Opthea Ltd — Investor Presentation 2018

Oct 25, 2018

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

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

Disclaimer

	Investment in Opthea Limited (‘Opthea’) is subject to investment risk, including possible loss of income and
	capital invested. Neither Opthea nor any other member company of the Opthea Group guarantees any
	particular 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 an
	investment is appropriate to their particular investment needs, objectives and financial circumstances and
	consult an investment advisor if necessary.
	This presentation may contain forward-looking statements regarding the potential of the Company’s projects and
	interests and the development and therapeutic potential of the company’s research and development. Any
	statement describing a goal, expectation, intention or belief of the company is a forward-looking statement and
	should 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 and
	effective for use as human therapeutics and the financing of such activities. There is no guarantee that the
	Company’s research and development projects and interests (where applicable) will receive regulatory approvals
	or prove to be commercially successful in the future. Actual results of further research could differ from those
	projected or detailed in this presentation. As a result, you are cautioned not to rely on forward-looking
	statements. Consideration should be given to these and other risks concerning research and development
	programs referred to in this presentation.

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2

OPT-302 Inhibits VEGF-C and VEGF-D

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Aflibercept Ranibizumab Neovascular AMD [1]
VEGF-B VEGF-C 66%
VEGF-A OPT-302
PlGF VEGF-D 10.00
8.91
9.00
8.00 6.91
7.00
VEGFR-1 VEGFR-2 VEGFR-3 6.00 5.37
5.00
4.00
3.00
2.00
1.00
0.00
Baseline 1m 2m
Bevacizumab Bevacizumab
Angiogenesis Angiogenesis
Vascular Permeability Lymphangiogenesis
Pathway blocked
Ligand Ig-like domain Kinase domain
by OPT-302
1 ARVO (Association for Research in Vision & Ophthalmology) Annual
Meeting 2016, Cabral et al., Program 3341, Poster D0144
Aqueous Humor VEGF-C (pg/ml)
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An Unmet Medical Need for nAMD & DME

: Despite receiving a VEGF-A inhibitor (Ranibizumab, Aflibercept or Bevacizumab)[*]

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50% Do not achieve significant vision gains
nAMD 2/3 Will continue to have fluid at the back of the eye
25% Will have further vision loss at 12 months
2/3 Do not achieve significant vision gains [#]
DME
25% Continue to have macula thickening/swelling [^]
Opportunity: New Products that Improve Efficacy and Durability
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* Based on randomised, controlled clinical trial data; # Fail to achieve ≥ 2 lines improvement in BCVA; ^ SD-OCT CST ≥ 300 µM or Time-Domain OCT CST ≥ 250 µM

OPT-302

Mean OPT-302 serum concentrations

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

• A ‘trap’ that blocks VEGF-C and VEGF-D binding to the receptors VEGFR-2 and VEGFR-3

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hVEGFR-3
hIgG1 Fc
VEGF-C/D VEGF-C/D
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Extra-Cellular Domains 1-3
hVEGFR-3
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100.0 OPT-302 Monotherapy (2 mg)
Combination OPT-302 (2 mg) +
Ranibizumab (0.5 mg)
10.0
1.0
0 24 48 72 96 120 144 168 192 216 240 264 288 312 336
Concentrations (ng/mL)
Mean (+SD) OPT-302 Serum
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Time (hours)

• Non-compartmental OPT-302 PK analysis indicated:

• Low systemic exposure

• 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.

5

OPT-302 Phase 1/2a First-in-Human Study in Neovascular AMD (n=51)

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Part 1: Dose-escalation Part 2: Dose-expansion
(Open-label) (Randomised 3:1)
OPT-302 (2 mg) OPT-302 (2 mg)
Monotherapy Monotherapy
IVT Q4W x 3 IVT Q4W x 3, n=8 pts
Cohort 4
OPT-302 (2 mg)
OPT-302 (2 mg) +
+ Ranibizumab (0.5 mg)
Ranibizumab (0.5 mg)
IVT Q4W x 3 IVT Q4W x 3, n=23 pts
Cohort 3
OPT-302 (1 mg) +
Ranibizumab (0.5 mg)
IVT Q4W x 3
Cohort 2
OPT-302 (0.3 mg) +
Ranibizumab (0.5 mg)
IVT Q4W x 3
Cohort 1
28 Day DLT window Follow-up to week 12
Primary Analysis after all
subjects complete 12 weeks
Long term follow-up at Week 24
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• Comprises of 4 treatment cohorts of 5 subjects each

• *Access to rescue anti-VEGF-A Tx

ClinTrials Identifier NCT 02543229

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OPT-302 +/- Ranibizumab - Phase 1/2a Safety Summary

OPT-302 + Lucentis administered by repeat IVT injection (Baseline, Week 4, Week 8)

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

• OPT-302 at ocular doses up to 2 mg + Lucentis (0.5 mg):

• No dose limiting toxicities (MTD was not reached)

• No drug-related serious adverse events or systemic adverse events

Majority of ocular emergent adverse events primarily related to IVT injection procedure

• (31 / 51 patients; 59%); majority Grade 1 / Mild or Grade 2 / Moderate and Manageable

Two patients (4%) had ocular adverse events related to OPT-302 study drug

• AEs were Grade 1 / Mild inflammation indicative of anterior uveitis in the low- and mid-dose combination

  • groups

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

• No clinically significant changes in IOP, ECG’s, blood pressure, vitals No evidence of OPT-302-related immunogenicity

OPT-302 has consistently demonstrated a favourable safety profile +/- ranibizumab

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Evidence of biological activity in patients treated with intravitreal OPT-302 (2 mg) monotherapy

• Of the 13 patients who received OPT-302 monotherapy treatment:

• 7/13 (54%) did not receive anti-VEGF-A rescue therapy through week 12

• An additional 5/13 (38%) received only 1 rescue injection through week 12

• One subject (8%) received 2 rescue injections.

• The mean time to rescue therapy was 58 days.

• Use of rescue therapy in 4/6 cases was based on Investigator discretion

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Mean Change VA from Baseline (letters) Mean Change in Visual Acuity
6
+5.6 letter s
+4.4 letters
4
+2.8 letters
2
0
B a s e lin e W e e k 4 W e e k 8 W ee k 12
V is u a l A c u ity
(M e a n C h a n g e fro m B a s e lin e )
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Mean Baseline VA = 55.7 Letters

Ranibizumab rescue therapy available week 2 through week 12 at investigator discretion or if patients met pre-defined criteria: <10% decrease in CST and ≥5 letter loss of BCVA

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Gains in Visual Acuity and Reduced Retinal Thickness in Patients with OPT-302 + Ranibizumab Therapy

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Change in mean BCVA Change in mean Central Subfield Thickness
Time (weeks)
15
Naïve pts (n=18)
0 2 4 6 8 10 12
Prior treated pts (n=20)
0
-20
+10.8 letters
10
-40
-54 µM
-60
-80
5 + 4.9 letters
-100
-120 -119 µM
-140
Naïve pts (n=18)
0 Prior treated pts (n=20)
-160
0 4 8 12
Time (weeks) Treatment Naïve Patients: n = 18; OPT-302 (0.3, 2.0 mg) + ranibizumab (0.5 mg) Prior-Treated Patients:n = 20 (wk 4, 8), 19 (wk 12); OPT-302 (0.3-2.0 mg) + ranbizumab (0.5 mg)
Error Bars: SEM
Mean Baseline VA = 56.5 Letters Mean Baseline VA = 64.5 Letters; Mean number prior anti-VEGF-A injections = 17
Change from baseline in CST (µM)
Change from baseline in Visual Acuity (ETDRS Letters)
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Error Bars: SEM
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Reductions in CNV in Treatment-Naïve Patients with OPT-302 + Ranibizumab Therapy

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Reduction in CNV Size on FA
9
7.71
8
7
6
5
3.74
4
3
2.03
2
1
0
Baseline Week 4 Week 12
)
2
CNV Size (mm
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% Patients with Absent CNV on FA
60
50 %
50
40
27.8 %
30
20
10
5.6 %
0
Baseline Week 4 Week 12
% Patients with Absent CNV on FA
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OPT-302 + Ranibizumab

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OPT-302 + Ranibizumab
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CNV: Choroidal Neovascularisation

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

10

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

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OPT-302 (2 mg) + Ranibizumab (0.5 mg) n=117
Treatment-Naive
OPT-302 (0.5 mg) + Ranibizumab (0.5 mg) n=117
Neovascular AMD
Sham + Ranibizumab (0.5 mg) n=117
Randomized 1:1:1 to treatment arms
IVT dosing at every 4 weeks (x 6)
Week 24 Follow-up
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• Currently enrolling

• Primary data analysis early 2020

ClinTrials Identifier NCT 03345082

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11

OPT-302 Mechanism of Action Supports Investigation in DME

VEGF-C and its interaction with VEGFR-2 and VEGFR-3 plays a functional role in pathogenesis of DME:

• OPT-302 has shown evidence of activity to resolve retinal fluid[1]

• VEGFR-2 expression is greater in diabetic retina than non-diabetics[2,3,4]

• VEGF-C is elevated in diabetic retinopathy[4]

• Vitreous levels of VEGF-D are elevated in diabetes[5]

• VEGF-C expression is elevated by glucose & pro-inflammatory cytokines[6,7]

• Inhibition of VEGF-C and VEGF-D in adipose tissue of mice improves metabolic parameters and insulin sensitivity[8,9]

• Advanced glycation end products accumulate faster in diabetics and stimulate VEGF-C expression and secretion from the RPE[6]

• Single nucleotide polymorphisms (SNPs) in diabetic patients indicate that genetic variation in the VEGF-C gene is associated with diabetic retinopathy and diabetic macular edema[10]

VEGF-C/D Signaling Pathway is Implicated in Diabetes

1. Phase 1/2a OPT-302 trial results: www.opthea.com; 2. Sun et al., 2014; 3. Witmer et al., 2002; 4. Zhao et al., 2007; 5. Kovacs et al., 2015; 6. Puddu et al., 2012; 7. Nagineni et al., 2011;

8. Karaman et al., 2014; 9. Karaman et al., 2016; 10. Kaidonis et al., 2015

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

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Phase 1b Dose-Escalation N=9 patients Phase 2a Dose-Expansion
(Randomised 2:1 ratio)
OPT-302 (2.0 mg) OPT-302 (2.0 mg)
+ Aflibercept (2.0 mg) + Aflibercept (2.0 mg)
IVT Q4W x 3, n=3 IVT Q4W x 3, n=~72 pts
Cohort 3
OPT-302 (1.0 mg) N=
Aflibercept (2.0 mg)
+ Aflibercept (2.0 mg)
IVT Q4W x 3, n=~36 pts
IVT Q4W x 3, n=3
Cohort 2
OPT-302 (0.3 mg)
+ Aflibercept (2.0 mg)
IVT Q4W x 3, n=3
ClinTrials Identifier
Cohort 1 NCT 03397264
14 Day DLT window Week 12 to 24
PRN anti-VEGF-A Primary Analysis after all
Follow-up to week 12 subjects complete 12 weeks
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Key Inclusion Criteria

Key Exclusion 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.

• 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

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13

Baseline Ocular Characteristics – Prior Treated

Characteristic
	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) 64.3(9) 64.6(5) 66.7(3.1) 3(100%) 3(100%) 3(100%) 0(0%) 0(0%) 0(0%) 460(103) 410(26) 432(24) 1(33%) 3(100%) 2(67%) 2(67%) 0(0%) 1(33%) 14 (7.9) 17.3 (13) 10.9 (12.6) 5 (2.6) 7.3 (2.5) 6.7 (2.3) 42(0) 33.7(7.2) 31(4.4) 7.5(2.4) 7.1(0.3) 7.4(1.4)	Total Number of Subjects (N=9)
Vision
Mean BCVA, ETDRS letters(SD)		65(5.5)
Better than 55 letters vision, n(%)		9(100%)
Worse than 55 letters vision, n(%)		0(0%)
Anatomic
Mean CST, µm (SD)		434(58)
CST ≤ 450µm, n(%)		6(67%)
CST ≥ 450µm, n(%)		3(33%)
Mean duration of diabetes at screening, years (SD)		14.1 (10.3)
Mean prior intravitreal injections of anti-VEGF-A therapy, number (SD)		6.3 (2.4)
**Mean time fromprior Tx to day 1, days **		35.6(6.5)
Mean HbA1c*, %(SD)		7.3(1.4)

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*HbA1c = glycated hemoglobin

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)

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15

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) 0 0 0 0 0 0 0 0 0 0 0 0 1* 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13.0;15.7(2.7) 17.3;15.3(-2.0) 16.7;17.0(0.3)	Total Number of Subjects (N=9)
Intraocular inflammation		0
Endophthalmitis		0
Retinal detachment		0
Vitreous hemorrhage		0
Hypertension		1*
APTC events#
Nonfatal myocardial infarction		0
Nonfatal stroke		0
Vascular or cardiac death or death of unknown cause		0
Combined APTC events		0
Any other death		0
IOP, mmHg: Baseline, week 12; (change from baseline)		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)

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Dose Response in BCVA changes from Baseline to Week 12

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Mean Change in BCVA Baseline to Week 12
20
Aflibercept (2 mg)
+ OPT-302
15 + 14.3 2 mg
1 mg
0.3 mg
10
+ 5.7
5
+ 3.0
0
-5
0 2 4 8 12
Mean Change from baseline in BCVA (Letters)
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Week
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17 Error Bars: SEM

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

0 5 1 0 1 5 2 0 0.3 mg OPT-302 1 mg OPT-302 2 mg OPT-302 0.3 - 2 mg OPT-302 (N=9) (N=3) (N=3) (N=3) +7.7 +14.3 +3.0 +5.7
	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

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+ 2 mg Aflibercept

18

Error Bars: SEM

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

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20
0
-20
-40
-60
- 71 µM
-80
-100
0 2 4 8 12
Week
CST on SD-OCT (µm)
Mean Change from Baseline in
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Error Bars: SEM; Mean Baseline CST = 434 µm

19

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

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Mean Change in BCVA Baseline Mean Change in CST (uM) Baseline
to Week 12 to Week 12
OPT-302 + Anti-VEGF-A OPT-302 + Anti-VEGF-A
Aflibercept Monotherapy Aflibercept Monotherapy
+10.0
-6.0 µM
+2.6
-80 µM
Patients with bilateral disease and persistent DME in the fellow eye receiving anti-VEGF-A (ranibizumab or aflibercept) monotherapy
Mean Change CST (µM)
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% Pts with ≥ 50% Reduction in
Excess Foveal Thickness
OPT-302 + Anti-VEGF-A
Aflibercept Monotherapy
60%
Percentage Patients 20%
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Mean Change BCVA (Letters)
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Study Eye:
0.3 – 2mg OPT-302 + 2 mg Aflibercept
Fellow Eye:
Anti-VEGF-A Monotherapy
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*Patients with bilateral disease and persistent DME in the fellow eye receiving anti-VEGF-A (ranibizumab or aflibercept) monotherapy Prior anti-VEGF-A therapy in Fellow Eyes BL to Wk 12: 3x Aflibercept, 3x Ranibizumab, 1x Ranibizumab, 4x Ranibizumab, 3x Aflibercept

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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 values

20

Phase 2a Randomised Dose Expansion study of OPT-302 + Aflibercept in Persistent DME

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Phase 1b Dose-Escalation Phase 2a Dose-Expansion
(Randomised 2:1 ratio)
OPT-302 (2.0 mg) OPT-302 (2.0 mg)
+ Aflibercept (2.0 mg) + Aflibercept (2.0 mg)
IVT Q4W x 3, n=3 IVT Q4W x 3, n=~72 pts
Cohort 3
OPT-302 (1.0 mg)
Aflibercept (2.0 mg)
+ Aflibercept (2.0 mg)
IVT Q4W x 3, n=~36 pts
IVT Q4W x 3, n=3
Cohort 2
OPT-302 (0.3 mg)
+ Aflibercept (2.0 mg)
IVT Q4W x 3, n=3
ClinTrials Identifier
Cohort 1 NCT 03397264
14 Day DLT window Week 12 to 24
PRN anti-VEGF-A Primary Analysis after all
Follow-up to week 12 subjects complete 12 weeks
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• Phase 2a currently enrolling patients in US and Australia

• Primary data analysis 2019

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21

OPT-302 Clinical Program

• Two ongoing randomised controlled clinical trials in nAMD & DME

Phase 1 Combination Agent Preclinical Phase 2a Phase 2b Phase 3 Status 1o Data Analysis	Phase 1 Combination Agent Preclinical Phase 2a Phase 2b Phase 3 Status 1o Data Analysis	Phase 1 Combination Agent Preclinical Phase 2a Phase 2b Phase 3 Status 1o Data Analysis	Phase 1 Combination Agent Preclinical Phase 2a Phase 2b Phase 3 Status 1o Data Analysis	Phase 1 Combination Agent Preclinical Phase 2a Phase 2b Phase 3 Status 1o Data Analysis	Phase 1 Combination Agent Preclinical Phase 2a Phase 2b Phase 3 Status 1o Data Analysis	Phase 1 Combination Agent Preclinical Phase 2a Phase 2b Phase 3 Status 1o Data Analysis	Phase 1 Combination Agent Preclinical Phase 2a Phase 2b Phase 3 Status 1o Data Analysis	Phase 1 Combination Agent Preclinical Phase 2a Phase 2b Phase 3 Status 1o Data Analysis
Neovascular AMD
OPT-302 Target: VEGF-C/D OPT-302 Target: VEGF-C/D	Ranibizumab Target: VEGF-A Ranibizumab Target: VEGF-A						Complete Ph 1/2a (n=51) Ongoing Ph 2b (n=351)	April 2017 Early 2020
Diabetic Macular Ed	ema
OPT-302 Target: VEGF-C/D	Aflibercept Target: VEGF-A, PlGF, VEGF-B						Ongoing Ph 1b/2a (n=117)	2019

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22

Conclusion

• Current treatments target primarily VEGF-A; OPT-302 inhibits VEGF-C/D

• The successful dose escalation of OPT-302 in combination with aflibercept in DME builds upon the similar favourable safety profile in combination with ranibizumab in nAMD

• Evidence of a dose response for OPT-302 combination treatment on gains in BCVA in persistent DME, together with biological responses on anatomic measures in nAMD and DME indicates that Pan-VEGF (A, C and D) inhibition may offer benefits that exceed the inhibition of VEGF-A alone

• Currently recruiting patients in two Phase 2 multi-center international trials:

• ~108 patient randomised controlled Phase 2a trial in DME

• 351 patient randomised controlled Phase 2b trial in nAMD

• Primary data readouts 2019 (DME) and early 2020 (nAMD)

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23

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Megan Baldwin, PhD CEO & Managing Director