TARGETINGBETACATENINASATREATMENTFORDESMOIDTUMORSSUNILSHARMAMDFACPPROFESSOROFMEDCICINEUNIVERSITYOFUTAHANDHUNTSMANCANCERINSTITUTESALTLAKECITY(UT)

2

βCateninImplicatedinNumerousCancers,AffectingMany

%ofCancerwithβCateninActivation/Mutation

90%+

40-50%

40%

20%

30%

50%

30%25%

30% 30%+ 30%

*AnnualNewPatients(USOnly)

TYPE Colon Breast Lung Prostate Melanoma Ovarian Liver Gastric AML CML MM

#AFFECTED* 100K 90K 85K 55K 20K 11K 8K 6K 5K 5K 5K

~400,000ANNUALUSINCIDENCE

Blood

3

b-CateninmutationspredominateinDesmoid tumors

-ThreeMutationsinb-CateninhavebeenidentifiedinsporadicdesmoidtumorsExon3(T41A,S45F,S45P)

-Mutationsareatsitesonb-Cateninthatareusuallymarkedforphosphorylationandproteasomal degradationbyAPC

-Mutationsleadtoimpaireddegradationofb-Cateninanditsretentioninthenucleus

-Thusb-CateninbecomestheoncogenicdriverinDesmoid Tumors

4

AFundamentalPathwaythatCancersUseinLaterStagesofDevelopment

WNT

DSH

GSK3

APC

AXIN

LRP5/6

Frizzled

GBP

NUCLEUS

Targets

CBP

TCF

CYTOPLASM

β-cat

β-cat

β-cat

β-cat

β-cat

CANCERCELL

βCateninMovestoNucleusWhereItPromotesTranscriptionandOncogenesis

ImproperDegradationofβCatenin

NoBlockingProtein;WntLigandEngaged

byFrizzle

CYTO

PLAS

M

WNT

sFRP

DKK

DSH

NUCLEUS

TargetsTCF

Ubiqutin-mediatedproteolysisβ-cat

P

GSK3

AXINAPC

BetaCateninDestructionComplexLRP5/6

Frizzled

NORMALCELL

βCatenin’sNormalFunction:CellGrowthRegulation

BlockingProteinStopsWntfromInteracting

βCateninDegradesinCytoplasm

TheWnt/βCateninPathway’sCentralRoleinRegulatingCellularReplication

5

CANCERCELL

b-catHookstoTCF5

Sumoylated TBL1/ b-catMovestoNucleus

4

TBL1-SumoylatesandPocketsChange

1RepressorProteins

DriftAway

2

BetaCateninsDockintoPockets

3

TranscriptionTurned“On”

6

UnderstandingtheBeta-Catenin/TBL1InteractionandOurNovelApproach

NORMALCELL

SMRT

NCORRepressorProteinsBindandPrevent

TBL1/TBLR1Activation

TranscriptionTurned“Off”

TBL1Tetramer

HydrophobicPockets:BindingSitesforProteins

6

Tegatrabetan helpstotoStoptheb-CateninCascade

Tegatrabetan –TREATEDCELL

TranscriptionTurned“OFF”

4

TegatrabetanBindsinPocket

1

KicksOutBetaCatenin,SMRTandNCORRe-attach

2‘Free’BetaCatenin

Proteolyzed

3

ADVANTAGESHydrophobicPocketsAllowOurInhibitortoBindDirectlytoTBL1andDisplaceBeta

Catenin;

FreeBetaCateninisImmediatelyProteolyzed

TBL1Tetramer

• Biologicallyelegant– sumoylated TBL1goesbacktoactinglikeregularTBL1

• Apoptotictocancercells• Potentandhighlyspecific• Noeffectonmembraneboundbetacatenin• Noeffectonnormalstemcellsrepopulating

theGItract

7

Tegatrabetan (BC-2059):SignificantActivityinMiceHumanXenograftDiseaseModels

AcuteMyeloidLeukemia(AML) MyelodysplasticSyndromes

AML:InCombinationwithNovartis’sPanabinostat

MultipleMyeloma

0 10 20 30 40 500

50

100

150Control15 mg/kg BC2059

Days

Perc

ent s

urvi

val

1 2 3 4 5 6 7 80

5 .0´1 0 0 9

1 .0´1 0 1 0

1 .5´1 0 1 0

2 .0´1 0 1 0

2 .5´1 0 1 0

w e e ks

To

tal

Flu

x (

ph

oto

ns

/se

c) V e h ic le

5m g r/k g r

1 0m g r/k g r

Weeks

0 20 40 60 800

50

100

150

vehicle10 mg/kg BC20595 mg/kg PS10 mg BC2059 + 5 mg/kg PS

Days Post Implantation

Per

cent

sur

viva

l

P< 0.0001

Treatment2xPerWeek,for3Weeks– 6Doses,ThenWatch(NoIntenttoCure)

8

PathForward:RegistrationinOrphan,AcceleratedApprovalDisease

Wnt/BetaCateninPathwayInhibition

AFundamentalCancerPathwayUniquelydrivingselectOrphancancers

Quickest,MostEfficientPathtoMarket:AcceleratedApproval

Advantages

• Orphandesignation

• Highunmetmedicalneed

• Potentialbreakthroughtherapy

• Potentialacceleratedapproval

InitialFocus:OrphanIndications

SingleAgentTrials

ComboTrials

• AML

• Desmoid tumors• GerminalcenterBcell

lymphomas• Osteosarcoma

9

BroadPotential:ManyCancersandFibroticDisease

Potential

Wnt/BetaCateninPathwayInhibition

WntImportantinScarHealing

(e.g.Dupuytren’sContracture,

PulmonaryFibrosis)

FibroticDisease

CommercializationFocus:MajorTumors&Fibrosis

ComboPotential- Cancer

• ColonCancers• BreastCancers• LungCancers• Melanoma• MultipleMyeloma

OtherCancers

AdditionalIndications

• PulmonaryFibrosis• Dupuytren’s Contracture

10

PhaseI/IITrialofTegatrabetan inAdvancedNonResectableDesmoid tumors

• Phase1/2Trialbeingplanned• LikelystartsQ4thisyear

• Willbeafirstinmansafety/efficacytrial

• Aimstobringapromisingdrugintoclinicaltrialsfordesmoid patients