Opthea Ltd — AGM Information 2014

Nov 17, 2014

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Annual General Meeting November 18 2014

Megan Baldwin , PhD CEO & Managing Director Circadian Technologies (ASX:CIR, OTCQX:CKDXY)

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Disclaimer

Investment in Circadian Technologies Limited (‘Circadian’) is subject to investment risk, including possible loss of income and capital invested. Neither Circadian nor any other member company of the Circadian 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 Circadian, 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

Corporate Achievements

Corporate

• Restructure to focus on ophthalmology

• A$17.4m capital raising

• A$2.5m R&D tax rebate (2012-13) on local & international R&D expenditure

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3

Program Achievements

Opthea

• OPT-302 designated lead program

• Signed cell line commercial license agreement

• Presented OPT-302 data at international ARVO conference

• Completed Pre-IND meeting

• Commenced IND-enabling GLP safety/toxicology studies

• Advanced OPT-302 manufacturing

• Successful grant application for OPT-302 manufacture

• Allowed key US patent for VEGFR-3 Traps

Ceres

• Completed Phase 1a/1b oncology clinical trial

• Selected to present clinical data at international ASCO conference

• Phase 2 ready

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4

Capital Raising – Key Objectives

Accelerate development of lead compound OPT-302

• Scale-up & manufacturing of OPT-302 for clinical programs

• Complete US IND filing

• Initiate Phase 1 dose escalation trial in combination with Lucentis® in Wet Agerelated Macular Degeneration (wet AMD) patients

• Advance OPT-302 through Phase 2a clinical studies in wet AMD

• Generate additional clinical & preclinical data to fully establish the profile of OPT302 in wet AMD & other eye diseases

R&D and Business Development

• Complete data analysis of Phase 1 clinical program for VGX-100 in solid tumours

• Advance business development to accelerate licensing opportunities for VGX-100

• Improve balance sheet to provide a strong position for partnering opportunities

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5

Capital Raising Overview

• Transformational $17.4m capital raising completed

• Expected to fund Circadian through Q4 2017

• $0.175 per share comprising

• Placement of A$14m

• Fully underwritten 2 for 5 non-renounceable Rights Issue raised $3.4m

• 1 free attaching option for every 2 shares subscribed for under the Offer

• Exercisable at $0.27 at any time before expiry on 25 November 2018

• Managed & underwritten by Bell Potter

• Solid uptake of shares by existing investors in Rights Issue

• 53% uptake of shares held by eligible shareholders

• 44% of total shares on offer

• Strong support from institutional & sophisticated investors in the US, Europe & Australia

• Validates CIR technology and strategy to advance OPT-302 to clinical milestones

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6

Financial Position Post-Capital Raise (Nov 25 2014)

• Ticker Symbol:

• Share Price:

• Total Shares on Issue

• New Options on Issue

• Market Capitalisation

• Trading Range

• Top 10 Shareholders Own

• Cash

• Listed Investments

ASX: CIR, OTCQX: CKDXY A$0.17 (as at Nov 18 2014) 148,086,328

49,726,669

A$25.2m

A$0.16 – 0.255 (last 12 months) 68%

A$20.5m

~A$1.7m

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7

Overview

Leader in VEGF-C/-D and VEGFR-3 targeting compounds in ophthalmology and oncology

• Extensive worldwide intellectual property platform in respect of VEGF-C, VEGF-D and VEGFR-3

• Lead compound OPT-302 blocks VEGF-C & VEGF-D

• OPT-302 expected to enter Ph 1 clinical trial for wet AMD

• Phase 1 clinical trial expected to commence 2Q15

• Results from Phase 1 clinical trial expected 1Q16

• Results from Phase 2a clinical trial expected 2Q17

• VGX-100 Phase 1a/b study completed enrolment

• Phase 2 ready asset poised for licensing/partnership

• Eli Lilly partnered compound IMC-3C5 to complete Phase 1 in solid tumours in 1H15

• Strong management team with experience in developing drugs targeting the VEGF pathway, wet AMD and oncology

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8

Program Update OPT-302 for Wet AMD

Lead Program

OPT-302 for Wet AMD

Lead molecule:

– OPT-302 (soluble VEGFR-3, VEGF-C/-D ‘Trap’)

Mechanism:

• Blocks VEGF-C and VEGF-D:

• Inhibits blood vessel growth

• Inhibits vessel leak

Strategy:

• To develop OPT-302 for use in combination with existing VEGF-A inhibitors for the treatment of wet AMD

• Achieve complete blockade of the VEGF pathway

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5

The normal retina and ‘wet’ (neovascular) AMD

Normal Retina

‘Wet’ AMD

Choroid

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11 Figure: The Angiogenesis Foundation

Wet (neovascular) AMD

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12 Photo: The Angiogenesis Foundation

Routine Non-Invasive Monitoring Procedures for Disease and Treatment Efficacy

Eye Chart (Visual Acuity)

Retinal Image

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13

Routine Non-Invasive Monitoring Procedures for Disease and Treatment Efficacy

OCT (Optical Coherence Tomography (Fluid, hemorrhage, retinal thickness, retinal detachment)

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14

Wet AMD is a major commercial opportunity

• “Few people are aware that macular degeneration is an incurable eye disease and that it …

• is the leading cause of blindness for those aged 55 and older in the United States” American Macular Degeneration Foundation

• Estimated >$US5B p.a. market opportunity in wet AMD in US alone

• Increasing with aging population

• Only two targeted therapies approved for wet AMD

• Both target VEGF-A

• Roche/Novartis: Lucentis®

• Regeneron/Bayer: Eylea®

• Roche/Genentech: Avastin® (off-label)

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15

The opportunity for OPT-302: An unmet medical need remains despite anti-VEGF-A therapy

• VEGF/VEGFR pathway recognised as most important pathway for blood vessel growth and vessel leakage

• Existing therapies target VEGF-A but not VEGF-C or VEGF-D

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EYLEA® OPT-302
VEGF-B VEGF-C
PlGF VEGF-A VEGF-D
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• Long-term single-agent anti-VEGF-A therapy (Lucentis®/Eylea®) results in a suboptimal visual outcome

• 50% of patients do not experience a significant vision gain

• Phase III trial results indicate that between 50-70% patients have retinal fluid despite anti-VEGF-A therapy

• Combined VEGF-A/VEGF-C inhibition has the potential to improve patient response by more complete blockade of blood vessel growth & vessel leakage

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16

More complete blockade of the VEGF/VEGFR pathway is clinically more effective than anti-VEGF-A therapy

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Wet AMD

Improved efficacy of Lucentis® that blocks all isoforms of VEGF-A compared to Macugen® that selectively blocks the VEGF-A165 isoform

Gastric Cancer

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Cyramza® (neutralising VEGFR-2 that blocks VEGF-A, VEGF-C and VEGF-D) is more effective than Avastin® (selective VEGF-A inhibitor) in gastric cancer

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17

Significant additive activity of OPT-302 & Eylea® in mouse AMD

Combined inhibition of VEGF-A (Eylea®), VEGF-C and VEGF-D (OPT-302) is more effective than inhibition of VEGF-A alone

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Control OPT-302
EYLEA ™ OPT-302 + EYLEA [® ]
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70%
78%
91%

Pairwise comparison: OPT-302 vs Eylea + OPT-302 (p<0.02)
Eylea vs Eylea + OPT-302 (p<0.05)
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18

Ophthotech and Opthea:

Distinct approaches for wet AMD combination therapy

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Control Macugen [®] Control OPT-302
Fovista [® ] Fovista + Macugen [®] EYLEA™ OPT-302 + EYLEA [® ]
p<0.02
p<0.05
Control Fovista [® ] Macugen [® ] Fovista [ ®] +
Macugen [® ]
“Macugen®” – targets VEGF-A165 isoform
“Fovista®” – aptamer targeting PDGF-b
Jo et al., Am.J.Pathol., 168(6), 2036-2053, 2006.
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19

OPT-302 Phase 1: Multiple Dose Combination & Monotherapy Study of Safety, PK & Efficacy

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OPT-302 (Dose level 3)
+ Lucentis® (0.5 mg)
IVT Q4W x3
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OPT-302 (Dose level 2)
+ Lucentis® (0.5 mg)
IVT Q4W x3
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OPT-302 (Dose level 3) Monotherapy IVT Q4W x3

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OPT-302 (Dose level 1)
+ Lucentis® (0.5 mg)
IVT Q4W x3
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Primary Outcomes: Safety: Ocular & Systemic AEs Secondary Outcomes:

Mean change from baseline in:

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Long term follow-up to 12 weeks
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• visual acuity

• central retinal thickness

• CNV area

Pharmacokinetics

Anti-Drug antibody formation Biomarkers

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20

Phase 2a Efficacy Study:

OPT-302 Combination versus anti-VEGF-A Monotherapy ( including extension sub-study of OPT-302 ‘Rescue’ therapy for a-VEGF-A “sub-responders ”)

Add-on OPT-302 ”rescue therapy” for Lucentis ”sub-responders”

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Lucentis® (0.5 mg)
IVT Q4W x 4
OPT-302 +
Lucentis® (0.5 mg)
IVT Q4W x 4 Primary Analysis at week 16
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Lucentis® (0.5 mg)
IVT Q4W x 4
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IVT Q4W x 3 Lucentis “sub-responders”

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wAMD
Patients
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Follow-up at week 24 for “rescue” therapy
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Key Endpoints:

Mean change from baseline in:

• visual acuity

• central retinal thickness & fluid

• CNV area

Safety: Ocular & Systemic AEs Pharmacokinetics

Anti-Drug antibody formation Biomarkers

• Dose level to be determined from Phase 1

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21

• Listed Ophthalmology Companies in Phase 1-3

Company	Market Capitalisation **(A$m)a **	Stage of Development	0.0 200.0 400.0 600.0 800.0 1000.0 1200.0 1400.0 1600.0
Ophthotech Corporation	1442.8	Phase 3
Avalanche Biotechnologies, Inc.	807.7	Phase 1/2
				Ave
Aerie Pharmaceuticals, Inc.	492.7	Phase 3
Ocular Therapeutix, Inc.	378.3	Phase 2/3
Applied Genetic Technologies Corporation	294.3	Phase 1/2
Ohr Pharmaceutical, Inc.	219.6	Phase 2
Circadian Technologies Limited	9.5	Phase 1 Start 1H15
Average	520.6

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22 a. Sept 15 2014, assumes A$1 = US$1.08

Expected News Flow

News	Estimated Date
Announce clinical advisory board	Q4’14
OPT-302 IND submission to FDA	Q2’15
OPT-302 Phase 1 clinical trial initiation in wet AMD patients	Q2’15
Primary analysis OPT-302 Phase 1 clinical trial data	Q1’16
Phase 2A clinical trial initiation	Q2’16
Primary analysis OPT-302 Phase 2A clinical trial data	Q2’17

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23

Lead Program

OPT-302 for Wet Age-related Macular Degeneration

• The VEGF pathway is a well validated target in wet AMD

• Annual global market for drugs targeting VEGF-A in wet AMD is in excess of $US5bn

• Impressive preclinical data provides strong positioning for OPT-302

• Animal data as single-agent equal to existing products – Lucentis® & Eylea®

• Data demonstrates improved efficacy in combination with approved products

• Preclinical data with OPT-302 in combination with Eylea® demonstrates comparable activity to Fovista® (OPHT lead compound) when used in combination in the same animal model

• Extensive worldwide intellectual property platform in respect of VEGF-C, VEGF-D and VEGFR-3

• Demonstration of safety & efficacy of OPT-302 in Phase 1 and 2 trials is expected to provide a substantial uplift in valuation

• Average valuation of ophthalmology listed companies in Phase 2 development for products targeting wet AMD is >$US400mn market cap

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24

Program Update VGX-100: A Phase 2 Ready Asset

VGX-100 is a Phase 2 ready program for oncology

• Clinical stage Phase 2 ready program

• Positive clinical experience in 43 patients with advanced solid tumors

• Including 24 patients when used in combination with Avastin®

• No overlapping toxicities with anti-VEGF-A therapy

• Favourable PK (pharmacokinetic profile)

• Supports weekly dosing

• No anti-VGX-100 drug antibody formation

• Doses ≥ 20 mg/kg provide adequate coverage of VEGF-C inhibition

• Combination with Avastin® shows no drug=drug interaction

• Some patients who are refractory to standard treatments, had durable stable disease ≥ 16 weeks

• Fully human monoclonal antibody produced in good-yield, proprietary manufacturing process (Lonza)

• Comprehensive patent portfolio protecting VGX-100 at least until 2022 in US/Europe

26 - License/partnership opportunities

VGX-100 Oncology: Ph1a/b Trial

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Treatment-Related Adverse Events

VGX-100 is a Phase 2 ready program for oncology

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- Five patients (13%) had durable stable disease ≥ 16 weeks

 2 patients with colon cancer

• Cohort A3: VGX-100 5 mg/kg, QW

• Cohort B1: VGX-100 2.5 mg/kg, QW + Bevacizumab 5 mg/kg, Q2W

• 1 patient with ovarian cancer

• Cohort A5: VGX-100 20 mg/kg, QW

 1 patient with renal cell carcinoma (RCC)

• Cohort B2: VGX-100 2.5 mg/kg, QW + Bevacizumab 10 mg/kg, Q2W

 1 patient with cervical cancer

• Cohort B5: VGX-100 20 mg/kg, QW + Bevacizumab 10 mg/kg, Q2W

• A patient with triple negative breast cancer had a 16% decrease in disease at all sites at the end of cycle 2

(Cohort B2: VGX-100 2.5 mg/kg, QW + bevacizumab 10 mg/kg, Q2W) – discontinued in cycle 3 (SAE)

28

Non-Core Assets

CUPGUIDE™

• Collaboration with Healthscope, Peter Mac and NICTA

• Healthscope funding ongoing clinical validation of test

VEGF-D LAM Diagnostic

• Maintain existing partnership with University of Cincinnati (UCin)

• Test offered through their Translational Trial Development and Support Laboratories, proportion of revenues to CIR

• Working with UCin towards Humanitarian Device Exemption (HDE) approval

• Funding through non-dilutive grant funding opportunities & UCin

Research Reagents

• Continue to sell VEGF-C/-D research reagents through www.vegenics.com

Syngene (52% CIR owned)

• Supported by ARC grant

• Collaborators progressing DiMiTech platform to build data package

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• Management of CIR investment, plan to assess partnership opportunities

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Summary

• Leader in VEGF-C/D and VEGFR-3 targeting compounds in ophthalmology and oncology

• Lead compound OPT-302 is a fully owned and valuable asset

• Phase 1 clinical trial for wet age-related macular degeneration (AMD) 2Q15

• Program expected to be funded through meaningful Phase 1 and 2A clinical milestones to Q4 2017

• Two oncology assets in clinical development

• VGX-100 Phase 2 ready asset poised for licensing/partnership

• Eli Lilly partnered IMC-3C5 to complete Phase 1 in solid tumours in 1H15

• Funding progresses ophthalmology program to value-adding milestones, accelerates licensing opportunities for VGX-100 and strengthens CIR balance sheet

• Clinical and business development news-flow over next 24 months

• Strong management team with experience in developing drugs targeting the VEGF pathway, wet AMD and oncology

• Extensive worldwide intellectual property platform in respect of VEGF-C/-D and VEGFR-3

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30

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Thank-you

Megan Baldwin , PhD CEO & Managing Director Circadian Technologies (ASX:CIR, OTCQX:CKDXY) Megan.baldwin@circadian.com.au +61 (0) 447 788 674

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