WHITE PAPER: A GUIDE TO UNDERSTANDING LARGE HEMISPHERIC INFARCTION

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ALARGEUNMETMEDICALNEEDStrokeisoneoftheleadingcausesofdeathanddisabilityintheworld,butnotallstrokesarethesame.Forexample,oftheestimated795,000strokesayearintheU.S.,approximately74%aretermed“ischemicstrokes”–thosethatoccurasaresultofanobstructionwithinabloodvesselsupplyingbloodtothebrain.ThispaperfocusesonaspecifictypeofischemicstrokecalledLargeHemisphericInfarction(LHI).LHImakesupasmanyas14%ofallstrokes(19%ofischemicstrokes).IntheU.S.,forexample,thatrepresentsabout110,000incidentseachyear.Whiletheoverallmortalityrateforstrokesisabout8%to10%,themortalityrateforLHIrangesfrom40%to80%.Importantly.FeweffectivetreatmentoptionsexistforLHIpatients--themostcommontreatmentsforischemicstroke,liketissueplasminogenactivator(tPA)andmechanicalthrombectomy,areofuncertainvalueand,inthecaseofthrombectomy,notrecommendedforLHIpatients.PuttingasidethecatastrophiceffectsonLHIvictimsandtheirfamilies,thefinancialandmanpower/resourceburdensonalreadystrainedhealthcaresystemsareenormous.Costsassociatedwithcaringforthesepatientsrunintotheseveralbillionsofdollars.WHATISLHIANDWHATMAKESITUNIQUE?LHIisdefinedasanischemicstrokeaffectingthetotalorsub-totalterritoryofthemiddle

cerebralartery(MCA),involvingthebasalgangliaatleastpartially,withorwithoutinvolvementoftheadjacent(i.e.,anteriorcerebralarteryorposteriorcerebralartery)territories.Asthenamesuggests,thisisalargeischemicstrokewithasignificantamountofinjuredbraintissue.

ThehallmarkofLHIisthehighlikelihoodoftheevolutionofclinicallysignificant,lifethreateningcerebraledema.Amonganteriorcirculationstrokes,clinicallysignificantedemaisrelevantonlytoLHI(Hackeetal.1996).Thishighriskoflife-threateningedemaisrelatedtothevesselaffectedbytheocclusion,alongwithinsufficientcollateralbloodflow,whichtogetherresultinalargevolumeofunsalvageable,deadtissue.Thisinitiatesacascadethatdisruptstheblood-brainbarrier,allowingfluidleakageintothebraini.e.swelling.Thisswellingcanfurthercompromisearterialinflowtosurroundingtissues,causingmoreischemicdamageandenlargementoftheinfarct,andfrequentlyresultsinbrainherniationanddeath.Clinicalcharacteristicscomprisesecondarydeteriorationof

LargeHemisphericInfarction(LHI)representsaminorityofstrokes,yetisresponsibleforadisproportionatelylargeshareofstroke-relatedmorbidityandmortality.TheprincipalreasonforsuchpoorprognosisisthatLHI’shaveahighlikelihoodofdevelopinglife-threateningcerebraledema(brainswelling).Space-occupyingedemaistheleadingcauseofdeathinLHI,andinsurvivorsitcontributestopoorneurologicaloutcomesandpermanentdisability.ThisWhitePaperexaminesLHI,anddescribessomeofthestepsbeingtakentoaddressthisdevastatingdisease.

LHIMAKESUPABOUT

14% OFALLSTROKES

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neurologicalsymptoms,particularlyadisturbanceofconsciousnessandfurtherclinicalsignsofbrainstemherniation,likepupillarydilation.Theprognosisforthesepatientsisfrequentlypoor,withcasefatalityashighas40%to80%(Hackeetal.1996,Berrouschotetal.1998).TheterminologysurroundingtheevolutionoflifethreateningedemainLHIhasbeenconfusing,oftenconflatingtheprospectively-definedpopulationat-risk,withthoseretrospectivelydefinedashavingsufferedlifethreateningedema.Thecomingledtermsinclude,forexample,malignantcerebraledemaandmalignantinfarction,MCAinfarctionandLHI(Wijdicksetal.2014,Torbeyetal.2015).Theterm‘malignantMCAinfarction’wasfirstintroducedin1996todescribethissevereMCAsyndromewithtypicalclinicalsymptoms,followingauniformclinicalcourseandendingintranstentorialherniation(Hackeetal.1996).AdoptingtheclarificationofTorbeyetal.(2015),LHIreferstotheconditionatpresentation,whereas“malignantMCAinfarction”referstothesyndrome,frequentlyobservedintheLHIpopulation,inwhich

clinicallysignificantedemathatultimatelycanleadtotranstentorialherniationhasformed.IDENTIFICATIONOFLHIPATIENTSIdentifyingapatientwithLHIrequiresquantificationoftheextentofischemicdamagei.e.thestrokelesionvolume.Therearethreecommonmethodsofestimatinglesionvolume,discussedbelow.Diffusion-weightedmagneticresonanceimaging(DW-MRI)isconsideredthe“goldstandard”inassessinglesionsize.Thomallaetal.(2010)definedthethresholdlesionsizeof82cm3byDW-MRIwith98%specificityforpredictinglifethreateningedemainLHI.WhileDW-MRIisveryprecise,asapracticalmatteritisnotavailabletomanycenterstreatingstrokeoritisnotavailableatapointintheassessmentprotocolstoberoutinelyusefulinthisregard(Leeetal.2015,Roladan-Valdezetal.2014).Accordingly,MRIisrarelyusedinthenormal,early-stagetriageprocesstoestimatelesionsize,andwouldonlyveryrarelybeusedtodiagnoseLHIearlyinitscourse.

Edemaleadstomidlineshift,asigntheuninjuredhemisphereiscompressed.Sincethebrainisthreedimensional,itlikelywill,ifenlargedenough,pushdownonthebrainstem,causingherniationanddeath.TheaboveimagesareofanLHIpatientwhodevelopededemathatwassevereenoughtopushthebrainmidlineovermorethan1.5cm.Thepatientsubsequentlydied.

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Computedtomography(CT)perfusionusesspecialx-rayequipmentandacontrastagenttoprovideareasonablyreliablelesionvolumewithfeweravailabilityandlogisticalconcernsthanMRI.Tothedownside,itisnotwidelyusedoutsideofthelargercentersfortriagingpatients,anditsuffersfromconcernsovertimeneededandadditionalradiation(Leeetal.2015).Themostcommonlyavailableandusedimagingmodalityinestimatinglesionsizeisnon-contrastCT(standardofcareatallcenters)usingAlbertaStrokeProgramEarlyCTscore(ASPECTS),whichisa10-pointquantitativetopographicCTscanscore.Previously,estimatessuchasahypodensityonNonContrastheadCT(NCCT)of>33%oftheMCAterritorywasusedtodetermineLHI.However,ASPECTSrepresentsareproduciblegradingsystemtoassessearlyischemicchangesinpatientswithacuteischemicstrokeoftheanteriorcirculationandhasthus,onthewhole,replacedthe33%rule.WhileASPECTSisnotameasureoflesionsizeperse,ingeneral,alowerscoreiscorrelatedwithlargersizeanditisusedthiswayinclinicalpractice(Schröderetal.2014).Ingeneral,ASPECTSscoresof<6representahighlikelihoodofalargelesionsizei.e.,LHI.CLINICALTREATMENTOFLHIAsrecognizedbytheAmericanHeartAssociationandtheNeurocriticalCareSociety,theuniqueclinicalcourseofLHI,involvinglife-threateningedema,warrantsseparateguidelinestomanagethispopulation,asdistinctfromthebroaderischemicstrokepopulation(Wijdicksetal.2014;Torbeyetal.2015).Whiletreatmentofischemicstrokefocusesonreperfusion,thisisofuncertainvalueandmay,infact,beharmfulinLHI.Improvedoutcomesfromreperfusioninischemicstrokesarebelievedtoresultfromrestoringbloodflowtoischemic,butsalvageabletissue(Leeetal.2015,Powersetal.2015,Ionitaetal.2009),whereasthelargeamountofnon-salvageabletissueinLHInotonlysupportstheonsetoflife-threateningedema,butalsomakesreperfusionlesslikelytoimproveoutcomes(Mlynashetal.

2011,Yooetal.2009,Sanaketal.2006).Accordingly,themanagementofLHIfocusesonclinicallysignificantedema,whichisuniquetoLHI.Infact,theprimaryreasonLHIpatientsareplacedinneurologicalintensivecareunits,orneuroICUs–wherepatientsaretreatedwith24/7personalizedcarefromateamofadvancedcriticalcaretraineddoctors,nursesandotherneurologicalspecialists–istocloselymonitorthemforsignsandsymptomsofbrainedema.

Thetwocommonreperfusionstrategiesforischemicstrokearetheuseofthrombolytictherapies,tPA,andmechanicalthrombectomydevices.Reperfusion,however,hasbeensuggestedtopromotethedevelopmentofclinicallysignificantedema(Belletal1985;Koudstaaletal.1988;Pillaietal.2009;Nielsenetal.2012).IthasalsobeennotedthattheuseofrtPAmayaggravatethedevelopmentofedema(Rudolfetal.1998)andrecanalizationofLHIpatientsprovidesnobenefit(Goyaletal.2011).Notably,AHAGuidelinesrecommendthrombectomyonlyinpatientswithanASPECTSscore≥6(Powersetal.2015),clearlyexcludingLHIpatients.TheevidencesuggestingLHIpatientsshouldbeexcludedfromreperfusionstrategies,alongwiththeuniquepathophysiologyofedemaintheLHIpopulation,hascausedLHItobecomerecognizedasauniqueconditionbythemedicalcommunity.Infact,theAmericanHeartAssociationhasissuedseparateguidelinesforthemanagementofclinicallysignificantcerebraledemafollowinginfarction(Wijdicksetal.2014),whichoccursexclusivelyinLHI,amonganteriorcirculationstrokes(Hackeetal.

THEPRIMARYREASONPATIENTS

AREPLACEDINNEUROLOGICAL

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1996).Morespecifically,theguidelinesissuedbytheNeurocriticalCareSocietyoutlinetheoveralldistinctmanagementapproachesrequiredbytheuniquepathophysiologicalprogressionofLHI(Torbeyetal.2015).DecompressiveCraniectomy(DC)hasimprovedthebleakoutlookforLHIpatientswhohaveprogressedto“malignantinfarction.”Inapooledanalysisofthreeprospectivetrials,DCwasfoundtosignificantlyreducepooroutcomeandcasefatalityinpatientswhowererandomizedwithin48hoursofstrokeonset.However,numerousfactorslimittheusefulnessofDCinLHIpatients,includinglimitedeligibilityforsurgeryamongpatientswhoaregravelyillandhaveseriousco-morbidities.Additionally,DCisahighlyinvasiveprocedure,involvingtwoseparatesurgeriesandalltheinherentassociatedrisksandadverseconsequences(Sarovetal.2010;Durgaetal.2011;Wazirietal.2007;Kurlandetal.2014).Also,DCisofuncertainutilityinpatients>60yearsofage,duetoahighincidenceofseveredisability,asreportedbyJüttleretal.(2014).Fromaphysiologicandclinicalperspective,preventingswellingispreferabletodecompressingthealreadyswollenbrain.DCdoesnotstopswelling–itcanonlyallowspaceforthebraintocontinueswellingoutward.Atpresent,nosatisfactorypharmacotherapyisavailabletoreducetheformationofedemaassociatedwithLHI.Mannitolisanosmoticagentthatisapprovedforreducingintracranialpressureandisusedtoreducebrainswelling,althoughAHAguidelines(Jauchetal.2013;Wijdicksetal.2014)statethattheeffectofmannitolinpatientswithischemia-relatedbrainswellingisunknown.Glucocorticoidse.g.,Decadron(Dexamethasone),aresimilarlyapprovedforthetreatmentofcerebraledema,butAHAguidelinesrecommendthatcorticosteroidsnotbeadministered(Jauchetal.2013;Wijdicksetal.2014).Accordingly,nohospitalsusecorticosteroidsinLHI.GiventhatmosttherapiesforischemicstrokedonotaddresstheuniquecharacteristicsofLHI,ormayevenbeharmful,thereisaclearand

urgentneedforinnovativemedicalstrategiestopreventormitigatemalignantprogressioninLHI.THISCOULDBETHEFUTUREOFLHITREATMENTRemedyPharmaceuticalshasdevelopedadrug,CIRARA™,toaddressedemathatcandevelopaspartofCNS-relatedinjuriesandconditions–LHIbeingonesuchexample.CIRARAreducestheformationofedemabyclosingtheSur1-Trpm4channel,anovelnonselectivecationchannelthatisexpressedinthecentralnervoussystemonlyunderconditionsofischemia,hypoxia,andtrauma(ChenandSimard2001;Chenetal.2003;Simardetal.2006)discoveredbyDr.J.MarcSimard.

Sur1-Trpm4channelopening,whichistriggeredbydepletionofATP,resultsincytotoxicedemaandoncoticcelldeath(Simardetal.2007).Ifthecellinvolvedintheabovepathophysiologicalsequenceisamicrovascularendothelialcell,thesemechanismsresultinformationofspace-occupyingedema(Simardetal.2006;Simardetal.2007).Brainedemaformationthroughthismechanismisaseriouscomplicationandcanleadtomechanicalcompressionofadjacentbrainstructures,herniation,anddeath.Additionally,itcanimpairregionalcerebralbloodflow,resultinginfurtherischemia.

CIRARAisahigh-specificityinhibitorofSur1-Trpm4channelsandthusspecificallytargetsakeymechanisminvolvedindevelopmentofedema,reducingtheformationofedemaandsecondarydamageresultingfromedemain

CIRARAREDUCESTHE

FORMATIONOFEDEMABY

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multiplemodelsofLHIwithtreatmentdelaysofupto10hoursfollowingLHI.CIRARAisanintravenous(IV)formulationdesignedtorapidlyreachandmaintainsteady-statetherapeuticlevelsinacuteCNSpatients.CIRARAissuitableforbothbolusinjectionandforcontinuousinfusion.PHASE2STUDYSHOWSTHEPOTENTIALOFCIRARAINTREATINGLHI

Inarandomized,double-blind,placebocontrolledphase2studyofCIRARAconductedat18leadingU.S.sitesinLHIpatients,edema-relateddeathswerecutby90%(2%intheCIRARAgroupversus22%inplacebopatients.p=0.01).Thisresultedin90-dayall-causemortalitybeingcutby53%(17%versus36%.p=0.06).Inpatients≤70yearsold,90-daymortalitywascutanastounding66%(11%versus33%.p=0.04).Theextentofedema,asmeasuredbyaveragemidlineshiftofthebrain,washalved(8.8mminplacebovs.4.4mminCIRARA-treatedpatients,p=0.0006).

Functionaloutcomes,measuredonthewidelyacceptedmodifiedRankinScale(mRS),showedacrosstheboardimprovementsinCIRARApatientswithanOddsRatioof1.9(p=0.12).TheOddsRatioforimprovementinmRSinpatients≤70yearsoldwas2.49(p=0.045).

Aphase3trialinLHIpatients,CHARM(CiraraforlargeHemisphericinfarctionAnalyzingmodifiedRankinscaleandMortality)isexpectedtobegininlate2016.ABOUTCIRARACIRARAisapatented,highaffinityinhibitorofSur1-Trpm4channels,whichareupregulated

followingischemiaandtrauma.Openingofthesechannelscanleadtoedema,midlineshift,increasedintracranialpressure,andbrainherniation,culminatinginpermanentdisabilityordeath.Sur1-Trpm4channelswerediscoveredbyUniversityofMarylandneurosurgeonDr.J.MarcSimard,scientificfounderandboardmemberofRemedyPharmaceuticals.CIRARAissuitableforintravenousdeliveryatthebedsideoreveninanambulance.CIRARAusesourproprietary,patentedMPD™technology.EdemacontributestothehighmortalityandmorbidityofLHI.CentralNervousSystem-relatededemaoccursnotjustinLHI,butinmanyotherCNS-relatedinjuriesandconditions,i.e.,subarachnoidhemorrhage,intracerebralhemorrhage,contusionaltraumaticbraininjury,spinalcordinjury,aswellasnumerousotherCNSconditionsandinjuries.CIRARAisatreatmentforalltheseindications.

CIRARAisaninvestigationaldrugandisnotapprovedbyFDA.ABOUTREMEDYPHARMACEUTICALSRemedyPharmaceuticals,Inc.isaprivately-held,clinicalstagepharmaceuticalcompanyfocusedondevelopingandbringinglifesavingtreatmenttopeopleaffectedbyacutecentralnervoussystem(CNS)edema–includinglargehemisphericinfarctionaswellasotherischemicinjuriesandneurologicaldisorders.FormoreinformationonLHIandCIRARA,pleasegoto:RemedyPharmaceuticals.com

EDEMA-RELATEDDEATHSWERECUTBY

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©2016.RemedyPharmaceuticals.ThisWhitePaperisnotadefinitivelookatLargeHemisphericInfarction.Itisintendedonlyasanintroductiontothesubject.ThematerialinthisWhitePapermaybeused,inwholeorinpart,withoutpermission,providedthefollowingattributionisgiven:“Source:RemedyPharmaceuticals,Inc.”

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