206) Adjustedratedifference(95%CI)

Diseaseworsening(allindica5ons)* 53(26.2%) 61(29.6%) -4.4(-12.7–3.9)

TheauthorsconcludedthatswitchfromINX(Remicade)toCT-P13wasnotinferiortocon5nuedtreatmentwithINX(Remicade)

An)-drugAn)bodies(ADAb)INX

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

IncidenceofADAb 17(7.1%) 19(7.9%)

Troughdruglevelsandfrequenciesofadverseeventsincludinginfusionreac5onsweresimilarbetweenINX(Remicade)andCT-P13

JørgensenK,etal.UEGW2016.Abstract#LB15.

DiseaseWorseningbyIndica)on1,2

1.JørgensenK,etal.UEGW2016.Abstract#LB15.2.GollGL,etal.ACR2016.Abstract#19L.

INX(N=202)

CT-P13(N=206)

Adjustedratedifference*(95%CI)

All 53(26.2%) 61(29.6%) -12.7–3.9%

Crohn’sdisease 14(21.2%) 23(36.5%) -29.3–0.7%

Ulcera5vecoli5s 3(9.1%) 5(11.9%) -15.2–10.0%

Spondyloarthri5s 17(39.5%) 14(33.3%) -14.5–27.2%

Rheumatoidarthri5s 11(36.7%) 9(30.0%) -20.3–29.3%

Psoria5carthri5s 7(53.8%) 8(61.5%) -45.4–28.1%

Psoriasis 1(5.9%) 2(12.5%) -26.9–13.2%

Thetrialwasnotpoweredtoanalyzenon-inferiorityindiseaseworseningbyindividualindica5on,thiswasclassedasanexploratoryanalysis

*The percentage rate difference for each indication was not reported in the abstract

Howtodealwithswitch,reverseswitch,crossswitchinthenearfuture?

Danese,S.etal.(2016)BiosimilarsinIBD:fromtheorytoprac)ceNat.Rev.Gastroenterol.Hepatol.doi:10.1038/nrgastro.2016.155

Conclusions

1.  Biosimilarsapprovaltothemarketfollowsacomprehensivecomparabilityexercise,whichisconsideredmoresensi)vetodetectBS-to-RMPdifferencesthanequivalenceclinicaltrials

2.  Biosimilarsareavaluablecontribu)ontoimproveefficiencyinprovidinghealthcaretothepopula)on:theyareanintegralpartofphysicians’prescrip)ons

3.  IBDspecialistsaregenerallywellinformedandeducatedaboutbiosimilars.Comparedwithin2013,therearenowfewerconcernsandmoreconfidenceabouttheiruseinclinicalprac)ce

4.  Increasedknowledgefrompostgraduateeduca)onandpublishedevidencefromclinicalprac)ceareprobablythemainreasonsforthischangeofmind

5.  Generaldisagreementwithautoma)csubs)tu)on:clearinterchangeabilityrulesareessen)altothisprocess,tosecurethetraceabilityofeachprescrip)onandofeachproduct

6.  Worldwidepharmacovigilanceisneededtodetectearlyanysafetyorlossofefficacysignal

7.  Pa)ents’knowledgeandinforma)onisessen)al