Clinical results of OPT-302 (VEGF-C/D ‘Trap’) Combination … · 2019-12-20 · Clinical...

Clinical results of OPT-302 (VEGF-C/D ‘Trap’) Combination Treatment in nAMD and DME

Ophthalmology Innovation Summit @ AAO, October 25 2018Megan Baldwin PhD, CEO & Managing Director

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Disclaimer

2

OPT-302InhibitsVEGF-CandVEGF-D

VEGFR-1 VEGFR-2 VEGFR-3

Ig-likedomain PathwayblockedbyOPT-302KinasedomainLigand

Aflibercept

AngiogenesisVascular Permeability

VEGF-BPlGF

VEGF-A

Ranibizumab

AngiogenesisLymphangiogenesis

VEGF-CVEGF-D OPT-302 66%

5.37

6.91

8.91

0.00

1.00

2.00

3.00

4.00

5.00

6.00

7.00

8.00

9.00

10.00

Baseline 1m 2m

Aque

ousH

umor

VEGF

-C(p

g/ml)

BevacizumabBevacizumab

NeovascularAMD1

1 ARVO(AssociationforResearchinVision&Ophthalmology)AnnualMeeting2016,Cabraletal.,Program3341,PosterD01443

AnUnmetMedicalNeedfornAMD &DME

Donotachievesignificantvisiongains>50%

Willcontinuetohavefluidatthebackoftheeye

Willhavefurthervisionlossat12months

Opportunity:NewProductsthatImproveEfficacyandDurability

nAMD

*Basedonrandomised,controlledclinicaltrialdata;#Failtoachieve≥2linesimprovementinBCVA;^SD-OCTCST≥300µMor Time-DomainOCTCST≥250µM

2/3

25%

Donotachievesignificantvisiongains#

Continuetohavemaculathickening/swelling^DME

2/3

25%

DespitereceivingaVEGF-Ainhibitor(Ranibizumab,AfliberceptorBevacizumab)*:

4

OPT-302• PotentinhibitorofVEGF-C(~5pM)andVEGF-D

(~0.5nM)• A‘trap’thatblocksVEGF-CandVEGF-D

bindingtothereceptorsVEGFR-2andVEGFR-3

VEGF

-C/D

VEGF

-C/D

hIgG1Fc

Extra-CellularDomains1-3hVEGFR-3 1.0

10.0

100.0

0 24 48 72 96 120 144 168 192 216 240 264 288 312 336

OPT-302 Monotherapy (2 mg)

Combination OPT-302 (2 mg) + Ranibizumab (0.5 mg)

MeanOPT-302serumconcentrations

Time (hours)

Mea

n (+

SD) O

PT-3

02 S

erum

C

once

ntra

tions

(ng/

mL)

• Non-compartmentalOPT-302PKanalysisindicated:• Lowsystemicexposure• Half-lifeof8± 2days• Mean Cmax of~21ng/mLat~31hourspostIVT

injectionatadoseof2mg• Noaccumulation• NoinfluencefromranibizumabonthePKprofile.

5

6• Comprises of 4 treatment cohorts of 5 subjects each *Access to rescue anti-VEGF-A Tx

OPT-302 (0.3 mg) + Ranibizumab (0.5 mg)

IVT Q4W x 3

OPT-302 (1 mg) + Ranibizumab (0.5 mg)

IVT Q4W x 3


IVT Q4W x 3

28 D

ay D

LT w

indo

w

OPT-302 (2 mg)Monotherapy*IVT Q4W x 3

Cohort 4

Cohort 3

Cohort 2

Cohort 1

Part 1: Dose-escalation(Open-label)

Prim

ary

Ana

lysi

s af

ter a

llsu

bjec

ts c

ompl

ete

12 w

eeks

Long

term

follo

w-u

p at

Wee

k 24

Follo

w-u

p to

wee

k 12

OPT-302 (2 mg)+ Ranibizumab (0.5 mg)IVT Q4W x 3, n=23 pts

OPT-302 (2 mg)Monotherapy*

IVT Q4W x 3, n=8 pts

Part 2: Dose-expansion(Randomised 3:1)

ClinTrials Identifier NCT 02543229

OPT-302Phase1/2aFirst-in-HumanStudyinNeovascularAMD(n=51)

OPT-302+/- Ranibizumab- Phase1/2aSafetySummaryOPT-302+ LucentisadministeredbyrepeatIVTinjection(Baseline,Week4,Week8)

• Nomisseddoses,safetyexperiencewith~150intravitreal(ocular)injectionsofOPT-302

OPT-302atoculardosesupto2mg+ Lucentis (0.5mg):

• Nodoselimitingtoxicities(MTDwasnotreached)

• Nodrug-relatedseriousadverseeventsorsystemicadverseevents

MajorityofocularemergentadverseeventsprimarilyrelatedtoIVTinjectionprocedure

• (31/51patients;59%);majorityGrade1/MildorGrade2/ModerateandManageable

Twopatients(4%)hadocularadverseeventsrelatedtoOPT-302studydrug

• AEswereGrade1/Mildinflammationindicativeofanterioruveitisinthelow- andmid-dosecombinationgroups

• NoOPT-302relatedAEsobservedinthehighdose(2mg)combinationormonotherapytreatedpatients(n=41)

NoclinicallysignificantchangesinIOP,ECG’s,bloodpressure,vitals

NoevidenceofOPT-302-relatedimmunogenicity

OPT-302hasconsistentlydemonstratedafavourable safetyprofile+/- ranibizumab7

8

MeanChangeVAfromBaseline(letters)

MeanBaselineVA=55.7LettersRanibizumabrescuetherapyavailableweek2throughweek12atinvestigatordiscretionorifpatientsmetpre-definedcriteria:<10%decreaseinCSTand≥5letterlossofBCVA

0

2

4

6

Vis

ual

Ac

uit

y(M

ea

n C

ha

ng

e f

rom

Ba

se

lin

e)

A ll M o no T x

N o n -R e s c u e

B a s e lin e W e e k 4 W e e k 8 W e e k 1 2

R e s c u e

MeanChangeinVisualAcuity• Ofthe13patientswhoreceivedOPT-302monotherapytreatment:

• 7/13(54%)didnotreceiveanti-VEGF-Arescuetherapythroughweek12

• Anadditional5/13(38%)receivedonly1rescueinjectionthroughweek12

• Onesubject(8%)received2rescueinjections.

• Themeantimetorescuetherapywas58days.

• Useofrescuetherapyin4/6caseswasbasedonInvestigatordiscretion

+4.4letters

+2.8letters

EvidenceofbiologicalactivityinpatientstreatedwithintravitrealOPT-302(2mg)monotherapy

+5.6letters

9

GainsinVisualAcuityandReducedRetinalThicknessinPatientswithOPT-302+RanibizumabTherapyChangeinmeanBCVA

+10.8 letters

+ 4.9 letters

TreatmentNaïvePatients:n=18;OPT-302(0.3,2.0mg)+ranibizumab (0.5mg)MeanBaselineVA=56.5Letters

0

5

10

15

0 4 8 12Time(weeks)

Changefrom

baselineinVisu

alAcuity

(ETD

RSLetters) Naïvepts(n=18)

Priortreatedpts(n=20)

Prior-TreatedPatients:n=20(wk 4,8),19(wk 12);OPT-302(0.3-2.0mg)+ranbizumab (0.5mg)MeanBaselineVA=64.5Letters;Meannumberprioranti-VEGF-Ainjections =17

ChangeinmeanCentralSubfieldThickness

-54 µM

-119 µM

-160

-140

-120

-100

-80

-60

-40

-20

00 2 4 6 8 10 12

Changefrom

baselineinCST(µ

M)

Time(weeks)

Naïvepts(n=18)Priortreatedpts(n=20)

Error Bars: SEM

0

1

2

3

4

5

6

7

8

9

Baseline Week4 Week12

ReductioninCNVSizeonFACN

VSize(m

m2 )

7.71

3.74

2.03

OPT-302+Ranibizumab OPT-302+Ranibizumab

0

10

20

30

40

50

60

Baseline Week4 Week12

%PatientswithAbsentCNVonFA

%Patientsw

ithAbsen

tCNVon

FA

5.6%*

27.8%

50%

ReductionsinCNVinTreatment-NaïvePatientswithOPT-302+RanibizumabTherapy

TreatmentNaïvePatients:n=18;OPT-302(0.3,2.0mg)+ranibizumab(0.5mg);*AbsentonFA,presentonOCT

CNV:ChoroidalNeovascularisation

10

OPT-302+/- RanibizumabPhase2bTrialinTreatment-NaïvenAMD (n=351)

Randomized 1:1:1 to treatment armsIVT dosing at every 4 weeks (x 6)

Treatment-NaiveNeovascular AMD


OPT-302 (0.5 mg) + Ranibizumab (0.5 mg)

Sham + Ranibizumab (0.5 mg)

Wee

k 24

Fol

low

-up

n=117

n=117

n=117

• Currentlyenrolling• Primarydataanalysisearly2020

ClinTrials Identifier NCT 0334508211

VEGF-CanditsinteractionwithVEGFR-2andVEGFR-3playsafunctionalroleinpathogenesisofDME:• OPT-302hasshownevidenceofactivitytoresolveretinalfluid1

• VEGFR-2expressionisgreaterindiabeticretinathannon-diabetics2,3,4

• VEGF-Ciselevatedindiabeticretinopathy4

• VitreouslevelsofVEGF-Dareelevatedindiabetes5

• VEGF-Cexpressioniselevatedbyglucose&pro-inflammatorycytokines6,7

• InhibitionofVEGF-CandVEGF-Dinadiposetissueofmiceimprovesmetabolicparametersandinsulinsensitivity8,9

• AdvancedglycationendproductsaccumulatefasterindiabeticsandstimulateVEGF-CexpressionandsecretionfromtheRPE6

• Singlenucleotidepolymorphisms(SNPs)indiabeticpatientsindicatethatgeneticvariationintheVEGF-Cgeneisassociatedwithdiabeticretinopathyanddiabeticmacularedema 10

1.Phase1/2aOPT-302trialresults:www.opthea.com;2.Sunetal.,2014;3.Witmeretal.,2002;4.Zhaoetal.,2007;5.Kovacsetal.,2015;6.Puddu etal.,2012;7.Nagineni etal.,2011;8.Karaman etal.,2014;9.Karaman etal.,2016;10.Kaidonis etal.,2015

OPT-302MechanismofActionSupportsInvestigationinDME

VEGF-C/DSignalingPathwayisImplicatedinDiabetes

12

Phase1bDoseEscalationstudyofOPT-302+AfliberceptinDME

N=

14 D

ay D

LT w

indo

w

Cohort 3

Cohort 2

Cohort 1

Phase 1b Dose-Escalation

Prim

aryAn

alysisafterall

subjectsco

mplete12weeks

PRN

ant

i-VEG

F-A

Wee

k 12

to 2

4

Follo

w-u

p to

wee

k 12

Phase 2a Dose-Expansion(Randomised 2:1 ratio)

OPT-302 (0.3 mg)+ Aflibercept (2.0 mg)

IVT Q4W x 3, n=3 ClinTrialsIdentifier NCT 03397264

• HbA1c≥12%• Uncontrolledhypertension≥180mmHgsystolicor

≥110mmHgdiastolic• EyesneedingPRPwithin3monthsofscreening• Concurrent/prioruseofintravitrealinjectionsof

steroidswithin4monthsofstudystart• Concurrent/prioruseofdexamethasoneor

fluocinoloneimplantinstudyeye

KeyExclusionCriteria


IVT Q4W x 3, n=3


IVT Q4W x 3, n=3


IVT Q4W x 3, n=~72 pts

Aflibercept (2.0 mg)IVT Q4W x 3, n=~36 pts

N=9 patients

KeyInclusionCriteria• Age≥18years;centre-involvingDME• CST≥335µm*• BCVA73– 24ETDRSletters(20/40– 20/320Snellen• Priorexposuretoanti-VEGF-Atherapywithsub-optimal

therapeuticresponse• ≥3intravitrealinjections• Lastinjection≤6wks priortostudyday1• PriorbevacizumabonlyallowedifswitchedtoIVTafliberceptor

ranibizumabpriortostudy

*CSTasmeasuredbySpectralis (Heidelberg)atscreening,≥320µmforCirrus.13

BaselineOcularCharacteristics– PriorTreated

CharacteristicOPT-302(0.3 mg)+Aflibercept(2.0mg)

(n=3)

OPT-302(1 mg)+Aflibercept(2.0mg)

(n=3)


(n=3)

TotalNumberofSubjects(N=9)

Vision

MeanBCVA,ETDRSletters(SD) 64.3(9) 64.6(5) 66.7(3.1) 65(5.5)Betterthan55lettersvision,n(%) 3(100%) 3(100%) 3(100%) 9(100%)Worsethan55lettersvision,n(%) 0(0%) 0(0%) 0(0%) 0(0%)

AnatomicMeanCST,µm(SD) 460(103) 396(42) 432(24) 430(63)CST≤450µm,n(%) 1(33%) 3(100%) 2(67%) 6(67%)CST≥450µm,n(%) 2(67%) 0(0%) 1(33%) 3(33%)

Meandurationofdiabetesatscreening,years(SD) 14(7.9) 17.3(13) 10.9(12.6) 14.1(10.3)

Meanpriorintravitrealinjectionsofanti-VEGF-Atherapy,number(SD) 5(2.6) 7.3(2.5) 6.7(2.3) 6.3(2.4)

MeantimefrompriorTxtoday1,days 42(0) 33.7(7.2) 31(4.4) 35.6(6.5)MeanHbA1c*,%(SD) 7.5(2.4) 7.1(0.3) 7.4(1.4) 7.3(1.4)

*HbA1c=glycatedhemoglobin14

OPT-302+AfliberceptSafetyResults• OPT-302(0.3,1or2mg)+ aflibercept(2mg)administeredbyIVTinjection(Baseline,Week4,Week8)

• OPT-302intravitrealdosesupto2mgincombinationwithaflibercept(2mg)

• Nodoselimitingtoxicities(MaximumToleratedDosenotreached)

• Nostudydrugrelatedadverseevents

• OcularAEsinthestudyeyeprimarilyrelatedtoIVTinjectionprocedure(Mild/moderate,resolved)

• NoclinicallysignificantchangesinIOP,ECG’s,orvitals.

• OPT-302wasgenerallysafeandwelltolerated+aflibercept

OPT-302hasafavorablesafetyprofilewhenadministeredwithaflibercept(DME)expandinguponsimilarresultswhengivenasmonotherapyorincombinationwithranibizumab(wetAMD)

15

OPT-302+Aflibercept– SafetySummaryofselectedAEsSelectedAdverseEvents:

OcularorSystemicOPT-302(0.3 mg)+Aflibercept(2.0mg)

(n=3)


(n=3)


(n=3)

TotalNumberofSubjects(N=9)

Intraocularinflammation 0 0 0 0Endophthalmitis 0 0 0 0Retinaldetachment 0 0 0 0Vitreoushemorrhage 0 0 0 0Hypertension 1(33%)* 0 0 1(11%)*

APTCevents#

Nonfatalmyocardialinfarction 0 0 0 0Nonfatalstroke 0 0 0 0Vascularorcardiacdeathordeathofunknowncause 0 0 0 0CombinedAPTCevents 0 0 0 0

Anyotherdeath 0 0 0 0

IOP,mmHg:Baseline,week12;(changefrombaseline) 13.0;15.7(2.7) 17.3;15.3(-2.0) 16.7;17.0(0.3) 15.7;16.0(0.3)

• Nosafetysignalsorunexpectedfindings#APTC=AntiplateletTrialists'Collaboration*Determinedbytreatinginvestigatorasunrelatedtostudydrug(s)16

DoseResponseinBCVAchangesfromBaselinetoWeek12

+ 14.3

Mea

n C

hang

e fr

om b

asel

ine

in B

CVA

(Let

ters

)

Week

+ 3.0

-5

0

5

10

15

20

0 2 4 8 12

+ 5.7

Aflibercept (2 mg) + OPT-302

2 mg

1 mg

0.3 mg

MeanChangeinBCVABaselinetoWeek12

Error Bars: SEM17

OPT-302+Aflibercept:GainsinBCVAatWeek12DoseResponseRelationship

Dose of OPT-302 + Aflibercept

(2 mg)

% of pts with BCVA gain≥ 5 letters

Mean # prior anti-VEGF-A

injections0.3 mg 1/3 (33%) 5

1 mg 2/3 (67%) 7.32 mg 3/3 (100%) 6.7

0.3 to 2 mg 6/9 (67%) 6.3

0

5

1 0

1 5

2 0

Mea

n C

hang

e fr

om b

asel

ine

in B

CVA

(Let

ters

)

0.3 mgOPT-302

1 mgOPT-302

2 mgOPT-302

0.3 - 2 mgOPT-302

+ 2 mg Aflibercept

(N=9)(N=3)(N=3) (N=3)

+7.7

+14.3

+3.0+5.7

Error Bars: SEM18

OPT-302(0.3-2mg)+Aflibercept(2mg):MeanchangesinCSTfromBaselinetoWeek12

Mea

n C

hang

e fr

om B

asel

ine

in

CST

on

SD-O

CT

(µm

)

Week

- 77 µM-100

-80

-60

-40

-20

0

20

0 2 4 8 12

Error Bars: SEM; Mean Baseline CST = 430 µm19

DMEPatientswithBilateralDisease*StudyEyevsFellowEye(N=5)

MeanChangeinBCVABaselinetoWeek12

Mea

n C

hang

e B

CVA

(Let

ters

)

OPT-302 + Aflibercept

Anti-VEGF-A Monotherapy

+10.0

+2.6

MeanChangeinCST(uM)BaselinetoWeek12

Mea

n C

hang

e C

ST (µ

M)



-90 µM

-6.0 µM

Perc

enta

ge P

atie

nts

%Ptswith≥50%ReductioninExcessFovealThickness



80%

20%

Study Eye: 0.3 – 2mg OPT-302 + 2 mg Aflibercept Fellow Eye: Anti-VEGF-A Monotherapy*

*PatientswithbilateraldiseaseandpersistentDMEinthefelloweyereceivinganti-VEGF-A(ranibizumaboraflibercept)monotherapyPrioranti-VEGF-AtherapyinFellowEyesBLtoWk 12:3xAflibercept,3xRanibizumab,1xRanibizumab,4xRanibizumab,3xAflibercept

Meanbaseline BCVA,CST:StudyEyes (63letters,437µM);FellowEye(73letters,383µM)#Excessfovealthicknesswasdeterminedbyusing300µmSpectralis scanvaluesand285µmCirrusscanvalues20

Phase2aRandomisedDoseExpansionstudyofOPT-302+AfliberceptinPersistentDME

14 D

ay D

LT w

indo

w

Cohort 3

Cohort 2

Cohort 1

Phase 1b Dose-Escalation

Prim

aryAn

alysisafterall

subjectsco

mplete12weeks

PRN

ant

i-VEG

F-A

Wee

k 12

to 2

4

Follo

w-u

p to

wee

k 12

Phase 2a Dose-Expansion(Randomised 2:1 ratio)


IVT Q4W x 3, n=3 ClinTrialsIdentifier NCT 03397264


IVT Q4W x 3, n=3


IVT Q4W x 3, n=3


IVT Q4W x 3, n=~72 pts

Aflibercept (2.0 mg)IVT Q4W x 3, n=~36 pts

• Phase2acurrentlyenrollingpatientsinUSandAustralia• Primarydataanalysis2019

21

OPT-302Target:VEGF-C/D



DiabeticMacularEdema

NeovascularAMDPhase1

CombinationAgent Preclinical Phase2a Phase2b Phase3 Status

1o DataAnalysis

RanibizumabTarget:VEGF-A

RanibizumabTarget:VEGF-A

AfliberceptTarget:VEGF-A,PlGF,VEGF-B

CompletePh1/2a(n=51) April2017

OngoingPh2b(n=351) Early2020

OngoingPh1b/2a(n=117) 2019

OPT-302ClinicalProgram

• TwoongoingrandomisedcontrolledclinicaltrialsinnAMD &DME

22

• CurrenttreatmentstargetprimarilyVEGF-A;OPT-302inhibitsVEGF-C/D• ThesuccessfuldoseescalationofOPT-302incombinationwithafliberceptinDMEbuildsuponthesimilarfavourablesafetyprofileincombinationwithranibizumabinnAMD

• EvidenceofadoseresponseforOPT-302combinationtreatmentongainsinBCVAinpersistentDME,togetherwithbiologicalresponsesonanatomicmeasuresinnAMDandDMEindicatesthatPan-VEGF(A,CandD)inhibitionmayofferbenefitsthatexceedtheinhibitionofVEGF-Aalone

• CurrentlyrecruitingpatientsintwoPhase2multi-center internationaltrials:• ~108patientrandomisedcontrolledPhase2atrialinDME• 351patientrandomisedcontrolledPhase2btrialinnAMD

• Primarydatareadouts2019(DME)andearly2020(nAMD)

Conclusion

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MeganBaldwin,PhDCEO&ManagingDirectorT+61(3)[email protected]

Suite0403,Level4,650ChapelStreet,SouthYarra 3141VictoriaAustralia

Clinical results of OPT-302 (VEGF-C/D ‘Trap’) Combination … · 2019-12-20 · Clinical...

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Transcript of Clinical results of OPT-302 (VEGF-C/D ‘Trap’) Combination … · 2019-12-20 · Clinical...