New HARNESSING THE IMMUNOGENICITY OF FOREIGN VIRAL CMV … · 2017. 8. 30. · NASDAQ: VBIV | TSX: VBV 1 VBI Vaccines, Inc. 222 Third Street, Suite 2241 Cambridge, MA 02142 (617)

NASDAQ:VBIV|TSX:VBV 1

VBIVaccines,Inc.222ThirdStreet,Suite2241

Cambridge,MA02142(617)830-3031

[email protected]

NASDAQ : VB I V T SX : VBV

IMMUNO -ONCOLOGY SUMMIT AUGUST 3 0 2 0 1 7

HARNESSINGTHE IMMUNOGENICITY OF FOREIGNVIRAL CMVANTIGENSTO

TARGETSOLIDTUMORS


Certainstatementsinthispresenta-oncontainforward-lookingstatementswithinthemeaningofthePrivateSecuri-esLi-ga-onReformActof1995orforward-lookinginforma-onunderapplicableCanadiansecuri-eslegisla-on(collec-vely,“forward-lookingstatements”)thatmaynotbebasedonhistoricalfact,butinsteadrelatetofutureevents,including,withoutlimita-on,statementscontainingthewords“believe”,“may”,“plan”,“will”,“es-mate”,“con-nue”,“an-cipate”,“intend”,“expect”,“goals”andsimilarexpressions.Allstatementsotherthanstatementsofhistoricalfactincludedinthispresenta-onareforward-lookingstatements.Suchforward-lookingstatementsarebasedonanumberofassump-ons,including,withoutlimita-on,assump-onsregardingthesuccessfuldevelopmentand/orcommercializa-onofthecompany’sproducts,suchasthereceiptofnecessaryregulatoryapprovals;generaleconomiccondi-ons;thatthecompany’sbusinessisabletooperateasan-cipatedwithoutinterrup-ons;compe--vecondi-ons;andchangesinapplicablelaws,rulesandregula-ons.Althoughmanagementbelievesthattheassump-onsmadeandexpecta-onsrepresentedbysuchstatementsarereasonable,therecanbenoassurancethataforward-lookingstatementcontainedhereinwillprovetobeaccurate.Actualresultsanddevelopmentsmaydiffermateriallyfromthoseexpressedorimpliedbytheforward-lookingstatementscontainedherein,and,evenifsuchactualresultsanddevelopmentsarerealizedorsubstan-allyrealized,therecanbenoassurancethattheywillhavetheexpectedconsequencesoreffects.Factorswhichcouldcauseactualresultstodiffermateriallyfromcurrentexpecta-onsinclude,withoutlimita-on:thefailuretosuccessfullydeveloporcommercializethecompany’sproducts;adversechangesingeneraleconomiccondi-onsorapplicablelaws,rulesandregula-ons;andotherfactorsdetailedfrom-meto-meinthecompany’sreportsfiledwiththeU.SSecuri-esandExchangeCommissionandtheCanadianSecuri-esCommissions.Giventheserisks,uncertain-esandfactors,youarecau-onednottoplaceunduerelianceonsuchforward-lookingstatementsandinforma-on,whicharequalifiedintheiren-retybythiscau-onarystatementandaremadeonlyasofthedateofthispresenta-on.Allforward-lookingstatementsandinforma-onmadehereinarebasedonthecompany’scurrentexpecta-ons,andthecompanyundertakesnoobliga-ontoreviseorupdatesuchforward-lookingstatementsandinforma-ontoreflectsubsequenteventsorcircumstances,exceptasrequiredbylaw.

CauHonaryStatementRegardingForward-LookingInformaHon


Agenda1

2

3

4

Intro&eVLPPlaWormOverview

SignificanceofCMVasaTumorTarget

VBI-1901IND-EnablingData

Summary


ConvergenceofVaccinology&Immuno-oncology–CancerVaccines3.0

XCancerTestesAnHgens

PepHde&AdjuvantTechnologies

AutologousDCVaccines

CheckpointBlockade

NeoAnHgens

?CAR-Ts

LiveViralVaccines

‘ReducHonist’PepHdeSubunitvaccines

RecProtein+/-Adjuvants

VLPs

? ?

mRNA&DNA

ThemesofConvergence:•  AnGgenselecGon

•  Immunogenicity•  SelfvsForeign

•  AnGgendelivery•  Recogni-onof

Threat

•  Safety•  Risk-benefit

•  Personalizedvs.universal

ViralVector

?

X

NASDAQ:VBIV|TSX:VBV 5NASDAQ:VBIV|TSX:VBV

eVLPPlaWorm:envelopedvirus-likeparHclesthatleverageinnateimmunesignalingtosHmulateanH-tumorimmunity

eVLPOverview

Customizable constructs that mimicenvelopedvirusesastheyoccurinnature:•  K e y s t r u c t u r a l c o m p o n e n t srepresented

•  AnGgensinnaturalconformaGon•  NoreplicaGonmachinery•  NaturallyprocessedbydendriGccells

ü NaGvely sGmulate adapGve and innateimmunity

ü Promote uptake by anGgen-presenGngcells

ü InternalanGgencapacityforCD8targetsü Surface anGgen capacity for CD4 and Bcell(anGbody)responses

ü Scalable and easy to manufacture @GMP

ü SafeinclinicLipidBilayer

MLVGagcreatesVirus-LikeStructure

CD8T-CellAnHgen

TargetSurfaceAnHgen

Poten-alforaddi-onalsurfaceimmunotherapytargets

eVLPFeatures

eVLPOp5mizedforSurfaceAn5gen

eVLPOp5mizedforInternalAn5gen


Target RaHonale

VBI-1901:TherapeuHcCMVforSolidTumors

SchemaHc

AnHbodyTargets gB

T-cellTargets gB(CD4+),pp65(CD8+)

TargetIndicaHonTreatmentofCMV+

glioblastoma,breastcancer,otherCMV+solidtumors

RaHonaleTargetsbothhumoral&cellularimmunitytopromotebroadimmunity&tumorclearance

VBI-1901:RaHonallydesignedtherapeuHcCMVvaccineforsolidtumors

CMV-gB

•  ViralfusionproteinforAPCuptake

•  Majoran-body&CD4T-cellepitopes

•  S-mulatesinnateimmunity

CMV-pp65•  PrimaryCD8T-celltarget•  FulllengthovercomesHLArestric-on

‘Foreign’TumorAssociatedViralAn-gens(TAVA)arenaturallyimmunogenic

Virus-likeStructureS-mulatesInnateImmunity&PromotesUptakebyAn-genPresen-ngCells(APCs)


SignificanceofCMVasaTumorTarget


Note:ImagederivedfromNatureReviewAr-cleon“NeoAn-gens”:Schumacher&Schrieber,Science,April2015

ForeignviralanHgens,likeCMV,enableimmunetargeHngin“cold”tumorswherecheckpointsinhibitorshavebeenlesssuccessful

FrequentNeoan5genForma5onTypically“HoFer”Tumors

OccasionalNeoan5genForma5onTypically“Colder”Tumors

Checkpointsuccessdependentonmuta-onfrequency,neoan-gens

Opportunitytotargetforeignviraltumoran5gensinCMV+tumortypes

•  ForeignviraltumoranGgensarehighlyimmunogenicandinherently‘hot’•  VBI-1901candrivepotentresponsesagainstCMV+tumorswhereneo-anGgensand‘self’

tumor-associatedanGgenshaveweakerimmunogenicity


GBM

BroadevidencesupportsCMVasacancerimmunotherapeuHctarget

BodyofEvidenceSuggestsaCMVVaccineThatCanS5mulateDCs&Res5mulateCMV-SpecificT-cellsHasPoten5alforClinicalEfficacy

•  PrinsRM(2008)–Autologous,GBMtumorlysateDCvaccineo  Singleimzn.increasedCMVpp65-specificCD8+Tcellsfrom0.2%to4.4%

•  CroughT(2012)–SinglepaGentreceiving4infusionsofautologousCMV-specificT-cellso  MRIrevealedimprovementwithstablediseasereportedfor17months

•  SchuesslerA(2014)–10paGentsreceiving3-4infusionsofautologousCMV-specificT-cellso  10recurrentGBMpts,3-4infusionsofautologousCMV-specificTcellso  AchievedmedianOSof403daysandonlyminoradverseevents

•  MitchellDA(2015)–CMV-specificDCvaccinewithtetanuspre-condiGoningo  OS(>36.6months)vs.controlcohortwithmedianOSof18.5monthso  SurvivalwascorrelatedwithincreasedlevelsofCCL3

•  BaGchK(2017)–CMV-specificDCvaccinewithGM-CSF&Temozolomideo  OSincreased(>41.1months)vshistoriccontrolo  SurvivalcorrelatedtoCMV-pp65-specificINF-gammaT-cells

OtherCMV+TumorsBroadSupportforHighCMVExpression,Poten5alfor

VBI-1901ClinicalEfficacy

•  Wolmer-SolbergN(2013)IntJCancer,133,2351-61Neuroblastoma

Medulloblastoma

Breast

Colorectal

•  BaryawnoN(2011)JClinInvest121,4043-4055;•  LibardS(2014)PLoSONE9,e108861

•  TaherC(2013)JClinVirol54,240;•  HarkinsLE(2010)Herpesviridae1,8

•  Wolmer-Solberg,InternaGonalCMVConference–April2017


Duke-ledstudydemonstratesthatCMVdendriHccellvaccinescanincreasepp65immunity(BaHchetal,2017)

•  >3Gmeslongerprogression-freesurvival•  >2Gmeslongeroverallsurvival•  pp65cellularresponseincreased

•  11paGentsreceivedatleast3dosesofpp65-dentriGccellsaierdose-intensifiedtemozolomide

TrialDesign ClinicalResults

RelevanceforVBI-1901:ü  BuildsonbodyofevidencedemonstraGngCMV-immunityimpactssurvivalü  pp65DCvaccineanalogoustoeVLP(whicharereadilytakenupbyDCsinvivo)ü  VBI-1901offerspotenGaltobuildonoutcomewith“Off-the-shelf”vaccine

Pre-vaccine Post3rdDose

pp65LoadedDendriHcCells+GM-CSF(ThreeDoses)


VBI-1901IND-EnablingData


VBI-1901:ElicitsBalancedCellular&HumoralImmunityTumorClearancebyCTLsisKnowntobeEnhancedbyCD4&AnHbodyResponses

Naïvemice(n=4or8/group)wereimmunizedsubcutaneouslyat0and4weeks,andsplenocytesharvested10dayslater.SplenocytesfromtheabovegroupsweresGmulatedwithrecombinantCMVgBorpp65anGgens;responsesagainstemptyeVLPsweresubtractedfromallresponses.TheendpointGter(EPT)isbasedonthehighestdiluGonofserareacGvewithrecombinantgBproteininELISAwithanO.D.of0.1orgreater.

pp65-specific Th1 cells

VBI-1901

GM-CSF

0

1

2

3

CD

3+ CD

4+ IFNγ+

(%)

gB-specific CTLs

VBI-1901

GM-CSF

0.0

0.2

0.4

0.6

0.8

1.0

CD

3+ CD

8+ per

forin

+ (%

) gB-specific antibody response

VBI-190

1

GM-CSF

100

101

102

103

104

105

An

tibo

dy

Tite

r (G

MT

)


•  ImmatureDCsgeneratedbycultureofMUTZ-3myeloidcelllinefor6daysinGM-CSF•  DCsexposedtoeVLPsorcontrolrecombinantprotein(humanserumalbumin)for48hours•  InducGonofproinflammatoryIL-8cytokineandCCL3chemokinedeterminedbyCBAassaywithcomparableresultsinrepeat

independentassays(n=3)

VBI-1901:PotenHal“Off-the-Shelf”DendriHcCellVaccine

VBI-1901Recruits(CCL3)andAcHvates(IL-8)DendriHcCells

CCL3

0 50 100 150 2000

20

40

60

80

Sec

retio

n (p

g/m

l)

Dose (µg)

CCL3: gB/pp65 eVLPsCCL3: Human serum albumin

IL-8

0 20 40 60 80 1000

500

1000

1500

2000

2500

Dose (µg)

Sec

retio

n (p

g/m

l)

gB/pp65 eVLPsHuman serum albumin


VBI-1901:SHmulatesInnateImmunity

IL-8-Monocytes

12.37

24.73 37

.149

.460

20000

40000

60000

80000

100000GaggB/pp65

TP (µg/mL)

IL-8

(pg/

mL)

IL-6-Monocytes

12.37

24.73 37

.149

.460

2000

4000

6000

8000

10000GaggB/pp65

TP (µg/mL)

IL-6

(pg/

mL)

IL-1b-Monocytes

12.37

24.73 37

.149

.460

1000

2000

3000

4000

5000

gB/pp65Gag

TP (µg/mL)

IL-1β

(pg/

mL)

TNF-Monocytes

12.37

24.73 37

.149

.460

50

100

150GaggB/pp65

TP (µg/mL)

TNF

(pg/

mL)

eVLPparHclessHmulateIL-8(independentofanHgen)InclusionofgB/pp65anHgenssHmulatesaddiHonalpro-inflammatorycytokines

Note:HumanmonocyteswerepurifiedbynegaGveselecGonto>90%purityandsGmulatedwithincreasingconcentraGonsofeVLPs.CytokinesweremeasuredbyCBA.


gBMonoclonalCanNeutralizeSHmulaHonofInnateCytokineProfile

71%ê

82%ê83%ê

46%ê

VBI-1901:SHmulatesInnateImmunityAnHgenspecificupregulaHonofpro-inflammatorycytokinesisdrivenbyCMV-gB


VBI-1901:Re-sHmulatesCMV-specificImmunityinHumanExVivoSamples

ResHmulaHonofCD4+&CD8+T-cellsinExVivoHumanSamples

CD4+IFN-γ+

VBI-190

1

Recom

binan

t gB+pp

650.0

0.2

0.4

0.6

0.8

1.0

Freq

uenc

y of

Res

pons

e (%

) CD8+IFN-γ+

VBI-190

1

Recom

binan

t gB+pp

650.0

0.5

1.0

1.5

2.0

2.5

CMV+ H

ealth

yGBM

Medull

oblas

toma

Breast

101

102

103

104

105

CC

L3 S

ecre

tion

(pg/

ml)

SHmulaHonofCCL3inCMV+Tumors–Correlatedto>O.S.byMitchelletal(2015)

•  VBI-1901sGmulateskeybiomarkersofeffecGveCMV-specificanG-tumorimmunity•  DeliveryofCMVpp65&gBineVLPenhancespotencyrelaGvetorecombinantprotein


VBI-1901:BoostsCMVpp65-specificIFN-γTcellResponsesinMacaques

VBI:CMV+Rhesusmacaque-matchedCMVpp65ELISPOTSbeforeandaier2vaccinaGonswithVBI-1901+GM-CSF.ELISPOTtestedforIFN-γusingoverlappingpp65pepGdepools.

BaHchetal(2017)ObservedCD8T-cellImmunityaqer3-doses&ImprovedOverallSurvivalVBI-1901ResHmulatesCD8ImmunityinCMV+Monkeys–BasisforClinicalEvaluaHon

VBI-1901+GM-CSF

Week 0 Week 60

50

100

150

200

250IF

N-γ

-sec

retin

g T

cells

(spo

ts/1

06 ce

lls)

Pre-vaccine Post2ndDose

VBI-1901+GM-CSF(TwoDoses)


ClarificaGon(DepthfiltraGon)

ConcentrateparGcles(TangenGalflowfiltraGon)

InacGvateresidualhostDNAandadvenGciousvirus

(Benzonase/βPLTx&diafiltraGon)

WashandConcentrate(DiafiltraGon&ultracentrifugaGon)

Sterilize(filter)

VBI-1901:OverviewofCMCProcessProcessopHmizedtopreserveparHcleintegrity&meetFDAstandards

AssayDescripHon TestResult

ResidualhostcellDNA(quanGtaGvePCR)

1.4ng/µgpp65

Residualhostcellprotein(ELISA)

4ng/µgpp65

ParGclecount(nsEM) 5.3x1010/ml


VBI-1901:INDEnablingTox&Safety

Prescan 5min 0.5hr 1hr 2hr

3hr 4hr 8hr 24hr 48hr

72hr 96hr 120hr 144hr 168hr

192hr 216hr 240hr 336hr

In Vivo Imaging ID injection of AF700-eVLP Dorsal

Peak fluorescence from whole body imaging appears to be at 1hr.

Site of injection

Brain

Prescan 5min 0.5hr 1hr 2hr


72hr 96hr 120hr 144hr 168hr

192hr 216hr 240hr 336hr



Site of injection

Brain Prescan 5min 0.5hr 1hr 2hr


72hr 96hr 120hr 144hr 168hr

192hr 216hr 240hr 336hr



Site of injection



72hr 96hr 120hr 144hr 168hr

192hr 216hr 240hr 336hr



Site of injection



72hr 96hr 120hr 144hr 168hr

192hr 216hr 240hr 336hr



Site of injection

Brain

Control m2-336hr

m3-336hr m4-336hr

Brain

Heart

Lungs

Liver

Kidneys

Spleen Pancreas

Brain

Heart

Lungs

Liver

Kidneys

Spleen Pancreas

Site of injection

Brain

Heart

Lungs

Liver

Kidneys

Spleen Pancreas

Site of injection

Brain

Heart

Lungs

Liver

Kidneys

Spleen Pancreas

Site of injection

Ex Vivo Imaging at 336hr ID injection of AF700-eVLP Organs

Only site of injection had a measurable signal at 336hr.

Control m2-336hr

m3-336hr m4-336hr

Brain

Heart

Lungs

Liver

Kidneys

Spleen Pancreas

Brain

Heart

Lungs

Liver

Kidneys

Spleen Pancreas

Site of injection

Brain

Heart

Lungs

Liver

Kidneys

Spleen Pancreas

Site of injection

Brain

Heart

Lungs

Liver

Kidneys

Spleen Pancreas

Site of injection

Ex Vivo Imaging at 336hr ID injection of AF700-eVLP Organs

Only site of injection had a measurable signal at 336hr.

•  StandardToxicologyü  NoadverseeventsseenwithVBI-1901ü  eVLPsalreadysafelyevaluatedinPhI

•  BiodistribuGonStudy

ü  VaccineobservedatinjecGonsiteforupto14days(depoteffect)

ü  NoaccumulaGoninmajororgans

•  Off-targetToxicology

ü  AvailableliteraturesaGsfiedFDAthatoff-targetCMVtoxicitywasunlikely(givenpredominanceofCMVintumorvshealthyGssueandhistoryofclinicalsafety)


VBI’sprophylacHcCMVvaccine(similardesignto1901)achieveddose-dependentimmuneresponsesagainstCMV(interimPh1data)

A[[email protected],100%ofsubjectsseroconvert-Excep5onallyimmunogenicvaccineplaborm

•  Seroconversion*in100%ofsubjects

•  eVLPshighlyimmunogenicplaxorm:2.0ugdoseis10-50Xlowerthanrecentlyapproved&late-stageVLPproducts

•  Adjuvant(alum)enhancesimmunogenicity

*Seroconversiondefinedas4x-foldabovebaseline-ter(industryconven-on)


Opportunity&ClinicalDevelopmentPlan


IniHalClinicalDevelopmentofVBI-1901WillFocusonGBM–AProfoundUnmetMedicalNeed

ü  GBMisthemostaggressiveformofbraincancer

ü  NostandardofcareopGonsaieriniGalsurgery/radiaGon/chemotherapy

ü  Invasiveprimarytumormarginsandsecondarytumorsareinterspersedamong

healthyglialGssueandcannotbesafelyoperatedon

ü  EsGmatedincidencevariesbycountry

ü  US:3.2/100,0001

ü  France:4.96/100,0002

ü  UK:3.43/100,0003

ü  42.4%survive6months

ü  ~90%ofpaGentswillexperiencerecurrentGBM4

1.  Ostrumetal,CBTRUSStaGsGcalReport:PrimaryBrainandOtherCentralNervousSystemTumorsDiagnosedintheUnitedStatesin2009–2013–Availableat:h{ps://doi.org/10.1093/neuonc/now207

2.  Baldi(2010):h{p://www.ncbi.nlm.nih.gov/pubmed/208697333.  www.ncin.org.uk/view?rid=26624.  GBIResearch:GlioblastomaMulGformeTherapeuGcsinMajorDevelopedMarketsto2020


Company/Inst. Approach KeyFinding Take-Away

NovarGs–CTL019 EGFRvIIIspecificCAR-T

EGFRvIIICAR-TcantraffictobrainandexertanG-tumoreffect,tumorselectedtoescape

TargeGngmulGpleepitopes&proteinsmayberequired

BMS–Checkmate143Merck–Keynote028

PD1,PDL1

Opdivo-alonenotsufficient.Keytrudatrialongoing

Fewneo-anGgenstypicalofGBMmaylimitefficacy

Duke– BaGch(etal)pp65loadedautologousDCs

Improvedoverallsurvivalto41monthswithhigh-doseTMZ

MulG-epitopeapproachcanleadtoimprovedsurvival

VBIVaccines

Off-the-shelfgB&pp65eVLPthattargetsDCs

ClinicalStudyThesis:MulGplefulllengthproteinscoveringthemajorCD8,CD4andADCCepitopes,presentedbyviruslikeparGclewillsGmulatebroadimmunitywithanoff-the-shelfapproach

VBI-1901ComparisontoRecentClinicalIOAdvancesinGBM

BreadthofReacHvitymaybeanImportantParameterforEfficacy


VBI-1901:PotenHal‘Off-the-Shelf’VaccineforCMV+SolidTumors

Off-The-ShelfDesign

BroadPotenHalinCMV+Tumors

StrongPreclinicalDataPackage

ClinicalRaHonale

Milestones

•  LeveragesinherentimmunogenicityofCMVtotargetCMV-posiGvetumors

•  Easilymanufacturedandscalable

•  CMVisexpressedinover90%ofGlioblastoma(GBM),Breast,Colorectal&othersolidtumors

•  Highunmetneedin~18,000recurrentGBMpaGents

•  ResGmulaGonofCD4andCD8T-cellresponsesinCMV+humansubjectsexvivo&inCMV+RhesusMacaques

•  Demonstratedsafetyandtolerability,readyfortheclinic

•  ExisGngCMV-targeGngdendriGccellvaccineshaveachieveda>2Xincreaseinoverallsurvivalinglioblastoma

•  VBI’sprophylacGcCMVvaccine(alsousingeVLPs)waswell-toleratedandimmunogenicaierjusttwoofthreescheduleddoses(interimPh1data)

•  VBIVaccineshasanacceptedINDforVBI-1901•  ClinicalstudiesinrecurrentGBMareexpectedtobeginH22017


VBIVaccines,Inc.222ThirdStreet,Suite2241

Cambridge,MA02142(617)830-3031

[email protected]

Documents

New HARNESSING THE IMMUNOGENICITY OF FOREIGN VIRAL CMV … · 2017. 8. 30. · NASDAQ: VBIV | TSX: VBV 1 VBI Vaccines, Inc. 222 Third Street, Suite 2241 Cambridge, MA 02142 (617)