WHITE PAPER: A GUIDE TO UNDERSTANDING SUBARACHNOID HEMORRHAGE

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LIFE-THREATENINGSUBARACHNOIDHEMORRHAGEStrokeisoneoftheleadingcausesofdeathanddisabilityintheworld,butnotallstrokesarethesame.Forexample,oftheestimated795,000strokesthatoccureveryyearintheU.S.,onlyabout15%aretermed“hemorrhagicstrokes”–thosethatresultfrombleedingthatspillsintooraroundthebrainandcreatesswellingandpressure,thusdamagingcellsandtissueinthebrain–yettheyareresponsibleforabout40percentofallstrokedeaths.Aspecifictypeofhemorrhagicstrokeissubarachnoidhemorrhage(SAH).SAHreferstobleedinginthesubarachnoidspace,theareabetweenthebrainandtheskullthatisfilledwithcerebrospinalfluidandprotectsthebrainfrominjurybyservingasacushion.Some30,000–35,000peopleayearintheU.S.fallvictimtoSAH,andanother300,000aroundtheworldsufferthesamefate.SAHcanleadtocoma,paralysis,andevendeath.SecondarydamageinSAHmaycontinueaslateas14daysafterinjury.Approximatelythree-quartersofSAHpatientsdieorsufferpermanentbraindamagewithin30daysoftheirstrokes.IntheU.S.alonethisresultsinoverallinpatientchargesofmorethan$5billionperyear.Moreover,thelifetimecostofcaringforchronicallydisabledpatientspresentsasignificanteconomicburdentohealthcaresystems.

WHATCAUSESSAHANDWHATMAKESITUNIQUE?RiskfactorsforSAHincludesmoking,hypertension,excessivealcoholconsumption,gender,andage.TheriskofSAHinwomenover55yearsoldis25%higherthaninmenofcomparableage.Geneticsplayarole,too.SAHriskisthree-xtofive-foldmorelikelyincloserelativesofpeoplewhohavehadaSAH.

ThecauseofmostcasesofSAHisruptureofacerebralaneurysm,abulging,weakareainthewallofabrainartery.TheimmediatedangerduetoSAH,otherthantheinitialbleed,isischemia,tissuedamagecausedbyrestrictedorblockedbloodflow.Theischemicareasofthebrainthatdonotreceiveadequatebloodandoxygencansufferirreparableinjury,leadingtopermanentbraindamageordeath.ThemostcommoncomplicationsfromSAHareintracranialhypertension,hydrocephalus,andvasospasm.

SubarachnoidHemorrhageisaserious,life-threateningtypeofhemorrhagicstrokecausedbybleedingintothespacesurroundingthebrain,usuallyastheresultofarupturedaneurysm.WhileSubarachnoidHemorrhagemakesupasmallpercentofallstrokes,uptohalfofallcasesarefatal.Moreover,thosewhodosurviveoftensufferlong-termfunctionalorcognitiveimpairment.

ThisWhitePaperexaminesthedevastatingeffectsofSubarachnoidHemorrhageonitsunfortunatevictims,anddescribesstepsbeingtakentonotonlysavelives,buthelpsurvivorstolivelifetothefullest.

EACHYEARINTHEU.S.

30-35k PEOPLEFALLVICTIMTOSAH

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Intracranialhypertension,orhighpressurewithinthebrain,isasignofedema(swelling).Itcanimpairbloodflow,whichkillsbraincellsandcandisrupttheblood-brainbarrier,leadingtofurtherbleedingfromdamagedbloodvessels—acomplicationassociatedwitha70%fatalityrate.Hydrocephalus,whichoccursinabout15%ofSAHcases,isanaccumulationoffluidinthechambersofthebrain(ventricles)duetorestrictedcirculationofcerebrospinalfluid.Becausecerebrospinalfluidcannotdrainproperly,pressureaccumulatesinthebrain,whichmaypromptfurtherischemiccomplications.Vasospasm,orbloodvesselconstriction,isanothercauseofsecondaryischemia.Whenthecerebralaneurysmruptures,itreleasesredbloodcellsintothesubarachnoidspace.Thebloodvesselsinthebrainconstrictinreactiontochemicalsreleasedbythebloodasitbreaksdown.Asthebloodvesselsbecomenarrower,bloodflowinthebrainbecomesincreasinglyrestricted.Someonethirdofsubarachnoidhemorrhagesarefollowedbyvasospasm.

IDENTIFICATIONOFSAHPATIENTSThemostcharacteristicclinicalfeatureofSAHisasuddenexplosiveheadache,sometimesreferredtoa“thunderclapheadache.”Othersignsincludevomiting,confusionoraloweredlevelofconsciousness,andsometimesseizures.Theremaybewarningsymptomsintheweeks

leadinguptoaSAH,causedbysmallbloodleaksfromabrainartery.Thesearecalledsentinelbleedsandareduetoexpansionofananeurysm.Theycauseheadachesin10-15%ofpatients.ThediagnosisofSAHusuallydependsonclinicalsuspicioncombinedwithradiologicconfirmationusingcomputedtomography(CT).Thisissometimesfollowedwithlumbarpuncture,inwhichaneedleisinsertedbetweentwolumbarbones(vertebrae)toremoveasampleofcerebrospinalfluid.AfterthediagnosisofSAHisestablished,furtherimagingistypicallyperformedtocharacterizethesourceofthehemorrhage.CLINICALTREATMENTOFSAHStabilizingtheSAHpatientisthefirstpriority.Ifacerebralaneurysmisfound,twoproceduresareavailabletoreducetheriskoffurtherbleeding:clippingandcoiling.Clippingrequiresacraniotomy–asurgerytoopenpartoftheskull–tolocatetheaneurysm.Oncetheaneurysmislocated,clipsareplacedaroundtheaneurysmnecktostopbloodflowintotheaneurysm.Coilingisasurgicalprocedurethatisperformedbyinsertingacatheterthroughthefemoralarteryinthegroin,feedingitupintothebrain,anddeployingplatinumcoilsattheinjuredsite.Thecoilscauseabloodclottoformintheaneurysm,whichpreventsbloodflowandeliminatestheriskofrupture.Generallyspeaking,thedecisionastowhichproceduretouse–clippingorcoiling–isdeterminedbythelocationandstructureoftheaneurysm.Aftertherupturedaneurysmissurgicallyisolatedtopreventre-bleeding,patientsremainatriskformultiplecomplicationsAstouchedonearlier,onecommoncomplicationofSAHisvasospasm,inwhichthebloodvesselsconstrictandreducebloodflow.Thiscancausewhatisreferredtoas“delayedischemia.”Whenareasofthebraindonotreceiveadequatebloodandoxygen,itcanleadtopermanentbraindamageordeath.About

ANNUALIN–PATIENTCHARGESINTHEU.S.OFMORETHAN

$5BILLION

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one-thirdofpatientsadmittedtohospitalwithSAHwillhavedelayedischemia.CurrenttreatmentguidelinesintheUnitedStates,CanadaandEuroperecommendthatpatientswithSAHbeadministerednimodipine,aL-typecalciumchannelblocker,whichreducestheneurologicaldeficitsassociatedwithSAH-relatedcerebralvasospasm.Unfortunately,nimodipinedoesnotaddressothercomplicationsassociatedwithSAH,mostnotablycerebralischemia,whichoccurssecondarytoprocessesincludingcerebralvasospasm,nordoesitattendtotheneuroinflammatoryprocessesthatcausevasospasm,oredemathatisfrequentlypresentathospitaladmissionordevelopsaspartoftheprogressionofSAH.WhileadvancementsintreatmentandpreventionofcomplicationsassociatedwithSAHhaveoccurred,thesehaveledtoonlymodestimprovementinoveralloutcome,leavingaclearandurgentneedforinnovativetreatmentsforSAH.

THISCOULDBETHEFUTUREOFSAHTREATMENTRemedyPharmaceuticalshasdevelopedadrug,CIRARA™,whichfocusestwoaspectsofSAHthatarenotaddressedbynimodipine:edemaandneuroinflammation.CIRARAreducestheformationofedemabyclosingtheSur1-Trpm4channel,anonselectivecationchannelthatisexpressedinthecentralnervoussystemonlyunderconditionsofischemia,hypoxia,andtrauma.Sur1-Trpm4channelopening,whichistriggeredbydepletionofATP,resultsincytotoxicedemaandoncoticcelldeath.Ifthecellinvolvedintheabovepathophysiologicalsequenceisamicrovascularendothelialcell,thesemechanismsresultinformationofspace-occupyingedema.Brainedemaformationthroughthismechanismisaseriouscomplicationandcanleadtomechanicalcompressionofadjacentbrainstructures,herniation,anddeath.Additionally,itcanimpairregionalcerebralbloodflow,resultinginfurtherischemia.

SubarachnoidHemorrhage(SAH)isaserious,life-threateningtypeofhemorrhagicstrokecausedbybleedingintothespacesurroundingthebrain,usuallyastheresultofarupturedaneurysm.

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PreclinicalstudieshaveshownthatSur1-Trpm4channelsareupregulatedfollowingSAH,andthatinhibitingSur1reducesneuroinflammationandedema.Mostimportantly,bytargetingtheunderlyinginflammatoryprocessresponsibleforsecondarybraininjuryfollowingSAH,CIRARAmayimproveoutcomes.APHASE2STUDYOFCIRARAINSAHPATIENTSINTHEPLANNINGSTAGE

RemedyPharmaceuticalsisplanningaphase2studytohelpdeterminethesafetyofCIRARAinSAHpatients,andtoobtaininformationabouttheeffectsofdifferentdosingdurationsofCIRARA.TheFDAhasgivenCIRARAanorphandrugdesignationforSAH.

ABOUTCIRARACIRARAisapatented,highaffinityinhibitorofSur1-Trpm4channels,whichareupregulatedintheCNSfollowingischemiaandtrauma.Openingofthesechannelscanleadtoedema,midlineshift,increasedintracranialpressure,andbrainherniation,culminatinginpermanentdisabilityordeath.Sur1-Trpm4channelswerediscoveredbyUniversityofMarylandneurosurgeonDr.J.MarcSimard,scientificfounderandboardmemberofRemedyPharmaceuticals.CIRARAissuitableforintravenousdeliveryatthebedsideoreveninanambulance.CIRARAusesourproprietary,patentedMPD™technology.EdemaandneuroinflammationcontributetothehighmortalityandmorbidityofSAH.CentralNervousSystem-relatededemaoccursnotjustinSAH,butinmanyotherCNS-relatedinjuriesandconditions,suchaslargehemisphericinfarction,intracerebralhemorrhage,traumaticbraininjury,andspinalcordinjury.CIRARAisunderinvestigationasatreatmentfortheseindications.

CIRARAisaninvestigationaldrugandisnotapprovedbyFDA.

ABOUTREMEDYPHARMACEUTICALSRemedyPharmaceuticals,Inc.isaprivately-held,clinicalstagepharmaceuticalcompanyfocusedondevelopingandbringinglifesavingtreatmenttopeopleaffectedbyacutecentralnervoussystem(CNS)edemaandneuroinflammation,suchasinsubarachnoidhemorrhageandotherischemicinjuriesandneurologicaldisorders.FormoreinformationonSAHandCIRARA,pleasegoto:RemedyPharmaceuticals.comNOTICE:©2016.RemedyPharmaceuticals.ThisWhitePaperisnotadefinitivelookatSubarachnoidHemorrhage.Itisintendedonlyasanintroductiontothesubject.ThematerialinthisWhitePapermaybeused,inwholeorinpart,withoutpermission,providedthefollowingattributionisgiven:“Source:RemedyPharmaceuticals,Inc.”

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