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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