Presentation by Leslie Chong at 9th Annual Biotech Showcase, San ...
Transcript of Presentation by Leslie Chong at 9th Annual Biotech Showcase, San ...
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ASX:IMU
B Cell Based Antibodies for Immuno-Oncology
LeslieChongChiefExecutiveOfficer09-January-2017
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Notice: Forward Looking Statements
Any forward looking statements in this presentation have been prepared onthe basis of a number of assumptions which may prove incorrect and thecurrent intentions, plans, expectations and beliefs about future events aresubject to risks, uncertainties and other factors, many of which are outsideImugene Limited’s control. Important factors that could cause actual results todiffer materially from any assumptions or expectations expressed or implied inthis brochure include known and unknown risks. As actual results may differmaterially to any assumptions made in this brochure, you are urged to viewany forward looking statements contained in this brochure with caution. Thispresentation should not be relied on as a recommendation or forecast byImugene Limited, and should not be construed as either an offer to sell or asolicitation of an offer to buy or sell shares in any jurisdiction.
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What Does Imugene Do?
We are developing cancer immunotherapy drugs based on
antibodies
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IMU’s Value Proposition
ü Promisingsciencewithimpeccableprovenanceinthehottestareaofcancertoday– immunooncology
ü BroadPipeline:HER-Vaxx &Mimotopes
ü BreastCancerclinicaltrialcomplete&onthecuspofrecruitmentonoursecondPhase1b/2clinicaltrialingastriccancer
ü TightshareregisterwithleadingFundManager,PlatinumAssetManagement
ü Frequent,rich,qualitynewsflowahead
ü AxelHoos Sr.VPofimmuno – oncologyatGSK,plusteamwithsuccessfultrackrecordindrugdevelopment
ü Lowmarketcap- undervaluedagainstASXpeers
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Imugene Operates in the most Promising area of Oncology Today…
Imugene isanimmunotherapycompanydevelopingB-cellbasedvaccinesinthemostpromisingareaofoncologytoday– IMMUNO-ONCOLOGY
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BCell
Antibody
TCell
What is Cancer Immunotherapy?
• Immunotherapyisthetreatmentofcancerwithsubstancesordrugsthatstimulatethepatient’simmuneresponse– knownasactiveimmunisation
• Unlikechemotherapy,immunotherapydrugsdonottargetthecancerdirectly
• Immunotherapyhelpsthepatient’sownimmunesystemrecognise &attackcancercells
• Typicalimmuneresponsesare:– BCellsmakingantibodiestoattackthecancer
– TCellsdevelopedbythethymustoattackthecancer
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Two Compelling Antibody Programs and Commercial Opportunities
Buildingonthemulti-levelsofyourownimmunesystem• Identificationofcancertargetsforvarietyofcancerindications• Immuneresponsesfromconjugatesandadjuvants• B-CellPeptidevaccinesagainstcheckpointtargets
Imugene’s PipelineBCellPeptidetechnology
Peptidesproducedviacomputeraidedprograms:
HER-Vaxx Vaccine
Peptidesidentifiedviamimotope technology
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What is an Antibody?A key Defense of the Immune System
BCells– arelikelittleantibodyfactoriesproducingmillionsofantibodiesagainstcancertargets
Inafactory UsingBcellsinyourownbody
Forexample,Roche’sHerceptin
Antibodies – LargeY-shapedprotein.Theyareexquisitelymadetoattachthemselvestoa targetsittingonaninvadingorganism
Thereare2waystomakeantibodies
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B-CellVaccinesofferauniqueopportunitytointerveneatmultiplepointsintheimmunesystemandcreateimmunememorywhichenhancesdurabilityofresponse.
Advantages of B-Cell Based Antibodies
Issue B-CellImmunotherapy MonoclonalAntibodies
Safety • StimulatestheimmunesystemtoproducenaturalAbs,potentiallysafer,asdemonstratedbyHER-Vaxx
• SyntheticAb,withsideeffects(includingventriculardysfunction,CHF,anaphylaxis,immunemediation)
Efficacy • PolyclonalAb responsereducesriskofresistanceandpotentiallyincreasesefficacy
• MonoclonalAb - singleshot
Durability • Antibodiescontinuouslyproducedalastingimmuneresponsetoinhibittumorrecurrence
• Halflifeupto12dayssometimesless
Usability • Potentiallylownumbersofvaccinationsrequiredperyear
• Requiresregularinfusion
Cost • Lowcostofproductionenablesgreaterpricingflexibilityfacilitatingcombinationsandopeningupadditionalmarkets
• Expensivecourseoftreatment>USD100KperyearintheUS
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A Mimotope Produces a Copy of an Antibody
• Amimotope isasmallmolecule,oftenapeptide,whichmirrorsthestructureofanepitope,thespecifictargetanantibodybindsto.Becauseofthispropertyitinducesanantibodyresponsesimilartotheoneelicitedbytheepitope.
• Amimotope causesyourBcellstoproduceanantibodycopyoftheantibodyyouwantto“mimic”
• Potentialtoolforselectingnovelvaccinecandidatesagainstavarietyoftumors
• GreatlyextendsIMU’soncologyfranchiseandpipeline.
• MonoclonalantibodymarketcurrentlyatUS$60bnannually
• December,2016progressedthemimotope platformwithfilingof4newpatentapplications
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ASX:IMU
HER-Vaxx is a peptide vaccine being developed for HER2+ gastric cancer
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B-Cell
HER-Vaxx: Mechanism of Action – How it Works
HER-VaxxImmunotherapy
B-cellActivation
HER-VaxxAntibodySecretion
TumorCell
P4
P6
P7
3Peptides
ViahelperT-cells
HER-2/neu
P4
P6
P7
HER-Vaxx attacksthesametargetasthetheworld’slargestsellingbreastcancerdrugHerceptin
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Phase 1 in Breast Cancer, Completed at MedicalUniversity of Vienna
*Wiedermann et.al.,BreastCancerResTreat.2010Feb;119(3):673-83.
• 10patients• Alllatestagebreastcancerpatients
• HER-2+/++• Lifeexpectancy>4months• ConductedatMedicalUniversityofVienna
❶ SafetyandTolerability
❷ Immunogenicity:antibodies andcellularresponses
Design• Patientsdevelopedanti-HER-2antibodies• Inductionofcytokines(Th1biased;IFNγ)• InductionofmemoryT&Bcellspostvaccination
• ReductioninTreg cellspostvaccination,indicatingstrongvaccineresponse
• Antibodiesinduceddisplayedpotentanti-tumoractivity
• Promisingresults- Patientswereendstageandnotprimarytargetgroup
• ReviewedinPeerPublication
ClinicalEndpoints
Results
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Ph1b/2 Formulation
HER-Vaxx Has Been Considerably Optimised Since Phase 1a
FirstGeneration• ThreeseparateBCellepitopesdeliveredinvirosomes (usedinPhase1a).
Third Generation • changed the delivery
system from virosomesto CRM197 (which gave CD4 T-Helper response), and added a montanide adjuvant
• >20x increase in antibody response in vivo (potentially extends patent life to 2036)
Second Generation • incorporated the three
B Cell epitopes into a single 49-mer peptide
• > 2x increase in antibody response in vivo compared to three single epitopes (extended patent life to 2030)
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0.00
0.20
0.40
0.60
0.80
1.00
1.20
1.40
1.60
OD 3 w. after 3 doses vacc.
8 w. after 3 doses vacc.
16 w. after 3 doses vacc.
6 mo. after 3 doses vacc.
Pre-immunization
10 25 50
P467-CRM-Montanide (µg)
HER-Vaxx Has Been Significantly Enhanced by the Carrier System and Adjuvant
In the mouse model the new formulation sees circulating antibodies maintained for 6 months which equates to many years in humans.
Her-2/neu specific IgG kinetic, after last immunization
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Phase 1b/2, in Gastric Cancer
• Openlabel
• ~18patientsin3cohortsofupto6ptspercohort
• Combinationwithchemo
• Endpoints:– RecommendedPhase2
DoseofHER-Vaxx– Safety:anyHER-Vaxx
toxicity– Immunogenicity(anti-
HER-2antibodytitres))
Phase1blead-in Phase2• Openlabel
• ~68patientsfromsitesinAsia
• Combinationwithchemo
• Randomized
• PrimaryEndpoints:– OverallSurvival– Progression-FreeSurvival
• Secondaryendpoint:– Immuneresponse
08-Nov,2016:Phase1b/2CommencesQ1,2017:PatientEnrolledQ1-Q2,2017:EarlyPatientDataAvailableQ32017:InterimPh1bPatientDataAvailableQ42017:FinalPh1bPatientDataAvailable
✓
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Huge Gastric Market Opportunity
• Gastriccanceristhesecondleadingcauseofcancermortalityintheworld&itsmanagement,especiallyinadvancedstages,hasevolvedrelativelylittle
• ~20%patientswithmetastaticgastriccancerareHER-2positive
• Surgery,chemotherapy,radiation&Herceptinarethekeytreatments
• Inmanycountries,particularlyAsia,chemotherapysuchascapecitibine and5-FU,isthestandardofcare,notHerceptin
• Asiaisthelargestmarketforgastriccancerglobally
Chemotherapy
Monoclonalantibody
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Licensee Licensor TotalSize(US$M)
Upfront(US$M)
Subject Stage PrimaryRxArea
1 Sanofi Hanmi $4,266 $445 Sanofl todevelopHanmi's Portfolio(specifically3assets)oflong-actingdiabetestreatment
Reformulation Endo/Meta
2 AstraZeneca lonis(fka Isis)
$4,090 $65 Discoveryanddevelopmentofantisensetherapiesforcardiovascular,metabolicandrenaldiseases
Discovery Diversified
3 Vertex CRISPR $2,625 $75 VertexandCRISPRtouseCR1SPR-cas9geneeditingtechnologytodiscoveranddevelopnewtreatmentforgeneticdiseases
Discovery Diversified
4 Gilead Galapagos $2,075 $300 GileadSciencestodevelopandcommercializeGalapagos'filgotlnlb againstrheumatoidarthritis
PhaseII Al/lnflam
5 Pfizer Heptares $1,890 Undisclosed Heptares andpfizer todevelopnoveldrugstargetingGPCRagainstmultipletherapeuticindications
Discovery Diversified
6 BMS FivePrime $1,740 $350 BMStodevelopandcommercializeFlve Prime'sCSFlR antibodyprogram,includingFPA-008forimmunologyandoncology
PhaseI Diversified
7 Sanofi Lexicon $1,730 $300 Sanofi todevelopandcommercializeLexicon'ssotagliflozin againstdiabetes,withanoptiontolicense
PhaseIII Endo/Meta
8 Amgen Xencor $1,702 $45 AmgentodevelopandcommercializeXencor'sbispecific cancerimmunotherapyandinflammationprograms
Preclinical Diversified
9 Sanofi Regeneron $1,665 $640 PD-1inhibitorandothernewimmuno-0ncologyantibodies,withanoption
PhaseI Cancer
10 Ultragenyx Arcturus $1,570 $10 Arcturus andUltragenyx todiscoveranddevelopmRNAtherapeuticsusingUNAOligomerchemistryandLUNARnanoparticledeliveryplatform
Discovery Diversified
2015 Big Pharma Antibody Deals20%ofthetop10BigPharma dealsin2015wereintheantibodyspace
Topten2015licensingtransactionsbyannouncedtotalsize
$640Mup-frontPhase1
$350Mup-frontPhase1
19HighlightsindicatePhaseILicensingSource:ThomsonReuters11Jan16,“LifeSciencesDealmaking 2015”
What Could an IMU Deal Look Like?
Licensee Licensor Upfront($M) Equity($M) Stage RxAreaSanofi Regeneron $640 PhaseI CancerCelgene MedImmune/AZ $450 PhaseIII CancerSanofi Hanmi $445 Reformulation Endo/MetaBristol-MyersSquibb FivePrime $350 PhaseI DiversifiedAstellas lmmunomic $300 Discovery Al/lnflamGilead Galapagos $300 $425 PhaseII Al/lnflamSanofi Lexicon $300 PhaseIII Endo/MetaMedlmmune /AZ. Innate $250 PhaseII CancerAllergan Merck $250 PhaseII NeurologyNovartis Aduro $200 $25 Preclinical CancerCelgene Juno $150 $850 PhaseII DiversifiedCelgene Nurix $150 Discovery DiversifiedMerckKGaA lntrexon $115 Discovery CancerCelgene Lycera $105 PhaseI CancerJanssen Hanmi $105 PhaseI Endo/MetaBayer lonis (fka ISIS) $100 PhaseII CardiovascularDiaVax CityofHope $100 PhaseI ViralInfectionBayer lonis (fka ISIS) $100 PhaseII HematologicMerck NGM $914 $106 Preclinical Endo/MetaVertex Parion $80 PhaseII PuIm/Resp
Top20LicenseswithUpfrontPayments>$50m
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Valuation and Licensing Deals in Immuno-Oncology
LicensingDeals Upfront(includesequity&cash)USDm
Milestonepayments(USDm)
UpfrontPaymentas%ofTotal
Totaldealsize
High 999.8 1835 100% 2,012.3Mean 87.6 433 22.9% 514.6Median 35.0 309 10.3% 363.5Low 1.0 0 0.7% 1.0
The average total deal size is $514.6m, and the median deal size is $363.5m
ValuationofCompanies
LicensingDeals
Company Valuation(USDm) DevelopmentStageofleaddrugAgios Pharmaceuticals,Inc. $1.829 Phase3Karyopharm Therapeutics,Inc. $288 Phase2Dicerna Pharmaceuticals,Inc. $68 PhaseIImmuneDesignCorp. $167 Phase2HeatBiologics,Inc. $14 Phase2LoxoOncology,Inc. $514 PhaseIEpizyme,Inc. $597 Phase2KitePharma,Inc. $2,609 Phase1/2IderaPharmaceuticals,Inc. $185 Phase1/2Ignyta,Inc. $213 Phase1/2InovioPharmaceuticals,Inc. $716 Phase2FivePrimeTherapeutics,Inc. $1.150 PhaseIOncoMed Pharmaceuticals,Inc. $387 Phase2
Mean $672
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Sample News Flow in the next 12 Months
ü Patentfilingsonmimotopes (2H,2016)ü PatientsdosedinthePhase1b/2trialingastric
cancer(1H,2017)ü RecruitmentprogressandinterimPhase1b/2data
(1H,2017)
ü Firstmimotope drugcandidateidentified(1H,2017)
ü Preclinicalinvivo/vitroresults(2H,2017)ü FinalPhase1b/2trialreadout(2H,2017)
mimotopeHER-Vaxx
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IMU broadens pipeline with acquisition from Baker IDI
ü ExclusiveagreementwithBakerIDI
ü Oncologyrightstodevelopaportfolioofsmallmoleculeargininemodulatorsforcancertreatment
ü ArginineisacriticalaminoacidforthehealthofcancerfightingT-cellsanddepletionofitlimitstheeffectivenessofT-cellstofighttumors
ü BakerIDIcompoundsincreasetheavailabilityofarginineinthecellularenvironment
ü MinimalcostandresourcesrequiredforPOCin2017
ü Newpatentfiledtoprotectcompoundsinthefieldofcancerandimmuno-oncology,includingcombinationwithcheckpointinhibitors
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LeslieChongChiefExecutiveOfficer• Over19yearsofoncologyexperienceinPhaseI- IIIofclinicalprogramdevelopment
• Leadershiproleinvolvementin2marketedoncologyproducts
• PreviouslySeniorClinicalProgramLeadatGenentech,Inc.,inSanFrancisco
PaulHopperExecutiveChairman• International&ASXbiotechcapitalmarketsexperienceparticularlyinimmuno-oncology&vaccines
• ChairmanofViralytics,DirectorofPrescient,FounderofPolynoma LLC,formerDirectorpSivida,Somnomed &Fibrocell Science
• HeadofLifeSciencesDesk&AustraliaDeskatLosAngeles-basedinvestmentbank,Cappello Group
Dr AxelHoosNon-ExecutiveDirector• CurrentlyVicePresidentOncologyR&DatGlaxoSmithKline
• PreviouslyClinicalLeadonIpilumimab atBristol-MyersSquibb
• Co-Directorofthethink-tankCancerImmunotherapyConsortium;Imugene ishisonlyBoardseatworldwide
A Team with Track Record in Drug Development
ProfUrsulaWiedermannChiefScientificOfficer• Co-inventorofHer-Vaxx;inventorofmimotope platformtechnology
• ProfessorofVaccinology atMedicalUniversityofVienna
Dr NickEdeChiefTechnologyOfficer• Over25yearspeptidevaccineanddrugdevelopment
• FormerCTOConsegna,CEOAdistem Ltd,CEOMimotopes P/L,COOEQiTX Ltd(ZingoTX &VacTX)
• VPChemistryChiron(nowNovartis),ResearchFellowCRCVaccineTechnology
Dr AnthonyGoodClinicalProgramManager• Over15 yearsoncology&immunologyexperienceinglobal clinicaldevelopment programs.IntegraltothedevelopmentofsignificantnewmedicinesincludingViagra,Revatio,Lipitor, SelzentryandSomavert.
• Ex PfizerGlobalResearchandDevelopment,CovanceClinicalandPeriapprovalServices andWesternSydneyUniversity
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Business Strategy and Partnering Opportunities
2017-2018?
Phase1bMimotope+others
2017-2018
Phase1bGastricStudy
2017
BigPharma?
License/Partner
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Options on issue (as at Dec. 2016)
Substantial holders (as at Dec. 2016)ASX:IMU, ISIN: AU000000IMU9
*Average
Our Stock
No of options Exercise Price Expiry
Listed (IMUO) 371,166,262 $0.015 31-Mar-17Unlisted 49,000,000 $0.0173* 30-Oct-17*TOTAL 420,166,262 $0.0155* 18-May-17*
Market Cap (22/Dec/16)
$32.5M AUD, $23.5M USD
Ordinary Shares 2.17 billion12 month price range 0.7 cents – 2.1 cents AUDAvg daily volume 10.5M shares (last three months)Investment to Date ~$12.2 mCash & Equivalents $3.82M as of 22/Dec/2016
No. of Shares % Capital
Platinum Asset Management
213,846,553 9.88%
Webinvest Pty Ltd<OLSB Unit A/C>
101,000,000 4.66%
National Nominees Limited
66,424,732 3.07%
Tisia Nominees 65,666,666 2.39%
Sarah Cameron 51,817,073 1.39%
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IMU’s Value Proposition
ü Promisingsciencewithimpeccableprovenanceinthehottestareaofcancertoday– immunooncology
ü BroadPipeline:HER-Vaxx &Mimotopes
ü BreastCancerclinicaltrialcomplete&onthecuspofrecruitmentonoursecondPhase1b/2clinicaltrialingastriccancer
ü TightshareregisterwithleadingFundManager,PlatinumAssetManagement
ü Frequent,rich,qualitynewsflowahead
ü AxelHoos Sr.VPofimmuno – oncologyatGSK,plusteamwithsuccessfultrackrecordindrugdevelopment
ü Lowmarketcap- undervaluedagainstASXpeers
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Appendix
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• MedicaloncologistattheMemorialSloanKetteringCancer• Specializesinthetreatmentofmalignanciesofthegastrointestinaltract,includingesophagusandstomachcancers.
Imugene Science Advisory Board
Christoph ZieliniskiMD
Ursula WiedermannMD, PhD
Neil SegalMD, PhD
Yelena JanjigianMD
• Director, Clinical Division of Oncology and Chairman, Department of Medicine at Medical University Vienna, Austria.
• Coordinator of the Comprehensive Cancer Center at Medical University Vienna and the General Hospital in Vienna, Austria.
• President, Central European Cooperative Oncology Group (CECOG).
• Chief Science Officer• Professor of Vaccinology and Head of the Institute of Specific
Prophylaxis and Tropical Medicine of the Medical University Vienna.• Speaker of the newly founded Centre for Geographic Medicine at the
Medical University Vienna
• Oncologist at the Memorial Sloan Kettering Cancer Center.• He holds a Doctorate of Medicine and Philosophy from University of the
Witwatersrand in South Africa.
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Phase Ia Study Design*
*BreastCancerResTreat.2010Feb;119(3):673-83.
Patientinclusion criteria• Metastatic breast cancer• HER2+,++• ER/PRpos.• Lifeexpectance >4mo
Primaryendpoint• Safety &Tolerability
Secondary endpoint• Immunogenicity
– Specific antibodies– Cellular responses
Blood draw
Vaccination with10μg of eachpeptide antigen
D0 D28 D56 D84
Administration & Readout Schedule
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Patient Characteristics – Ages 55-84 *
Patient ID Age Metas. disease since Prior chemotherapy Current antihormonal therapy
1 55 Oct. 2006 no Anastrozol
2 66 May 2004 yes (1 adj) Fulvestrant
3 84 Mar. 1999 no Anastrozol
4 79 Sept. 2003 no Anastrozol
5 67 Apr. 2004 no Fulvestrant
6 69 Sept. 2004 no Anastrozol
7 60 Aug. 2002 yes (3 met) Fulvestrant
8 76 Apr. 1999 no Fulvestrant
9 63 Jun. 2006 yes (1 met) Exemestan
10 70 Apr. 2008 No Anastrozol
* Breast Cancer Res Treat. 2010 Feb;119(3):673-83.
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Safety and Tolerability – Few Grade 1 Local Reactions, None Systemic*
Patient ID Local vaccination reaction grade Systemic grade 3/4 toxicity
1 1 no
2 0 no
3 0 no
4 1 no
5 1 no
6 0 no
7 0 no
8 0 no
9 1 no
10 0 no
* Breast Cancer Res Treat. 2010 Feb;119(3):673-83.
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c.
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Phase I - Secondary Endpoint: Immunologic Responses
kappa IgG lambda IgG0
1
2
3
Her
-2/n
eu a
b tit
er in
crea
se
pre- post- pre- post- pre- post-0
1020304050607080
P4 P6 P7
pept
ide
ab ti
ter
pre- post-0
100200300400500600700800
IFN
- γγ γγ p
g/m
lpre- post-
0100200300400500600700800
TNF-αα αα
pg/
ml
pre- post-0
20
40
60
80
100
120
140
IL-2
pg/
ml
P<0.05
185 kDa
1 2 3 4
Cellular responses show Th1 profile
• 8/10 developed significant anti-peptide antibody levels• In all but one the antibodies were also directed against Her-2/neu • The majority also showed a 4-fold increase in influenza titers (HHT)16
Phase 1 Secondary Endpoint –Immunologic Responses
• 8/10developedsignificantanti-peptideantibodylevels• InallbutonetheantibodieswerealsodirectedagainstHer-2/neu• Themajorityalsoshoweda4-foldincreaseininfluenzatitres (HI)
c.
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Phase I - Secondary Endpoint: Immunologic Responses
kappa IgG lambda IgG0
1
2
3
Her
-2/n
eu a
b tit
er in
crea
se
pre- post- pre- post- pre- post-0
1020304050607080
P4 P6 P7
pept
ide
ab ti
ter
pre- post-0
100200300400500600700800
IFN
- γγ γγ p
g/m
lpre- post-
0100200300400500600700800
TNF-αα αα
pg/
ml
pre- post-0
20
40
60
80
100
120
140
IL-2
pg/
ml
P<0.05
185 kDa
1 2 3 4
Cellular responses show Th1 profile
• 8/10 developed significant anti-peptide antibody levels• In all but one the antibodies were also directed against Her-2/neu • The majority also showed a 4-fold increase in influenza titers (HHT)16
c.
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Phase I - Secondary Endpoint: Immunologic Responses
kappa IgG lambda IgG0
1
2
3
Her
-2/n
eu a
b tit
er in
crea
se
pre- post- pre- post- pre- post-0
1020304050607080
P4 P6 P7
pept
ide
ab ti
ter
pre- post-0
100200300400500600700800
IFN
- γγ γγ p
g/m
lpre- post-
0100200300400500600700800
TNF-αα αα
pg/
ml
pre- post-0
20
40
60
80
100
120
140
IL-2
pg/
ml
P<0.05
185 kDa
1 2 3 4
Cellular responses show Th1 profile
• 8/10 developed significant anti-peptide antibody levels• In all but one the antibodies were also directed against Her-2/neu • The majority also showed a 4-fold increase in influenza titers (HHT)16
c.
29
Phase I - Secondary Endpoint: Immunologic Responses
kappa IgG lambda IgG0
1
2
3
Her
-2/n
eu a
b tit
er in
crea
se
pre- post- pre- post- pre- post-0
1020304050607080
P4 P6 P7
pept
ide
ab ti
ter
pre- post-0
100200300400500600700800
IFN
- γγ γγ p
g/m
l
pre- post-0
100200300400500600700800
TNF-αα αα
pg/
ml
pre- post-0
20
40
60
80
100
120
140
IL-2
pg/
ml
P<0.05
185 kDa
1 2 3 4
Cellular responses show Th1 profile
• 8/10 developed significant anti-peptide antibody levels• In all but one the antibodies were also directed against Her-2/neu • The majority also showed a 4-fold increase in influenza titers (HHT)16
Cellular responses show Th2 profile
* Breast Cancer Res Treat. 2010 Feb;119(3):673-83.
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Reduction in Regulatory T Cells*
• SignificantlyhighernumberofCD4+Foxp3+regulatoryTcellsintumour patientsthanhealthycontrols
• VaccinationsignificantlyreducedTregcellsinbothgroups
c.
30
• Significantly higher number of CD4+Foxp3+ regulatory T cells in tumor patients than healthy controls
• Vaccination significantly reduced T reg cells in both groups
pre- post- pre- post-0.0
2.5
5.0
7.5
10.0
patients normal donors
p=0.007
p=0.033
%C
D4+
CD
25+F
oxp3
+
Phase I - Regulatory T cells:Cancer Patients vs.Healthy Controls
0.94 2.1288.74 8.20
100 101 102 103 104
post-vaccinationpre-vaccination
CD4+CD25+
100 101 102 103 104
2.29 6.2164.26 27.24
0.77 2.5187.16 9.56
Pat 01
Pat 02
Normal donor
100 101 102 103 104
1.31 4.3673.22 21.10
100 101 102 103 104
0.86 7.58 65.78 25.79
Data.026
100 101 102 103 104CD25 PE
1.06 8.32 60.84 29.78
CD
4+Fo
xp3+
c.
30
• Significantly higher number of CD4+Foxp3+ regulatory T cells in tumor patients than healthy controls
• Vaccination significantly reduced T reg cells in both groups
pre- post- pre- post-0.0
2.5
5.0
7.5
10.0
patients normal donors
p=0.007
p=0.033
%CD
4+CD
25+F
oxp3
+
Phase I - Regulatory T cells:Cancer Patients vs.Healthy Controls
0.94 2.1288.74 8.20
100 101 102 103 104
post-vaccinationpre-vaccination
CD4+CD25+
100 101 102 103 104
2.29 6.2164.26 27.24
0.77 2.5187.16 9.56
Pat 01
Pat 02
Normal donor
100 101 102 103 104
1.31 4.3673.22 21.10
100 101 102 103 104
0.86 7.58 65.78 25.79
Data.026
100 101 102 103 104CD25 PE
1.06 8.32 60.84 29.78
CD4+
Foxp
3+
CD
4+Fo
xp3+
CD4+CD25+
* Breast Cancer Res Treat. 2010 Feb;119(3):673-83.
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Excellent Immunogenicity, even at low dose, and in Patients ages up to 84 years, with no Cardiotoxicity
• Strongimmunogenicityin8/10patientsinPhase1studywith10μg of peptide antigen
• Goodcorrelationwithcellularresponses(cytokines)
• Safeandwelltolerated,inparticularnocardiotoxicity
• Protectiveefficacyofpeptidesdemonstratedinpreclinicaltumormodelinmiceshowingdelayofonsetandreducedtumorgrowth
*BreastCancerResTreat.2010Feb;119(3):673-83.
Pat. # Peptide-specific abP4, P6, P7
HER2-specific
ab
Infl. HIT
IL-2, IFNγ, TNF
T reg
1 ↑ ↑ ↑ ↑ - - - - ↓
2 ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↓
3 ↑ ↑ ↑ ↑ (+/-) - ↑ - - ↓
4 ↑ ↑ ↑ ↑ ↑ - ↑ ↑ ↓
5 ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↓
6 - - - - - ↓ ↓ ↓ ↓
7 ↑ ↑ ↑ ↑ ↑ - - - ↓
8 ↑ ↑ ↑ ↑ (+/-) ↑ ↑ ↑ - ↑
9 ↑ +/- +/- ↑ ↑ ↑ ↑ ↑ ↓
10 - - - - - +/- ↓ +/- ↓
HER-Vaxx breast cancer vaccine – Phase 1 trial 10 μg group
Antibody and cellular responses in human
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Tumor Growth Inhibition in vivo*
• Prolongedtimetodiseaseprogression
• Immunization of c-neutransgenic mice (recognizedHER2cancer model)withtetanus toxoid-conjugatedpeptides P4,P6and P7
• Vaccinated animals showsignificant delay intumor onsetand reduced growth kinetics
• Co-administrationof IL-12further improves the vaccineperformance
Days after randomization
Preclinical study with tetanus toxoid–conjugated peptide antigens
d170 d235d65
Cum
ulat
ive
prop
ortio
n tu
mor
-free
Time to disease progression
* Breast Cancer Res Treat. 2010 Feb;119(3):673-83.
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No toxicity, in Particular No Cardiotoxicity
• RepeatdosetoxicitystudywithTT-conjugatedpeptidesinmice
• RepeatdosetoxicitystudywithHER-Vaxxinrats
• Localtolerability&immuno-genicitystudywithHER-Vaxxinrabbits
• Invitrotoxicitystudywithpurifiedserumfromimmunizedanimalsonratcardiomyocytes
In vitro toxicity study on rat cardiomyocytes
Rat cardiomyocytes
* Breast Cancer Res Treat. 2010 Feb;119(3):673-83.