04-08-09 athersys slides (investor day - final)

8/14/2019 04-08-09 Athersys Slides (Investor Day - Final)

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ForwardLookingStatements

The statements and discussions contained in this presentation that are not historical facts constitute

forwardlooking statements, which can be identified by the use of forwardlooking words such asbelieves, expects, may, intends, anticipates, plans, estimates and analogous or similar

expressions intended to identify forwardlooking statements. These forwardlooking statements and

estimates as to future performance, estimates as to future valuations and other statements contained

herein regarding matters that are not historical facts, are only predictions, and that actual events or

results may differ materially. We cannot assure or guarantee you that any future results described inthis presentation will be achieved, and actual results could vary materially from those reflected in such

forwardlooking statements.

Information contained in this presentation has been compiled from sources believed to be credible and

reliable. However, we cannot guarantee such credibility and reliability. The forecasts and projections of

events contained herein are based upon subjective valuations, analyses and personal opinions.

This presentation shall not constitute an offer to sell or the solicitation of an offer to buy any securities.

Such an offer or solicitation, if made, will only be made pursuant to an offering memorandum and

definitive subscription documents.

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TodaysObjectives

(Re)Introduceyoutoourexcitingcelltherapyroduct latform

Updateyouonourpharmaceuticalprogramstatusandstrategy

Illustratewhywearewellpositionedtocreate

substantialvalue Strongsciencefoundation

Strongcollaborationnetwork

Smart&e icient eve opmentapproac Portfolioofopportunities

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TodaysAgenda

Value creation strate roduct develo ment hiloso h & criteria

HighLevelStrategicOverview

MultiStem

Overviewofkeyprograms&coretechnologies

Productprofile,manufacturing,distinctivenessrelativetoothercelltypes,MOAs,IPsummary

Cardiovasculardisease

Strokeandotherneurologicalindications

Immunologicalconditions

Pharmaceuticalprograms

5HT2cagonistprogramforobesity

H3antagonist/inverseagonistprogramforconditionsaffectingcognition,attention,wakefulness

FinancialUpdate

4

Q&A


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SeniorManagementTeam

GilVanBokkelen,Ph.D.

William(B.J.)Lehmann,J.D.

President&COO

JohnHarrington,Ph.D.

ChiefScientificOfficer

, . .

SeniorVicePresident,RegenerativeMedicine

LauraCampbell

VicePresident,Finance

DeborahLadenheim,Ph.D.

VicePresident,RegulatoryAffairs

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CompanyHighlights

Emergingportfolioofbestinclassproductcandidatesandtechnologies

HighlystandardizedOfftheshelfcelltherapyproduct,producedatscale

MultipleclinicaltrialsinitiatedwithMultiStem,adistinctivebiologic

m n stere w t outt ssuematc ngor mmunesuppress on

Multiplediseaseindicationsindevelopment multiplemechanismsofbenefit

Frost

&

Sullivan

2008

Product

Innovation

of

the

Year

Award

FocusedonCNS/metabolicrelatedindications,includingobesity,cognitionandothers,in

two programareas:5HT2cagonistsandH3antagonists

Attractivesmallmoleculepreclinicalpipeline

RecentsuspensionofdevelopmentofATHX105(5HT2cagonist)forobesity

Publiccompanywithstrongcashposition

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OurBusiness/ValueCreationStrategy

Definingexistingfundamentalchallengesinareasofactivity

Efficientlydevelopaportfolioofprogramswithbestinclasspotential

Committedtomaintainingleanoperationalinfrastructure/modestcoreburn

ApplyaFastFollowerstrategyinmultipleareas

Provenstrategythatofferssubstantialpotentialtoreduceriskanddevelopment

costs,canleadtosuperiorvaluecreationovertime

Leveragepriorknowledge,validation,developmenteffortsofotherstoproducea,

Multiplepotentialadvantagestobeingbestbutnotfirst(butalsoleveraging

earlymoveropportunityinareaswhereitmakessense)

Substantialvaluecreationispredicated onsuccessfulproductdevelopment

Givenattritionindrugdevelopment,mostoneshotwondersdonotsurvive

Portfoliobasedapproachenablesdevelopment&partneringflexibility

Withourcapabilitiesandapproachwehavemultipleshotsongoalandcan

evaluate,pursue

multiple

partnering

opportunities

as

we

advance

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MultiInstitutionCollaborativeCenterofExcellence

inCellTherapy

Founding Members:

9

Deep research /

translational capabilityClinical network

Infrastructure,

support, processing


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SelectedCollaboratingClinicalResearchCenters

10Note:notanendorsement


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SelectedCollaboratingResearchInstitutions

11Note:notanendorsement


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CorporatePartners&Licensees


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GrowingInterestinStemCells&RegenerativeMedicine

November2008 PfizerannounceslaunchofRegenerativeMedicine

Centers

$100millionprogramtodeveloptherapies,focusedinCambridgeUK(brain/sensory)andCambridgeMA(heartdisease/diabetes)

commercializeProchymalandChondrogen(MSC)

$130millionupfront/committed,$1.25billioninpotentialmilestones

OsiristocommercializeinU.S.;GenzymeinRoW

July2008 GSKannouncescollaborationwithHarvardStemCell

Institute

$25millionresearchpartnership

June2008 PfizerannouncesinvestmentinEyeCyte

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MultiStem:Biologic

ProductPlatform

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MultiStem:

A

drug

like

cell

therapy

with

potentia app icationinmu tip e iseaseareas

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WhatisMultiStem?

byisolatingapatentedclassofearlyprogenitorstemcells

(Multipotent AdultProgenitorCells)obtainedfrombonemarrow

.

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MultiStem: BestinClassPotentialAmongCellTherapies

Offtheshelfadministration

Nonimmunogenic Noimmunosuppressionrequired

Welldefined,FDAapprovedmanufacturingprocessinplace(withLonza)

Bankedproduct,highlycharacterized

Largescaleproduction/yield(100kstomillionsofdosespossiblefromasingledonor

representsasubstantialadvantageoveralternativestemcellplatforms)

Wellvalidated&consistentsafetyprofilebasedonextensivepreclinicaltesting

Multiplepotentialmechanismsoftherapeuticbenefit

AdrugliketherapythatisdynamicallyresponsiveTherapeuticeffectprimarilyfactormediated:antiinflammatory/immunomodulatory,

cytoprotective,trophic&growthfactors,angiogenic /vasculogenic

LeadingIPpositionforpluripotent,multifunctionalnonembryonicstemcells

rectce t ssuerep acementp aysam norro e

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MultiplePotentialMechanismsofBenefit

SHIFTINGBALANCE INREPAIRPROCESSES

IMMUNOMODULATION

INFLAMMATIONREDUCTION

CertainSecretedProteins

CYTOPROTECTIONCytokines/Chemokines

GrowthFactors

ANGIO VASCULOGENESISOtherProteins

MultiStem cells

REPLACEMENT

express multipletherapeuticallyrelevant

proteinsatsignificantlevels

&candynamicallyregulate

o erce ypes


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RecentInvestigationalNewDrugApplications

3 MultiStem INDs authorized by FDA within ~12 months (12/07 12/08)

ro oco e ey e emen s

PhaseI, Multicenter,DoseEscalationTrialEvaluatingMaximumToleratedDoseofSingleandRepeatedAdministrationof

Allogeneic MultiSteminPatientswithAcuteLeukemia,Chronic

IVdelivered productPhaseI:openlabel SAD,

MAD

MyeloidLeukemia,orMyelodysplasia AdjunctivetoBM/HSC

transplant

PhaseI,Multicenter, DoseEscalationTrialEvaluatingtheSafetyof

Allogeneic AMIMultiSteminPatientswithAcuteMyocardial

Catheterdelivered product

PhaseI:openlabel(w/reg s ry

PhaseI, Multicenter,DoseEscalationTrialEvaluatingtheSafetyof

Allogeneic MultiSteminPatientswithIschemicStroke

IVdeliveredproduct

PhaseI:blinded, placebo

controlled

Working within Master File framework enables efficient advancement of

20

mu t p e opportun t es


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AthersysStemCellPatentPortfolio

Freedomtooperate

7patent am es

11grantedpatents,approximately110applicationsinglobalprosecution platformcoverage20192028

Coverscellcompositions,methodsofmakingthem,methodsofusingthem

NewIPgeneratedinternally,andthroughongoingoutsidecollaborations

,

Activemanagement,withviewtocompetitiveefforts

targetedresearch,certaingrantfundedprojects

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OverviewofMultiStem ProductionProcess

LotRelease&ProductCharacterization

Testing

Sterility

Potency

PurityandViability

StableCytogenetics

Absenceoftumorigenicpotentialinvivo

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MultiStem:AdditionalSafetyStudies

GLPToxicologyandClinicalPathology(2week,4week)

Studiesindicatenoevidenceofacutetoxicityorabnormalclinicalpathology

GeneticStabilityandTumorigenicityTesting

Karyotypicstability

MCB/clinicalproducttestedinstandardNudemousetumormodels(bothi.v./s.c.)

LongTermGLPHistopathologyAnalysis(oneyearforstroke)

ExtensivehistopathologyanalysisofanimalsreceivingclinicalgradeMultiStemindicatesnoevidenceoftumorigenicityorectopictissueafteroneyear

Nootherabnormalitiesorotheradverseeventsnoted

ImmuneSensitizationAnalysis

sensitizationorabnormalclinicalpathology

GeneExpression,ProteinExpressionandSNPArrayAnalysis

Noevidenceofvariabilit betweenworkin cellbanksand roductionrunsaftersignificantexpansionofclinicalgradecellularproduct

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AdvantagedExpansionProfileforMultiStem

CellExpansionoverTimeHumanCellsIsolatedFromSameDonor

Ex ansion rofile

enablessignificant

manufacturing

advantage,using

Master/Working

CellBank

approach

Days

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MasterCellBankCreation

Isolation/expansionresearchgradeproduct

Routineinternal roductionoflar escaleresearchbanksofhuman,ratandporcinecells

Consistentandvalidatedmanufacturingprocess

Morethan50donormarrowsprocessedwith~7580%successrate

Continuingprocessdevelopment&optimizationwithLonza,butalreadyhaveacommerciallyviableprocess

Clinicalgradeproduct TwoMCBestablishedunderGMP,fullycharacterizedtoenableproduction

runsforclinicaluse(providesamplebasisforproducingmaterialformultipleclinicalstudies,programs)

C inica

gra e

onors:

meet

stringent

p ysica

ea t

screening

in

accordancewithGoodTissuePractices(GTP),withhistoryofpriormarrowdonations

stability)

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CellExpansionfromMasterCellBank(MCB)

CellExpansionfromMCBAveragesfromlongtermexpansionsofclinicalproduct

Stability

(e.g.,growth,

cytogenetics)

ou ngs

4050

we eyon

targetedcell

expansionrange

forclinical

MultiStem expansion

range

10

20

30

2

product

Days

* AdditionaldoublingsfromMCB(itselfexpanded~18doublingsfromdonorisolation)

0

1 4 7 10 13 16 19 22 25 28 31 34 37 40

Cellexpansionrange:productionrundirectfromMCB

Cellexpansionrange:productionrunfromWorkingCellBank

1

2

26Confidential

es a s e rom


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Consistent&WellValidatedProductionProcess

ProductionRuns

(n=8)

from

MCB

AggregateAvg Doublings

Consistentproduct Consistentmorphology,markerprofile Absenceofhematopoieticcontaminants

10

15

ecrete prote nexpress on

Stableproduct

Stablecytogeneticprofile

1,000foldexpansionpotential

0

5 Consistentpotency,viability

Ongoingproductshelflifestudies 2year+realtimedata(viability,cell

Day3 Day

6 Day

9 count,

sterility,

flow) 5yearstabilitytargeted

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ConsistentExpressionofRelevantFactors

ProteinConcentration,MeasuredbyELISAAverageConcentration/StandardizedDose

14

InterleukinC

4.5

5

ml]

GrowthFactorA

180

Chemokine B

46

8

10

12

1.52

2.5

3

3.5

4

Conc

entration[pg/

anda

rdizedtoDose

60

80

100

120

140

0

2

X7032 x7057 x7792 x7793

0

0.5Avg. St

X7032 x7057 x7792 x7793

0

20

X7032 x7057 x7792 x7793

Productionlot

Expressionofproteinsrelevanttopotentialtherapeuticbenefit/

productidentity providesfoundationforpotencyassay

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Mu t tem

ADistinctiveProduct

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TheDistinctiveProfileofMultiStem

,

e.g., Substantialexpansion/productionadvantage

Distinctivephenotypicandfunctionalprofile/characteristics

Somedistinctivemechanismsofaction,thoughsomepotentiallycommon

mechanismsaswell

MultiStem differentiatedrelativetootherstemcelltypes,e.g.,

Immunoprivileged,enablingallogeneic andpotentialofftheshelfusage

o us o og ca ac v y,mu p epo en a mec an smso ene

Manufacturabilityofcellproduct

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DistinctiveTranscriptionProfilesforMultiStem andMSC

ATH113

ATH114

ATH102

ATH104ATH107

ATH103MultiStem

ATH105

ATH117

ATH116

ATH115

0.125 0.100 0.075 0.050 0.025 0

ATH110

ATH111

ATH112

BlindedanalysisofgeneexpressiondemonstratesdistinctivetranscriptionprofilesforMultiStem andMSC

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ax srepresentst ecorre at onva ue.


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DistinctiveProteinExpression

MultiStem MSC

Protein1

MultiStem MSC

Protein2

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Heatmap ofDifferentiallyExpressedGenes:MSC,MultiStem

0.0150 0.009 0.038 0.12

MultiStem1MultiStem2MultiStem3

MSC 1

MSC 2MSC 3

I II I I

MultiStem4go_compon

ent:c

go_compon

ent:e

go_compon

ent:n

go_compon

ent:c

go_compon

ent:n

go_compon

ent:ri

go_compon

ent:n

go_compon

ent:l

go_compon

ent:u

go_compon

ent:n

go_compon

ent:p

go_compon

ent:u

go_compon

ent:n

go_compon

ent:e

go_compon

ent:n

go_compon

ent:c

go_compon

ent:n

go_compon

ent:u

go_compon

ent:n

go_compon

ent:ri

go_compon

ent:n

go_compon

ent:

go_compon

ent:i

go_compon

ent:e

go_compon

ent:l

go_compon

ent:i

go_compon

ent:b

go_compon

ent:u

go_compon

ent:c

go_compon

ent:e

go_compon

ent:u

go_compon

ent:

go_compon

ent:

go_compon

ent:u

go_compon

ent:c

go_compon

ent:e

go_compon

ent:e

go_compon

ent:e

go_compon

ent:c

go_compon

ent:u

go_compon

ent:e

go_compon

ent:e

go_compon

ent:i

go_compon

ent:c

go_compon

ent:e

go_compon

ent:n

go_compon

ent:u

go_compon

ent:c

ytoplasmicvesicle

xtracellularmatrix

ucleus

ytoplasm

ucleus

bosome

ucleus

sosome

ncharacterized

ucleus

eripheralplasmamem

ncharacterized

ucleus

xtracellular

ucleus

ytoplasm

ucleus

ncharacterized

ucleus

bosome

ucleus

icrofibril

tegrincomplex

xtracellular

sosome

tegraltomembrane

asementmembrane

ncharacterized

ytoplasm

xtracellularmatrix

ncharacterized

olgiapparatus

embrane

ncharacterized

ytoplasm

xtracellularmatrix

xtracellular

xtracellularmatrix

ytoplasm

ncharacterized

xtracellularmatrix

xtracellularmatrix

tegraltomembrane

ytoplasmicvesicle

xtracellular

ucleus

ncharacterized

ytoplasm

bran

e

~48,000transcriptssurveyed Correlation>0.99withinMultiStem andMSCsamples,~0.85betweenMultiStem andMSC

Samplingof48genesshowingsubstantialdifferencesbetweenMultiStem andMSC Parametersforaboveheatmap:MultiStemSignal>500andMSC500andMultiStem


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MultiplePotentialMechanismsofBenefit

SHIFTINGBALANCE INREPAIRPROCESSES

IMMUNOMODULATION

INFLAMMATIONREDUCTIONCertain

Secreted

Proteins

CYTOPROTECTIONCytokines/Chemokines

GrowthFactors

ANGIO VASCULOGENESISOtherProteins

MultiStem cells

REPLACEMENT

express multipletherapeuticallyrelevant

proteinsatsignificantlevels

&candynamicallyregulate

o erce ypes


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SelectedResearchonMechanism:Immunomodulation

Broadpotentialrelevanceacrossmultiplediseaseareas

DonotelicitTcellresponseinvitro

(e.g.,MLR)

Immunosuppression notrequiredwithMultiStem administeredallogeneically or

xenogene ca y uman ro ent or ene t nacute orstro emo e s

MultiStem serialadministrationsafe noevidenceofalloantibody/Tcell

sensitization

response

Dosedependentdownregulation ofallo Tcellresponseinvitro(e.g.,MLR)

Reductioninimmuneresponseinvivo(e.g.,GvHD models,AMImodels)

Immuneresponsemo u at onappearstooperate oca yats teo n ury notaglobalimmunosuppressiveeffect(e.g.,ovalbumin studies,homing)

Multiplepathwaysinvolved

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Antiinflammatorycytokines

Otheruniquemechanisms

M l iS I P i il d I Vi


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MultiStemImmunoPrivilegedInVitro

Mixed Lymphocyte Reaction MultiStem does not elicit In VitroT-

Donor 1 Cells

(Rare alloreactive T-cells in red)

Donor 2 Cells

Cell Response in MLR Studies

Mixture

Allogeneic T-cell controls

Recognition of allogeneic cellscauses T-cell activation and

proliferation

Proliferation measurable byincrease DNA synthesis Self to self

T-cells dont reactto MultiStem (MAPC)

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l ll ll


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MultiStemImmunosuppressAllogeneicTCells

MultiStem(likeMSC)Exhibits DoseDependentSuppressionofAllogeneicTCell

ImmunosuppressiveEffectsOnMLR

(human)

160,000

180,000

ResponseinMLR(Lewisrat)

80,000

100,000

120,000

140,000

midinecounts

None 0.03x10 5

0.06x10 5 0.125x10 5

0.25x10 5 0.5x10 5

20,000

40,000

60,0003H-th x x

MAPC(MultiStem)

SuppressesImmune

Response

R (Lewis)+ S (DA) R (Lewis) No responder or stimulator

DoseDependent

Effect

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M ltiSt A ti t d T C ll R lt i G E i Ch


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MultiStem+ActivatedTCellsResultinGeneExpressionChanges

MultiStemresponsewhenexposedtoActivatedPBMCs

MultiStem+Ab,MultiStem+Ab +

activated

PBMC

ActivatedPBMCresponsewhenexposedtoMultiStem

ActivatedPBMC,

activated

PBMC

+MultiStem+Ab

MultiStemresponsetoPBMCactivationagent(control)

MultiStem,MultiStem +

Tcell

activator

(MultiStem+Ab)

ActivatedPBMCs (changerelativetounactivated PBMCs)

PBMC,PBMC

plus

Tcell

stimulator

(activated

PBMC) 38

D namic Reg lation of Acti ated T Cells


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DynamicRegulationofActivatedTCells

3chemokines

ActivatedTCells

13chemokines

5 c tokines

3cytokines

>10receptors

>25secretedfactors >20intracellularproteins

> secre e ac ors

>40receptors

MultiStem3receptors

>40intracellularfactors

39

>10intracellularfactors

F t d i M d l ti f T C ll R b M ltiSt


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FactordrivenModulationofTCellResponsebyMultiStem

EvaluationofContactIndependent/DependentInhibition

inTCellProliferationAssay

100000

120000

3HThymidineIncorporation

60000

80000

ineuptake

20000

40000

Thymi

0

40

MultiStem Inhibits Leukocyte Extravasation


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MultiStemInhibitsLeukocyteExtravasation

MultiStem associatedwithdownregulationofkeyfactorslimitingcellsurfaceexpression

o s eci icrece tors andinhibitin extravasation intoareaso in lammation

Leukocyteextravasation: Contributestoinflammation

andtissuedamage(e.g.in

regionsofischemia)

Occursmainlyinpostcapillaryvenules (minimized

hemodynamicshearforces) Includesseveralsteps,

includingchemoattraction,

rollingadhesion,tight

adhesion,(endothelial)

transmigration

ofthese

steps

is

suppressed

41

MultiStem Reduces Adhesion Receptor Expression on


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MultiStemReducesAdhesionReceptorExpressionon

ActivatedLymphocytes

PBMCPBMC

PBMC+CD3/28

PBMC+CD3/28

FACSprofilesofactivatedlymphocytescoculturedfor72hourswithMultiStem

3% 2% 23% 2%

CD

3% 3% 11% 1%

CD

8

42

CD15s

Y-axes (identified immune cell markers), x-axis (certain adhesion receptor)

In Vivo Studies Confirm Favorable Immunological Profile


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InVivo StudiesConfirmFavorableImmunologicalProfile

Immunosu ressionnot re uiredwithMultiStemusedallogeneicallyorxenogeneically(human rodent)for

benefitinacuteMIorstrokemodels

MultiStemserialadministrationsafe noevidenceofalloantibody/Tcellsensitizationresponse

u u u yresponseregionally,notglobally

Nointerferencewiths stemicimmuneres onse asevaluatedinovalbumin

antigenchallenge

studies

MultiStemhomes/accumulatesinsitesofinjuryinpreclinicalanimalmodels

43

M ltiSt N I t f ith S t i I R


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MultiStem NonInterferencewithSystemicImmuneResponse

Designs

2 5

3

t

Ova-Antibody Measurement

HealthybuffaloratsimmunizedIP

withovalbumin (OVA) Antibodystudy

1.5

2

.

inElisaR

ead-ou

PBS u p e u em n ec onsan

evaluationpointsovertime

Tcellstudy

SingleIVMultiStem injections

0

0.5

1/100 1/200 1/400 1/800 1/1600 1/3200 1/6400 1/12800

Ovalbu

MultiStem

Control

OVAAntibodies:nodifference

Results

200000

250000

PM)

T-Cell Responses

PBS

MultiStem

PBScontrolgroups Tcellresponse: nodifference

betweensystemicallytreated 50000

100000

150000

3H-Thymidin

e(C Nave

Mu t tem an PB groups

44

0

Day 3 Day 4

Day of Measurement

Pathophysiology of Neuronal Retraction Following Injury


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PathophysiologyofNeuronalRetractionFollowingInjury

Immediate

14days

2days

28days

DexTR=Neurons

ED1=Macrophages

CSP=Scar(siteofinjury)

Ratspinalcordcrushmodel

45

Inhibition of Pathways of Inflammation & Neuronal Damage


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InhibitionofPathwaysofInflammation&NeuronalDamage

MultiStemmodulatesmultiplemechanismsthatcandirectlycontributetoreducinginflammation

46

an neuro og ca amage,an sp ays s nc erencesre a ve oo erce ypes.

Figure modified from Jeyakumar et al., Nat Rev Neurosci6:713-725 (2005)


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ClinicalDevelopment

47

FocusedProductDevelopmentApproach


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p pp

o Chronicischemia/CHF

o Peripheralvasculardisease

Acute/Ischemic

Injury

o AcuteMyocardialInfarction

o OtherNeurologicalIndications

o Otherischemicinjury(e.g.,kidney)

(Ph1ongoing)

o IschemicStroke(INDauthorized)

o

InflammatoryBowelDisease

ImmuneSystem

Modulation

o HSC/BoneMarrowTransplant Support/ o MultipleSclerosis

o Diabetes(type1)

o Transplantation

GVHD

(Ph

1

ongoing)o

Otherautoimmunedisorders

Nextgenerationo OtherNeurologicalIndications

Otherthemes,e.g.,proteindeficiencies,

bonegrowth

48


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MultiStemforAcute

MyocardialInfarction

49

MultiStem: AcuteMyocardialInfarction


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y

AMIremainsamajorareaofneedforimprovedtherapies

865,000heartattacksannuallyintheU.S.

156,000deaths

Local(catheter)deliveryofMultiStemfollowingheartattack

Re ucesin ammationre ate amagean promotesrevascu arization

Alsoexploringadministrationviai.v.

INDapproved,clinicaltrialinitiatedwithcodevelopmentpartner(Angiotech)

50

InnovativeApproachtoTreatingHeartConditions


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pp g

Administrationofofftheshelfcellularbiologictoimproveoutcomesandfunction

an ar ze pro uc a m n s ere w ou ma c ng, mmunosuppress onagen s

Productionoftrophicfactorslikelydriverofbenefit

Stimulaterevascularizationandimprovedcirculation

Interveneininflammatoryprocesses

Overrideprocessesofcell/tissuedecline,contributetoendogenoustissueregeneration

Efficientdeliverytoinjurysitewithmicroinfusioncatheter

m n s ra ono ce pro uc n oper vascu arreg on

Relativeeaseofuse,comparabletostandardangioplasty

AlsoexploringIVdeliveryascomplementaryapproach(ifmultipletreatmentbelievedtobebeneficial)

oralternative

51

ExtensiveCardiovascularPreclinicalDevelopmentEfforts


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CellSafety/Biodistribution

. ., , , , ,allogeneic;humancellsinNOD/SCIDmice;human&pigcellsinnudemousestudies

Absenceoftumororectopictissueformationinallmodels nudemicei.v.&s.c.;NOD/SCID

Preclinicalproofofconcept:allogeneicutilityanddose

Rodents permanentischemia(vantHofetal,Cytotherapy,2007)

Pigs permanentischemia,directinjection(Zengetal,Circulation,2007)

Pigs transientischemia,catheterdelivery,exploringadministrationtiming,alternativecatheters

Deliverydeviceperformanceandsafety

Biocompatibilitystudiesshowhighviabilityandefficientdelivery

Stentandtraumastudiesshowedsafedeliveryinmodelsreflectinghumandisease

GLPstudy

Pi s transientischemia catheterdeliver

52

RatLADLigationModel PotentialMechanisms


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g

Neutrophil countininfarcted hearts Reductioninneutrophil tissueelastase

RatIschemiaModels directinjectionininfarctzone

p=.005 PBS MultiStem

Day3

esse ens y

40

sels/mm^2 * p


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y pp

MercatorMedSystems,510(k)approvedMicroSyringe InfusionCatheter

Sitespecificdeliveryintoperivascular spaceandadventitia

Retaingreaternumberofcellsat/nearinjurysite(reducewashawayofcellsintobloodstream)

Relativeeaseofuse

Goodcellviability,efficienteaseofuse

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BiocompatibilityofMultiStemwithCatheterDelivery


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MultiStem followingcatheter

Viablecellrecovery,

passage(micrograph)

200

250

300

Millioncells

0

50

100

150

Cellsinfused Viablecellspostinfusion

55

ImprovementsinFunctionalPerformanceObservedinGLPStudy


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LongtermsafetystudyinAMIpigs

DeliveryofMultiStem withthetransarterial catheter2daysafter

LeftVentricular

Ejection

Fraction Wall

Motion

Score

(Echo)

trans ent sc em a

*

*

56

PhaseIClinicalProtocolSummary AMI


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PhaseIStudy,openlabel,doseescalation

STEMI,LVEFbetween3045%

AdministrationofMultiStemincoronaryartery(viatransarterial catheter)

deliveredonday25afterAcuteMI

Objectives

Multiplesites,largelyregional

Primaryendpoints:safety (drugorprocedurerelatedarrhythmias,acute

toxicity,hospitalization, death,mechanicalcomplication)

Secondaryendpoints:functionalitymeasures(e.g.LVEF)

Strategy

Providesafetyfoundationandinformationtoenabledesignofmeaningful

P aseIIexp oratorystu y e.g., ose eve s, e iverytiming

57


58/122

UpdatefromOngoingPhaseIStudy


59/122

Sevenclinicalsitesscreening,enrollingpatients

Leadingcardiovasculartreatmentcenters,clinicalresearchers

participatingintrial

ClevelandClinic,Henr Ford,Universit ofMichi an,ColumbiaUniversit ,CareGroup

Selectregionalcardiovasculartreatmentcentersalsoparticipating

, ,

registrypatientsonstudy

8th siteinitiatingandpotentialtoaddotherclinicalsitesifnecessary

Targetenrollmentcompletionbyendofyearandannouncementof

toplineresultsshortlythereafter

59

CardiovascularAreaStrategy


60/122

Establish,andthenleverage,initialproofofconcept

Standardized/scalableproductmanufacturing,preclinicaldata,delivery,mechanism,basicsafetyinhumans

EstablishinitialhumansafetyinAcuteMIsetting:allogeneic MultiStem,catheterdeliveredincriticalsetting

Leveragedatafromother(noncardiovascular)trialsasnecessary(e.g.,IVdelivery)

Establishefficacyproofofconceptinspecificindicationsthroughfocused

exploratorydevelopment Studieswithdiscreetendpoints/readoutsovershortterm showingofdesired

biologicalactivityandbenefit

Levera e BB13554 to ste out into other indications where a ro riate

Sharerisksandinvestment cardiovasculardevelopmentcanbedifficult

Somestategrantfunding

60

Partnership(e.g.,Angiotech)


61/122

MultiStemforIschemicStroke

andOtherCNSIndications

61

MultiStem: IschemicStroke


62/122

SubstantialunmetneedinthetreatmentofIschemicStroke

Approximately780,000strokesannuallyinU.S.in2008,and~85%+ischemicstrokes

(Note:Thisnumberexpectedtoincreaseovertimeasrisktoboomersgrows)

Substantialfunctionallossandrehabilitationandfollowupcarecosts

Limitedtreatmentoptions,rtPA mustbeadministeredwithin3hrsofstroke

IVdeliveryofMultiStem 48 60hoursfollowingIschemicStroke

Broadpotentialtreatmentwindow

Benefittrophicfactormediated:reduceinflammation,stimulaterevascularization,

overrideprocessesofcell/tissuedecline&contributetotissueregeneration

INDauthorizedDecember2008

MultiStem demonstratedsafe

and

effective

in

pre

clinical

models

62

AnimalModelsofCerebralIschemia


63/122

MCA Occlusion

MCA Ligation

63

Motor and Neurological Tests Overview


64/122

EBST(ElevatedBodySwingTest)

GrossMotorTest

50%=NormalBehavior

Bederson Test

Batteryof4NeurologicalTests

EachTestcanbescoredfrom0(NormalBehavior)to3(AbsoluteNeurological

All4scoresareaddedthendividedby4togiveanaveragescore

Tests:

ps a era rc ng ross es

2) HindLimbReplacement(GrossTest)3) BeamWalking(FineTest)

4 Bilateral Fore aw Gras Fine Test

64

PreClinicalExperimentalApproach


65/122

Experimentalapproach

Immunosuppression notrequiredforsafeimprovementto

neurologicalfunction

Significantfunctionalimprovement(locomoter,neurological)

1. Immunosuppression(+/)withallo/

xenogeneic cells,intracranialdelivery

2. Routeofadministration:viabilityofIV

statisticallyovercontrol

Comparableimprovementinlocomotor orneurologicalfunctionobservedamonganimalsreceivingcellsat1,2or7

days

3. Deliverywindow:17dayspoststroke

4. Doseescalation

DoseresponseobservedwithIVinfusedcells,asmeasuredbyneurologicalimprovement

Engraftedcellsdisplayneuronalmarkersinneonatalmodel

Noabnormaltissuesorabnormalpathologyobservedin

animalskeptonstudyfor1yearpostcelltransplantation

65

Allogeneic/XenogeneicCellsShowSignificantImprovement+/ CsA


66/122

3re

2logicsc

1

****anneur

**** * * * ** * * ***0

Baseline Post 14 28 42 56

M * * * ** * * ***

ICRatMPCs+Vehicle ICRatMPCs+CsA

IC Human MPCs + Vehicle IC Human MPCs + CsA

stroke

ICRatMultiStem +Vehicle ICRatMultiStem +CsA

IC Human MultiStem + Vehicle IC Human MultiStem+ CsA

Daysposttransplant:

66

Control(IrradiatedMPCs+CsA)

Control(IrradiatedMultiStem +CsA)

IVDeliveryWindow:EquivalentBenefitacrossWindow


67/122

EquivalentFunctionalImprovementSeenWhen1MillionXenogeneic

MultiStem AreTransplantedIVonDays1,2or7PostStroke

67

CellDeliveryonDay1 CellDeliveryonDay2 CellDeliveryonDay7 NonViableCellDelivery

onDay7

EarlierIVdeliveryResultsinGreaterCellSurvival


68/122

Day1celldeliveryprotectspenumbrabetterthanday2

andday7delivery

68

SingleDoseofHumanMultiStem ProvidesRobust,DurableImprovement

inRodentModelofIschemicStroke


69/122

Bederson Composite Score of Neurological Function,IV-deliveryof MultiStem day 2 post-stroke

Dose response

Therapeutic benefitproportional to doseS

core

2.5

delivered

Treatment timing Improvement

e

urologica

1.5

day 1, 2 or 7

MeanN

0.5

Baseline

Pos

t-

Stroke

Day14

Day28

Day

42

Day56

.

1 units

2 units

10 units20 units

10 units non-viable cells (control)

69

AthersysinLeadershipPositionforStrokeCellbasedTherapy


70/122

Stemcell

Therapeutics

as

an

Emerging

Paradigm

in

Stroke

(STEPS)Conference

BridgingBasicandClinicalScienceforCellularandNeurogenicFactorTherapyinTreatingStroke,ArlingtonVA,October27 28,2007

50participants/6countries(Academia,Industry,FDA,NINDS)

Athersyswasanorganizer/contentleader

Positionedtodefinethelandscapeforcellbasedtherapyinstroke

Majortopicsofdiscussionincluded:(1)mechanismsofactionsofcellular

t erapy, trans at on roman ma mo e sto umanc n ca s tuat on,an

clinicaltrialdesign

Publication,BridgingBasicandClinicalScienceforCellularandNeurogenic

. . .

Athersyspositionedasanindustryleader IncreasedFDA/thoughtleaderexposuretoAthersysapproachandperspectives

Newcenters/investigatorsandadvisorsidentifiedandbroughtonboard

70

PhaseIClinicalProtocolSummary IschemicStroke


71/122

PhaseIstudy,doubleblind,placebocontrolleddoseescalation

Ischemic stroke: DWI lesion defined severit arm weakness

AdministrationofsingledoseofMultiStemintravenously,48 60hpoststroke

Fourdosetiergroupsincludingplacebo(2:1)

Modifiedcontinualreassessmentmethodology

Multiplesites

Objectives

Primar end ointssafet maximumtolerateddosebasedoncom ositeofDLTsandAEsthroughfirst14days

Secondaryendpointsincludefunctionalityoutcomesat30,90,180days,and1year

Strategy

Establishdosesafetyandtolerabilityofcellproduct(e.g.,doselevels,deliverytiming)toenablephaseIIproofofconceptstudy

71

AdditionalResearchCollaborationsinCNSArea


72/122

Researchstrategy

Workwithinde endentresearchlaboratoriestoestablish reclinical roofofconceptinselecteddiseases/conditions

DevelopbetterunderstandingofMultiStemsmodesofactionindifferent

Researchcollaborations

, ,

Spinalcord&neurologicalinjury,CWRU

Amotro hic Lateral Sclerosis U. of Wisconsin

ParkinsonsDisease,U.ofCincinnati

Lysosomaldisorders(Hurlers),U.ofMinnesota

72

Stroke,TraumaticBrainInjury,UTHouston

MultiStem: PotentialinOtherNeurologicalInjuryModels


73/122

Profileforneurologicalinjuryanddisease

MultiStem associatedwithsubstantial,durablefunctionalimprovementinmultiple

models(e.g.,ischemicstroke,neonatalhypoxicischemia,orphandiseaseindications)

Benefitsseenusinglocalizeddeliveryorintravenousadministration

Inindependentstudiesconductedinleadingneurosciencelabs,biological

mechanismsofbenefitobservedthatarenotseenwithothercelltypes

Multipletrophic factorsexpressedbyMultiStem thatappeartodirectlyaffectfunctionandhealthofneurologicaltissue

Substantialunmetmedicalneedsexist

Hypoxicinjury neonatalhypoxicischemiaisaleadingcauseofCerebralPalsyProgressiveneurologicalconditions,especiallythosewherechronicinflammation

73

MAPCProvideBenefitinHypoxicIschemiaModel


74/122

Surgicallyinducedhypoxicischemicinjury

afterbirth

Syngeneic v.allogeneic (ICdelivery)study

n racran a v. n ravenous(allogeneic)study

Vehiclecontrols

Behavioraltests(rotarod,EBSTatays7an 4posttransp ant

Sacrificeatd14posttransplant,followedbytissueevaluation

74

See Yasuhara etalCellTransplant(2006);Yasuhara et

alJCerebralBloodFlowMetabolism (2008)

MAPCReducesDamagefromInjury


75/122

ControlIntact

AllogeneicSyngeneic75

ReductioninCellLossRelativetoVehicle


76/122

CellLossinHippocampal CA3Region,MeasuringInjuredSideRelativetoIntactSide

100

tsid

e

* *

60tointa

40

),injure

0Ratio

(

Syngeneic Allogeneic Vehicle

76

IVdeliveredMAPCReduceCellLoss


77/122

Intact Vehicle

MAPC,ICMAPC,IV

77


78/122

SupportintheHematological

Malignancies

78

MultiStem: Transplantation(GvHD)


79/122

Frequent,potentiallylifethreateningconsequenceofHSC/BMtransplants

Clearneedforimprovedtreatmentsbeyondbroadimmunosuppression

Limitedtreatmentoptionsforcomplications(e.g.,GvHD)

. .,

IVdeliveryofMultiSteminconjunctionwithHSC/BMtransplant

Re uctiono GvHD impactan promotiono tissueregenerationan engra tment

PotentialforGvHD intervention

INDapproved,clinicaltrialinitiated

79

MultiStemProvidesSurvivalAdvantageinRatAcuteGvHD Model


80/122

Design

Ratssublethally irradiatedandinjectedwithbonemarrowcellsandTcellsfromdifferentratstrain creatin 80%

90%

100%

Survival

Graftvs.Hostimmuneresponse

MultiStemadministeredI.V.atday1,oratdays1and8 50%

60%

70%

10%

20%

30%No treatment

Treatment, day 1

Treatment days 1+8Results

benefitversusanimalsreceivingnotreatment

BenefitsobservableforotherGvHD

0%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Days

Significant survival advantage in MultiStem treated animals

n ca ors o ywe g ,ac v y,posture,furtexture,skin)

Note: Published work from other labs did NOT demonstrate a durablesurvival advantage following administration of MSCs in GVHD models

80

MultiStemHominginMouseGvHDModel


81/122

MultiStemIntravenousInfusioninMouseGvHDModel

6hoursposti.v. 24hoursposti.v.

81

GutPathologyinRatAcuteGVHDModel


82/122

Day15Pathology,MultitreatmentGroup

GVHD,PBSControl

Treated

,

Treated

Substantiallyless

gastrointestinaldamage

animals

82

PhaseIClinicalProtocolSummary


83/122

PhaseIstudy,openlabel,doseescalation

Patients(leukemia,myelodysplasia)undergoingPBSC/bonemarrowtransplantation

AdministrationofMultiStemintravenously

Twotreatmentarms:Singledosecoadministeredwithtransplant,multipledoses

Objectives

Continualreassessmentmethodology

Primaryendpoints:safety:maximumtolerateddosebasedoncompositeofDLTsand

AEsthrough30days

Secondaryendpoints:incidenceandseverityofGVHD,survival,infection

Strategy

Providesafetyfoundationtoallowfor(a)prophylactictreatmentandinterventionfor

GVHD,and(b)singleandmultipledosetreatmentapproaches

83

UpdatefromOngoingPhaseIStudy


84/122

Threeclinicalsitesscreening,enrollingpatients

Leadingbonemarrowtransplantclinicalresearchersatacademic&

clinicalresearchinstitutions(UniversityHospitals,OregonHealthSciencesUniversity,OhioStateUniversity)

Firstdosingcohort(lowestdose)enrolledandtreatmentadministered;

CRMusedtogovernstepupsinsubsequentdosinglevel(s)

Enrollmentslowerthanexpected

Activities&optionstoaccelerateprogress

Improveenrollmentdynamicsandperformance

Increasenumberofsites,potentialprotocolamendmentstoincrease

numberofeligiblepatients

ConsideringpossibleimplementationofGvHD treatmentarm

Maysupportstepouttotreatmentofotherimmunologicalconditions

84

OtherImmunomodulationOpportunities


85/122

Treatingemergentorchronicautoimmunedisease

ImmunomodulatoryactivityofMultiStemforGVHDismechanisticallysimilarto

biologicalconditionsinmanyotherindications

Rapidclinicalentryispossible(leveragingoffofexistingpreclinicalandclinicaldata)

Multipleindicationspossible

Manufacturingcapabilityalreadyinplace

Widerangeofautoimmuneconditionswithunmetmedicalneedaspotential

therapeutictargetsforMultiStem

Otherpotentialbenefitstohelpaddresstissuedamage

I.V.delivery

PotentialtoleverageINDBB13507(EvaluationofMTDofSingleandRepeated

AdministrationofAllogeneicMultiSteminPatientswithAL,CMandMyelodysplasia)

85

RecentPublications


86/122

Cardiovascular Vant HofW,MalN,HuangY,etal. Directdeliveryofsyngeneic andallogeneic largescaleexpanded

multipotent adultprogenitorcellsimprovescardiacfunctionaftermyocardialinfarct. Cytotherapy. 2007

9(5):477487.

Zeng L,Hu Q,WangX,etal. Bioenergetic andFunctionalConsequencesofBoneMarrowDerived

Multipotent ProgenitorCellTransplantationinHeartswithPostinfarction LeftVentricularRemodeling.

Circulation. 2007115:18661875.Aranguren X,McCueJ,Hendrickx Betal. Multipotent adultprogenitorcellssustainfunctionofischemic

limbsinmice. J.Clin.Investigation.2008118(2):505514.

Wragg A,Mellad JA,etal. VEGFR1/CXCR4positiveprogentior cellsmodulateinflammationandaugment

tissueperfusionbyaSDF1dependentmechanism. JMolMed.200886(11):122132.

Hematology/ Kovacsovics M,StreeterP,Mauch Ketal. Clinicalscaleexpandedadultpluripotent stemcellsprevent

Immunology graftversushostdisease. CellularImmunology. 2008.

YSerafini M,Dylla S,WeismannIL,etal.Hematopoetic reconstitutionbymultipotent adultprogenitor

cells:precursorstolongtermhematopoetic stemcells.J.ExperimentalMedicine.2007

CNS/Stroke MaysR,Van't HofW,DeansR,etal.Developmentofadultpluripotent stemcelltherapiesforischemic

injuryanddisease.ExpertOpin.Biol.Ther.2007;7(2):173184.

Yasuhara T,HaraK,MakiM,etal.Intravenousgraftsrecapitulatetheneurorestoration affordedbyintracerebrally deliveredmultipotent adultprogenitorcellsinneonatalhypoxicischemicrats.JCerebral

BloodFlow&Metab.2008,17.

Yasuhara T,MatsukawaN,YuG,etal.Behavioralandhistologicalcharacterizationofintrahippocampal

graftsofhumanbonemarrowderivedmultipotent progenitorcellsinneonatalratswithhypoxic

ischemicinjury.CellTransplant.200615(3):231238.

86

ThinkingAheadPlatformforMultipleProductOpportunities


87/122

Potentialforaddressingmultipleindications

MultiplepossiblemechanismsofactionfromMultiStem

Broadlyapplicable

mechanisms

of

action,

e.g.,

immunomodulation

Administration,dosing,formulation

Newproductdevelopment;certainvariantsmayperformbetterthanothersforcertainindications

Broadtechnologyplatformandintellectualpropertycreates

Enhancedbiologicalactivitytargetedtocertainconditions,indications

87

Furtheradvantagedproductionandadministrationcharacteristics


88/122

PharmaceuticalPrograms

88


89/122

Obesity

5HT2cAgonistProgram

ObesityMarketOpportunity


90/122

ClinicalLandscape

Growing,globalhealthepidemiccontributingtoheartdisease,diabetes,cancerandstroke

Estimated30%ofAmericansareclinicallyobese(BMI> 30);anadditional~30%are

overweight(BMI> 25)

. .

Trueblockbusterpotentialforsafeandeffectivetherapies

Increasingrecognitionofobesityasseriousmedicalcondition

Nohighlyeffective&safedrugtherapiescurrentlyonmarket fewinclinicaltrials

Severaltargetsarewellknownbuthavenotbeeneffectivelyexploitedtodate

Largepotentialmarket,patientvariability(efficacyandtolerability)createsroomformultipleplayersandMOAs

ObesityProgram Overviewof5HT2cAgonists


91/122

5HT2c(serotonin)receptoragonistswellknowntosuppressappetite&causeweightloss

Mechanismextensivelyvalidatedinhumans(e.g.fenfluramine,

dexfenfluraminerecognizedashighlyeffectiveweightlossagents,recent

Lorcaserin data)but

onse ect veagents en uram ne, ex en uram ne a soact vatet e

receptorintheheartandcausecardiovasculartoxicity(valvular hypertrophy=

valvular regurgitation/heartmurmur)

Effectalsoobservedclinicallywithotheragents(pergolide,cabergoline)that

activate5HT2breceptor,butnot5HT2c,5HT2a(NEJMJan,07 seeRothetal)

Otheragents(lisuride)thatarehaveagonistactivityat5HT2cand5HT2adonot

causevalvulopathy

Selective5HT2cagonists(i.e.thatdonotstimulate5HT2b)believedtobesaferecentLorcaserin clinicalexperienceprovidesimportantvalidation

Selectivityrelativeto5HT2aimportanttolimitingCNSrelatedsideeffects

ATHX 5HT2cAgonistProgramSummary


92/122

Programthesisandfocus

Thesis:Compoundsthatdisplaysuperiorselectivityfortarget(5HT2c)relativetoother

serotoninreceptors(5HT2b,5HT2a)willbebettertolerated,safer,andmoreeffective

Focus:Developmentofasafer,bettertolerated,andmoreeffective5HT2cagonist

Highbindingaffinity,fullagonistactivityattarget5HT2creceptor

Highqualityportfoliooftherapeuticcompoundsestablished

u s an ngse ec v y oro ersero onerg c recep ors, npar cu ar an a

Extensivelyscreenedtoensureselectivityagainstbroadrangeofotherreceptorsystems

ATHX105wasourlead(3PhaseItrialscompletedin2008demonstratinggoodsafety

andtolerability,outstandingregionalabsorption,highrelativeexposurelevels)

ATHX105placedonclinicalholdduetocompoundspecificnonclinicaltox finding(prior

tocommencementofplannedPhaseIIstudy) subsequentlysuspended

Programcurrentlyfocusedonidentificationofclinicalcandidatewithbestinclass

potentialbuildinguponsubstantialexperiencebase

ATHX105 DemonstratedReductioninFoodIntake&Weight


93/122

AdministrationofATHX105toObeseZucker Rats(QD)

200

250

300

take(g)

*

Vehicle

Fen(10mpk)

ATHX105

(2.5

mpk)

ATHX105(5.0mpk)

ATHX105(10mpk)

EffectonFoodIntake

6.0*

Administrationof5HT2c

antagonistreverseseffect

50

100

150

CumulativeFoodIn

*

***

* **

*

****

*

**

mp

ATHX105(40mpk)

nsumption(g)

3.0

4.0

5.0

*

00 2 4 6 8 10 12 14

TimeAfterInitialDose(days)

4HoursAfterDosing

FoodCo

0.0

1.0

2.0

*

EffectonBodyWeight

0

Vehicle

Fenfluramine(10

mpk)

ATHX105(10mpk)

SB242084(3mpk)50

40

30

20

100

ngeinBodyW

eight(g)

*

*

*

* *

**

**

*

*

*

*

93

SB242084(3mpk)+

ATHX105(10mpk)

p


94/122

Keystudyobjectivesandparameters

,

StudyconductedintheU.K.withCharlesRiverLabs

Basic

design: Doubleblind,placebocontrolled

Twopartstudy:SADandMADadministration

MalesandfemaleswithtargetBMI25 35(overweighttomodestlyobese)withinagerange

18to65years

Typically8subjectspercohort(6subjectsonATHX105and2onplacebo)

107totalsubjectsevaluatedinthestudy

Evaluatedfollowin doses:2m 6m 20m 50m 100m 150m

Singleascendingdosestudy

Multipleascendingdosestudy

Fedfastedarmconductedat50mgdoseleveltoevaluateeffectoffoodondrugabsorption

AdministrationofATHX105orplaceboforoneweek

Evaluatedfollowingdoses:25mg,50mgand75mgQD,and50mgBID94

ATHX105 SummaryofPhaseIResults

Good safety and tolerability profile observed


95/122

Goodsafetyandtolerabilityprofileobserved

Maximumtolerateddose=100mg

Generallywelltoleratedatdoselevelsbelow100mg

Nosevereadverseeventsoccurredatanydose

Noseriousadverseeventsordiscontinuationsduetoadverseevents

Adverseeventsgenerallymildandtransient(e.g.headaches,nausea,dizziness)

Noclinicallysignificanteffectsonheartrate,bloodpressureorEKGparametersat

anydose

Otherhighlights

Noclinicallysignificanteffectsonanyhematologyorclinicalchemistryparameterat

anydose

Wellabsorbed gooddrugexposureobservedFoodhadnoeffectontotaldrugexposure

Maximumdrugconcentrationobservedtobedoseproportionate

SubsequentPhaseIstudydemonstratedoutstandingregionalabsorption95

ATHX105: SuperiorSelectivityvs.Lorcaserin,Fenfluramine

SelectivityRatiosfor5HT2cvs.5HT2b,5HT2a


96/122

Selectivity Ratios for 5HT2c vs. 5HT2b, 5HT2abasedonbindingaffinity(Ki)ateachreceptor

235250 50

5HT2c/5HT2a5HT2c/5HT2b

100

150

200

20

30

40

0.512

0

50

Fenfluramine*

(Norfenfluramine)

Lorcaserin** ATHX10 5

3

8

0

10

Fenfluramine*

(Norfenfluramine)

Lorcaserin** ATHX105

ATHX105displayssubstantiallybetterselectivityfortargetrelativeto5HT2b

res onsibleforcardioAEs

ATHX105displayssubstantiallybetterselectivityfortargetrelativeto5HT2a

res onsibleforCNSAEs e. .nausea,dizziness

* FromFitzgeraldetal(2000)Mol.Pharmacol.57:7581

** FromThomsenetal(2008)J.Pharmacol.&Exp.Therapeutics,Online,02/05/08. Basedonfunctionalassays,Lorcaserinsreported2c/2band2c/2a

selectivityis105xand19x,respectively(whichisalsoinferiortoATHX105sselectivitybasedonfunctionalassays).

ATHX105WelltoleratedatHighPlasmaDrug

Concentrations

Plasma Drug Concentrations at MTD


97/122

3

PlasmaDrugConcentrationsatMTD

1

1.5

2

.

* Arena Poster Presentationat 2009 NAASO meeting

** Athersys Phase I study

0

0.5

Lorcaserin* ATHX105**

Lorcaserin hassimilarpotencyat5HT2c,butATHX105isapproximately5foldmore

selectiveat5HT2a

,

thanlorcaserin

Higherselectivityat5HT2aappearstoleadtobettertolerabilityathighdrug

concentrations,allowinghigherdosestobeadministeredtoachievesuperiorefficacy

97

RelativeDrugLevelsofATHX105


98/122

300

250

ml)

150

HX-105(ng

Immediate ReleaseDistal Small Intestine ReleaseColon Release

50

100A

0

0 5 10 15 20 25 30

Time Post-Release (hrs.)

98

CompetitiveLandscape RecentResultswithLorcaserin

Top line BLOOM date announced March 30, 2009


99/122

ToplineBLOOMdateannouncedMarch30,2009

Wei htlossstatisticall si nificant but erha slessthanwhatwasho edfor

Importantly Noevidenceofvalvulopathy issuesseenpreviouslywithfenfluramine

anddexfenfluramine

Rimonabant andotherCB1antagonists(i.e.anxiety,depression,suicidalideation)

Appearstobeclearroomforimprovementinmultipledimensions,includingefficacy,

tolerabilit convenience

FenPhen stillappearstobemosteffectivecombinationtherapydevelopedtodate

Historicalsafetyliabilitiesforthisclassnowwellunderstood,clinicallyvalidated

.

Selectivityfor5HT2creceptorvs.5HT2areceptorimportantfortolerability,maximizing

exposurewhileminimizingCNSsideeffects

Wei htlosseffectisdose ro ortional,soex osurelevelandthera euticindex/windowis

keytoachievingmaximumtherapeuticeffectwhileachievingtolerability,convenience

99

CombinationWeightLossAgents


100/122

Trial

Agent %WeightLoss(placeboadjusted)

Duration(weeks)

Fenfluramine/Phentermine (FenPhen) 1112% 34 wk(1992 Weintraub etal.)

Topirimate/Phentermine (Qnexa)(Phase3Equate trial)

7.5% 28wk

Bupropion/Naltrexone (Contrave)(Phase3NB302trial)

4.2% 56wk

(Phase2 trial)

. .

100

5HT2cAgonistProgramSummary


101/122

5HT2cReceptornowextensivelyvalidatedasanobesitytarget

Inourviewtheidealcompoundorcombinationforobesityisyettobedeveloped

BestinclassselectivityachievedbyATHXforcompoundstargeting5HT2creceptorvs.

5HT2b,2a

SubstantiallyhigherdrugexposurelevelsforATHX105relativetoLorcaserin

ExtensiveknowledgedevelopedaroundMOAandSAR

,

,

focusedon:

Continueddevelopmentofpotent,selective5HT2cagonistswithimprovedcharacteristics

, , ,

Improvedpotency,selectivity,halflife&retentionofotherdesirablecharacteristics

EliminationofcompoundspecificliabilityseenwithATHX105

Evaluatingpotentialpartneringopportunities

101

Cognition&Wakefulness H3AntagonistProgram

Histamine H3 Receptor is a Highly Validate Target


102/122

HistamineH3ReceptorisaHighlyValidateTarget

ow osesan agon s sor nverseagon s s ncrease s am ne eve s,promo e

wakefulness,attentionandcognitiveperformance

Multipleindicationspossible(i.e.recognizedintheliterature)includingnarcolepsy/EDS,chronicfatigueassociatedwithParkinsonsorotherconditions,ADD/ADHD,

Schizophrenia,Alzheimersandotherdementias

Athigherdoses,potentialtoreduceappetiteandfoodintake?

Multiplehighlypotent,selectivechemicalseriesdeveloped

Initialsafetyandefficacydatademonstratedinanimalmodels

u p epa en app ca ons e

Initiallead

compound

highly

effective

but

produced

phospholipidosis in

rats

(also

observedwithothercompoundsdescribedinliterature)

notproducephospholipidosis

Multiplepromisingpotentialclinicalcandidatesunderevaluation 102

HistamineH3ReceptorBiology


103/122

Esbenshade et al., Molecular Interventions(2006) 103

EarlyLead(ATH90879)Profile

Highlyefficaciousinanimalmodels

Minimumefficacydoseinsleep


104/122

Minimumefficacydoseinobesity200mg/kginrats

NoCNSclinicalobservationsatanydosetested

ExcellentPharmacokineticProfile

LongHalflife(6hrs.inrats,4.5hrs.inmonkeys,>10hourspredictedforhumans)

Orallybioavailable(50%inrats,35%indogs)

Excellentbrainpenetration(22foldhigherbrainexposurevs.plasma)

Hi hl Selective

>1000foldvs.otherhistaminereceptors

NomeaningfulinteractionatHergchannel,oranyofthe70otherreceptors,channels,andenzymestestedtodate

NogenotoxicityobservedinAmesandChromosomeAberrationassays

Noorgantoxicityorclinicallymeaningfulbloodchangesobservedin14dayratsafetystudy;however,dosedependentphospholipidosisobservedinthelungs

Extensiveeffortundertaken toidentifyaclinicalcandidatethatdoesnotproducephospholipidosis

104

ATH90879 PositiveEffectonWakefulness


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Adultmaleratsfittedwithelectrodestorecordbrainwavesleeppatterns 70

80

90

* * *

% Total Response Time - Wakefulness

Drugsadministeredi.p.immediatelypriortostartoftheanimalssleepcycle

40

50

60

WakefulnesssignificantlyincreasedbyATH90879and theeffectofmodafinil Provi il 0

10

20

30

Noobservablehyperactivitycausedby

ATH90879

Vehicle 1.25mpk

5mpk

20mpk

Caffeine300mpk

Modafinil150mpk

ATH-90879

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SafetyProfileConsiderationsforH3Antagonists

Potency and selectivity are key parameters


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Potencyandselectivityarekeyparameters

Selectivityagainstbroadrangeofotherreceptorsystems

Phospholipidosis Anunderappreciatedpotentialriskfactor

Phospholipidosis =phospholipid accumulationthatmayoccurincertainorgansthat

canresultinlongtermtoxicityandtissuedamage(e.g.interstitiallungdisease)

phospholipidosis

Easytomissinanimalmodelsduetotypicallyshorthalflifeofcompoundsinrodent

models,limitedexposures

Sensitiveinvitro assa sdesi nedtodetect hos holi idosis

ATHXhasestablishedrigorousscreeningcapabilitiesforphospholipidosis

Carefulinvivoassessment

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InVitro EvaluationofPhospholipidosis

Acetominophen10uM


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p

(NegativeControl)

Competitors

CompoundATH91313

Amiodarone10uM

(PositiveControl)

ClinicalstageH3antagonistsdevelopedbyother

109

ATH91263isaPotentInverseAgonist

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100

60

80

ima

l)

20

40

inding(%ma

20

0

vehicle 100nMRa 10uM 10nMATH

GTPSb

IC50

(nM)

ATH0.71

60

40

110

PharmacokineticsofATH91263inRats

Drug Concentrations Following


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Dose ProportionalityDrug Concentrations Following

5000

6000

16001800

2000

/ml)

Plasma

Brain

3000

4000

ax(ng/ml)

800

1000

1200

1400

ntration(n

0

1000

0 50 100 150 200 250 300 350

C

0

200

400

600

Conc

Dose (mg/kg)Time (hrs.)

- , ,dose proportionate

111

ATH91263IncreasesCumulativeWakefulness


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112

ATH91263IncreasesWakefulness


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Oral administration at beginning of dark cycle, n=8 rats, cross-over design

ATH91263DoesNotProduceHyperactivity


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PropertiesofHistamineH3Leads

HighlyPotentandSelective 300pMathumanH3,3nMatmouseH3

1 000 f ld h hi i


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>1,000foldvs.otherhistaminereceptors

NomeaningfulinteractionatHergchannel(>10uM)

NocytochromeP450interactions(IC50 >10uMforeachmajorCYP)

Nointeractionsinbroadselectivityscreen(IC50 >10uMforallproteinsinPanLabspanel)xce en armaco ne c ro e

LongHalflife(>6hrs.inrats) Orallybioavailable >60%freedrugconcentrationinratsandhumans

Goodbrainpenetration(IC50) NoevidenceofPhospholipidosisusinginvitroassay

Welltoleratedathighdoses AcuteMTD>300mg/kginrats

Efficaciousinanimalmodels

Efficacyatdoses>5mg/kginratsleepmodel Weightlossobservedatdoses>100mg/kg

study

115

H3Antagonist/InverseAgonistProgramSummary

Extensivepreclinicalandemergingclinicalvalidationaroundtarget


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Portfolioofextremel otent hi hl selectivecom oundsestablishedatATHX

Rigorousassessmentforphospholipidosis andothercharacteristicspartofourevaluation

Extensive

knowledge

base

developed

internally

regarding

SAR,

other

parameters

. . ,

Phospholipidosis particularlysignificantwithlonghalflifecompounds,clinicalindications

thatrequireextendeduse

u ngo our n erna exper ence, s or ca va a onan recen resu s romo erprograms,wearefocusedon:

Continueddevelopmentofpotent,selectiveH3antagonistsandinverseagonistswith

bestinclassprofile

Avoidanceofliabilitiesseenwithothercompounds

Opportunitytodevelopfirstlonghalflifecompoundfreeofphospholipidosis andsuitablefor

oncedailyadministration,applicationinclinicalindicationswithextendeduse

Evaluatingpotentialpartneringopportunities

RAGEVTProgramSummary

Productionofcelllinesexpressingwellvalidatedtargetsfordugdevelopment

RAGE (Random Activation of Gene Expression) technology developed at ATHX


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RAGE(RandomActivationofGeneExpression)technologydevelopedatATHX

Extensivelyvalidated,patentedw/multiplescientificpublicationsillustratingusein:

Genediscovery

Phenotypicscreeningandpathwayanalysis

Drugdevelopment(creationofcelllinesforHTSscreeningandoptimization)

Proteinexpression(alternativeapproachtotraditionalcDNA)

Overpastfewyears,partnerships/licensingagreementsestablishedbyATHXwith

multiplemajorpharma companiesandotherpartners

, , ,

Successfuldeliveryandacceptanceof~24targets(coveringarangeoftherapeuticareas)

Mostadvancedpartneredprogramsnowinmidstageclinicaldevelopment(PhaseII)

Hasalsoprovidedaccesstomultipletargetsforinternalprograms

Todate~$14Millioninrevenuegeneratedwithmeaningfulfuturerevenue

potentialasprogramscontinuetomature&advance

Biopharma Summary

Multipleproprietarytechnologies,capabilitiesdeveloped&validatedatAthersys


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majorpharma andemergingbiopharma partners

Benefitsincluderevenuegeneration&establishmentofrelationshipswithpartners

CNSfocused

Focused,costeffectiveapproachimplementedforinternalprograms

Buildingoffofknowledgebasedevelopedbyothers,focusedonaddressing

fundamentalgapstoachievebestinclass

LeveragingcoreinternalcapabilitiesandoutsourcedcapabilitiesthroughCROs,CSOs

Activelyexploringpartnerships

118


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Financials

119

SummaryFinancialData

$ ThousandsYear ended

December 31, 2008


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ece be 3 , 008

Revenues $3,105

Operating expenses (22,197)

Interest income and other, net 1,100

Net loss 17 992

Net Cash Use in Operating Activities (15,711)

Cash and Investments 31,613

Debt 0

120

FinancialConsiderations

Favorable cash osition


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Favorablecash osition

Almost$32millionincashandinvestmentsatendof2008

Operationalfocusandmanageableburnrateconstructedtoallowapproximate yt reeyearso operationswit currentcas Q1,

2011)

Exploringpotentialforcollaborationsacrossprograms,andnon

ut ve e.g.,grant opportun t es

Substantialupsidepotential

or o oo po en a es nc assoppor un es,w nearer erm

impactpossiblewithcelltherapeuticprograms

Lowerrelativevaluation,comparedtootherpublicstemcell/product

p a ormcompan es

121


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Athersys,Inc.

R&D/Investor/AnalystDay

April8th,2009

04-08-09 athersys slides (investor day - final)

Documents