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AlnylamPharmaceuticalsIncRNAiRoundtable:ALN-HBVforthetreatmentofhepatitisBvirus
(HBV)infection
11-Oct-16 ConferenceTranscript
AlnylamPharmaceuticalsIncRNAiRoundtable:ALN-HBVforthetreatmentofhepatitisBvirus
(HBV)infection
CambridgeOct11,2016(ThomsonStreetEvents)--EditedTranscriptofAlnylamPharmaceuticalsIncconferencecallor
presentationTuesday,October11,2016at1:00:00pmGMT
CORPORATEPARTICIPANTS
JoshBrodsky,AlnylamPharmaceuticals,Inc.-AssociateDirector,IR&CorporateCommunications
PushkalGarg,AlnylamPharmaceuticals,Inc.-SVP,ClinicalDevelopment
LauraSepp-Lorenzino,AlnylamPharmaceuticals,Inc.-VP,Entrepreneur-in-Residence
HeinerWedemeyer,HannoverMedicalSchool-ManagingSeniorPhysician&AssistantProfessor,Departmentof
Gastroenterology,Hepatology,andEndocrinology
PRESENTATION
Operator
Thankyou,ladiesandgentlemen,forjoiningtoday'sRNAiroundtable.(OperatorInstructions)Iwouldnowliketoturnthecallover
toJoshBrodskyforopeningremarks.Josh,youmayproceed.
JoshBrodsky,AlnylamPharmaceuticals,Inc.-AssociateDirector,IR&CorporateCommunications
Goodmorning,everyone.Thanksforjoiningusfortoday'sRNAiRoundtabletodiscussourprogresswithALN-HBV,in
developmentforthetreatmentofchronichepatitisBvirusinfection.I'mJoshBrodsky,AssociateDirectorofInvestorRelationsand
CorporateCommunicationsatAlnylam.
WithmetodayarePushkalGarg,SeniorVicePresidentofClinicalDevelopmentatAlnylam;HeinerWedemeyer,ManagingSenior
PhysicianandAssistantProfessoratHannoverMedicalSchool;andLauraSepp-Lorenzino,VicePresident,Entrepreneur-inResidenceatAlnylam.
BeforeIturnthecallovertoPushkal,Ijustwanttomakeafewcomments.Today'sRNAiRoundtablefocusedonALN-HBVisthe
lastoneinaseriesofroundtablesthatwehavebeenhostingthissummerandearlyfall.Today'seventwillendataround10:00AM
EasternTime.PushkalwillmoderateaQ&Asessionattheconclusionofthepresentationsandifyouwouldliketosubmita
question,youcandosoatanytimeduringtheeventbyclickingtheAskaQuestionbuttonlocatedabovetheslidewindowonthe
webcastplayer.
Finally,asareminder,wewillbemakingforward-lookingstatementsandweencourageyoutoreadourmostrecentSECfilingsfor
amorecompletediscussionofriskfactors.AndsowiththatIwillnowturnitovertoPushkal.
PushkalGarg,AlnylamPharmaceuticals,Inc.-SVP,ClinicalDevelopment
Thanks,Josh,andthanks,everyone,forjoiningustodaytohearaboutourALN-HBVprogram.
Asallofyouknow,AlnylamistheindustryleaderinRNAitherapeutics,whichrepresentsawholenewclassofinnovative
medicines.RNAiisapowerfulapproachforgenesilencingthatharnessesanaturalandcatalyticmechanism,andthrough
Alnylam'sefforts,RNAiisaclinically-provenapproach.
Asyou'llseeonslide7,Alnylamhasdevelopedapipelineofproductsfocusedinthreestrategictherapeuticareas,orSTArs.
Thesearegeneticmedicines,cardio-metabolicdiseases,andhepaticinfectiousdiseases,representingarangeofdisease
opportunitiesfromraretocommontoglobal.
Onslide8youcanseeeachofthespecificprogramslistedbySTAr,showingtheeightproductsthatwehavecurrentlyinclinical
development.TodaywewillfocusonALN-HBVwithinourhepaticinfectiousdiseaseSTAr,ashighlightedonslide9.
Slide10showsyoutheagendafortoday'sRNAiRoundtable.WewillbeginwithLauraSepp-Lorenzino,whowillprovidean
overviewoftheALN-HBVprogram.Aftersheconcludes,Dr.WedemeyerfromHannoverMedicalSchoolwillprovideanoverview
ofchronichepatitisDvirusinfection.FollowingDr.Wedemeyer'spresentation,wewillbegintheQ&Asessionsopleaseremember
tosubmityourquestionsaswego.
©2015,AlphaSense,Inc.AllRightsReserved.AlphaSenseisaservicemarkofAlphaSense,Inc.Allothertrademarksmentionedbelongtotheirrespectiveowners.
AndwiththatIwillhanditovertoLaura.Laura?
LauraSepp-Lorenzino,AlnylamPharmaceuticals,Inc.-VP,Entrepreneur-in-Residence
Thankyou,Pushkal.Goodmorning,everybody,andthankyouforjoiningourRNAiRoundtable.
Asshownonslide11,hepatitisBinfectionisthemostcommonseriousliverinfectionintheworld.Worldwidethereis2billion
people,thatisoneinthreepeople,whohavebeeninfectedwithHBVandthereareapproximately290millionpeoplethathave
chronicdiseases.Andalthoughprophylacticvaccineshavebeenavailableforovertwodecades,there'sstill10millionto13million
newinfectionsperyearwithmostpatientsbeingunawareoftheinfectionandmany,manypatientsbeinguntreated.
Chronicinfectionresultsinfibrosis,cirrhosis,andistheleadingcauseinthedevelopmentofhepatocellularcarcinoma,orHCC,
andresultsinabout1milliondeathsannually.
TherearetwoapprovedclassesofdrugsforchronicHBV,onearetheoralnucleotideinhibitorsoftheviralpolymerase,often
knownasnukes.Thesearegivenchronically.Thesecondclassisthepegelatedinterferon,whichisgivenasaninjectableweekly
for48weeks.
Thesetwoclassesofdrugsareefficaciousinreducingviremia,decreasinginflammation,decreasingfibrosis.Theyreducetherisk
ofdevelopmentofHCC,buttheydonoteliminateit.And,importantly,neitherclassresultsinsignificantcurerates.Andbycure,
wearetalkingabouttheabsenceofviralproductsinbloodandareflectionofcontrol,immunologicalcontroloftheviralinfection.
Itisclearthatpatientsneednewoptions,patientsthatarefacinglifelongtherapyinthisgroupofnukes.Interferonshavepoor
tolerability;newantiviraltherapiesareneeded.
Sobysilencingallviralproducts,aswewilldiscussinthefollowingslides,ALN-HBVisexpectedtoelicitacombinationofantiviral
mechanismsthatwillleadtoincreasedviralsuppressionwithinthehepatocytesandreactivationofaneffectiveimmuneresponse
thatwillleadtocontroloftheviralinfection,alsoknownasfunctionalcure.
Ifwegotoslidenumber12,forALN-HBVweapplythesameframeworkthatweuseforalltheotherprogramsintheAlnylam
pipeline.Itstartswithagenetically-validated,liver-expressedtargetgene;andliverbecausetheliveriswhereourdelivery
solutionsfunctionmostefficiently.InthecaseofALN-HBV,theHPVvirus,whichisthedirectdisease-causingagent,isthetarget.
ThesecondpartoftheframeworkistheincorporationofbiomarkersinPhase1toevaluatethedrugcandidatepharmacodynamic
performanceandtounderstandthedoselevelandthedoseregimenthatcanbeappliedinsubsequentPhase2and3trials.
Thelastaspectoftheframeworkistheincorporationofwell-definedendpointsforapproval.ForHBV,wewouldbelookingtoelicit
asustainedvirologicalresponseafterdiscontinuationofalltherapies.SonotonlyofALN-HBV,butanyothertherapiessuchas
nucleosideanalogues,andthesewouldbefollowingafinitecourseoftreatment.
Slidenumber13shows--beginstoshowmoredataonthecandidateandthisisdatathatwehadsharedbefore.Wehavechosen
ansiRNAtargetsitethatishighlyconservedacrossallviralgenotypes.Ithasa97%perfecthomology,which,ifweallowone
mismatch,thathomologyacrossgenotypesAtoJrisesvirtuallyto100%.
ThesiRNAtargetsiteislocatedintheXopenreviewframe.Thatisaregionthatispresentinallviraltranscripts,whichinthe
graphiconthetoparedepictedasbluelines.
BasedonbioinformaticsandlimitedexpressionanalysesofRNA,weexpectthatthistargetsitewillnotonlyleadtosilencingofthe
viralgenomeexpressedtranscripts,butalsotranscriptsthatareexpressedfromintegratedviralgenomeintothehostDNA.By
beingpresentinallthetranscripts,asinglesiRNAwillbecapableofsilencingalltheRNAs.ThesearethelongRNAsthatcodefor
thepre-genomicRNA,thetranscriptthatservesasthetemplateforviralreplication,aswellastheRNAsthatcodeforthecore
protein,theEantigen,thepolymerase;andthosethatarecodedbysmallertranscriptscodingforthesmall,medium,andlargeS
antigenandtheXprotein.
Bysilencingalltheseviralproductsatonce,wearedefactoelicitingacombinationofantiviralmechanisms,similarlyofwhatwould
beachievedifweweretocombineanucleosideanalogtoinhibitapolymerase,acoreinhibitor,asecretioninhibitor,andthefuture
Xproteintargetingtherapies.
Ifwegotoslidenumber14,onthetopthereisadepictionoftheconjugatestructure.SothesiRNAthatwasselectedtotargetthis
targetsiteintheXopenreviewframewasmodifiedapplyingourenhancedstabilizationchemistryanditwasconjugatedfromthe
three[prime]endofthesensestrandorthepassengerstrandtoa[tri]N-acetylgalactosaminesugar.Aswehaveshownwithother
candidates,thistriGalNAcmechanismofdeliveryisveryeffectivefortargetingsiRNAstohepatocytesafterasubcu
administration.
ButshownonthebottomleftisastudydoneinasurrogatemousemodelofHBVinfectionusingtheadenoviralvectorexpressed
HBVgenomeandmeasuringthelevelsofSantigenreductionintheserumofthemiceafterasinglesubcuinjection.Asyoucan
see,thereisadose-dependent,profound,anddurablesilencingofSantigen.
Wehaveseenthatthesinglesubcudoseachievesover2logsandthatreductioncouldlastoveramonthtotwo.Instudiesnot
shownherethatwerepresentedbefore,wehaveshownthatmultipledosingcanfurtherextendduration.
©2015,AlphaSense,Inc.AllRightsReserved.AlphaSenseisaservicemarkofAlphaSense,Inc.Allothertrademarksmentionedbelongtotheirrespectiveowners.
Ontheright,therearetwoimages.TheseareimmunohistochemistryofSantigenexpressionintheliveroftheseAAV-HBVmice.
Andasyoucouldsee,asingledoseof3milligramsperkilogramofALN-HBVcanleadtosignificantsuppressionofSantigen
proteinlevels.
Inslidenumber15,weareshowingthetargetproductprofileforALN-HBV.Again,bysuppressingtheproductionofallviral
products,wearegoingtobeelicitingacombinationofantiviralmechanisms.Andbysuppressingtheproductionoftolerogenic
HBVantigens,wewillbepromotingtheemergenceofaneffectivehostimmunityagainstthevirus,whichinturnwouldleadtoa
long-termfunctionalcure.
Wearelookingtohaveasix-dosemonthly100to200milligrams,acourseoftreatmentthatwouldbe12to24months,afterwhich
wewouldbelookingtohavesustainedbiologicalresponseaftercessationofalltherapies.Forsafety,obviouslywe'relookingto
haveawell-tolerateddrug,includingincombinationwithothertherapiesexistingandindevelopmentforHBVinfection,including
immunomodulatorytherapy.
Slidenumber16depictstheongoingPhase1/2studyforALN-HBV.AswithallPhase1studies,theprimaryobjectiveissafetyand
tolerability.Thesecondaryobjectiveispharmacokineticsofthedrugandantiviralactivity,lookingattheproductionofviralantigens:
inbloodSantigenandEantigenforEantigenpositivepatients.Andplanned,butnotshownhere,wouldbeeffectsonHBVDNA.
Thestudyhasthreeparts.PartAisasingleascending-dosestudyinhealthyvolunteers.Thedosestartsat0.1milligramsper
kilogram,0.3,1,3,andwouldhavetwooptionalcohorts.PartAofthisstudywasinitiatedinJuly2016intheUK.
ThiswillbefollowedbyaPartB,asingleascendingdoseinchronicHBVpatientswhoarestablysuppressedwithnucleoside
analoguesforover12months.Again,thedosesaresimilar,0.1,0.3,1,3andwehavethreeoptionalcohorts.Thiswillbefollowed
byPartC,multipleascendingdoseinpatients,alsostablysuppressedonnucleosidetherapyforover12months.Herewewould
belookingatfourmonthlydoses.
Soslide17givesasnapshotofthecompetitivelandscapeforHBV.AndbeforeIgointomoredetail,Iwanttohighlightamistake
ontheslideforARC-521:thetextonthefirstrowitshouldbeonthenextrowforArbutus-1467.Thatmistakewillbecorrectedin
theslidethatwillbedownloadablefromourwebsite.
SoforALN-HBVwearelookingatasubcuinjection,noneedforpremedication,well-behaveddrugasprovenbyotherpipeline
candidatesformultipletherapeuticindicationsandtargetintheliver.Weunderstandtheperformanceofthesedrugcandidates,the
doseresponse,theduration,andthisiswhatweareexpectingtoseeforALN-HBV.
Theotherprogramsaremoreadvanced.WehaveARC-520andARC-521.BothusetwocholesterolsiRNAsthataregivenbyIV
infusionincombinationwithanagentthatisrequiredforendosomalreleaseofthesiRNAandactivityofthesiRNAliver;thatisthe
GalNAcmellitin-likepeptide.ThesearegivenbyIVinfusionwithoralantihistaminepremedication.SofaronlydataforARC-520
hasbeenreleasedandhasshownlowactivity,lowefficacyinEantigenpositivepatientswithverypoorefficacyinEantigen
negative.
TheArrowheadteamhasdoneveryelegantstudiesinchimpsshowingthecontributionofSantigenfromintegratedDNAasa
possibleinterpretationforthelackofefficacyofthecandidateintheEantigennegativepatients.Forthattheyhavedeveloped
ARC-521asafollow-ontherapyinwhichinadditionoftargetingansiRNAtotheXopenreadingframe,theyhaveasecondsiRNA
targetingtheSantigenfrombothsources,theintegratedDNA,aswellastheviralgenome.
Arbutushastwocandidates:1467isintheclinic,afollow-onis1740.Inthiscaseitisalipid,notaparticleformulation,thatisgiven
byIVinfusionandrequirespretreatmentwithsteroids.AndknowthatsteroidpretreatmentiscontraindicatedinchronicHBV.
TheemergingdataforArbutus1467alsoshowssignificantunderperformancewith0.1to0.6logdeclineofSantigenin--sorryin
Eantigennegativepatients.ThenextcandidatewillbetheIonisGalNAc-targetedanti-sense,whichisgivenbysubcuinjection.It
leveragestheAlnylamGalNActechnologyfordeliveryandiscurrentlyinPhase2andnodatahasbeenreleasedyet.
But,again,goingbacktoALN-HBV,weareexpectingthatitwillbewellbehaved;thatthesiRNAwillbeabletotargetbothS
antigenfromthe--notonlytheDNAgenomeofthevirus,butalsotheintegratedfragments.And,importantly,thereisnoneedfor
premedication.
Goingtoslide18,aswethinkoftheperformanceofALN-HBV,wearealsothinkingofadditionalindicationsthatwillbeappropriate
forourdrugcandidate.AndweareusingthisopportunitytodaytointroducetheconceptoftargetingALN-HBVinchronichepatitis
Dvirusinfection.
ProfessorWedemeyerisgoingtogointomoredetailaboutthediseaseandtheopportunity,butjustasaquickintro,thechronic-theHDVvirusisanRNAsub-virusthatdependsonpre-existingorco-infectionwithHBVinorderforthevirustopropagate.There
isabout5%,5%to10%ofpatientswhohavechronicHBVinfectionareco-infectedorsuperinfectedwithHDV.There'satotalof
about15millionto20millionpatientsinfectedworldwidewithabout80,000patientsintheUS.
Itisaverysevereinfectionandtherearenocurrentcurativetherapiesavailable.Peginterferonhassomesmallresponse,butit's
notdurable,andthereisatremendousneedfornewtherapies.SoaswethinkofALN-HBVanditsabilitytosuppressthisantigen
frombothsources,theintegratedDNAandtheCCCDNA,wearelookingattwopotentialoutcomesinHDV.
OnewouldbeHDVsuppression,wherepatientswillreceivechronic,ongoingtherapyforreductionofSantigen;thereby,directly
suppressingHDVreplicationandHDVviremia.ThenextisthatifweareabletoinduceanimmunecontroloftheHBVinfection,
©2015,AlphaSense,Inc.AllRightsReserved.AlphaSenseisaservicemarkofAlphaSense,Inc.Allothertrademarksmentionedbelongtotheirrespectiveowners.
thenthatbyitselfwillresultinachronicHDVcure.
Sotowrapupmypartofthepresentation,weareexcitedofthinkingaboutALN-HBV,notonlytoelicitfunctionalcuresforchronic
hepatitisB,butalsoforchronichepatitisDelta.Imadeallthesepointsduringmytalk.
Again,Iwanttohighlightthatwiththismechanism,thisdrugformatwearelookingatlowvolume,infrequent,subcudosing;no
needforpremedication.Wearethinkingthatthiswillleadtoimprovedcomplianceduetoconvenienceofthisinfrequentdosing,
goodtolerability,andwe'reexpectingthatwewillbeabletoreachacrossthedifferentchronicHBVpatientsegmentsincluding
youngimmunetolerantandpatientsthattodayareoutsidethetreatmentguidelines.
Anotherpointisthat,forourdrugs,theyarestableatroomtemperatureandaswearethinkingofchronicHBVbeingaglobal
problem,particularlyinAsiaandAfrica,nothavingacoldchainitreallysimplifiesglobaldistributionandaccessingthepatientsin
need.SowiththatIwillpassitontoPushkal.
PushkalGarg,AlnylamPharmaceuticals,Inc.-SVP,ClinicalDevelopment
Thankyou,Laura.AndthankyouforgivingusagreatoverviewoftheALN-HBVprogram,thepharmacology,thenonclinicaldata
andframingoutthisinterestingopportunityinhepatitisD.
WeareveryfortunatetodaytohaveProfessorHeinerWedemeyerherewithus,whoisamanagingseniorphysicianandassistant
professorintheDepartmentofGastroenterology,Hepatology,andEndocrinologyatHannoverMedicalSchool.Dr.Wedemeyeris
anexpertinhepatitisDvirusandhehasagreedtotalktousandgiveus--educateusallabouttheunmetneedandbiologyofthis
infectionandwhereALN-HBVmayplayarole.
Dr.Wedemeyer?
HeinerWedemeyer,HannoverMedicalSchool-ManagingSeniorPhysician&AssistantProfessor,Departmentof
Gastroenterology,Hepatology,andEndocrinology
Thankyouverymuch,Pushkal,forthekindintroduction.And,indeed,IalwaysliketospeakabouthepatitisDelta,whichisa
largelyunderestimatedliverdiseaseworldwide.Notonlyin,let'ssay,developingcountries,butinparticularalsoinWestern
countriesandalsoNorthAmerica,theimportanceofhepatitisDeltaandseverityhas,inmyview,notbeenappreciatedenough
overthelastyears.
WhatIthoughtisbrieflytointroducetoyouthediseaseandalsothecurrenttreatmentlandscapeandverybrieflythentogive
someideashowto--whatcouldbepassedtonewtherapiesforhepatitisDelta.
Onslide22,Ihavetohighlightmydisclosures,whichisobviouslyimportant.Thisincludesalsoconnectionstocompanies
developingdrugsnotonlyforhepatitisB,butalsospecificallyforhepatitisDelta.
Onslide23youcanseeanotherpictureoftheschemeofthehepatitisDeltavirus.Lauramentionedalreadythatthisisaquite
uniquevirus.ItisanRNAvirusthathijackshepatitisB.
Itisthesmallestofallknownanimalviruses.IthasaveryparticularstructurewithRNA.Importantly,thevirusitself,thegenome,
doesnotencodeforownviralenzymes.Meaningitisnotpossibletodevelop,let'ssay,polymerizeinhibitorsorproteaseinhibitors
againstHDVbecauseHDVuseshostenzymesforreplication.
Itdoesonlyencodeforonesingleantigenwithsomepost-translationandmodificationstepssothatintheendinthecellthereare
twoantigens,thesmallandthelargeHDantigen,butencodesonlyoneantigen.AndthenbasicallyaroundthisHDVRNAwiththe
antigen,youhavethesurfaceantigenofthehepatitisBvirus.Thisisbasically--therefore,youhavetheidenticalmodesof
transmission;it'saco-infectionofhepatitisBvirus.
Weareunderstandingnowinmoredetailthebiology,theimportanceofthedifferentHDVantigens,butagainIhavetohighlight
herethatwehaveyetnodirectmechanismstotargetvirus-specificproducts.
Soifthisisaco-infection,thenobviously,asshownonslide24,youhaveeithersimultaneousco-infectionoryouhavepatients
whocarryalreadythehepatitisBvirusandhavebecomesuperinfectedwithHDV.Incaseofacuteco-infection,thisusuallyleads
toverysevereacutedisease;morefrequentfulminantdisease,frequentlywithfataloutcomes,butthisfortunatelyhasbecomea
ratherrareevent.Whatismorecommonisthesuperinfection,soyouhavepatientscarryingHBVwhobecomesuperinfectedwith
HDVandthenthesepatientsdevelopchronicdiseasein90%ofthecases,whichalsoismoresevere.
Theprevalenceworldwide,shownonslide25,andthereyoucanseeaquiteheterogeneouspicture.Youhavecountrieswithlow
HDVprevalenceandthenyouhavedistincthotspots.Forexample,intheAmazonianareainwesternBraziltheyhavesome
villageswithextremelyhighDeltaprevalence.
YoualsohavecountrieslikeMongolia.InMongolia,therearemorepatientsdyingfromHDVthanfromcardiovasculardisease.So
it'sextremelyprevalentthere.
AndalsoinEuropewehavesomecountrieswithhighprevalence.Forexample,inRomaniaupto20%ofthehepatitisBpatients
areco-infectedwithHDV.
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Theotherpointisthatwehave,likeforotherviruses,alsodifferentgenotypes.ThemostfrequentgenotypeintheWesternworldis
genotype1infection,whileyouhaveothergenotypesinAfricaandSouthAmericaandalsoinEasternAsia.Butforusgenotype1
isthechallengeandthebiggestproblem.
Onslide25,thisisjustoneexampleshowing--or26--thatit'salsoprevalentinHIV-infectedpersons.Ithasbeenshownthatthis
isassociatedwithmorbidityandmortality.SoifDeltais--youcanfinditfrequentlyworldwide,thenthenextquestionis,well,why
hasitbeenunderestimated?ThebiggestchallengeisforusdoctorstoeducatethecolleaguesthattheysimplytestforDelta.
Justoneexampleonslide27,thatintheUSlessthan10%ofHBSantigenpositivepatientshaveactuallybeentestedforantiHDV.AndasIgivemyeducationaltalkstogeneralpractitioners,togastroenterologists,usuallymyfirstslideforDeltaisremember
onlyonethingfromthistalk:TestyourBpatientsforDelta.Andthisisthemostimportantfactoratthisstage.
Justoneexampleonslide28thatDeltaisreallytakingaseverecourse.ThisisdatafromGreece,wheretheycomparedthe
outcomeofco-infectedpatients,D/Bco-infected,versusBmono-infectedpatients.Reallyshowingtheseverityofthediseasethat
afteronlyfiveyearsorsixyearsofinfection,morethanone-thirdoftheDeltapatientshadalreadydevelopedcomplicationsofliver
disease.Andthere'sotherdatafromdifferentcountriesreallyconfirmingtheseverityofthischronicviralinfection.
Onslide29,thisiskindofhistoricalviewwherewehaveseen,let'ssay,anevolutionofclinicalpresentationofpatients.Whilein
the1980sand1990swehaveseenyoungpatients,frequentlyIVdrugusers,wenowseeolderpatients,immigrantpopulations
whichhaveseveredisease.AndontheleftsideoftheslideyoucanseesomereferencesconfirmingtheseverityofDeltawith
cohortsfromItaly,fromSpain,fromGermany,andalsofromothercountries.
Brieflyonslide30,itisshownthattheHBVgenotypematters.VeryunfortunatelythegenotypewearetalkingaboutinWestern
EuropeandinNorthAmerica,HDVgenotype1,showsamoreseverecauseofliverdiseasethan,forexample,genotype2,which
canbefoundinEasternAsia.Andmostlikelythemostseveregenotypeisgenotype3infection.
Thereisonepapershownonslide31fromSouthAmericareallyshowingthatratheryoungpatients--youcanseeinthethirdrow
thattherearemanypatientsbelowtheageof25whohavealreadydevelopedadvancedliverfibrosiswhichisreallyremarkable.
YoudonotseethisinhepatitisCmono-infectionandhepatitisBmono-infection,butyoucanseepatientsatanageof20,25years
whohavedevelopedlivercirrohosisincaseofhepatitisDelta.
Sothenthenextquestionthenobviouslyonslide32is,ifthiscanbereallyaseveredisease,doesittakeaseverecourseinevery
patient?Howcanwe,fromtheclinicalperspective,identifypatientswithahigherriskfordiseaseprogressionandthenobviously
alsowithahigherneedfornovelantiviraltreatmentapproaches?
Wecanlookforsimplebiomarkers.Forexample,onslide33thisisapaperfromourgroupshowingthatyoucanlookforanti-HDV
IgMantibodies,whichyoucanalsofindinchronicdisease.Andiftheseantibodiesareabsent,thenyouusuallyhaveamilder
courseofdisease.Whileiftheseantibodiesarepresent,thenthesepatientshaveahigherriskfordiseaseprogression.
Andonslide34weareshowingaclinicalscorewhichwedevelopedhereinHanoverwherewecoulddistinguishthreegroupsof
patientswithanintermediatecourse,abenigncourse,andaseverecourseofliverdisease.Thisisaclinicalscorewhichweusein
ourpracticetoidentifypatientswhich,forexample,shouldreceiveinterferontreatment,whichIwillmentioninoneminute.Andon
slide35,youcanseethatthisscoredoesn'tonlyworkinmycourthereinHanover,butalsoinBarcelonaandDusseldorf.
Okay,sowhatcanwedonow?TreatmentofhepatitisDelta,slide36;Ishowedyouthisdiseaseisnotinfrequent.Ishowedyou
thatthediseaseissevere.Whatcanwedo?
AsImentionedbefore--thisistheslideIshowedinthebeginningonslide37already--therearenoHDV-specificviralenzymes.
SonoHDVprotease,noHDVpolymerase,whichisobviouslyachallenge.Wehaveinprinciplethentheoptionoftargeting
somethingcommontoHBVandHDV:soHBVentry,targetingthemothervirus,HBV,orsome,let'ssay,post-translationalspecific
stepstoHDV,whichisalittlemorechallenging.
AndasthedrugswehaveforHBVdonottargetdirectlyHBV,obviouslytheHBVpolymeraseinhibitorsdonotwork.Therefore,we
areleftwithinterferon,sotheotherconceptthatLauraintroducedtoyoualsoforHDVinfection.Thisisshownonslide38.This
wasthelandmarkpaperthatweperformedwithGermancenterstogetherwithcentersinGreeceandTurkeywhereweused
interferon--peginterferonalfa-2a,eitheraloneorincombinationwithapolymeraseinhibitoragainstHBV,whichwasatthattime
adefovir.
Themessageofthatslideisbasicallythat,yes,interferonworksagainstHDV,butonlyin,let'ssay,one-quartertomostlyone-third
ofthepatients.Andalsothat,astobeexpected,thecombinationtherapywasofsimilarefficacyascomparedtotheinterferon
monotherapy,wheretherewasnoeffectofthepolymeraseinhibitoragainstHBValone.
Sothiswasthemainmessageofthatpaperandwhatwefoundatthatstageisthattheremayhavebeenasynergisticeffectof
bothdrugsagainstthemothervirus,orHBV,intermsofHBSantigensuppression,whichwasaninterestingnote.Butadefovir
todayisnolongerusedbecauseadefovirisassociatedwithrenaltoxicityand,therefore,itbasicallyisnolongerrecommendedby
guidelines.Andasadefovirisnolongerrecommended,thequestionnowwhataboutcombininginterferonwithtenofovir,the
currentstandardofcareforhepatitisB.Wealsoperformedatrialinvestigator-initiatedandonslide41youcanseethedesign.
Sowedidinvestigateinterferonplustenofovirandthenweusedthisregimennotonlyforoneyearbutalsofortwoyears.96
weekswetorturedourpatientswithinterferon.Icantellyouthiswasinclinicalpracticenotfunatthatstage,butwedidit.We
completedthetrialandonslide42youcanseetheresults.
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It'sabusyslide.Themessageforyouistheunfortunatethingisthatevenbyextendingtreatmentdurationto96weeks,wecould
notincreaseoverallresponseratesandthisisshown.So24weeksaftertheendoftherapyonlyaroundone-quarterofpatients
werestillHDVRNAnegative.Westillhadpost-treatmentrelapsesandthiswasveryunfortunate.Sopersonalizingtreatment
durationdidnotreallyhelptothepatients.
Andonslide43wealsolookedfortheHPSantigen.TheslidebeforewasHDVRNA;nowwe'relookingtothehepatitisBsurface
antigenandsotheeffectonHBV.Andtherewasnolongeranysynergisticeffectbetweentenofovirandinterferon,soitdidnot
makeadifferencewhetherweusedinterferonaloneorincombinationwithtenofovir.Meaningthatthereis,atthisstage,noroleof
combinationtherapyforhepatitisDelta.
Andthenwehadafurtherchallengeandthisisintroducedonslide44andthenslide45.Sowhatishappeningifyoufollowour
patientsafterinterferontherapyfurther?SomeofyoumayfollowtheHCVfieldandthereweareusedtotheendpointsustained
virologicalresponse.Meaning,ifIamnegative12or24weeksaftertheendoftherapy,thisisalmostequivalenttoviralelimination
fromthebody,sothisisreallycure.
ForDelta,thisisnotthecase.SomepeoplemakejokesaboutmebecauseIpublishedintheNewEnglandJournalofMedicine
thatIcured25%ofHDVRNApositivepatientsandthreeyearslaterwepublishedinHepatologywewereactuallywrong.Thatwe
disprovedourNewEnglandJournalofMedicinepaperbecausethosepatientswhowerenegative24weeksaftertheendof
therapy--andthisisshownontherightsideofslide45--thatmanypatientsrelapsedthereafter.SointerferoncansuppressHDV
insomepatients,butitdoesnotinducelong-termcure.
Forclinicaldevelopment,it'sstillimportantdoesthistreatmenthaveclinicaleffects?FDAandEMA,theywillnotonlyaskformy
surrogatesHDVRNAsuppressionalso,buttheyobviouslywanttoapproveadrugonlyifthereisaclinicallong-termeffect.And
thishasbeenquestionedbytheagenciesandbymanycolleaguesinthefieldwhetherthepatientbenefitsifIsuppressHDVRNA
andmaybeevenifIloseSantigen.
There'sveryolddatabyPatriciaFarcishownonslide47,whereshelooked10yearsafterinterferontherapyandcouldseeif
patientsreceivedhighdosesofinterferonthatthenthesurvivalofpatientswasbetter.Butthiswas,let'ssay,interferonusedinthe
early1990s,oldinterferons;threetimesweeklyinjections.
WejustpublishedinHepatology--thepaperisinpress,notyetonline;shouldgoonlinenextweekorso--thatinterferon-treated
patientsorpeginterferontreatedpatientsreallybenefitiftheyrespondtotherapyandthattheyhaveabetteroutcomethanpatients
whohavenotbeentreatedwithinterferonorreceivednukesHBValone.Thisisshownonslide48.
Andveryimportantly,onslide49,whichmaybethenrelevantforthenewideastogetridofHBsantigenfromthebody.For
example,rightnowourapproachistoreduceSantigen,andevenmaybetoeliminateHBsantigen,isthisagoodthingforthe
patient?Youcanclearlyseeherethatthosepatients,veryfewpatientswholostHBsantigeninourcohorthereinHanover,they
hadamuchbetteroutcomethanpatientswhoremainedHBsantigenpositive.Suggestingthatthisisaveryhardendpoint,which
hopefullythenalso--nothopefully;whichshouldbeacceptedalsobyagencies.
Onslide50thenthisisasummaryofthemanagementofhepatitisDelta.Fromaclinicalperspective,Icandistinguishpatientswith
milddiseasebutalsoveryseveredisease,sothoseguyswhorequireimmediatetreatment.Wehaveonlyinterferonastheonly
effectivetreatmentoptions.However,long-termfollow-upisrequiredandIshowedyouthatthereisnocureforhepatitisDelta.
Andtheproblemisalsothatonlyone-quarterofpatientsintheendbenefitfrominterferontreatment.Andtheotherproblemisthat
it'snotonlythatonlyone-quarterofpatientsrespondtointerferon,theproblemisthatmostlyhalfofthepatientscan'tactuallybe
treatedwithinterferon,becausethemajorityofpatientshaseithertooadvanceddiseaseorhascontraindicationsforinterferon.
Sothelong-termbenefitofinterferontreatmentforDeltaisintheendonlylessthan10%ofpatientshavealong-termbenefitof
interferontherapy.Therefore,wehaveahighurgentneedfornoveltherapiesagainstDelta.
Maybewecanswitchslide51and52anddirectlymovetoslide54,wherewecanhaveanothersketchofthelifecycleofHDV,
whicharethepossibleideastotreathepatitisDelta.Oneobviouslyistoblocktheentryoftheviruses,bothBandD.
Thereisdata;thereistheentryinhibitormyrcludexdevelopedbyStephanUrbanandfirstproof-of-concepttrialinveryfew
patients,14patients,hasrecentlybeenpublishedintheJournalofHepatologyinSeptember,showingthatmyrcludexisableto
blockHBVandHDVentryandthismayhaveaneffectonHDVlevels.Buttherearemoretrialsneededreallytoidentifythose
patientswhoreallybenefit.
Onslide56,thereisillustratedthattheremaybeanotherspecificstepoftheHDVlifecyclewhichcouldbeusedasanantiviral
target.Thisistheso-calledprenylationinhibition,sothisisadistinctstepwhichblocksvirionassemblyandpackingofviral
particlesbyblockingthefarnesyltransferase.Andindeed,herewehavealsothefirstproof-of-conceptdatabeingpublishedand
thisisshownonslide57.
LastyearattheNIHtrialontheprenylationinhibitorlonafarnib,whichshowedadose-dependentreductionofHDVviralloadin
thesepatients.ThesepatientsreceivedtreatmentforfourweeksatASLD;thisyearinBostontherewillbemoredatawhereI,for
example,willpresentadoseescalationstudyonthiscompound.Butthecompoundalsohassideeffects,GItoxicity,andwehave
toseehowtheclinicalimportancewillbetheninthelongterm.
ThelastoptionfortreatmentofDeltawouldbethentoblocksubviralparticleformation.Thereisalsosmallproof-of-concepttrials
whichhavebeeninitiated.Alsoherewearelackingyetfully-publisheddata,butthisisanothertheoreticalideaforanewtreatment
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inhepatitisDelta.
Sotosummaryonslide59,asImentionedinterferonremainstheonlytreatmentoption.WehaveHBVentryinhibition,prenylation
inhibition,andblockofparticleformationaspotentialnewideaswhicharecurrentlyexploredinclinicaltrials.
Butthemostimportantmessageisobviouslyintermsoforconsideringtheseverityoftheliverdisease,weneedreallynovel
strategiestoachieveHBsantigenclearancebecause,obviously,cureofHBVwillalsobecureofHBV/HDVinfections.Andone
may--fromtheclinicalperspectivepeoplemayquestiondowereallyneednewtherapiesforhepatitisBifwehavealreadythe
goodnukes?IcantellyouwedefinitelyneednewtherapiesforhepatitisDelta.It'sanunmetneedandmanyofthesenew
strategiesshouldurgentlybeexploredalsoagainsthepatitisDelta.
Finally,onslide60IwanttohighlightthatwehaveinitiatedaninternationalhepatitisDeltanetwork,whichisalargedatabaseof
morethan1,000patients,whichshouldallowusalsotovalidatesurrogatesforthelong-termoutcomeandalsotoidentifypatients
beingtreatedindifferentregionsoftheworld.
SothiswasmyintroductiontoDeltaandIturnitbacknowtoPushkal.Thankyou.
QUESTIONSANDANSWERS
Answer–PushkalGarg:Thankyou,Dr.Wedemeyer.ThatwasreallyelucidatingandveryhelpfuloverviewofhepatitisDeltaand
thebiologyandemergingtherapies.
Atthispoint,we'regoingtoopenitupforquestion-and-answerforbothofourspeakers.Asareminder,pleasesubmityour
questionsbyclickingtheAskaQuestionbuttonlocatedabovetheslidewindowonthewebcastplayer.
We'llgiveamomentforquestionstocomein.We'vestartedtogetsomecomingin,somaybe--thefirstone,Laura,isforyou
whichisyou'vetalkedaboutthePhase1/2studythat'songoing.Whataretheplansnowintermsofwhenefficacyand/orsafety
datawillbereportedoutfromthatstudy?Andcanyoucommentonthestatusatall?
Answer–LauraSepp-Lorenzino:ThePartAofthestudystartedinJulyofthisyear.WearedoingPartAintheUKandPartsB
andCarebeingdoneintheUKandsixAsiancountries.We--aswehadannouncedbefore,weexpecttoprovideanupdatemid
2017,soatthisstagethereisnothingtoreport.
Answer–PushkalGarg:Great,great.Theotherquestionthatcameinforyou,Laura,wasyouhadspokenabitaboutsingle
agentversuscombination.SocanyoutalkalittlebitabouthowyouarethinkingaboutwhetherALN-HBVwillbepositionedand
howit'sgoingtobestudiedandwhatpotentialtherapiesmightitbecombinedwithgoingforward?What'stherangeofoptionsand
howwillyouunderstandthat?
Answer–LauraSepp-Lorenzino:That'sanimportantquestion.InourPhase1trialit'salreadydesignedasacombination
therapy,sowearelookingatpatientswhoarestablysuppressedbynucleosideanaloguestenofovirandentecavir.SotheirDNA
replicationshouldbeorviremiashouldbecontrolled.
However,asweknow,nucleosideanaloguesdonotsignificantlyimpactSantigensasareflectionofcontinuedtranscription
happeninginthehepatocytes.ThefirstcombinationthatwearedoingisalreadyinPartsBandCwithnucleosideanalogues.And
althoughwedon'texpecttoseeanydeclinesinDNAbecauseit'snotdetectable,wedoexpecttoseeinhibition,knockdownofS
antigen,andEantigenintheEantigenpositivepatients.
ForthePhase2,wearegoingtobeexpandingthenumberofcombinations.OneobviouslyisthecombinationofnukeswithALNHBVsuccessiontoleadtofunctionalcureinapercentageofpatients.Butthenwhatothertherapies?
IntheUSpegylatedinterferonisnotcommonlyused;however,weareconsideringthatcombinationex-US.Andthenasnew
mechanismsarebeingdeveloped,likecoreinhibitorsforexample,thisisofinterestforustoevaluateinvestigationaldrugs.And
it'simportantaswethinkofthestrategyoftakingtwoinvestigationaldrugsintoshort[biomarketrange]Phase2studies.
Last,butobviouslyveryimportantly,isalsoanyimmunomodulatorytherapies,notonly--.Sothereissomeworkon(inaudible),but
wehaveseenpresentedby,forexample,Dr.UlrikeProtzerveryinterestingpreclinicaldatainwhichanimalsweretreatedwitha
shorthairpinRNAtoreduceexpressionofallviraltranscripts,similarlytowhatwearedoingwithALN-HBV.Andfollowedbya
therapeuticvaccine.
InthissequentialtherapytherewasasignificantincreaseinTcellsspecificforHBV.Sothatleadsintoapotentialcombination
therapyinwhichpatientswillbefirsttreatedwithALN-HBVandthenfollowedupwithatherapeuticvaccine.Andthatmaybe,
obviously,veryimportantinthosepatientsinwhichimmunesuppressionisalmostorcompletelysuppressed.
SoifthereisnoT-cellfunctiontobereactivated,wemayneedtogeneratenewTcells,whichintheabsenceofantigensmaylead
toasustainedvirologicalcontrol--immunologicalcontrolofinfection.
Answer–PushkalGarg:Great.Thankyou,Laura.ProfessorWedemeyer,aquestionforyou.Thequestionisjustaroundisthe
incidenceand/orprevalenceofHDVgrowingandwhy?Isitamatterjustofdiagnosisorwhat'shappeningintermsoftheoverall
epidemiologyofthedisease?Istheincidenceactuallyofnewinfectiongrowing?
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Answer–HeinerWedemeyer:Thisisdifferentfromcountrytocountry.InWesterncountrieslet'ssaythenumberofpatientswe
seeintheclinicisincreasing,butthis,inmyview,reflectsabetterdiagnosticfrequency.Thatphysiciansarefollowingour
guidelines.
Whiletherearesomecountries,likeinMongolia,whereitreallylooksliketheincidenceisstillincreasing.There'sstillpatientpatienttransmission.Inothercountries,likeinItaly,therehasbeenasignificantdeclineoverthelast10,15,20yearswith
concurrentpreventivemeasuresalsotopreventHBVinfection.
So,overall,it'sdiverse,butIthinkit's--forusit'snotreallythequestionwhetherthediseaseisincreasingyesorno.Ithinkwefirst
havetodoourhomeworkandsimplytodiagnosethosepatientswhoarewalkingaroundthere.AndoncewehavedonethatjobI
thinkwehaveidentifiedsomanypatientswhichrequireurgenttreatment,sothisshouldbethepriorityofourpublic-healthefforts
forDelta.
Answer–PushkalGarg:That'sgreat.Maybeafollow-upquestionthatcameinforyou,Dr.Wedemeyer;wastalkingaboutthe
unmetneed.You'vecertainlyhighlightedthecriticalityofthisdisease,butaretheresubsetsofthepopulationthathaveparticular
unmetneedorthatmaybe,conversely,moreamenabletotreatment?
Youtalkedaboutariskstratificationscorethatyoudeveloped.Maybeyoucanelaboratealittlebitmoreonwheretheunmetneed
isgreatestandwhichpopulationmaybemostamenabletoanRNAitherapeuticapproach.
Answer–HeinerWedemeyer:Obviously,fromaclinicalperspective,Ihaverightnowmyinterferon.Ihaveusedinterferonon
manypatients,sothemosturgentneedisforthosepatientswhoareeitherintoleranttointerferonorwhereinterferonhasalready
failed.Thosepatientsareleftwithnothing,soIurgentlyneedsomething.
Fromtheoverallclinicalperspective,obviouslywehavemanyratheryoungpatientswhoareintheageofwithin20,30,35and
whohaveaprettyprogressivecourseofliverdisease.Andtheonlyoptionfortheseyoungindividualsisactuallyliver
transplantation.
YoucanimaginethatifIwouldhavesomethinginhandthatwouldreduceHDVreplication,thatwouldreduceHBsantigen
replication,Iwouldimmediatelyusethis,butparticularlyintheseyoungadultswithchronicadvancedHDVinfectionwhoareat
highriskofdiseaseprogression.
AndwhereIcantellyouit'snofunintheclinictocounselthesepatientsandtotellthem--whentheyask,whatcanyouofferme?
Andyousay,well,nothing;justwaitforyourcomplicationoryourcancerand,ifyou'relucky,Imaygetanorganforyou.Andthat's
allIhave.SothisisreallysomethingwhereIneedsomethingnew.
Answer–PushkalGarg:That'sreallyhelpful.Anotherquestionthathascomeinisaround--youbothtalkedabouttargetingHB
surfaceantigenasawaytopreventhepatitisDortotreatortocurehepatitisD.Canyou--maybeDr.Wedemeyerandthen,
Laura,youcanfollowifyouhaveanythingtoadd.
Whatshouldbethetarget?We'vetalkedalittlebit--LauratalkedalittlebitabouttargetsintermsofwhatwewouldlookforinHB
surfaceantigenknockdown.ButforhepatitisD,whatshouldbethetargetlevelofhepatitisBsurfaceantigenknockdownthat's
neededtoclearHDV?AndcouldevenasmallamountofresidualsurfaceantigenbepermissivetoHDV?
Answer–HeinerWedemeyer:Thisiscertainlysomethingwhichneedstobe--thehonestanswerisIdon'tknowwhetherthereis
aspecificlevelwhichwestillcouldtolerateandwhetherthismayalterthenaturalcourseofdisease.Whatisveryimportanthere
forDeltaisthatwereallyneedtogetridofSantigeningeneral.Notonlytotarget,let'ssay,theviraltranscripts,butalsotheS
antigenwhichcancomefromintegratedformsofHBV.
Andthisis,Ithink,crucialthattheRNAitargetsconsiderthisasapotentialsource,whichwouldbestillsufficienttopropagateHDV
replication.Soinmyview,mostlikelyweneedreallytosuppressHBVasmuchaspossibleandalsoSasmuchaspossibleto
haveaclinicaleffectonDelta,butanexactthresholdneedstobedeterminedinclinicaltrials.
Answer–PushkalGarg:Great.Laura,anythingyouwanttoaddtothat?
Answer–LauraSepp-Lorenzino:That'srighton.Whatwedoknowfrompreclinicalstudiesisthatbothdependingonthe
sequencethat'sintegratedandwhattypeofSantigentheproteincanexpress,itmaybesufficienttosupportHDVreplication.So,
yes,itwillbeimportanttobeabletosuppresswithanRNAidrugbothsourcesofSantigen,theintegratedDNAandtheCCCDNA.
Sothatbeingsaid,howmuchdoweneedtoknockdown?Ithinkit's--rightnow,asHeinerclearlyoutlined,therearenotherapies.
Sothelowerbarwouldbecanweknockdown1logofSantigenfrombothsources?Andwill--thatisexpectedtoalreadybelead
toadecreaseinHDVRNAinviremia.NowthatcouldleadtochronictreatmentofHDVandcontroloftheinfection.
Now,gettingbetterandmoreefficaciousobviouslywouldbebetter.Ultimately,if,viathismechanism,wecancureHBV,wewill
alsobecuringHDV.ButIthinkthatwecanwalkbeforewerunandfirstunderstandingthedoseescalation.WouldSantigen
knockdowncanleadtosignificantantiviraleffectsandthenfromtheregowhataretheregimens,thecombinationsthatwewilllead
toaneffectiveHBVcureleadingtoanHDVcure?
Answer–PushkalGarg:That'sgreat,thankyou.Ithinkwehavetimeforonelastquestion.Justlookingdownthelist;andmaybe
ittiesintothelastconceptthatyoubothwerespeakingaboutandthisone'sforyou,Laura.
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YouhighlightedthevisionoffunctionalcureinhepatitisB.Maybeyoucouldjustcommentonwhatexactlythatvisionisandwhat
doesthatmean?Idon'tknowthatweallunderstandfullywhatthatconceptis.
Answer–LauraSepp-Lorenzino:Yes,thereisalotofdiscussionbutalsoagreementonwhatweareenvisioningasafunctional
cure.Sowhatwearelookingisaftercessationoftherapyitwouldbeademonstrationofimmunologicalcontrolofinfection,as
reflectedbythebloodbiomarkerswithHBVDNAbeingnegative,undetectable,butalsotheSandEantigensbeingundetectable.
Andthiscouldbeaccompaniedornotbythepresenceofanti-Santibodies.
Ofcourse,everybodywouldwanttoseeafurthercureinwhichwehadasignofcompleteeradicationoftheCCCDNAand
integratedDNA.ButIthinkrightnow,giventhestateoftheHBVdrugdevelopment,achievingfunctionalcurewouldbegamechangingformany,manypatients.
Answer–PushkalGarg:That'sgreat.Thankyou,Laura,andthankyou,Dr.HeineWedemeyer.WiththatI'mgoingtoturnitover
toJosh.
Answer–LauraSepp-Lorenzino:Okay.Thankyou,Pushkal,andthankstoourspeakers,LauraandDr.Wedemeyer,aswellas
toallofyouonthewebcastforjoiningustoday.
ThereplayandslideswillbepostedontheAlnylamwebsitelatertodayatalnylam.com/roundtables,andthetranscriptwillfollow
shortlythereafter.Youcanalsoviewthatpagetoaccessanyoftheotherroundtablesfromthisyear'sseries.
Thisconcludestoday'sevent.Thanks,everybody,andhaveagreatday.
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