precision cancer therapeutics - 2x oncology · 2017-11-07 · about us •precision therapeutics...
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Precision Cancer Therapeutics
CONFIDENTIAL
GeorgeO.Elston,CEOMarieFoegh,MD,CMO
November2017
AboutUs
• Precisiontherapeuticsaddressingsignificantunmetmedicalneedsinhard-to-treatcancers
• PipelineofPhase2compounds- PARPinhibitorpositionedforQ42017Phase2studyinitiation
• Initialstudiesplannedinmetastaticbreastandprostatecancer
- Leveragingprioractivityobservedinovarian,pancreatic &braincancers
• DrugResponsePredictor(DRP®)companiondiagnosticleveragedtoidentifydrugrespondersandnon-respondersforfocusedstudies
• Phase2Dataanticipated2H2018- Positivedatatriggersacceleratedapprovalfiling(s)
• RaisingInstitutionalfinancing- $3.5Mseedroundcomplete2
ExecutiveTeam
3
Peter Buhl Jensen, MDChairman
• FounderandCEOofTopoTarget A/S• SecuredEMAandFDAapprovalofSavene©/Totect©• DevelopedBelinostat,FDA-approvedin2014
George ElstonCEO
• 20+yearsveteranlifescienceexecutive• Oncology,ophthalmologyandwomen’shealth• BoardmemberDeutscheBankDBXTrustandpreviouslyCelldexTherapeutics
Marie Foegh, MDCMO
• 28yearsinpharmaceuticalandbiotech• ExecutiveatIPSENandBayerPharmaandAgile• 10+drugstakenthroughdevelopmentandFDAapproval
Jarne ElleholmCFO
• 20+yearsinpharmaceuticalandbiotech• VCpartnerandPharmaexecutiveexperience• ChairmanofScandinavianMicroBiodevices,Meta-IQ
ProgramDevelopmentTeam
Ulla H. BuhlFounder Clinical Liaison
Steen Knudsen, Ph.D. DRP founder
Bruce Pratt, Ph.D. CMC
Dr. Joyce A. O’ShaughnessyBaylor University,US Oncology
Dr. Daniel D. Von HoffU. of Arizona, Mayo Clinic,US Oncology
Dr. Mansoor Raza MirzaNSGO/DBCG Rigshospitalet, U. of Copenhagen
Dr. Mary Lake Polan, Yale University,Dept. of OB/Gyn
Dr. Henry S. FriedmanDuke UniversityTisch Brain Tumor Center
Oncology Venture team
Scientific Advisory BoardDr. Ursula A MatulonisDana-Farber Cancer InstituteSmith Center for Women’s Cancers
Mogens WinkelMadsen, Ph.D. Manufacturing
James G. Cullem J.D. FounderBD Liaison
Phase2Pipeline
5
Phase2DRP®Selected
Phase22018PotentialMilestones
2X-121PARP1/2and
Tankyrase 1/2Inhibitor
• Metastatic breast cancer
• Prostate cancer (mCRPC)
• Recurrent ovarian cancer
• Pancreatic cancer Phase2studyresults
Positionedforaccelerated
approvalfilings
2X-111Glutathione-enhancedPEGylatedLiposomal
Doxorubicin
• Brain metastases from breastcancer
• Recurrent glioblastoma multiforme
2X-131Topoisomerase1
Inhibitor
• Recurrent ovarian cancer
DRP®CompanionDiagnostic
①Patternsindrugsensitivityfromhumancelllines(e.g.NCI60)reflectmechanismofactionofaspecificdrug.Thisidentifiesasubsetofgenesresponsibleforsensitivityandresistancetothatdrug.Thisnarrowsthegeneanalysisfrom20,000intothe“hundreds,”providingarawDRPscoreadrugforadditionalfilteringbasedonactualpatienttumordata.
② TherawDRPisfilteredforclinicalrelevanceagainstaproprietarydatabaseofover3,250humantumorsamplesfrom27differentcancers.Thismetadataanalysiseliminatesclinicallyirrelevantgeneexpressions(“backgroundnoise”),creatingthedrug-specificDRP.
③ Thedrug-specificDRPproducesascorefrom0-100basedonthespecificgenesrepresentedinapatient’stumor.A100scorewouldidentifyatumorasahighlylikelyresponder,withallgenesrepresentedforsensitivityandnoneforresistance.
④mRNAdatafrompatientbiopsiesarecomparedtothedrug-specificDRP,producinganindividualscore.ADRPcutoff(e.g. 70%)isselectedbasedonclinicalexperiencewithaparticularcancertypeanddrug.
APatient-unique“Fingerprint”ofGenesPredictsResponsivenesstoaDrug
Drug-specific DRP
DRP®Validatedin40+ClinicalTrials
• Epirubicin inmetastaticbreastcancerhttp://abstracts.asco.org/199/AbstView_199_192238.html
• Epirubicin,Exemestan,Anastrozole,and Fulvestrant inadvancedbreastcancerhttp://www.medical-prognosis.com/investor-and-media/20170124-drp-successfully-predicts-effect-of-4-breast-cancer-drugs-for-personalized-medicine/?origin=announcements
• Cisplatin,Epirubicin and Capecitabine ingastroesophaeal cancerhttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0148070
• Adjuvant 5FUincoloncancer http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0155123
• Belinostat inAMLhttp://www.oncologyventure.com/wp-content/uploads/2016/04/Bullinger_ESMO2012.pdf
• Adjuvant CisplatinandVinorelbine inNSCLChttp://oncologypro.esmo.org/Meeting-Resources/ESMO-2016/Multigene-expression-profile-for-predicting-efficacy-of-cisplatin-and-vinorelbine-in-non-small-cell-lung-cancer
• Fulvestrant inbreastcancerhttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087415
• CHOPand CHOEPinlymphomas https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333339/
DRP®EnablesDynamicStudyDesigns
8
NovelPrecisionMedicineTrialDesigns
JAMAOncology: doi:10.1001/jamaoncol.2106.5299
2X-121:PARP1/2andTankyrase 1/2Inhibitor
• Orallybioavailable,brainpenetrable,smallmoleculedrug
• Potentinhibitor of
• Dualinhibitoryactionof2X-121againstPARP1/2andTankyrase 1/2providesbroaderactivitythancurrentPARPinhibitors
• LackoftransportbyP-glycoproteinpotentiallyovercomesresistancetocurrentPARPinhibitors
• Establishedefficacy&safetyprofile;nomyelotoxicityobservedinPh1study9
PARP1Akeymoleculeinsensingandrepairingsingle-strandDNAbreaks
PARP2Anadditionalrepairmechanism
Tankyrase 1/2ImportantregulatorsofcanonicalWnt/β-catenin,acriticalcheckpointinmetastases,particularlyintriple-negativebreastcancer
PARP:Poly(ADPribose)polymerase
olaparibNiraparibE7449
Responsebiomarker
PgP mediatedresistance Myelotox Tankyrase WNT PARPtrapping BBB
penetration
Strongmaintenanceopportunity
olaparib BRCA Yes(1,2) Yes No(8) No Yes No(1) Yes
niraparib BRCA/Myriad(3)HRD YesSPC Yes No No Yes No Yes
veliparib BRCA Yes(4,5) Yes No No No(4,5)
rucaparib BRCA Yes(6) Yes Yes(8) Yes(7) Yes No(6) Yes
talazoparib BRCA Yes No(10) No Yes No(11) Yes
BGB-290(12) BRCAHRD Yes Yes Yes Yes
2X-121 DRP(9) No No Yes Yes Yes Yes Yes
a) in: Profile of veliparib and its potential in the treatment of solid tumors https://www.ncbi.nlm.nih.gov/pmc/articles/PMC45245911) http://www.nature.com/nm/journal/v19/n11/full/nm.3369.html?message-global=remove2) http://www.pnas.org/content/105/44/17079.long https://www.genomeweb.com/cancer/myriad-genetics-stock-drops-after-study-shows-niraparib-may-not-need-cdx3) http://dmd.aspetjournals.org/content/39/7/11614) https://www.ncbi.nlm.nih.gov/pubmed/246475725) https://www.ncbi.nlm.nih.gov/pubmed/24962512 ; http://www.ascopost.com/issues/may-1-2014/preliminary-study-suggests-veliparib-may-be-effective-in-resistant-brca-mutated-ovarian-cancers/6) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882768/pdf/bjc201641a.pdf7) http://www.nature.com/scibx/journal/v5/n13/pdf/scibx.2012.323.pdf8) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027629/pdf/ml400292s.pdf9) Novel strategies in biomarker discovery are determination of the genomic or expressional signatures of PARP inhibitor sensitive tumors. The rationale behind this approach is that one can define a specific profile of, for
example, HR-deficient tumors. RNA profiling or gene expression arrays have been used for this purpose and show potential in identifying PARP inhibitor sensitive tumors http://www.medscape.com/viewarticle/842072; http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0064268&type=printable; ttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053087/pdf/bcr3625.pdf;
10) http://files.shareholder.com/downloads/MDV/2370126714x0x898732/BB3A5044-7FBC-4CDA-96CB-810A55269B7D/Talazoparib_IR_Presentation_2016-07-06_FINAL.pdf11) http://www.nature.com.ep.fjernadgang.kb.dk/nchembio/journal/v13/n2/pdf/nchembio.2248.pdf12) Source: Beigene filing with SECon19Jan2016
“Forthetranslationalscientist,theidentificationofreliablebiomarkerswillbecriticalforthesuccessofthistargetedagent”aPARPOverview
2X-121: PARP1/2andTankyrase 1/2InhibitorEstablishedClinicalHistory
SingleAgent Patients Indication Results
Phase1 (UK) 41(28atRx dose)
SolidTumors(includingbreast,
pancreaticandovarian)
• Welltolerated• 46%diseasecontrol• 7.1%partialresponsesinallcomers• 2durablepartialresponses,200+days
Priorclinicalstudycompletedwithout useof2X-121DRP®CDx toselectlikelyresponders
2X-121:PatientBiopsiesforDRP®Validation
12
2X-121:StrongDRP®Prediction
• Blindedstudy,13patients
• 2X-121DRPpredictedpatientslikelytorespondandnotrespondtotreatment
• 2X-121DRPcorrectlypredictedresponsetotreatmentandOverallSurvival(p=0.07)- HazardratioonOverallSurvival=0.26
• Clearseparationbetweenresponders&non-responders
• IdentifiedrespondersirrespectiveofBRCAmutationstatus
Total PatientsinGroup OverallSurvivalPredictedresponders 7 5
Predictednon-responders 6 1
13 OverallSurvival:survivalat400daysfromcommencementoftreatmentwith2X-121
Four-folddifferenceinOverallSurvival
Phase1Trial:E7449/2X-121
Responders Nonresponders
010
2030
4050
6070
Clinical response
DRP
pred
icted
2X−
121
sens
itivity
(adju
sted
for d
ose
50−8
00m
g)
●
●
●
●
●
●
● ●
●
●
●
●
●
Responders Nonresponders
010
2030
4050
6070
CC=0.45, P=0.06
Unblinding:ClinicalResponse
2X-121DRPcorrectlyidentified• The2patientswithpartialresponse• Non-responders
2X-121:StrongDRP®Prediction
15
Prospective/RetrospectiveDRPValidation
16patientswithbiopsiesmRNAextractedfrom13
0 200 400 600 800
0.00.2
0.40.6
0.81.0
Days
Overa
ll surv
ival
Predicted sens to E7449Predicted resistant to E7449
P=0.07 HR=0.26
Predicted sensitive to 2X-121Predicted resistant to 2X-121
2X-121:PARP1/2andTankyrase 1/2Inhibitor
16
ClinicalOpportunitieswithDRP®CDx
Other DRP®andWnt pathways
Other homologousRecombination deficient
BRCA1+2mutated
Likely non-responders to2X-121
Highlikelihoodsensitivesubgroupsareidentifiedbythe2X-121DRP®
MetastaticbreastcancerOvariancancerPancreaticcancerBrainmetastasesfrombreastcancerEndometrial cancerProstate cancer
2X-121:Phase2ClinicalPlans- InitialFocusedStudies
MetastaticBreastCancer
• Selecttop20%DRP®• <30heavilypre-treatedpatients• Utilize1,200+patientregistryinDenmark
• 2H2018dataexpected• 30%+responserateanticipated• Potentialforacceleratedapproval
ProstateCancer
• Selecttop20%DRP®• <30heavilypre-treatedpatients• InitialEUstudy
• 2H2018dataexpected• 30%+responserateanticipated• Potentialforacceleratedapproval
17
Phase2StudyPlan
PotentialOutcomePathways
2X-121:Phase2ClinicalPlans– U.S.Studies
RelapsedOvarianCancer
• Selecttop20%DRP®• Enroll<30heavilypre-treatedpatients(incl.priorPARPrefractory)
• 30%+responserateanticipated• Potentialacceleratedapproval
PancreaticCancer
• Selecttop20%DRP®• Enroll<30heavilypre-treatedpatients
• Opportunityforacceleratedapprovalandorphandesignation
18
Phase2StudyPlan
PotentialOutcomePathways
2X-121:Phase2ClinicalPlans- Basket
NCICollaboration– PediatricCancer
• CancertypeselectionbasedonknownPARPi activity- e.g.Neuroblastoma
• DRP®cutoffTBD
• Minimumofdoublingexistingresponseratevs.otherPARPi
• Opportunityforacceleratedapproval
PARPi TumorStudies
• SelectionbasedonknownPARPiactivityinspecifictumortypes
• DRP®cutoffTBD
• Minimumofdoublingexistingresponseratevs.otherPARPi
• Opportunityforacceleratedapproval
19
Phase2StudyPlan
PotentialOutcomePathways
2X-121:CurrentStatus
• ProductavailablefromEisai- 13Kcapsulesforinitialstudies- 14kgofAPI- 78kgofintermediateproduct
• 2X-121DRP®established&validated
• Phase2mBC studyinitiationexpectedQ42017- Registryof~1,200DRP-screenedbreastcancerpatientsinDenmark
• U.S.pre-INDmeetingrequested
• INDfilingexpectedQ12018
20
2X-111: Glutathione-enhancedPEGylatedLiposomalDoxorubicin
• Glutathione(GSH)– enhancementofPEGylatedliposomeexploitstheGSHtransportpumpintheBBBtoallowtransferof2X-111intothebrain
• IPincludesGSH-PEGylatedliposomedeliverysystemincombinationwithanthracyclines
NovelTrans-BBBDrugCandidate
glutathione
PEG
doxorubicin
liposome
DRP®forAnthracyclinePredictsResponseinmBC
13months PFSwithDRP®at75%
7months PFSwithDRP®at25%
In135patientswithmBCtreatedwithepirubicin theDRPpredictedPFSwitha
HazardRatioof0.5(p=0.02)
PredictedResponse
0%
100%
Buhl et al. Retrospective-prospective blinded evaluation predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort. J Clin Oncol 35, 2017 (suppl; abstr 1071).
2X-111:Glutathione-enhancedPEGylatedLiposomalDoxorubicin
23
EstablishedClinicalHistorySingleAgent Patients Indication Results
Phase1 37 Safety Welltolerated
Phase2a 17 Brain metastasesfrombreastcancer
PR:2(12%)SD:9(52%)
Phase2a 20 GBM PR:1(5%)SD:7(35%)
Priorclinicalstudiescompletedwithout useof2X-111DRP®CDx toselectlikelyresponders
2X-111:ClinicalDevelopmentPlans
GlioblastomaMultiforme• Selecttop20%DRP®• Enroll<20patients
a) 4+patientsPR/SDat6+months→ acceleratedapprovaldiscussionwithFDA
b) 2-3patientsPR/SD→enroll10additionalpatients
BrainMetastasesfromBreastCancer• Selecttop40%DRP®• Enroll<20patients
a) 6+patientsPR→ repeatstudy;acceleratedapprovaldiscussionwithFDA
b) 4-5patientsPR→ pivotalPhase2withevaluationofothermetastases
24
Phase2StudyPlan
PotentialOutcomePathways
2X-111:Glutathione-enhancedPEGylatedLiposomalDoxorubicin
• U.S.INDobtainedJune2017• Drugproductmanufacturingunderway(Taiwan)• 2X-111DRP®established&validated• Danishregistryof~1,200DRP-screenedbreastcancerpatientsavailableformBC Phase2study– umbrellastudy
• Glioblastomapatientstobescreenedwith2X-111DRP®CDx atCopenhagenandDukeUniversityHospitals
25
CurrentStatus
2X-131:Topoisomerase1Inhibitor
• Orallybioavailablesmallmoleculecamptothecin
• Bindstothetopoisomerase1-DNAcomplex
• Preventsre-ligationofsinglestrandbreaksthatareinducedbytopoisomerase1torelievetorsionalstraininDNA
• MOA:cytotoxicityfromdoublestrandDNAdamageproducedduringDNAsynthesis
• Favourablesafetyprofile
• Clinically-demonstratedefficacyinwiderangeofcancers
26
2X-131:EstablishedClinicalHistory
27
CompletedPhase1&Phase2Studiesin>300PatientsConductedinEU,US,JapanandChina
Phase TreatedPatients Tumor types1 108 Solidtumors1 35 Solidtumors1 43 Glioma1 4 ADME1 157 Solidtumors1 26 Solidtumors
250 Breast69 Ovarian
ADME-AbsorptionDistributionMetabolismExcretion
2X-131: Topoisomerase1InhibitorEstablishedClinicalHistory
SingleAgent Patients Indication Results
Phase2 69 Ovariancancer • Welltoleratedwithimprovedefficacy &safety profilevs.topotecan &irinotecan
• 47%responserate in19patientswithPlatinumFreeInterval(PFI)≥6months
• 16%PRinpatientswithPFI<6months
Priorclinicalstudycompletedwithout useof2X-131DRP®CDx toselectlikelyresponders
2X-131:Phase2ClinicalDevelopmentPlan
OvarianCancer
• Selecttop30%DRP®• Enroll<20heavilypre-treatedpatientswithPFI<6months
a) 3+patients→ repeatstudy;discussacceleratedapprovalwithFDA
b) <3patients→ revisitDRP®cutoff
EndometrialCancer
• Selecttop20%DRP®• Enroll<20late-stagepre-treatedpatients
• Opportunityforacceleratedapprovalandorphandesignation
29
Phase2StudyPlan
PotentialOutcomePathways
2X-131: CurrentStatus
• DrugproductavailablefrompartnerforPhase2studies
• PlanningDRP®-selectedPhase2studyinrecurrentovariancancer
• ExpandedcollaborationdiscussionswithChinapartner
• U.S.INDfiling/reopeningplannedforQ12018
DevelopmentTimelineQ42017 Q12018 Q22018 Q32018 Q42018 2019
2X-121Metastaticbreastcancer- Phase2
2X-121 RecurrentovarianCancer- Phase2
2X-121PancreaticCancer- Phase2
2X-111 BCBM– Phase2
2X-111 Glioblastomamultiforme– Phase2
2X-131RecurrentovarianCancer– Phase2
Potential2018CompanyProfile
• 2X-121mBC inpivotalphase2studyforacceleratedapproval
• 2X-111 Brainmetastasesfrombreastcancerconfirmatorystudyforacceleratedapproval
• 2X-111 GBMpositionedforacceleratedapproval
• 2X-131 Recurrentovariancanceracceleratedapprovalstudy
• Endometrialcancerstudiesunderway
PositionedforPartnering,M&Aand/orIPO
Contacts
GeorgeO.ElstonChiefExecutiveOfficer
Jarne ElleholmChiefFinancialOfficer
AmyRaskopfIR/[email protected]