“beyond anti-vegf-a for - opthea · “beyond anti-vegf-a for retinal diseases” new york city,...

“Beyond anti-VEGF-A for

Retinal Diseases”

New York City, KOL Forum, November 6 2018

Megan Baldwin PhD, CEO & Managing Director

NEOVASCULAR AMDCURRENT TREATMENT PARADIGMS AND UNMET NEEDS

ARSHAD M. KHANANI MD,MAM A N A G I N G PA R T N E R , D I R E C T O R O F C L I N I C A L R E S E A R C H , D I R E C T O R O F F E L L O W S H I PS I E R R A E Y E A S S O C I A T E SC L I N I C A L A S S O C I A T E P R O F E S S O R U N I V E R S I T Y O F N E V A D A - R E N O

OBJECTIVES

▪ PR ACT ICE SE T T ING

▪ STANDAR D OF CAR E DOSING ST R AT EGIES

▪ CL INICA L T R IA L S DATA HIG HL IG HTING UNME T NE E DS

▪ NEW T R EAT MENT S ON T HE HOR IZ ON

PRACTICE SETTING

▪ PR IVAT E O FFICE B A SE D PR ACT ICE

▪ MULTISPECIALT Y WIT H 2 R ET INAL PHYSICIANS

▪ 55 E MPLOYE ES TOTA L

▪ 7 T E CHNICIA NS, 3 R E SE A R CH CO O R DINATO RS

▪ 1 5 - 20 ACT IVE CL INICA L T R IA L S

▪ 70 PAT IE NT S A DAY O N AVE R AG E

▪ A PPR OXIMATELY 50 0 INJ E CTIO NS A MO NT H

ANGIOGENESIS IN AGE-RELATED MACULAR DEGENERATION COMPLEX CASCADE OF EVENTS

Griffioen AW, et al. Pharmacol Rev. 2000;52(2):237-68; Das A, et al. Prog Retin Eye Res. 2003;22(6):721-48;Davis GE, et al. Circ Res. 2005;97(11):1093-107.

Basementmembranedegradation

Tubeformation +remodeling

VEGF

Vascular Endothelial

Growth Factor

Endothelial cell activation

Endothelial cell proliferation,migration

CURRENT PARADIGM – BLOCK VEGF-A

Griffioen AW, et al. Pharmacol Rev. 2000;52(2):237-68; Das A, et al. Prog Retin Eye Res. 2003;22(6):721-48;Davis GE, et al. Circ Res. 2005;97(11):1093-107.

Basementmembranedegradation

Tubeformation +remodeling

VEGF

Vascular Endothelial

Growth Factor

Endothelial cell activation

Endothelial cell proliferation,migration

CURRENT ANTI-VEGF-A THERAPIES FOR nAMD

▪ ANTI-VEGF-A THERAPY HAS REVOLUTIONIZED THE MANAGEMENT OF nAMD IN THE PAST 10-15 YEARS

▪ THREE MOLECULES CURRENTLY USED:▪ RANIBIZUMAB (LUCENTIS)▪ BEVACIZUMAB (AVASTIN)▪ AFLIBERCEPT (EYLEA)

ANTI-VEGF-A DOSING STRATEGIES USED IN CLINICAL TRIALS TO OPTIMIZE OUTCOMES AND MANAGE nAMD DISEASE

MONTHLY- ANCHOR- MARINA

- CATT- HARBOR

PRN- SAILOR

- CATT

- HARBOR

TREAT AND

EXTEND- LUCAS

- TREX

- ALTAIR

1. Rosenfeld PJ et al. N Engl J Med. 2006;355:1419-1431. 2. Brown DM et al. N Engl J Med. 2006;355:1432-1444. 3. Heier JS et al. Ophthalmology. 2012;119:2537-2548.

CONTINUOUS FIXED MONTHLY DOSING: VISUAL ACUITY FROM

BASELINE THROUGH MONTH 24

MONTHS MONTHSMARINA1 ANCHOR2

VIEW 1 and 23

CONTINUOUS MONTHLY DOSING

WHY DO IT?▪ EVIDENCE OF IMPROVING VISION▪ MAINTAIN VISION AND RETINAL DRYING▪ AVOIDS UNDER-TREATMENT

WHY NOT DO IT?▪ NOT INDIVIDUALIZED▪ nAMD IS HETEROGENEOUS▪ VARIABLE NATURAL HISTORY AND TREATMENT RESPONSE▪ MANY PATIENTS DO WELL WITHOUT MONTHLY TREATMENT▪ VEGF-A SUPPRESSION VARIES BETWEEN PATIENTS▪ RESULTS BEYOND 2 YEARS LARGELY UNKNOWN

CONSEQUENCES OF OVERTREATMENT

▪ E X PE NSE : DIR E CT A ND INDIR ECT CO ST S

▪ INCONVENIENCE: FR EQUENT VISIT S

▪ INCR E A SE D R ISK (CUMULATIVE )

▪ INFECTION

▪ SUSTAINED IOP ELEVATION/GLAUCOMA

WHY?AVOID OVERTREATMENT

SAFER

MORE

COST-EFFECTIVE

HOW?

PRN (AS NEEDED)

TREAT-AND-EXTEND

GOALS

SUPPRESS CNV GROWTH, EXUDATION

FREQUENT OCT IMAGING WITH “ZERO

TOLERANCE”

INDIVIDUALIZED ANTI-VEGF TREATMENT

PRN DOSING IN HARBOR

Ho AC, Busbee BG, Regillo CD, et al. Ophthalmology. 2014;121(11):2181-2192.

DISTRIBUTION OF THE NUMBER OF RANIBIZUMAB INJECTIONS OVER 2 YEARS

UNDERTREATMENT COMPROMISES VISUAL ACUITYPOSITIVE CORRELATION OF VA GAINS AND NUMBER OF

ANTI-VEGF-A INJECTIONS OVER 12 MONTHS

Hussain RM et al. Ophthalmic Surg Lasers Imaging Retina. 2017;48:780-784.

MANY PATIENTS RECEIVE FEWER INJECTIONSIN REAL-WORLD VS CLINICAL STUDIES

US medical claims database:Patients received a mean of only 4.6 and 6.9 injections of bevacizumab & ranibizumab over 12 mo, respectively

PRO RE NATA (PRN) DOSING

PATIENTS RECEIVE:

▪ A SER IES OF MONT HLY LOADING INJ ECT IONS OF ANT I - VEGF T HER APY

▪ R E G ULA R O FFICE VISIT S FO R A SSE SSMENT O F VISUA L ACUIT Y

▪ A NATO MIC ME A SURE S B A SE D O N O CT, FA O R OT HE R IMAG ING MO DA L ITIES

▪ A L LO WS FO R R E CUR R E NCE O F NE OVA SCULA R L E A K AG E A ND G R O WT H

▪ MULTIPLE R E CUR R ENCES L E A DS TO PR O G R ESSIO N O F DISE A SE

▪ PO O R E R LO NG -TER M VISUA L O UTCO MES IN SO ME PAT IE NTS

Wai KM et al. Am J Ophthalmic Clin Trials. 2018;1:1.

POTENTIAL LIMITATIONS OF DISCONTINUOUS PRN

▪ SER IES OF LOADING ANT I - VEGF INJ ECTIONS, (T YPICALLY 4 - WK INT ER VAL S), WIT H VA A ND A NATO MIC A SSE SSMENT

▪ WHE N CR IT E R IA INDICAT ING NO DISE A SE ACT IVIT Y A R E ME T, PAT IE NTS R E CE IVE A N INJ E CTIO N; T R E AT MENT INT E R VA L IS E X T E NDE D, USUA L LY B Y 2 WEEKS AT A T IME, UNT IL MAX IMUM INT ER VAL OF 1 2 – 1 6 WEEKS IS R EACHE D

▪ IF CNV L E SIO NS A R E R E ACT IVAT ED, T R E AT MENT INT E R VA L IS R E DUCED

Spaide R. Am J Ophthalmol. 2007;144:679-680

TREAT-AND-EXTEND DOSING: WHAT IS IT?

▪ CONTINUOUS (PROACTIVE)

▪ MINIMIZES RECURRENCES/SETBACKS

▪ VARIABLE (INDIVIDUALIZED)

▪ MINIMIZES OVERTREATMENT

▪ MINIMIZES TREATMENT BURDEN

▪ MAXIMIZES SAFETY

▪ COST-EFFECTIVE

▪ MINIMIZES DRUG USE, TESTING, AND OFFICE

Spaide R. Am J Ophthalmol. 2007;144:679-680

BENEFITS OF TREAT-AND-EXTEND DOSING

CURRENT UNMET NEEDS IN nAMD

+25

-20

-15

-10

-5

0

5

10

15

0 6 12 18 24

Me

an

Ch

an

ge

i in

ET

DR

S B

CV

A

Months ANCHOR, MARINA, HARBOR, CATT, VIEW1/2

NEOVASCULAR AMD ANTI-VEGF A BLOCKADE

20/100

20/63

Brown DM, et al. Ophthalmology. 2009 Jan;116(1):57-65.e5; Rosenfeld PJ, et al; N Engl J Med. 2006;355:1419-1431; Ho AC, et al. Ophthalmology. 2014 Nov;121(11):2181-92; Martin DF, et al. Ophthalmology. 2012; 119(7):1388-98; Heier JS, et al. Ophthalmology. 2012 Dec;119(12):2537-48

-25

-15

-5

5

15

25

35

0 6 12 18 24

Me

an

Ch

an

ge

i in

ET

DR

S B

CV

A

MONTHS

20/100

20/20

#1 EFFICACY


NEOVASCULAR AMD – SHORTCOMINGS OF VEGF-A BLOCKADE

>70% VA REMAINS TO BE GAINED

20/200

20/200

20/40

X 8 #2 Durability

0

5

10

15

0 3 6 9 12

Me

an C

han

ge in

ETD

RS

BC

VA

Months

MARINA 0.5 mg

ANCHOR (0.5 mg)

HARBOR 0.5 mg Monthly

CATT Ranibizumab Monthly

HARBOR 0.5 mg PRN

CATT Bevacizumab Monthly

CATT Ranibizumab PRN

CATT Bevacizumab PRN

VIEW1 (0.5q4)

VIEW1 (2q8)

VIEW1 (2q4)

VIEW2 (0.5q4)

VIEW2 (2q8)

VIEW2 (2q4)

11.3

5.9

ANCHOR, MARINA, HARBOR, CATT, VIEW1/2

ANTI-VEGF-A TREATMENT OF nAMD - PROSPECTIVE FIXED OR PRN DOSING

Mean = 8.4

InjectionsMean = 10.2

Range = 6.6-12.3


0

5

10

15

0 3 6 9 12

Me

an C

han

gei i

n E

TDR

S B

CV

A

Months

LUCAS Ranibizumab

LUCAS Bevacizumab

TREND

TREX AMD

10.5

6.6

LUCAS, TREND, TREX-AMD

ANTI-VEGF-A TREATMENT OF nAMD - PROSPECTIVE TREAT & EXTEND DOSING

InjectionsMean = 8.9

Range = 8.0-10.1

Mean = 8.6

Berg K, et al. Ophthalmology. 2015 Jan;122(1):146-52; Silva R, et al. Ophthalmology. 2018 Jan;125(1):57-65; Wykoff CC, et al. Ophthalmology. 2015 Dec;122(12):2514-22.

REAL-WORLD DATA: MAJORITY OF nAMD PATIENTS LIKELY UNDERTREATED 1ST YEAR OF MANAGEMENT

Holz FG, et al. Presented at: EURetina 2017; September 7-10, 2017; Barcelona, Spain.

7.48.5

19.6

12.213.5

11.7

9.5

5.95.1

2.92.1

1.0 0.5 0.1 0.00

5

10

15

20

1 (n=250)

2(n=287)

3(n=661)

4(n=412)

5(n=455)

6(n=396)

7(n=322)

8(n=199)

9(n=173)

10(n=97)

11(n=72)

12(n=35)

13(n=17)

14(n=2)

15(n=1)

Pro

po

rtio

n o

f p

atie

nts

(%

)

Number of ranibizumab injections up to Month 12

≈73% ≤ 5 injections LUMINOUS

KEY POINTS & ISSUES WITH CURRENT ANTI-VEGF-A THERAPY

▪ U P P E R L I M I T F O R VA ~ 9 L E T T E R S F O R n A M D▪ I M P R O V E M E N T S I N VA A P P E A R D E P E N D E N T U P O N

▪ NUMBER OF INTRAVITREAL INJECTIONS

▪ CLOSE MANAGEMENT OF ANATOMICAL CHANGES

▪ AV O I D U N D E R T R E AT M E N T

▪ UNDER-TREATMENT IS COMMON AND PROHIBITS PATIENTS FROM ACHIEVING EXPECTED VA GAINS

▪ “MORE IS BETTER” BUT MAY COME AT A PRICE IN nAMD WHICH IS A CHRONIC DISEASE

▪ P O S S I B I L I T Y TO I N D I V I D U A L I Z E T R E AT M E N T W I T H P R N O R TA E

▪ >12 WEEK TREATMENT INTERVAL POSSIBLE IN ~25-50% OF PATIENTS

▪ N E W T R E AT M E N T M O D A L I T I E S I N C L U D I N G C O M B I N AT I O N T H E R A P Y A R E N E E D E D TO I M P R O V E V I S I O N A N D / O R D U R A B I L I T Y O F R E S P O N S E

▪ VEGF-A JUST ONE MOLECULAR PATHWAY IN THE PATHOGENESIS OF nAMD

Wai KM et al. Am J Ophthalmic Clin Trials. 2018;1:1.

DUAL-TARGETING

▪ GENE THERAPY ▪ STEM CELLS▪ DROPS ▪ PILLS

DRUG DELIVERYAPPROACHES

ADDITIONAL ANTI-VEGF AGENTS BROLUCIZUMAB & ABICIPAR

VE

GF

-C/D

VE

GF

-C/D

hIgG1 Fc

Extra-Cellular Domains 1-3hVEGFR-3

FARICIMAB(RG7716)

VEGF-C/D BLOCKADE: OPT-302

INTO THE FUTURE

MOONSHOTS

COMPARISON OF CURRENT VS EMERGING ANTI-VEGF-A AGENTS

Bevacizumaba Ranibizumab Aflibercept Brolucizumabb Abicipar pegolb

FormatFull antibody

(IgG1)

Monoclonal humanized

antibody fragment

VEGFR-1/2-Fc fusion protein

Single-chain antibody fragment

(scFv)

Designed ankyrin repeat protein

(DARPin)1

Molecular structure

Molecular weight 149 kDa 48 kDa 115 kDa 26 kDa 34 kDa

Clinical dose for nAMD

1.25 mg(unlicensed use)

0.5 mg 2.0 mg 6.0 mg 2.0 mg

aOff-label; not FDA-approved for any ocular indicationsbUnder investigation for treatment of nAMD

1. Molecular Partners. www.molecularpartners.com/our-products/abicipar/. Accessed 7/17/18.

BROLUCIZUMAB: PHASE 3 STUDY DESIGN

Dugel PU et al. Oral Presentation at the American Academy of Ophthalmology Meeting, Chicago, USA, October 2018.

BROLUCIZUMAB WAS NON-INFERIOR TO AFLIBERCEPT

Dugel PU et al. Oral Presentation at the American Academy of Ophthalmology Meeting, Chicago, USA, October 2018

BROLUCIZUMAB ACHIEVED SUPERIOR REDUCTIONS IN CENTRAL SUBFIELD THICKNESS (CST) AT WEEKS 16, 48 and 96.

Dugel PU et al. Oral Presentation at the American Academy of Ophthalmology Meeting, Chicago, USA, October 2018

Abicipar Pegol: Phase 3 CEDAR and SEQUOIA Study Design

▪ RANDOMIZED, TRIPLE-MASKED TRIALS

▪ CEDAR: N=939

▪ SEQUOIA: N=946

▪ TWO DOSES ABICIPAR PEGOL 2 MG Q8WK VS ABICIPAR PEGOL 2 MG Q12WK VS RANIBIZUMAB 0.5 MG Q4WK THROUGH 96 WK

▪ PRIMARY OUTCOME: BCVA CHANGE FROM BASELINE

1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02462928. 2. ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT02462486.

Abicipar pegol 2 mg

Ranibizumab 0.5 mg

Sham treatme

No treatment

n = 900 (1:1:1)

BL 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100

2Q8

2Q12

RQ4

PRIMARY ENDPOINT

Week

CEDAR PRIMARY ENDPOINT: STABLE VISION AT WK 52 ABICIPAR Q8WK AND Q12WK NONINFERIOR TO RBZ Q4WK

RBZ, ranibizumabAllergan. 7/19/18. www.allergan.com/investors/events-presentations/events/abicipar-cedar-and-sequoia-topline-phase-3-clinica.aspx. Accessed 7/22/18.

INCIDENCE OF INTRAOCULAR INFLAMMATION EVENTS

SEQUOIA STUDY

15.7% 15.3%

0.6%

CEDAR STUDY

15.1% 15.4%

0.0%0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Abicipar Q8 Abicipar Q12 Ranibizumab Q4

Intraocular Inflammation Events

Intraocular Inflammation Events

Allergan. 7/19/18. www.allergan.com/investors/events-presentations/events/abicipar-cedar-and-sequoia-topline-phase-3-clinica.aspx. Accessed 7/22/18.

PORT DELIVERY SYSTEM WITH RANIBIZUMAB (PDS): HOW DOES IT WORK?1

▪ NONBIODEGRADABLE REFILLABLE PORT PLACED BENEATH THE CONJUNCTIVA

▪ RESERVOIR REFILLED VIA SUBCONJUNCTIVAL OPENING USING CUSTOM REFILL NEEDLE

▪ PROVIDES CONSTANT LEVELS OF RANIBIZUMAB

1. Barakat MR et al. Retinal Physician. 10/1/15. www.retinalphysician.com/issues/2015/october-2015/new-developments-for-the-treatment-of-exudative-an#ref17. Accessed 6/7/18. 2. Helzner J. Retinal Physician. 1/18/17. www.retinalphysician.com/issues/2017/january-2017/genentech-acquires-developer-of-sustained-release. Accessed 6/15/18.

FARICIMAB OVERVIEW: FIRST BISPECIFIC ANTIBODY DESIGNED FOR INTRAOCULAR USE

Regula JT et al. EMBO Mol Med. 2016;8:1265-1288.

• ANG-2 IS A KEY DRIVER OF ANGIOGENESIS• UPREGULATION OF ANG-2 (OBSERVED IN NAMD) LEADS TO DECREASED TIE2 ACTIVATION

• SUBSEQUENT VASCULAR LEAKAGE AND NEOVASCULARIZATION

AVENUE:PHASE 2, MULTICENTER, RANDOMIZED, CONTROLLED CLINICAL TRIAL

Khanani AM, et al. Simultaneous Inhibition of VEGF and ANG-2 with Faricimab in Neovascular AMD: STAIRWAY Phase Results. Presented at the 2018 American Academy of Ophthalmology (AAO) Annual Meeting: 2018 Oct 26; Chicago, United States.

TOTAL N = 273 PATIENTS*

• AGE ≥50 YEARS

• TREATMENT-NAÏVE NAMD

• SUBFOVEAL CNV LESION

• BCVA 20/40–20/320 (73–24 ETDRS LETTERS)

0 4 8 12 16 20 24

TIME, WEEKS

R

28 32 36

STUDY TREATMENT FINAL VISIT

6.0 MG FARICIMAB

1.5 MG FARICIMAB

0.5 MG RANIBIZUMAB

PRIMARY ENDPOINT

SHAM

AVENUE: MEAN CHANGE IN BCVA FROM BASELINE TO WEEK 36

Khanani AM, et al. Simultaneous Inhibition of VEGF and ANG-2 with Faricimab in Neovascular AMD: STAIRWAY Phase 2 Results. Presented at the 2018 American Academy of Ophthalmology (AAO) Annual Meeting: 2018 Oct 26; Chicago, United States.

LEAST SQUARES MEANS FROM LINEAR MODEL ANALYSIS OF STUDY EYE BCVA CHANGE FROM BASELINE, ERROR BARS REPRESENT 80% CI. AVENUE CLINICAL TRIAL (NCT02484690).

0

5

10

15

0 4 8 12 16 20 24 28 32 36

Time, Weeks

Ad

just

ed

Me

an B

CV

A C

han

ge F

rom

B

ase

line

, ETD

RS

Lett

ers

+ 9.1 letters

+ 7.6 letters

+ 7.2 letters

+ 6.0 letters

+ 5.9 letters

6.0 mg faricimabQ4W

6.0 mg faricimabQ4W/Q8W

1.5 mg faricimabQ4W

0.5 mg ranibizumab Q4W/ 6.0 mg faricimab Q4W

0.5 mg ranibizumabQ4W

AVENUE: MEAN CHANGE IN CST FROM BASELINE TO WEEK 36

Khanani AM, et al. Simultaneous Inhibition of VEGF and ANG-2 with Faricimab in Neovascular AMD: STAIRWAY Phase 2 Results. Presented at the 2018 American Academy of Ophthalmology (AAO) Annual Meeting: 2018 Oct 26; Chicago, United States. .

LEAST SQUARES MEANS FROM LINEAR MODEL ANALYSIS OF STUDY EYE CST CHANGE FROM BASELINE. ERROR BARS REPRESENT 80% CI. AVENUE CLINICAL TRIAL (NCT02484690). CST = CENTRAL SUBFIELD THICKNESS.

-300

-200

-100

0

0 4 8 12 16 20 24 28 32 36

Time, Weeks

Ad

just

ed

Me

an C

ST C

han

ge

Fro

m B

ase

line

, µm – 147 μm

– 156 μm

– 172 μm

– 175 μm

– 185 μm

6.0 mg faricimabQ4W

6.0 mg faricimabQ4W/Q8W

1.5 mg faricimabQ4W

0.5 mg ranibizumab Q4W/ 6.0 mg faricimab Q4W

0.5 mg ranibizumabQ4W

STAIRWAY: PHASE 2, MULTICENTER, RANDOMIZED, CONTROLLED CLINICAL TRIAL


Study Treatment

0 4 8 12 16 20 24

Time, Weeks

28 32 36 40 44 48 52

Final Visit

Q12W dosing

Q16W dosing

Active disease at Week 24†

Q4W dosing

R

Total N = 76 patients*

• Age ≥50 years

• Treatment-naïve nAMD

• Subfoveal CNV lesions

• BCVA 20/40–20/320 (73–24 ETDRS letters)

6.0 mg faricimab

0.5 mg ranibizumab

Primary endpoint

Sham

Prespecified disease assessment at Week 24

BCVA OUTCOMES WITH Q16W AND Q12W FARICIMAB WERE COMPARABLE TO Q4W RANIBIZUMAB


CONCLUSIONS

▪ NEOVASCULAR AMD MANAGEMENT HAS EVOLVED GREATLY

▪ CURRENT MANAGEMENT

▪ INDIVIDUALIZED MONOTHERAPY

▪ SHORT-ACTING DIRECT PAN-VEGF-A INHIBITORS

▪ INDUCTION F/B INDEFINITE, FREQUENT MAINTENANCE RX

▪ LACK OF SUSTAINED VISION GAINS OVER TIME IN PRACTICE

▪ FUTURE MANAGEMENT: EFFICACY AND DURABILITY

▪ OTHER VEGF-A BLOCKERS (BROLUCIZUMAB AND ABICIPAR)

▪ SUSTAINED DELIVERY OF VEGF-A INHIBITORS (PDS)

▪ TARGETS IN ADDITION TO VEGF-A BLOCKADE

▪ VEGF-C AND VEGF-D (OPT-302)

▪ VEGF-A AND ANG-2 (FARICIMAB)


Retinal Diseases”



Cole Eye Institute

Beyond Anti-VEGF-A for Diabetic Macular Edema

Rishi P. Singh, MD

Staff Physician, Cole Eye Institute

Associate Professor of Ophthalmology

Medical Director, Clinical Systems

Cleveland Clinic, Cleveland Ohio

Cole Eye Institute

Financial Disclosures

● Consultant For Regeneron, Genentech, Shire, Zeiss, Optos, Allergan

● Sponsored Researched – Apellis, Genentech/Roche, Regeneron,

Alcon/Novartis

Cole Eye Institute

How Common Is Diabetes?

Age-adjusted Prevalence of Diagnosed Diabetes in US Adults1,2

1994 1998 2003 2008 2015

4.5%‒5.9%

7.5%‒8.9%

<4.5%

6.0%‒7.4%

≥9.0%

1. Centers for Disease Control and Prevention. http://www.cdc.gov/diabetes/statistics/slides/maps_diabetes_trends.pptx. Accessed March 5, 2018.

2. Centers for Disease Control and Prevention. http://gis.cdc.gov/grasp/diabetes/DiabetesAtlas.html. Accessed March 5, 2018.

Cole Eye Institute

Future Prevalence Projections Of Diabetes

Rowley et al. Popul Health Manag. 2017;20:6.

Percent of Total Population With Diabetes (Diagnosed and Undiagnosed)

2020

9%-11%

15%-17%

7%-8%

12%-14%

18%-20%

20202020 2025 2030

Cole Eye Institute

≈13.6% have diabetic macular edema (DME)2

Diabetes Is Associated With Serious Comorbidities

Diabetic retinopathy1

28.5% in patients aged ≥40

Diabetic nephropathy3

29.9% in diabetic patients

Stroke4

11.5 per 1000 persons with diabetes

Diabetic neuropathy1

60%-70% in diabetic patients

Ischemic Heart Disease4

18.3 per 1000 persons with diabetes

1. Centers for Disease Control and Prevention. 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed June 11, 2018. 2. Varma, et al. 2012 Joint Meeting of the American Academy of

Ophthalmology and Asia-Pacific Academy of Ophthalmology; November 10-13, 2012; Chicago, IL. Poster PO252. 3. United States Renal Data System. 2012 atlas of CKD and ESRD. Bethesda, MD:

National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2012. http://www.usrds.org/atlas.aspx. Accessed February 7, 2013.

4. Centers for Disease Control and Prevention. 2017 National Diabetes Statistics Report. https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Accessed July 10, 2018.

Cole Eye Institute

Chronic Hyperglycemia Initiates a Number of Inter-related Pathways that Lead to DME

Boyer DS, et al. Ther Adv Endocrinol Metab. 2013;4(6):151-169.

Inflammation

↑ AGEs

↑ ROS

↑ ICAM

PKC activation

↑ Nitric oxide

↑ Polyols

↑ Eicosanoids

Microvascular damage Leukostasis

Pericyte loss

Endothelial damage

VEGF overexpression

DME

AGEs = advanced glycation end-products

ICAM = intercellular adhesion molecule

PKC = protein kinase C; ROS = reactive oxygen

species

Cole Eye Institute

● Approved Treatments

● Anti-VEGF

● Lucentis –

Genentech/Roche

● Eylea – Regeneron

● Steroid

● Ozurdex – Allergan

● Iluvein – Alimera

Current Approved and Off-label Therapies for Diabetic Macular Edema

● Unapproved Treatments

● Anti-VEGF

● Avastin –

Genentech/Roche

● Steroid

● Triamcinolone

● Triescence - Alcon

Cole Eye Institute

Why we need additional treatments

• Post hoc analysis

demonstrate not all patients

respond to treatment

• Persistent retreatment of

patients

• We currently only address two

pathways in DME with

intermittent treatment

Cole Eye Institute

Anti-VEGF-A has limited efficacy

Elman MJ, Aiello LP, Beck RW, et al. Ophthalmology. 2010;117(6):1064-1077; Korobelnik J-F, Do DV, Schmidt-Erfurth U, et al. Ophthalmology. 2014;121(11):2247-2254.

Michaelides M, Kaines A, Hamilton RD, et al. Ophthalmology. 2010;117(6):1078-1086; Nguyen QD, Brown DM, Marcus DM, et al. Ophthalmology. 2012;119(4):789-801.

CLINICAL TRIAL TREATMENT DOSAGE(S) UNDER STUDYNUMBER OF

PATIENTS

≥15-LETTER BCVA INCREASE AT 1 YEAR

(%)

RISE ranibizumab0.3 mg 125 45%

0.5 mg 125 39%

RIDE ranibizumab0.3 mg 125 34%

0.5 mg 127 46%

DRCRPROTOCOL I

ranibizumab + prompt laser

0.5 mg ranibizumab+ focal / grid laser 3-10 days after first IVT

187 30%

ranibizumab + deferred laser

0.5 mg ranibizumab+ focal / grid laser ≥24 weeks after first IVT

188 28%

BOLT bevacizumab 1.25 mg 42 12%

VISTA* aflibercept2 mg every 4 weeks 154 42%

2 mg every 8 weeks* 151 31%

VIVID* aflibercept2 mg every 4 weeks 136 32%

2 mg every 8 weeks* 135 33%

*2 mg every 8 weeks after initial loading period of 2 mg every 4 weeks for first 5 doses.

Even when treatment regimens are optimized under

clinical trial conditions, meaningful visual acuity

increases are only achieved by 30% to 45% of DME

patients

Cole Eye Institute

Patients With DME Can Be Categorized Based on Types of Response to Anti-VEGF-A Treatment

From the DRCR.net trial of ranibizumab and laser for patients with DME

* OCT thickness decreased ≥20% from baseline.Bressler SB, et al. Arch Ophthalmol. 2012.

Early and

Consistent

Early but

Inconsistent

Slow and

Variable

No

Response

Type of

Response

Improvement*

at 16 Weeks

Improvement*

at 32 Weeks

and/or 1 Year

% of Patients 49.6%n=143/288

14.9%n=43/288

12.5%n=36/288

22.9%n=66/288

✓✗

✗

✓✓✗✓ ✗✓

✗

= 50.4%

Non responders

Cole Eye Institute

We Know Very Quickly Whether or Not Patients Will Respond to Anti-VEGF-A

-0.3

2.8 3.0

6.9 8.2 8.2

15.2

16.5

13.8

-5

0

5

10

15

20

BL 12 16 20 24 28 32 36 40 44 48 52 . .. … 68 . .. … 84 . .. … …. 104 . ..

…

120 . ..

…

136 . . . .. . … . …. 156

BC

VA

Ch

an

ge f

rom

Baselin

e

p<0.001

Weeks

≥10 letters

at 12w (N=126)

5-9 letters

at 12w (N=79)

<5 letters

at 12w (N=135)

Am J Ophthalmol. 2016 Dec;172:72-79. Early and Long-Term Responses to Anti-Vascular Endothelial Growth Factor Therapy in Diabetic Macular Edema: Analysis of Protocol I Data. Gonzalez VH, Campbell J, Holekamp

NM, Kiss S, Loewenstein A, Augustin AJ, Ma J, Ho AC, Patel V, Whitcup SM, Dugel PU.

Cole Eye Institute

Targets for future DME treatment

● A better Anti-VEGF-A molecule/Steroid Molecule● eg. Brolucizumab, DARPin

● Sustained delivery of anti-VEGF-A● eg Port Delivery System

● A new mechanism of action

● PlGF Inhibition• THR-317 (Thrombogenics)

● Ang2/Tie2 Pathway• RG7716 (Roche/Genentech)

• AKB-9778 (Aerpio)

● Targeting Integrin• Luminate (Allegro)

● VEGF-C/D inhibition• OPT-302 (Opthea)

Cole Eye Institute

Anti-PLGF: THR-317 (Thrombogenics)

PlGF expression is elevated in hypoxic human RPE cells in vitro

PlGF is elevated in aqueous humour in patients with DME and PDR

Vitreous PlGF and VEGF-A are elevated 3x and 1.8x respectively in patients with active PDR compared to quiescent PDR

Phase 1/2: 49 patients, including anti-VEGF-A naïve patients as well as sub-optimal anti-VEGF-A responders

30% of the anti-VEGF-A treatment naïve study subjects treated with THR-317 in the 8mg group showed a > or equal to 15 letter gain from baseline at Day 90 versus 5.3 % in the 4mg group

Phase 2 clinical study by Q2 2018

Ando R et al. Acta Ophthalmol 2014; 92 (3): e245–e246; Mitamura Y et al. Diabetes Care 2002; 25 (12): 2352; Miyamoto N et al. Diabetologia 2007; 50 (2): 461–470; Martinsson-Niskanen

et al; 2011 Clinical Therapeutics 33:1142-1149

PGF is elevated in aqueous humour in patients with DME and PDR

Control DME PDR

Not detected

***

**

PG

F (

pg

/mL

)

100

0

20

40

60

80

Cole Eye Institute

Ang-2 Being Investigated In Two Studies

● Boulevard

● Phase 2 – Roche/Genentech – Bispecific molecule with both Ang-2 and anti-

VEGF-A (RG7716)

● Ruby

● Phase 2 – Bayer/Regeneron – Co-formulation of Ang-2 and aflibercept

● Did not meet the primary endpoint of superiority of co-formulated

compound versus aflibercept

Cole Eye Institute

Faricimab (RG7716) Molecular Structure

Cole Eye Institute

BOULEVARD Trial

Cole Eye Institute

Secondary endpoints from the BOULEVARD Study

Cole Eye Institute

Activating the Tie-2 Receptor Pathway - Aerpio

● Tie‐2 is a key control axis for retinal vascular stability

● Inhibiting HPTPβ removes “the brake” on Tie‐2, activating it and affecting the

vascular stability

● AKB‐9778 is a potent, specific inhibitor of HPTPβ

Cole Eye Institute

TIME-2 tested AKB-9778 alone and in combination with Lucentis

STUDY

VISITS

56-day observation period, with

LUCENTIS® treatment allowed as

needed

PLACEBO subcutaneous BID

3 doses intravitreal LUCENTIS (0.3

mg) q4

15 mg AKB-9778 subcutaneous BID

3 SHAM injections q4

15 mg AKB-9778 subcutaneous BID

3 doses intravitreal LUCENTIS (0.3

mg) q4

N=144

R 1:1:1

Intravitreal LUCENTIS

injectionSham injection65

Cole Eye Institute

-10 -8

60

-91

-102

-110-106

-146-164

-170

-150

-130

-110

-90

-70

-50

-30

-10

10

Baseline Month 1 Month2 Month 3

Change in CST from Baseline to Month 3

AKB-9778 (N=46)

Lucentis (N=47)

AKB-9778 + Lucentis (N=48)

AKB-9778 + Lucentis significantly reduced retinal thickness compared to Lucentis alone,

66

p = 0.008

CS

T R

eduction (

µm

)

Cole Eye Institute

Integrin Inhibition for DME: Allegro - Risuteganib

Cole Eye Institute

Del Mar Phase 2b With Risuteganib (Luminate)

Phase 2b – Stage 1: Monotherapy vs Avastin with 6-month follow-up (n=136)

Phase 2b – Stage 2: Avastin pretreatment vs combination therapy with 5-month follow-up (n=80)

Drug Safety

Dose Ranging

Durability

Efficacy vs anti-VEGF-A

Goal

Increase efficacy by

clearing out pre-

existing VEGF-A load

Goal

Cole Eye Institute

Phase 2b DEL MAR Stage 1: Primary and Secondary Endpoints Were Met (n=136)

Secondary Endpoint

Mean OCT CMT non-inferiority at study week 20 (≤30µ)

NO LUMINATE DOSING NO LUMINATE DOSING

Primary Endpoint

Mean BCVA non-inferiority at study week 20 (≤3 letters)

Cole Eye Institute

Conclusions

● Still unmet need in the treatment of diabetic macular edema

● Multiple promising avenues are being studied

● Hopefully combinations of the current drugs and drugs in the

pipeline will improve the quality of vision for our patients with

DME


Retinal Diseases”



Targeting a More Complete Blockade of VEGF:

Results from the Phase 1b/2a Trial of OPT-302

(anti-VEGF-C/D “Trap”) and Ranibizumab in

Neovascular AMD

Nathan Steinle, MD

California Retina Consultants

Financial Disclosures

Consultant for:

• Alimera Sciences, Genentech, Regeneron,

Regenerative Patch Technologies

Speaker for:

• Genentech, Notal Vision, Regeneron

Research Funding:

• Genentech, Zeiss

VEGFR-1 VEGFR-2 VEGFR-3

Ig-like domainPathway blocked by OPT-302

Kinase domainLigand

Aflibercept

Angiogenesis

Vascular Permeability

VEGF-B

PlGFVEGF-A

Ranibizumab

Bevacizumab

Angiogenesis

Lymphangiogenesis

VEGF-C

VEGF-DOPT-302

ARVO (Association for Research in Vision & Ophthalmology) Annual Meeting 2016, Cabral et al., Program 3341, Poster D0144

VEGF-A Inhibition Upregulates VEGF-C/D

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

Aq

ueo

us

Hu

mo

rV

EG

F-C

(pg/

ml)

BevacizumabBevacizumab

Neovascular AMD Patients2

OPT-302 (anti-VEGF-C/-D):

• Inhibits angiogenesis &

vascular leakage

• Overcomes escape mechanism

to VEGF-A suppression

Control OPT-302

Aflibercept OPT-302 + Aflibercept

70%78%

91%

*

* Pairwise comparison: OPT-302 vs Aflibercept + OPT-302 (p<0.02)Aflibercept vs Aflibercept + OPT-302 (p<0.05)

Combined inhibition of VEGF-A (Aflibercept) and VEGF-C/-D (OPT-302)

is more effective than inhibition of VEGF-A alone

VE

GF

-C/D

VE

GF

-C/D

hIgG1 Fc

Extra-Cellular Domains 1-3hVEGFR-3

• OPT-302

• A ‘trap’ molecule that binds & neutralises the activity of

VEGF-C/-D, blocking their activation of receptors VEGFR-

2 and VEGFR-3

• Potent inhibitor of VEGF-C (~5pM) and VEGF-D (~0.5 nM)

OPT-302 a Novel ‘Trap’ Inhibitor of VEGF-C/D

OPT-302 Inhibition of CNV in Rodent Model of AMD

OPT-302 (0.3 mg) +

Ranibizumab (0.5 mg)

IVT Q4W x 3

OPT-302 (1 mg) +


IVT Q4W x 3

OPT-302 (2 mg) +


IVT Q4W x 3

28

Day D

LT w

ind

ow

OPT-302 (2 mg)

Monotherapy*

IVT Q4W x 3

Cohort 4

Cohort 3

Cohort 2

Cohort 1

• Comprises of 4 treatment cohorts of 5 subjects each

Part 1: Dose-escalation

(Open-label)

Pri

ma

ry A

na

lysi

s a

fte

r a

ll

su

bje

cts

co

mp

lete

12

we

eks

Lo

ng

te

rm fo

llow

-up

at

We

ek 2

4

*Access to rescue anti-VEGF-A Tx

Fo

llow

-up

to

we

ek 1

2

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)

OPT-302 Phase 1b/2a First-in-Human Study in nAMD Patients (n=51)

ClinTrials Identifier NCT 02543229

Treatment Groups

OPT-302 + ranibizumab

Combination TherapyN=38

Prior-Treated

with anti-VEGF-A

N=20

OPT-302

Monotherapy

N=13

Wet AMD Patients

N=51

Treatment

Naïve

N=18

Prior-Treated

with anti-VEGF-A

N=6

Treatment

Naïve

N=7

• Mean Age: 77.4 years

• 32/51 (63%) female and 19 (37%) were male

• 49% treatment-naive

• 51% were difficult to treat patients who were heavily pre-treated and sub-responsive to prior anti-VEGF-A therapy

• Mean number prior anti-VEGF-A injections = 17

• Lesions: 73% Occult, 23% Minimally Classic, 4% Predominantly Classic

OPT-302 ± Ranibizumab Safety Results in nAMD

• OPT-302 ranibizumab administered by IVT injection (Baseline, Week 4, Week 8)

• No missed doses, safety experience with ~150 intravitreal (ocular) injections of OPT-302

• OPT-302 intravitreal doses up to 2 mg ± ranibizumab 0.5 mg

• No dose limiting toxicities (MTD not reached)

• No study drug related serious adverse events or systemic AEs

• AEs primarily related to IVT injection procedure (Mild/moderate, manageable)

• Two patients (3.9%) had treatment-related AEs of Grade 1/Mild anterior chamber inflammation /

anterior uveitis in the low and mid-dose combination groups

• No OPT-302 related AEs observed in high dose (2mg) combination or monotherapy patients (n=41)

• No clinically significant changes in IOP, ECG’s, blood pressure, vitals

• No evidence of OPT-302-related immunogenicity

• OPT-302 was generally safe and well tolerated ± with ranibizumab

Summary of Adverse Events Reported in ≥ 5% of all Subjects

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

(n=5)

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

(n=5)

OPT-302 (2 mg) + RBZ (0.5 mg)

(n=28)

OPT-302 (2 mg)Monotherapy

(n=13)

Total Number of Subjects(N=51)

Total pts with at least one AE 5 4 22 9 40 (79%)

Total pts with at least 1 Ocular AE 5 4 18 8 35 (69%)Ocular AEs

Conjunctival Haemorrhage 4 3 9 4 20 (39%)Punctate Keratitis 1 2 6 2 11 (22%)Eye pain 2 2 5 2 11 (22%)Retinal haemorrhage 1 - 1 2 4 (8%)Eye irritation - 1 2 - 3 (6%)Ocular discomfort 1 - 2 - 3 (6%)Vitreous floaters - 1 - 2 3 (6%)

Total pts with at least 1 Non-Ocular AE 3 3 13 4 23 (45%)Non-Ocular AEs

Nasopharyngitis 1 - 1 1 3 (6%)

OPT-302 Serum Pharmacokinetic Profile (± Ranibizumab)

Intravitreal OPT-302 (2 mg)(± 0.5 mg ranibizumab)

Cmax

(ng/mL)Tmax

(hours)AUC0–last

(ngh/mL)T1/2

(days)

Mean ± SD(n)

21.1 ± 17.3(n = 41)

31 ± 24(n = 41)

2760 ± 1110(n = 30)

8 ± 2(n = 10)

• Non-compartmental OPT-302 PK analysis indicated:

• low systemic exposure

• a half-life of 8 ± 2 days

• mean Cmax of ~21 ng/mL at ~31 hours post IVT injection

at a dose of 2 mg

• no accumulation

• no influence from ranibizumab on the PK profile.

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) +


Mean OPT-302 serum concentrations

Time (hours)

Me

an

(+

SD

) O

PT

-30

2 S

eru

m C

on

cen

tratio

ns

(ng

/mL

)

Intravitreal OPT-302 (2 mg) monotherapy

Change in mean Best Corrected Visual Acuity

from Baseline to week 12

+5.6 letters

+4.4 letters

+ 2.8 letters

OPT-302 Monotherapy Patients:n = 13 (wk 4, 8), 12 (wk 12); Mean Baseline VA = 55.7 Letters

• OPT-302 monotherapy at 2 mg to assess biological

activity in absence of standard of care

• Anti-VEGF-A (ranibizumab) rescue therapy criteria:

• <10% decrease in CST and ≥ 5 letter loss of BCVA

• 7/13 (56%) patients (4 treatment-naïve, 3 prior treated)

did not require ‘rescue’ therapy through week 12

• 5/13 (38%) patients received one rescue injection to

week 12

• 1 pt (8%) had 2 rescue injections to week 12

• Mean time to rescue therapy was 58 days

OPT-302 + Ranibizumab: Gains in BCVA & Reduced Retinal Thickness

Change in mean BCVA Change in mean Central Subfield Thickness

+10.8 letters

-54 µM

+ 4.9 letters

-119 µM

Treatment Naïve Patients: n = 18; OPT-302 (0.3, 2.0 mg) + ranibizumab (0.5 mg)Mean Baseline VA = 56.5 Letters

Prior-Treated Patients:n = 20 (wk 4, 8), 19 (wk 12); OPT-302 (0.3-2.0 mg) + ranbizumab (0.5 mg)Mean Baseline VA = 64.5 Letters

0

5

10

15

0 4 8 12

Time (weeks)

Ch

ange

fro

m b

asel

ine

in V

isu

al A

cuit

y (E

TDR

S Le

tter

s) Naïve pts (n=18)Prior treated pts (n=20)

-160

-140

-120

-100

-80

-60

-40

-20

0

0 2 4 6 8 10 12

Ch

ange

fro

m b

asel

ine

in C

ST (

µM

)

Time (weeks)

Naïve pts (n=18)Prior treated pts (n=20)

OPT-302 + Ranibizumab: Gains in BCVA & Reduced Retinal Thickness

Reduction in CNV size on FA % Patients with absent CNV on FA

0

1

2

3

4

5

6

7

8

9

Baseline Week 4 Week 12

CN

V S

ize

(mm

2 )

7.71

3.74

2.03

OPT-302 + Ranibizumab

Treatment Naïve Patients: n = 18; OPT-302 (0.3, 2.0 mg) + ranibizumab (0.5 mg); * Absent on FA, present on OCT

OPT-302 + Ranibizumab

0

10

20

30

40

50

60


% P

atie

nts

wit

h A

bse

nt C

NV

on

FA

5.6 %*

27.8 %

50 %

Case Study Naïve Patient (Occult): OPT-302 + Ranibizumab


VA: 53 letters VA: 64 letters VA: 73 letters

CNV: 3.11 mm2 CNV: 2.91 mm2 CNV: 0 mm2

CST: 279 µMSRF: 192 µMSHRMw: 1053 µMSHRMh: 94 µM



OPT-302 (2 mg) + ranbizumab (0.5 mg)

Case Study Prior Treated Patient (Occult): OPT-302 + Ranibizumab


VA: 72 letters VA: 78 lettersVA: 65 letters

CNV: 5.28 mm2CNV: 11 mm2 CNV: 8.04 mm2




Patient was heavily pre-treated with Ranibizumab (0.5 mg) x 28 IVT injections

OPT-302 (2 mg) + ranbizumab (0.5 mg)

• Current treatments target primarily VEGF-A

• OPT-302 is a novel biologic that binds and neutralizes VEGF-C/-D

• Dual targeted inhibition of VEGF-C/-D (with OPT-302) and VEGF-A signaling pathways may offer

benefits that exceed the inhibition of either target alone

• Multiple dosing with OPT-302 ± ranibizumab was well tolerated with a favourable safety profile in 51

patients with nAMD

• Improvements in BCVA and key OCT / FA parameters were observed in eyes that were either

treatment-naïve or suboptimal responders despite being heavily pre-treated with multiple anti-

VEGF-A treatments,

• These results warrant further evaluation of OPT-302 in larger patient populations with retinal

diseases.

Conclusion

“Beyond anti-VEGF-A for Retinal Diseases”



Investment in Opthea Limited (‘Opthea’) is subject to investment risk, including possible loss of income andcapital invested. Neither Opthea nor any other member company of the Opthea Group guarantees anyparticular rate of return or performance, nor do they guarantee the repayment of capital.

This presentation is not an offer or invitation for subscription or purchase of or a recommendation of securities.It does not take into account the investment objectives, financial situation and particular needs of the investor.Before making any investment in Opthea, the investor or prospective investor should consider whether such aninvestment is appropriate to their particular investment needs, objectives and financial circumstances andconsult an investment advisor if necessary.

This presentation may contain forward-looking statements regarding the potential of the Company’s projects andinterests and the development and therapeutic potential of the company’s research and development. Anystatement describing a goal, expectation, intention or belief of the company is a forward-looking statement andshould be considered an at-risk statement. Such statements are subject to certain risks and uncertainties,particularly those inherent in the process of discovering, developing and commercialising drugs that are safe andeffective for use as human therapeutics and the financing of such activities. There is no guarantee that theCompany’s research and development projects and interests (where applicable) will receive regulatory approvalsor prove to be commercially successful in the future. Actual results of further research could differ from thoseprojected or detailed in this presentation. As a result, you are cautioned not to rely on forward-lookingstatements. Consideration should be given to these and other risks concerning research and developmentprograms referred to in this presentation.

Disclaimer

88

OPT-302

Target: VEGF-C/D

OPT-302

Target: VEGF-C/D

OPT-302

Target: VEGF-C/D

Diabetic Macular Edema

Neovascular AMD

Phase 1

Combination

Agent Preclinical Phase 2a Phase 2b Phase 3 Status1o Data

Analysis

RanibizumabTarget: VEGF-A


AfliberceptTarget: VEGF-A,

PlGF, VEGF-B

Complete

Ph 1/2a (n=51) April 2017

Ongoing

Ph 2b (n=351) Early 2020

Ongoing

Ph 1b/2a (n=117) 2019

OPT-302 Clinical Program

• Two ongoing randomised controlled clinical trials in nAMD & DME

89

OPT-302 +/- Ranibizumab Phase 2b Trial in Treatment-Naïve nAMD (n=351)

Randomized 1:1:1 to treatment arms

IVT dosing at every 4 weeks (x 6)

Treatment-Naive

Neovascular AMD

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

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

Sham + Ranibizumab (0.5 mg)

We

ek 2

4 F

ollo

w-u

p

n=117

n=117

n=117

• Currently enrolling

• Primary data analysis early 2020ClinTrials Identifier NCT 0334508290

Phase 1b Dose Escalation study of OPT-302 + Aflibercept in DME

N=

14

Day

DLT

win

dow

Cohort 3

Cohort 2

Cohort 1

Phase 1b Dose-Escalation

Pri

ma

ry A

na

lys

is a

fte

r a

ll

su

bje

cts

co

mp

lete

12

we

ek

s

PR

N a

nti-V

EG

F-A

We

ek 1

2 to

24

Fo

llow

-up

to

we

ek 1

2

Phase 2a Dose-Expansion

(Randomised 2:1 ratio)

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

IVT Q4W x 3, n=3ClinTrials Identifier

NCT 03397264

• HbA1c ≥ 12%• Uncontrolled hypertension ≥ 180 mmHg systolic or

≥ 110 mmHg diastolic• Eyes needing PRP within 3 months of screening • Concurrent / prior use of intravitreal injections of

steroids within 4 months of study start• Concurrent / prior use of dexamethasone or

fluocinolone implant in study eye

Key Exclusion Criteria


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

Key Inclusion Criteria

• Age ≥ 18 years; centre-involving DME• CST ≥ 335 µm*• BCVA 73 – 24 ETDRS letters (20/40 – 20/320 Snellen• Prior exposure to anti-VEGF-A therapy with sub-optimal

therapeutic response• ≥ 3 intravitreal injections• Last injection ≤ 6 wks prior to study day 1• Prior bevacizumab only allowed if switched to IVT aflibercept or

ranibizumab prior to study

*CST as measured by Spectralis (Heidelberg) at screening, ≥ 320 µm for Cirrus. 91

OPT-302 + Aflibercept Safety Results• OPT-302 (0.3, 1 or 2 mg) + aflibercept (2 mg) administered by IVT injection

(Baseline, Week 4, Week 8)

• OPT-302 intravitreal doses up to 2 mg in combination with aflibercept (2 mg)

• No dose limiting toxicities (Maximum Tolerated Dose not reached)

• No study drug related adverse events

• Ocular AEs in the study eye primarily related to IVT injection procedure (Mild/moderate, resolved)

• No clinically significant changes in IOP, ECG’s, or vitals.

• OPT-302 was generally safe and well tolerated + aflibercept

OPT-302 has a favorable safety profile when administered with aflibercept (DME) expanding upon similar results when given as monotherapy or in combination with ranibizumab (wet AMD)

92

OPT-302 + Aflibercept – Safety Summary of selected AEs

Selected Adverse Events:Ocular or Systemic

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

(n=3)

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

(n=3)

OPT-302 (2 mg) + Aflibercept (2.0 mg)

(n=3)

Total Number of Subjects

(N=9)

Intraocular inflammation 0 0 0 0Endophthalmitis 0 0 0 0Retinal detachment 0 0 0 0Vitreous hemorrhage 0 0 0 0

Hypertension 1* 0 0 1*

APTC events#

Nonfatal myocardial infarction 0 0 0 0Nonfatal stroke 0 0 0 0Vascular or cardiac death or death of unknown cause 0 0 0 0Combined APTC events 0 0 0 0

Any other death 0 0 0 0

IOP, mmHg: Baseline, week 12; (change from baseline) 13.0; 15.7 (2.7) 17.3; 15.3 (-2.0) 16.7; 17.0 (0.3) 15.7; 16.0 (0.3)

• No safety signals or unexpected findings#APTC = Antiplatelet Trialists' Collaboration*Determined by treating investigator as unrelated to study drug(s)93

OPT-302 + Aflibercept: Gains in BCVA at Week 12Dose Response Relationship

Dose of OPT-302

+ Aflibercept

(2 mg)

% of pts with

BCVA gain

≥ 5 letters

Mean # prior

anti-VEGF-A

injections

0.3 mg 1/3 (33%) 5

1 mg 2/3 (67%) 7.3

2 mg 3/3 (100%) 6.7

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

0

5

1 0

1 5

2 0

Mean

Ch

an

ge f

rom

baselin

e i

n B

CV

A (

Lett

ers

)

0.3 mg

OPT-302

1 mg

OPT-302

2 mg

OPT-302

0.3 - 2 mg

OPT-302

+ 2 mg Aflibercept

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

+7.7

+14.3

+3.0+5.7

Error Bars: SEM94

OPT-302 (0.3-2 mg) + Aflibercept (2 mg):Mean changes in CST from Baseline to Week 12

Mean

Ch

an

ge f

rom

Baselin

e i

n

CS

T o

n S

D-O

CT

(µ

m)

Week

- 71 µM

-100

-80

-60

-40

-20

0

20

0 2 4 8 12

Error Bars: SEM; Mean Baseline CST = 434 µm95

DME Patients with Bilateral Disease* Study Eye vs Fellow Eye (N=5)

Mean Change in BCVA Baseline to Week 12

Mean

Ch

an

ge B

CV

A (

Lett

ers

)

OPT-302 +

AfliberceptAnti-VEGF-A

Monotherapy

+10.0

+2.6

Mean Change in CST (uM) Baseline to Week 12

Mean

Ch

an

ge C

ST

(µ

M)

Anti-VEGF-A

Monotherapy

OPT-302 +

Aflibercept

-80 µM

-6.0 µM

Study Eye:

0.3 – 2mg OPT-302 + 2 mg Aflibercept

Fellow Eye:

Anti-VEGF-A Monotherapy*

*Patients with bilateral disease and persistent DME in the fellow eye receiving anti-VEGF-A (ranibizumab or aflibercept) monotherapyPrior anti-VEGF-A therapy in Fellow Eyes BL to Wk 12: 3x Aflibercept, 3x Ranibizumab, 1x Ranibizumab, 4x Ranibizumab, 3x Aflibercept

Mean baseline BCVA, CST: Study Eyes (63 letters, 445 µM); Fellow Eye (73 letters, 389 µM)# Excess foveal thickness was determined by using 300 µm Spectralis scan values and 285 µm Cirrus scan values96

Perc

en

tag

e P

ati

en

ts

% Pts with ≥ 50% Reduction in Excess Foveal Thickness

OPT-302 +

AfliberceptAnti-VEGF-A

Monotherapy

20%

60%

OPT-302

Target: VEGF-C/D

OPT-302

Target: VEGF-C/D

OPT-302

Target: VEGF-C/D

Diabetic Macular Edema

Neovascular AMD

Phase 1

Combination

Agent Preclinical Phase 2a Phase 2b Phase 3 Status1o Data

Analysis



AfliberceptTarget: VEGF-A,

PlGF, VEGF-B

Complete

Ph 1/2a (n=51) April 2017

Ongoing

Ph 2b (n=351) Early 2020

Ongoing

Ph 1b/2a (n=117) 2019

OPT-302 Clinical Program

• Two ongoing randomised controlled clinical trials in nAMD & DME

97

Megan Baldwin, PhDCEO & Managing DirectorT +61 (3) 9826 0399M +61 447 788 674E [email protected]

Suite 0403, Level 4,650 Chapel Street,South Yarra 3141 Victoria Australia

mailto:[email protected]

“beyond anti-vegf-a for - opthea · “beyond anti-vegf-a for retinal diseases” new york city,...

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