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28/08/19
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Hiecoool2...thanksforyouprescientandexcellentpost.Myinitialthoughtsareasfollows. 1).Confirmatorytrialwasalwaysgoingtobepreconditionformarketingapproval.Thishadbeenclearlystatedclearlyininvestorbriefing/s.IthinkwearemostfortunatetohavereceivedNIHfundingforthefirsttrialof159patientsandithinkfundingislikelytocomefromthesamesourcethistime.Iwouldexpectapprox150-200patientsbeingenrolled.TheprevioustrialwasdoneindependentlyoftheCompanyandthepatientprofilingdidnotoptimisetheclinicalopportunity....forexampleenrollingyoungerfemalesundergoingbridgetotransplanttreatmentskewedtheresultsofthetrial,ratherthananoldermaleswithischemicheartdiseasehavinganLVADimplantedfor“destinationtherapy”.AddedtowhichwehadthethromboticeventsfiascowiththeLVADswhichofcoursehadnothingtodowithMesoblast. Shareholderswhoareconcernedaboutthebalancesheetshouldbedelightedthattheapprovalpathwayforthisindicationdoesnotrequireanymajorclinicaltrialfunding...apointwhichwillnotbelostonpotentialpartners.IthinkthatMesoblastwillbeconfidentthatastheconfirmatorytrialformspartoftheirINDapplicationtheywillhavesignificantweightindeterminingallaspectsofthetrialdesign. 2)Timelines.Iwouldspeculateasfollows.Plansforthedefinitivetrialwillbetieddowninthenextmonthorso.Thepoweringofthetrialcouldbe1for1randomisedbuttheymightstaywiththe2for1oftheprevioustrial.Iwouldanticipate6-9monthsforenrolment...andafurther6-12monthstobuildadataset...followedbyaBLAsubmission....Shareholdersshouldnotethat~Mesoblastknowsthatitwilltakeapproximately12monthstocertifyandbuildupnewmanufacturingprotocolsandprocessessoeverythingisgoingaccordingtoschedule. 3)Whichsecondaryendpointswillbechosen? Whatissoencouraginginthisstatementisadefinitiverestatementofsomeofthetrialsresults....inparticular: ”Inaposthocanalysisinpatientswithanischemiccauseofheartfailure,theseeffectsofRevascorwereevengreater,aswellasanobservedsignificantincreaseintheabilitytoweanoffdevicesupport,suggestingstrengtheningofthenativeheartmuscle” Remember,wearetalkingaboutClassIV,orendstageheartdisease.Revascorisnowproven,notjusttostoptheseveredeteriorationoccurringbutinmanyischemiccaseswasobservedtomoderatelyimprovetheconditionofthemusclesintheleftventricle.....REMEMBEROURDREAMPHASEIIITRIALFORCHF,WHICHWILLSHORTLYCONCLUDEISLARGELYPOPULATEDBYISCHEMICPATIENTSwithClassIIandIII. Forthereasonstatedabove,IbelieveoneofthemostimportantsecondaryendpointswillbetheabilitytosuccessfullyweanischemicpatientsofanLVADdevice. Othersecondaryendpointswillnodoubtrelatetoqualityoflifetestsandhavebeencorrectlyidentifiedinecoool2’spost. 4)LABELEXTENSIONOPPORTUNITIES TherealelephantintheroomisnottheLVADopportunity,whichisextremelyvaluablenicheinitself...buttheopportunitytousethistherapyinbypasssurgery.IntheUSthereareabout200,000proceduresperformedeachyear...withmorethan30%ofpatientspresentingashighriskandhavepredictedmorbidityandmortalityratesgreaterthan80%.Youcanobviouslymorethantreblethatnumberworldwide.Mostofthehighriskpatientgrouparelikelytobeischemicpatientssufferingfromcoronaryheartdisease. 5)cGVHD(Chronic) ThemarketforChronicasopposedtoAcuteispotentiallylargerforMesoblast.Thisisbecausethisconditionissufferedevenbyrelatedand“matched’donors.Thesurvivalratesandincidenceratios(themediantimefromtransplanttodiagnosisistypically0.49years).https://www.bbmt.org/article/S1083-8791%2814%2901247-6/pdf TherehavealreadybeenpublicationsinboththeUSandJapanabouttheuseofmesenchymalcellsfortreatmentofchronicCGVHDandJoanneKurtzberg’strialshouldhopefullybedefinitiveconfirmationthatRemestemcel-Lhasthegreatestefficacy...particularlywithregardstothesafetyprofile.IdoubtthatanacknowledgedworldexpertlikeJoanneKurtzbergwouldbeundertakinganInvestigatorInitiatedtrialwithouthavingexperimentedherselfalready. 6)Epistaxis. Interestinglyepistaxis(nosebleeds)wasaddedtothelistofmucosalbleedingevents.Thisisbecauseischemicpatientsoftenhavetostopanticoagulationwhentheyexperienceepistaxis..whichgreatlyincreasestheriskofthromboticevents.Eventhenosebleedsthemselvescanhaveamajortreatmentcost...apparentlyinarecenttrial,therewere5patientswhichhadtohavemajorbloodtransfusionstostopthebleeding. ThereasonwhytheseeventsoccurmaybeafurthersymptomofArteriovenousMalformationscausedbyvascularremodelling.Angiopoetin2whencombinedwithEndothelialGrowthFactorpromotesneovascularisation.....https://www.medpagetoday.com/cardiology/chf/79091 NOWPAYATTENTION.......THISISVERYIMPORTANTRevascorinPatientswithmoderatetoAdvancedHeartFailure. Wearenowinformedthatthetrialhasaccruedandvalidatedapproximately90%ofitsrequiredtargetofprimaryendpoints.Itisexpectedthatallrequiredprimaryendpointeventswillbeaccruedandvalidated bytheendofCY2019. AtfirstlooksthissuggestsaslowernumberofMACEeventsinthelast3months.ThesharpeyedamongyouwillrecalltheJune24th2019disclosurefromMesoblastthatinrelationtoDreamCHF: ”Thetrialhasaccruedapproximately85%ofitsrequiredtargetofprimaryendpointevents”. Onthelateroccasiontheword“validated” wasnotused. TheCompanyhasalreadymentionedthattheyexpecttoseea“JCurve”inMACEsowhyhasthenumberonlyincreasedby5%inthelast3months?(Suggestingarunrateof5%perquarter)...yetthetrialisnowconfidentlypredictedto“concludeandbevalidatedbytheendoftheCY2019!!! Theanswerliesinthewaytheinformationiscollated.Aspartofthescrupulousindependentoversightofthetrial,inowunderstandthatanindependentcommitteeatHarvardMedicalSchool,examinesallclinicaldatawhichissenttotheminbatcheseverytwomonthsbytheDataMonitoringControllersothatthecauseofdeathcanbefurtherverified.ThiswouldbesupplementarytonormalproceduresfollowedaspartofissuingDeathCertificateswhicharepromptlyregisteredbythehospital.Thismeansthatthe90%numberwehavejustbeeninformedof,couldbelaggingupto1-3monthsbehindthecurrenttotal !Thefactthatwearenowforecasttohaveallresultsevaluatedwiththenext4monthssuggestsinmyopinionthatbetween94-98%ofMACEeventsmayhavealreadyoccurred....butwithoutknowingthenumberinthebacklogthisisjustawellinformedguess .Hopefullysomefurthergranularitywillbegivenonthenextinvestorcall. Lastly,beforethemoreimpatientamongyouexpressfrustrationataconfirmatorytrial...eventhoughweareonthehomestraight...Ishouldremindinvestorsthatthepotentiallabelexpansionopportunitiesgroweverbigger...firstlyEB,thenHIEandnowcGVHD.Combinethesewithsignificantobviousopportunitiesforuse“offlabel”intheUSfortreatmentofadultswithgut,liverormultiorgansrGVHDanditisfairtoconcludethatsomeanalystsarewaybehindthecurveonestimatingpotentialcommercialisationrevenuesfromRemestemcel.Toaddinsulttoinjury,manyusehighdiscountratestocompoundthediminutionofvalue.Let’srememberthatTemcellisregularfirstlinetreatmentforadultsrGVHDinJapan!TheminutesfromtheFDAfurthervalidateMesoblastspropositionthatthedramaticdeclineinthesharepricefollowingthereleaseoftheLVADPhaseIIBtrialresultswasafailureoftheCompanyandtheanalystscommunitytocorrectlyexplainitsoutcome.IbelievethatthecurrentmarketcapitalisationofMesoblastcaneasilybejustifiedbyprospectsforUSsrGVHDandknownlabelextensioninitiativesontheirown(assumingasuccessfulBLAfilinginthenextmonthorso).Havingsaidthis,manypeoplemayfirstwantreassurancethattheCompanywilladdressthefundingshortfallof$40m?requiredbyQ22020.ThisistheamountIbroadlyestimatewillneedtobefoundtoallowtheCompanytoreachpositivecashflow(basedoncurrentknownclinicalprogrammes).Basedonitsprevioustrackrecord,theCompanypresumablyhasanumberofnondilutivewaysofraisingthiscapital(aroyaltydealforsrGVHDinEuropebeingthemostobvious)...justtrytobeonboardwhenthefundinghurdleiscleared! Lastly,ifImaydream.Withinthenext1-10weeks?IsuggestthenumberofMACEeventswillneedtohavebeenreachedtoallowtimefor independentverificationprocesstobeconcludedbytheendofcalendar2019 .Remember,wewerepreviouslygivenguidanceofCALQ12020. WhenthishappenstherewillnoneedtowaitforfurtherMACEbeforesendingtheclinicaldataasabatch.TheDMCandtheFDAwillthenpresumablyhavenosubstantivereasontostoptheunblindingofthetrial...(evenifastrictNDAisrequiredfromprospectivepartnersbeforeresultsareofficiallyknown.)ApositiveresultwilltransformMesoblast.Itwilltakelessthan24hourstoseecertainheadlinenumbers.IF,thereisasignificantdifferenceinmortalityeventscomparedtothecontrolgroup,IbelievethatafurtherconfirmatorytrialisunlikelytoberequiredbytheFDAbeforemarketingapproval. Pleasetakeyourtimetorereadthatlastsentence.Itisofcrucialimportance.Goodluckall.OP Another awesome post thank you otherperspective find your posts so informative, knowledgeable and with enthusiasm that is based on insights that make sense to this tiny share holder