CEO, Genervon Biopharmaceuticals New York - … · CEO, Genervon Biopharmaceuticals ... cure for the diseases and disorders of the central nervous system. ... determined when clinical

PartnershipPresentationbyWinstonKoCEO,GenervonBiopharmaceuticals2018BIOCEO&InvestorConferenceNewYork

PartnershipPresentation-Page2of20

1 OverviewandOpportunitiesGoodMorning!Iamhappytobeherewithyoutoday.MynameisWinstonKo,andIamtheFounderandChairmanofGenervonBiopharmaceuticals.20yearsago,Iwaslookingforaninvestmentopportunityandembarkedonfindingacureforthediseasesanddisordersofthecentralnervoussystem.Manyofyouarethinking,“Goodluckwiththat.”Ontheotherhand,manyofyouhavehadrelativesorfriendswhohavesuffered,orevendied,fromterribleCNSdiseasesandneurodegenerativedisorders,andyouwishedsomeonewouldhelpthem.Iknewthiswouldindeedbeaveryhigh-riskinvestment,butIalsosawthatIhadanopportunitytomakeameaningfuldifferenceintheworld.So,IdecidedtofundtheR&Danddrugdevelopmentcostmyselfinsteadofspendingmytimelookingforgrantsandfinancing.Now,IamhappytoreportthatGenervonisreadytoadvanceourdevelopment-stagedrugcandidatestomarketabletherapiesforthemanyvictimsofneurodegenerativediseasesanddisorderswhodesperatelyneedhelp.Afterfundingourownoperationsuptothispoint,GenervonisnowreadytolicensetoandpartnerwithPharmaceuticalcompanieswhohavethecapacityforcommercializingdrugsforneurodegenerativediseases.

PioneeringNeuroprotectionandRegenerationforNeurodegenerativeDiseasesandDisorders

OverviewandOpportunities

February2018


2 MNTFDiscoveryMulti-targetHypothesisTodate,noeffectivetherapyhasbeendevelopedforcentralnervoussystem(CNS)andneurodegenerative(ND)diseasesanddisorders.Thesediseasesarecomplexwithmultifactorialconditions.Multiplebiologictargetsmustbemodulatedinordertoaffectthediseaseinquestion.Itisnotsurprising,then,thatthecurrentparadigmofsingle-targetdrugdevelopmentforCNSandneurodegenerativediseasescontinuestoresultinfailuresinclinicaltrials.Fromthebeginning,Genervonpursuedanewparadigmofdrugdiscoveryinthebeliefthatmulti-targetdrugdevelopmentisthekeytocuringcomplexneurologicaldisorders.Thiscorehypothesisguidesallofourresearchanddrugdevelopment,andwemadeacommitmentnottobeconfusedordistractedbytheconventionalsingle-targetdrugdevelopmentmindset.

MNTFDiscoveryMulti-target Hypothesis

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Multi-targetdrugdevelopmentisthekeytocuringcomplexneurologicaldisordersThiscorehypothesis—ratherthantheconventionalsingle-targetdrugdevelopmentmindset—guidesallofourresearchanddrugdevelopment


3 MNTFDiscoveryGenervonlookedfor,anddiscovered,whatitbelievesistheregulatorofthedevelopmentofthehumannervoussystem,calledthe“motoneuronotrophicfactor,”orMNTF(3Dpicture).MNTFisendogenouslyexpressedatitshighestlevelsatweeknineoffetalgestationandremainsdetectableatverylowlevelsinadulttissue.ThisexplainswhythebodydoesnotrejecttheinjectionofMNTForitsactiveanalogsfortherapeuticpurposes.TheupperpanelshowsthatthefetaltissuesdetectedhighlevelsofMNTFanditsanalogsinthebrain,lung,thymus,kidney,heart,liverandplacentawiththehighestlevelatthymusandheart.

MNTFDiscovery

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4 MNTFTrophicFunctionWemadetwoastonishingfindingsregardingthisregulator:First,wefoundthatwhenarat’ssciaticnervecordwascut,andagelcontainingMNTFwasplacedinthegap(seepicture),thenumberofrejoinedneuronssignificantlyincreased.MNTFpromotedmotorneuronregenerationacrossthegapinadose-dependentfashionaswellaspromotedDRGneuronregenerationathighdoses.

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MNTFTrophicFunction

An8mmgapintheratsciaticnervewasbridgedwithsilicontubingfilledwith90%Vitrogen thatcontained

research-gradeMNTFinconcentrationsfrom10-3Mto10-7M.ControlscontainedVitrogen alone.Afterone

month,neuronsthatprojectedaxonsthroughthetubewerelabeledfromthedistalstumpwithFluoro-Gold.

MNTFpromotedmotorneuronregenerationacrossthegapinadose-dependentfashion,andpromotedDRGneuronregenerationathighdoses.


5 MNTFTropicFunctionTheseconddiscoveryisthatwhenafemoralnervewascutandtreatedwithMNTF,theregeneratedaxonpreferentiallywentmoretowardsthemotorbranchthanthecutaneousbranch.TheseexperimentswereperformedatJohnsHopkinsforoverthreeyears,andthesetworesultingfindingsdemonstratethatMNTFhasbothatrophiceffectandatropiceffect.WealsoperformedextensivepreclinicaltestingwhichsuggeststhatMNTFregulatesmultiplekeyCNS-relatedbiologicalfunctionsincludingneuronaldifferentiation,axonalregeneration,reinnervation,andinflammationandapoptosis.Wewouldbehappytoprovideyouwithourcompleteslidedeckwhichcontainsmoredatafromourstudies.AdditionalconfidentialinformationcanbemadeavailabletothosereadytoengageinaseriousconversationwithGenervonaboutpartnering.

MNTF TropicFunction

LabeledmotorneuronsinmuscleLabeledmotorneuronsincutaneousDouble-labeled

RatFemoralNerveRepair

GM6Concentrations

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GM6concentrationsaslowas10-6Mresultedinpreferentialmotorreinnervationinmuscletissue

MNTFregulatesmultiplekeyCNS-relatedbiologicalfunctionsincluding:• neuronal

differentiation,• axonal

regeneration,• reinnervation,• inflammation• apoptosis.


6 GM6Development,PassThroughBBBFollowingamulti-yearresearchanddrugdevelopmenteffort,GenervonhasadvancedGM6,a6-amino-acidactiveanalogpeptideofMNTF(3Dpicture),intoPhase2clinicaldevelopment.GM6successfullytransitstothebrainandwasdetectableinadosedependentmanneratastatisticallysignificantlevel,p=0.0001.

GM6Development,PassThroughBBB

0.4050±0.3027µM

1.76±0.9834µM

12.92±4.635µM

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2

4

6

8

10

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Vehicle GM6- 0.2mg/kg GM6- 2.0mg/kg

MouseBrainGM6Levelsat4hours

• C57BL6micewereinjectedwithasinglebolusintravenoustailveininjectionofGM6at0.2and2.0mg/kg

• Atfourhours,theanimalsweresacrificedandhalfofthebrainwasfrozenforELISAanalysis

• ELISAassaywiththesupernatantfromthebrainhomogenatedetectedGM6atstatisticallysignificantlevels,atalldoses,comparedtocontrol(p=0.0001)

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7 GM6TreatedPatients’NeuronSurvivalIncreasedWeincubatedratcorticalbrainneuroncellswiththecerebrospinalfluidfromCNS-diseasepatientsprovidedbytheUCLABrainandTissueCenter.ThesampleswhichwereincubatedtogetherwithGM6experiencedasignificantincrease-aboutdouble-incellsurvivalrate,indicatingclearlythatGM6hasaneuroprotectivefunctioninCNSdiseasepatients.GM6demonstratedastatisticallysignificantincreaseinneuronsurvival(p<0.0001)in:

ALS(175%)MultipleSclerosis(246%)Alzheimer’sDisease(191%)Huntington’sDisease(273%)Parkinson’sDisease(198%)Stroke(205%)

• GM6demonstratedastatisticallysignificantincreaseinneuronsurvival(p<0.0001)in:o ALS(175%)o MultipleSclerosis(246%)o Alzheimer’sDisease(191%)o Huntington’sDisease(273%)o Parkinson’sDisease(198%)o Stroke(205%)

• GM6increasedneuronsurvivalwithoutstatisticalsignificancein:o NeuropathicPain(120%)o Batten’sDisease(114%)

GM6TreatedPatientsNeuronSurvivalIncreased

NeurologicalDisorders

%Survival(Ra

tCorticalNeu

rons)

0.0

20.0

40.0

60.0

80.0

100.0

120.0

HS ALS NP MS AD BD HD PD Stroke

CSF(N=5)CSF+10nM GM6(N=5)

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8 GM6PreclinicalStudyALSMouseModelInALSmousemodelpreclinicalexperiments,weobservedthatGM6candelaydiseaseonset(leftchart)andimprovesurvivalrateintheSOD1transgenicmouse(rightchart).

GM6 PreclinicalStudyALSMouseModelSOD1-G93Atransgenicmousemodel

SOD-G93Atransgenicmicewereinjectedwithvehicle(control)orGM604intravenouslyatday80anddailythereafteruntilsacrifice.Clinicalscoresforeachanimalweretalliedeverythirddayaftertreatment.Onsetofdiseaseisdeterminedwhenclinicalscoreis1orhigher.Probabilityofdiseaseonsetisdefinedasthenumberofmicewithdiseaseonsetdividedbythetotalnumberofanimalsineachstudygroup.Percentincreaseinageofonset:GM61mg/kg12%P<0.001GM65mg/kg27%P<0.001

SOD1-G93Atransgenicmousewereinjectedwithvehicle(control)orGM604intravenouslyatday80anddailythereafteruntilsacrifice.Clinicalscoresforeachanimalweretalliedeverythirddayaftertreatment.Whenclinicalscoreis4,theanimalissacrificedforhumanereasonsandtimeofdeathisrecorded.Probabilityofdeathisdefinedasthenumberofmicealreadydeaddividedbythetotalnumberofanimalsineachstudygroup.Percentincreaseinageatdeath:GM61mg/kg16%P<0.001GM65mg/kg30%P<0.001

ControlGM6 (1 mg/kg)GM6 (5 mg/kg)

ControlGM6 (1 mg/kg)GM6 (5 mg/kg)

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9 GM6PreclinicalStudyALSMouseModelFromthesameexperiment,wecanalsoseeafunctionalimprovementintheGM6treatedmiceincludingrotarodfrequency,gripstrength,andrelatedclinicalscoreswith53%increaseinage,p<0.001.

GM6PreclinicalStudyALSMouseModelSOD1-G93Atransgenicmousemodel

Rotarod:Theabilitytoremainontherotatingrod(“rotarod”)wastestedeverythirddayaftertreatment.Theaveragevalueofthetimeeachanimalremainedontherotarodforeachstudygroupisplottedasafunctionofage.Percentincreaseinageatmedianrotarodperformance:GM61mg/kg14%P<0.001GM65mg/kg41%P<0.001

Gripstrength:Gripstrengthwasmeasuredeverythirddayaftertreatment. Theaveragevalueofgripstrengthforeachstudygroupisplottedasafunctionofage.Percentincreaseinageatmediangripstrength:GM61mg/kg14%P<0.001GM65mg/kg41%P<0.001

Clinical scores: Clinical scores were tallied everythird day after treatment: No sign of weakness(0); tremor and loss of splay reflex (1); paresis inone hindlimb (2); paresis in both hindlimbs (3);paralysis of one or both hindlimbs (4). Theaverage score for each study group is plotted as afunction of age.Percent increase in age at median clinical score:GM6 1 mg/kg 23% P<0.001GM6 5 mg/kg 53% P<0.001

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10 GM6PreclinicalIndicationIntheWobblerMouseneurodegenerationmodel,GM6wasabletoincreaselifespaninadosedependentmanner.Inparticular,atadoseof20mg/KgGM6,thelifespanwasextendedfromabout10weeksto56weeks.ThesegreatfindingsareallpositivesignsoftherapeuticefficacyforneurodegenerationbytreatmentwithGM6.

GM6 PreclinicalIndication

• Malewobblermiceweresubjectedtoweeklysubcutaneousinjectionsof0,1,5,10or20mg/kgGM604andthetimeofdeathwasdetermined;thegraphindicatesmean+/- SDoftenanimals

• GM6extendedsurvivalinadose-dependentmanner

WobblerMouseModelCreatedbyNIH

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11 GM6Phase2AClinicalData(ALSFRS-R)OurALSPhase2AtrialwasconductedatColumbiaPresbyterianandMassachusettsGeneralHospital.Normally,forasmallPhase2Aclinicalstudy,mostpeopledonotexpectanymeaningfuldata.However,GenervonwasconfidentourFDAapprovedprotocoldesignforthepilotclinicaltrialcouldproducemeaningfulclinicaldata:• 12fastprogressiondefiniteALSpatients,8patientsreceivedGM6and4received

PlaceboviaIVdosingfor6timesovertwoweekswithevaluationsperformedafterdosingatweek2,week6,andweek12.

GenervonishappytoreportpositivesignalsofimprovementfromthePhase2Aclinicaltrial:• Therewerenoclinicallysignificantadverseevents.Adverseeventsweresimilar

betweenthetreatedandplacebogroups.• ThesimilarsafetydatawasfoundinourPhase1safetyclinicaltrialdata.• GM604slowedfunctionaldecline,asmeasuredbyALSFRS-R,whencomparedtoa

historicalcontrol(P=0.005).

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GM6Phase2AClinicalData(ALSFRS-R)

• Genervon’s ALS Phase 2A trial was conducted at Massachusetts General and at Columbia Presbyterian.

• Meaningful data is seldom expected to come from a small pilot Phase 2A clinical study. However, Genervon was confident the protocol design for the pilot clinical trial could produce meaningful clinical data: o 12 fast progression ALS patients diagnosed with definite ALS according to the El Escoria

scale. o 8 patients received GM6 and 4 received Placebo via IV dosing six times over two weeks

with evaluations performed after dosing at week 2, week 6, and week 12. • Genervon is happy to report positive signals of improvement from Phase 2A clinical trial:

o No clinically significant adverse events. Adverse events were similar between treated and placebo groups. The same safety data was found in our Phase 1 safety trial.

o GM604 slowed functional decline, as measured by ALSFRS-R, when compared to a historical control approved by FDA with definite ALS patients (P = 0.005).


12 GM6Phase2AClinicalData(FVC)OurPhase2AclinicaldatafoundthattheFVCchangefrombaselinetoweek12atSite001hadstatisticalsignificance,P=0.0268.Site001consistentlyusedthesameclinicalresearchassociate(CRA)toobtainFVCforallsubjectsatalltimepoints.*ThestatisticianfoundsomeunreasonabledatafromSite002andlearneduponinvestigationthatSite002didnotconsistentlyusethesameCRAtoobtainFVCforallsubjectsatalltimepoints.

GM6Phase2AClinicalData(FVC)*Site002didnotconsistentlyusethesameCRAtoobtainFVCforallsubjectsatalltimepoints.Oneplacebopatientwasrecordedtohavea23%dropfromscreeningtobaselinewhenmeasuredbydifferentCRAs.OnetreatedpatientreturnedtoaforeigncountrywithoutcompletingFVCforweek12andN=3fortheGM6treatedgroup.Atweek12Placebosawameanincreaseof5%whichisnotreasonable.

TimePointSite001 *Site002 AllSites

Placebo(N=2)

GM6(N=4)

Placebo(N=2)

GM6(N=3)

Placebo(N=4)

GM6(N=7)

BaselinemeanFVC(%)

73.5 89.5 89.0 93.4 81.3 91.1

Week12meanFVC(%)

45.5 84.8 94.0 88.7 69.8 86.4

ChangefromBaseline(%)

-28.0 -4.8 5.0 -4.7 -11.5 -4.7

P-value .0268 .0856 .5393

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TheSite001FVCchangefrombaselinetoweek12hasstatisticalsignificance.Site001consistentlyusedthesameCRAtoobtainFVCforallsubjectsatalltimepoints.


13 GM6Phase2ABiomarkersGM6wasnotcustomdesignedtobeanagonistorantagonistagainstanydefectivepathways,genes,biomarkers,ortargetproteins.GM6isonlyananalogofanaturallyoccurringregulator.YetGM6decreasedplasmalevelsofkeyALSbiomarkersrelativetotheplacebogroup.GM6-treatedpatientsweredownregulatedatdifferenttimepointsandimprovedfunctionalmeasuresduringthePhase2Astudy.

• PlasmaSOD1:ThebarchartsandthegraphshowadecreaseinthetreatedgroupandanincreaseintheplacebogroupfromVisit1toVisit6(week2):P=0.009.

• PlasmaTau:thetreatedgroupdecreasedwhiletheplacebogroupincreasedatVisit7(week6):P=0.03

• TDP43:Theslopeof%changefrombaselinethroughweek12intreatedpatientsis-3.513(redline)andinplacebopatients(blackdottedline)is0.493.P=0.0078

GM6 Phase2ABiomarkers

Treated v4 Treated v6 Treated v8

75

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0Placebo v4 Placebo v6 Treated v7 Placebo v7 Placebo v8

-25

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Treated v4 Treated v6 Treated v7

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0Placebo v4 Placebo v6 Placebo v7

-25

-50

-75

-80

-40

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0 5 10• PlasmaSOD1changefromVisit1

toVisit6(week2):P=0.009.

• PlasmaTau:treatedgroupdecreasedwhiletheplacebogroupincreasedatVisit7(week6):P=0.03

• 3PlasmalevelBarChartsfrombaselineonleft:Treatedgroups(Red)andPlacebo(Grey)groupsatvisit4,visit6,visit7andvisit8.

• PlasmaTDP-43:Theslopeof%change frombaselinethroughweek12intreatedpatientsisdecreaseto-3.513.

• Theslopeof%change frombaselinethroughweek12inplacebopatientsisincreaseto0.493.

• P=0.0078

Treated v8

Placebo v8

PlasmaSOD1

PlasmaTau

PlasmaTDP-43

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14 GM6BioinformaticsAnalysisIndicatesTowardstheMulti-targetHypothesis

Toproveourcoremulti-targethypothesis,weusedbioinformaticsresearch,includingDNAmicroarrayandRNAseq,andfoundthatGM6canaltertheexpressionlevelofmanydiseasepathogenesisrelatedgenessignificantly-notonlyinALS,butinotherneurodegenerativediseases.ThisisapartiallistofgenesmodulatedbyGM6.

GM6BioinformaticsAnalysisIndicatesTowardstheMulti-TargetHypothesis

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15 ALS-AssociatedGenesAlteredbyGM6ThisanalysisidentifiedALS-associatedgenesregulatedbyGM6consistentwith6potentialmechanismsofaction.ThefiguresummarizesthesemechanismsandlistsGM6-regulatedgenesthatmayplayamediatingrole.AllgenesshowninthefigurewereregulatedbyGM6ineitherorbothRNA-seqexperiments.Weidentified6potentialMechanismsofActionofGM6inALS:GM6downregulate:Oxidativestress&ApoptosisGM6upregulate:Neurogenesis,Microtubulestability,Immune-mediatedneuroprotection,Synaptictransmission,Glutamateclearance

ALS-AssociatedGenesAlteredByGM6

ThisanalysisidentifiedALS-associatedgenesregulatedbyGM6consistentwith6potentialmechanismsofaction.ThefiguresummarizesthesemechanismsandlistsGM6-regulatedgenesthatmayplayamediatingrole.AllgenesshowninthefigurewereregulatedbyGM6ineitherorbothRNA-seq experiments.

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16 Alzheimer’sDisease-AssociatedGenesAlteredbyGM6Weidentified4potentialMechanismsofActionofGM6inAlzheimer’sDisease.BecauseofthefailureofallA𝛽clinicaltrialsinthelastseveraldecades,theoldA𝛽hypothesishasbeenquestioned.ManypharmaceuticalcompaniesareevenquittingthesearchforanAlzheimer’scure.OurdatashowedthatGM6upregulateA𝛽degradation&clearanceanddownregulateA𝛽toxicity&production.OurdatashowedthattheA𝛽hypothesisisnotwrong,buttargetingitalonecannotcurethepatients.ThemultipleMechanismsofActionrequiredtomodulatepathwaysandgenesmayincludeGM6downregulationofNeuroinflammationandIntrinsicApoptosis

Alzheimer’sDisease-Associated GenesAlteredByGM6

ThisanalysisidentifiedAD-associatedgenesregulatedbyGM6consistentwith4potentialmechanismsofaction.ThefiguresummarizesthesemechanismsandlistsGM6-regulatedgenesthatmayplayamediatingrole.AllgenesshowninthefigurewereregulatedbyGM6ineitherorbothRNA-seq experiments.

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17 Huntington’sDisease-AssociatedGenesAlteredbyGM6InHuntington’sDisease,weidentified6potentialMechanismsofActionofGM6:GM6upregulates:Neurogenesis,Stressresistance,Lysosomebiogenesis&autophagy,andCholesteroltransportGM6downregulates:ApoptosisandMitochondriadysfunction

Huntington’sDisease-AssociatedGenesAlteredByGM6

ThisanalysisidentifiedHD-associatedgenesregulatedbyGM6consistentwith6potentialmechanismsofaction.ThefiguresummarizesthesemechanismsandlistsGM6-regulatedgenesthatmayplayamediatingrole.AllgenesshowninthefigurewereregulatedbyGM6ineitherorbothRNA-seq experiments.

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18 Parkinson’sDisease-AssociatedGenesAlteredbyGM6Weidentified6potentialMechanismsofActionofGM6inParkinson’sDisease:GM6Downregulates:Kinasedysfunction,Cholinergicsignaling,andFreeradicalgenerationGM6Upregulates:GABAactivity,GDNFactivity,andOxidativestressdefense

Parkinson’sDisease-AssociatedGenesAlteredByGM6

ThisanalysisidentifiedPD-associatedgenesregulatedbyGM6consistentwith6potentialmechanismsofaction.ThefiguresummarizesthesemechanismsandlistsGM6-regulatedgenesthatmayplayamediatingrole.AllgenesshowninthefigurewereregulatedbyGM6ineitherorbothRNA-seq experiments.

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19 PartnershipForACureGenervonholdsmorethan80patentsworldwideforMNTF,GM6,andrelatedcompoundsandmethodsanduses.GM6hasobtainedorphan-drugdesignationfrombothFDAandtheEuropeanMedicinesAgency,aswellasafast-trackdesignationtotreatALSfromFDA.Genervoniscurrentlyplanninglate-stageclinicaltrialsforGM6forALS,Alzheimer’s,Parkinson’s,andMSindications.After20yearsoffundingitsownresearchandoperations,GenervonisnowinvitingPharmaceuticalpartnerstohelpadvanceGM6fromadevelopment-stagedrugcandidatetoamarketabletherapyforthemanyvictimsofneurodegenerativediseasesanddisordersthatdesperatelyneedourhelp.Thankyouverymuchforyourattention!

PartnershipForACureAdvancingGM6toamarketabletherapyforthemanypatientsdesperatelyseekinghelp

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CEO, Genervon Biopharmaceuticals New York - … · CEO, Genervon Biopharmaceuticals ... cure for the diseases and disorders of the central nervous system. ... determined when clinical