Opthea Ltd — Investor Presentation 2011

Jun 15, 2011

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ASX and Media release

16 June 2011

Circadian provides market update on clinical development plans for VGX-100 in oncology and eye disease indications

Circadian Technologies Limited (ASX.CIR, OTCQX.CKDXY) provided a market update presentation to shareholders and market participants today on the clinical developments plans for its lead VEGF-C antibody therapeutic candidate –VGX-100 – over the next 2-4 years.

A copy of the presentation is attached.

It can also be accessed via the company’s website www.circadian.com.au

Company Enquiries:

Media Enquiries – Australia:

Robert Klupacs Kyahn Williamson Managing Director - Circadian Buchan Consulting Tel: +61 (0) 3 9826 0399 or Tel: +61 (0) 3 9866 4722 robert.klupacs@circadian.com.au kwilliamson@bcg.com.au

Media Enquiries – International:

Lauren Glaser The Trout Group LLC 251 Post Street, Suite 412 San Francisco, CA 94108 Tel +1 215 740 8468 lglaser@troutgroup.com

Level 1 10 Wallace Avenue Toorak Victoria 3142 Australia T +61 (3) 9826 0399 F +61 (3) 9824 0083 www.circadian.com.au

ABN 32 006 340 567

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About Circadian Technologies Limited

Circadian (ASX:CIR) is a biologics drug developer focusing on cancer therapies. It controls exclusive worldwide rights to a significant intellectual property portfolio around Vascular Endothelial Growth Factor (VEGF) C and D. The applications for the VEGF technology, which functions in regulating blood and lymphatic vessel growth, are substantial and broad. Circadian’s internal product development programs are focussed on novel anti-cancer therapeutics for large unmet needs. Circadian has also licensed rights to some parts of its intellectual property portfolio for the development of other products to ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company, including the antibody-based drug IMC-3C5 targeting VEGFR-3.

About Circadian’s pipeline of treatments for cancer

The clinical and outstanding commercial success of Avastin®, an antibody that blocks the activity of VEGF-A, clinically validated anti-angiogenic drugs as an effective means of inhibiting solid tumour growth. By blocking the interaction of VEGF-A with its receptors, primarily VEGFR-2, the multi-billion dollar cancer therapeutic slows tumour growth by inhibiting blood vessel recruitment into the tumour, effectively starving tumours of essential nutrients and oxygen required for growth. Avastin®, which is sold by Genentech, now part of Roche, had U.S. sales in 2009 of US$5.7 billion and worldwide sales in excess of US$8.6 billion. Avastin® is approved by the US FDA in the following indications: metastatic colorectal cancer, non-squamous-cell lung cancer, metastatic breast cancer, glioblastoma, metastatic renal cell carcinoma.

The VEGF-C inhibitor, VGX-100, a key therapeutic in Circadian’s portfolio, block this alternative stimulator for VEGFR-2. As such, it has the potential to block blood vessel growth in tumours resistant to anti-VEGF-A therapy and, when used in combination with drugs like Avastin®, may completely shut down angiogenesis (the growth of blood vessels) mediated by VEGFR-2, resulting in greater clinical efficacy.

VEGF-C along with the molecule VEGF-D. are also the only known proteins to bind and activate VEGFR-3 which drives lymphatic vessel and tumour-associated blood vessel growth. Inhibitors of VEGF-C thus have therapeutic potential to inhibit not only primary tumour growth through their anti-angiogenic activities, but to also inhibit tumour spread or metastasis via the lymphatic vessels - a mechanism of tumour dissemination that is often the deadliest aspect of many tumour types and a mechanism that is not effectively blocked by anti-VEGF-A or anti-VEGFR-2 therapeutics.

Inherent risks of Investment in Biotechnology Companies

There are a number of inherent risks associated with the development of pharmaceutical products to a marketable stage. The lengthy clinical trial process is designed to assess the safety and efficacy of a drug prior to commercialisation and a significant proportion of drugs fail one or both of these criteria. Other risks include uncertainty of patent protection and proprietary rights, whether patent applications and issued patents will offer adequate protection to enable product development, the obtaining of necessary drug regulatory authority approvals and difficulties caused by the rapid advancements in technology. Companies such as Circadian are dependent on the success of their research and development projects and on the ability to attract funding to support these activities. Investment in research and development projects cannot be assessed on the same fundamentals as trading and manufacturing enterprises. Thus investment in companies specialising in drug development must be regarded as highly speculative. Circadian strongly recommends that professional investment advice be sought prior to such investments.

Forward-looking statement

Certain statements in this ASX announcement may contain forward-looking statements regarding Company business and the therapeutic and commercial potential of its technologies and products in development. Any statement describing Company goals, expectations, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those risks or uncertainties inherent

Level 1 10 Wallace Avenue Toorak Victoria 3142 Australia

T +61 (3) 9826 0399 F +61 (3) 9824 0083 www.circadian.com.au

ABN 32 006 340 567

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in the process of developing technology and in the process of discovering, developing and commercialising drugs that can be proven to be safe and effective for use as human therapeutics, and in the endeavor of building a business around such products and services. Circadian undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Actual results could differ materially from those discussed in this ASX announcement.

Level 1 10 Wallace Avenue Toorak Victoria 3142 Australia T +61 (3) 9826 0399 F +61 (3) 9824 0083 www.circadian.com.au

ABN 32 006 340 567

Circadian Technologies Limited (ASX:CIR, OTCQX:CKDXY) Market Update

June 16, 2011

Robert Klupacs, CEO Mark Sullivan, Head of Development Megan Baldwin, Head of Preclinical R&D

Disclaimer

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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 also 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.

The Journey

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3 years ago we undertook a radical change in strategy: To take an extensive and tremendously exciting early stage IP portfolio in the field of angiogenesis and lymphangiogenesis, which had been transformed by the emergence of drugs such as Avastin[®] and Sutent[®]

AND

To convert it into therapeutic and diagnostic products which could improve the treatment of cancer and potentially other serious diseases.

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3

The issues we needed to address

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• What is our niche?

• What will be our product?

• How best to develop?

• Who best to develop for?

• Cost of development?

• Time of development?

• Getting the expertise to develop

4

Our Product (s)

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• A VEGF-C antibody used in conjunction with standard of care chemotherapy, which includes anti-angiogenic agents (“VGX-100”)

• VEGF-C and VEGF-D diagnostics which can help identify patients likely to most benefit from our therapy

• Other cancer diagnostics to give us presence in the clinical oncology setting and also provide ongoing revenues

5

Combination targeted therapies is the way of the future in oncology

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Since most tumors eventually find a way to get around blocked pathways,

"there is widespread understanding that we are going to need to learn how to combine two or more targeted therapies to block the main road and the side road and the dirt road…"

ASCO Chief Executive Dr. Allen Lichter, ASCO Annual meeting June 2011.

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Today

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1. The rationale for the role of VEGF-C inhibition as a cancer therapeutic and supporting pre-clinical data – Dr Megan Baldwin

2. VGX-100 development to date and clinical development plans in oncology – Mr Mark Sullivan

4. The opportunity and development pathway for VGX-100 in “front of the eye” disease – Dr Megan Baldwin

6. Wrap Up and Q&A

7

VEGF-C Inhibition: Rationale

Dr Megan Baldwin Head of Preclinical R&D

VGX-100 Program

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• VGX-100 is a fully human, high affinity, neutralising

• monoclonal antibody for VEGF-C.

• Development and clinical program designed to improve

• anti-angiogenic therapies for cancer and eye disease.

• Preclinical data demonstrating inhibition of primary tumor

• growth in several mouse xenograft models.

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VEGF-C is a member of the VEGF family that binds VEGFR-2 and VEGFR-3

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Angiogenesis ANGIOGENESIS ANGIOGENESIS
Monocyte Migration LYMPHANGIOGENESIS
Hematopoiesis
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Mechanism of Circadian’s Drugs: VGX-100 inhibits VEGF-C

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Mechanism of Circadian’s Drugs: VGX-100 inhibits VEGF-C

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VEGF-C in Avastin[®] ‘escape’

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• Avastin[®] : Effective but not in all patients

• Not all patients respond to therapy (30-50% response rate)

• 25-50% of responders become “resistant” within 12 to 18 months

• Likely reasons:

  • Tumor growth due to factors other than VEGF; and/or

  • Other angiogenic factors being turned on when VEGF blocked (eg. VEGF-C)

• VEGF-C is a likely candidate mediating the tumoral growth ‘escape’ in anti-VEGF -resistant tumors.

• Upregulation of VEGF-C could maintain signaling through VEGFR-2, despite VEGF inhibition.

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Our Approach: Targeting Resistance to Anti-VEGF Therapy

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Bergers et al., Nat.Reviews Cancer, 8: 592-602, 2008.

VEGF-C

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VEGF-C
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VEGF-C
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VEGF-C in Avastin[®] ‘escape’

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• Collaborative study with the MD Anderson Cancer Center

• Multiple samples were taken from each patient prior to and during the course of their treatment and disease course*.

• 42 patient cohort

• Circulating levels of VEGF-C significantly elevated in patients treated with Avastin[®] /FOLFIRI just prior to the onset of progressive disease.

• This data implicates VEGF-C as a key mediator driving tumor growth in Avastin[®] relapsed/refractory patients.

• Kopetz et al., JCO, 28(3): 453-9; 2010. 15

Avastin[®] /FOLFIRI Circulating VEGF-C levels are elevated in treated patients prior to disease progression

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[ ]

C.Lieu et al., "The Association of Alternate VEGF Ligands with Resistance to Anti-VEGF Therapy in Metastatic Colorectal Cancer (mCRC)“ , J.Clin.Oncol. 29:2011 (suppl; Abstract #3533). 16

VEGF-C is a risk factor for colorectal cancer

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Low VEGF-C
High VEGF-C
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69 CRC

VEGF-C correlated with:

• LN Metastases

• Clinical Stage

• Elevated VEGF-C associated with: • Decreased DFS • Decreased OS

Hu et al., Eur Surg Res, 39: 229-238, 2007.

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VGX-100 Efficacy in Mouse Models of Human Cancer

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VGX-100 Inhibits Tumor Growth in Mouse Models of Human Cancer

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• VGX-100 has inhibitory activity in a wide variety of human tumor xenografts, including:

• Prostate

• Glioblastoma

• Lung

• Ovarian

• Pancreatic

• Breast

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U87MG Glioblastoma Tumor Xenografts: VGX-100 effective in combination with Avastin

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2600
Negative Isotype Control
2400
Avastin
2200
2000 VGX-100
1800
1600
1400
1200
1000
VGX-100 + Avastin
800
600
400
200
0
0 10 20 30 40
Days Post-Tumor Implant
Mean Tumor Burden (mg) +/- SE
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At Day 49, VGX-100 + Avastin reduces tumor burden by:

• 42% compared to control IgG

• 33% compared to single-agent Avastin.

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VGX-100 single-agent & combination therapy in PC-3 prostate cancer xenografts

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2200
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1000
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0 20 40 60 80 100 120 140 160
Days Post-Tumor Implant
Mean Tumor Burden (mg) +/- SE
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Negative isotype Control
Avastin
VGX-100
Docetaxel
Avastin + Docetaxel
VGX-100 + Docetaxel
VGX-100 + Avastin
VGX-100 + Avastin + Doc e
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Docetaxel: Weekly IV at 10 mg/kg for 3 weeks. Vehicle: 10% EtOH, 10% Tween 20, 80% water.

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H292 NSCLC Tumor Xenografts: VGX-100 effective in combination with Avastin

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Isotype Control
Avastin
2000 VGX-100
VGX-100 + Avastin
Docetaxel
Avastin + Docetaxel
1500
VGX-100 + Avastin + Doc etaxel
1000
500
0
10 20 30 40 50
Days Post-Tumor Implant
Mean Tumor Burden (mg) +/- SE
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VGX-100 enhances Avastin + Docetaxel therapy in OVCAR-8 Ovarian Cancer Tumors

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2000
Isotype Control
Docetaxel
Avastin + Docetaxel
1500 VGX-100 + Avastin + Doc etaxel
1000
500
0
10 20 30 40 50 60 70 80 90 100 110 120 130
Day Post-Implant
Mean Tumor Burden (mg) +/- SE
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Summary

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• VEGF-C is an alternate, pro-angiogenic growth factor that signals through VEGFR-2 and VEGFR-3, that may modulate sensitivity to anti-VEGF therapy and allow regrowth of tumor vasculature.

• VEGF-C is elevated in CRC patients treated with Avastin[® ] /FOLFIRI just prior to and during disease progression.

• In several preclinical mouse models of human cancer, addition of VGX-100 to Avastin[®] +/- chemotherapy prolongs

• tumor response.

• Clinical program to co-administer VGX-100 and Avastin[®] to improve patient response in multiple tumor types.

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VGX-100 ONCOLOGY DEVELOPMENT

Mark Sullivan Head of Development

Idealised Timelines for Development of a Monoclonal Antibody in Oncology

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	Pre Clinical Testing		Phase I	Phase II	Phase III		FDA	Approval
Years	3.5		1	2	3		1.5	Total = 10-12
Test Population	Laboratory and Animal Studies	D	20 to 80 late stage cancer patients	100 to 300 patients with particular tumour type and chemotherapy regimen	300 to 1000 patients with particular tumour type and chemotherapy regimen	A	Review	Post Marketing Commitments and safety Monitoring
Purpose	Assess Safety and Biological Activity	FILE IN	Determine safety and dosage	Evaluate effectiveness, look for side effects	Verify effectiveness, monitor adverse reactions from long-term use	FILE BL	Process	Large Scale Manufacturing -------------- Distribution -------------- Education
% of all new drugs thatpass	50 to 100 screened			5 enter trials			1

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VGX-100 Target Product Profile in Oncology

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• Indication:

• Co-administered with anti-angiogenic agent (Avastin®) and standard of care

• » Targeting glioblastoma, colorectal cancer

• » At least one of breast, lung, renal and/or potentially ovarian cancer in combination with Avastin[® ]

• Optimal timing of treatment

• First line with Avastin[® ]

• In the treatment of Avastin[®] resistance

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VGX-100 Oncology Product Development

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Clinical Biomarker

Regulatory Toxicology Manufacture Research Cancer

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Ocular
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VGX-100 Lead Candidate

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VGX-100 Oncology Product Development

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Clinical

Biomarker

US-based contract research laboratory

Regulatory

and academic collaborators

Toxicology

Extensive preclinical studies √

• In vivo and in vitro models √

Manufacture

Research

• Optimal in combination with Avastin[®] and chemotherapy

Cancer

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VGX-100 Lead Candidate

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VGX-100 Oncology Product Development

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Clinical

Biomarker

Lonza, UK

800L clinical grade (cGMP) √

Regulatory

• Yield >2g/L √

Toxicology

• Stable formulation √

Assay development √

Manufacture

• Clinical √

Research

• Preclinical √

• Manufacture release √

Research grade batch √

Cancer

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VGX-100 Lead Candidate

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VGX-100 Oncology Product Development

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Clinical

Biomarker

Regulatory

Major global toxicology laboratory

Completed according to FDA regulations √

Toxicology

• Pivotal toxicology studies in two species √

Manufacture

• Pre-toxicology “dose range finding” studies √

• Species selection √

Research

• Pharmacokinetics in 3 species √

• Biodistribution √

Cancer

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VGX-100 Lead Candidate

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VGX-100 Oncology Product Development

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Clinical

Biomarker

Regulatory

Toxicology

Manufacture Research

Conduct under United States Food and Drug Administration Standards Pre-IND √ IND (Q3 ‘11)

Cancer

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VGX-100 Lead Candidate

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VGX-100 Oncology Product Development

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Clinical

Biomarker

Regulatory

Kopetz, MD Anderson

Toxicology

Initial clinical biomarker data √

• Repeat and expand

Manufacture

Program to accompany Phase I designed √

Research

Cancer

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VGX-100 Lead Candidate

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Avastin[®] /FOLFIRI Circulating VEGF-C levels are elevated in treated patients prior to disease progression

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[ ]

C.Lieu et al., "The Association of Alternate VEGF Ligands with Resistance to Anti-VEGF Therapy in Metastatic Colorectal Cancer (mCRC)“ , J.Clin.Oncol. 29:2011 (suppl; Abstract #3533). 34

VGX-100 Oncology Product Development

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Clinical Biomarker

Regulatory Phase I Clinical Trial Toxicology Sites selected √ Manufacture Monotherapy and Combination Therapy Research

Cancer

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VGX-100 Lead Candidate

35

Background & Benefits of the program design

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• Rapidity

• Speed through Phase I

  • » Gain monotherapy and combination data

• Moves quickly to homogeneous population

• Preserves options

• Multiple cancer type

  • » Glioblastoma

    • Important, unmet medical need

    • Readouts are clear, fast

    • Opportunity for accelerated registration

  • » Colorectal Cancer

    • Significant cancer

    • Important, unmet medical need

» Other

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Phase I and II clinical program

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Phase I VGX-100 and VGX-100 + Avastin[® ] Arm A (mono), Arm B (combo) Phase II VGX-100 + Avastin[®] + selected standards of care Part A Metastatic Lung Breast Renal cell Gliocolorectal cancer cancer cancer blastoma cancer NonMetastatic Phase II Phase II squamous HER2 Part B non-small negative cell (with (with (with (with (with Avastin [®] + Avastin [®] , Avastin [®] Avastin [®] Avastin [®] ) FOLFOX) paclitaxel and and and carbo.) paclitaxel) interferon alpha)

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Phase I and II clinical program

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Phase I VGX-100 and VGX-100 + Avastin[® ] Arm A (mono), Arm B (combo) Phase II VGX-100 + Avastin[®] + selected standards of care Part A Metastatic Lung Breast Renal cell Gliocolorectal cancer cancer cancer blastoma cancer NonMetastatic Phase II Phase II squamous HER2 Part B non-small negative cell (with (with (with (with (with Avastin [® ] Avastin [®] , Avastin [®] Avastin [®] Avastin [®] ) + paclitaxel and and FOLFOX) and carbo.) paclitaxel) interferon alpha)

38

Phase I First-in-Human Study

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Legend :
A - Avastin®
100 – VGX-100
100 L1 L – dose level
Solid tumour
100 L2
(advanced or
metastatic) 100 L3
No further
100 L4
treatment
options 100 L5
Multicentre 100 L6
“3+3” design
(N = approx 27
A+100 L2
to 33)
A+100 L3
A+100 L4
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Glioblastoma

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• In the US in 2010[1]

• Estimated diagnosed: 22,020

• Estimated fatalities: 13,140

• The most aggressive malignant primary brain tumor in adults

• Nearly always fatal

• Pre-Avastin[® ]

• 6-month progression-free survival for relapsed or progressive glioblastoma is 9% to 21%

• objective response rate is less than 10%

• median overall survival (OS) is 7 months or less

• With Avastin[®]

– Median OS: 9.2 months

1 Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2008 , National Cancer Institute. seer.cancer.gov/csr/1975_2008/ based on November 2010 SEER data submission, posted to the SEER web site, 2011.

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Avastin[®] Registrational Study in Glioblastoma

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Metastatic colorectal cancer

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• In the US[1]

• 2[nd] most common cause of cancer deaths[2 ]

• Estimated diagnosed in 2010: 142,570

• Estimated fatalities in 2010: 51,370

• At presentation (% 5-year relative survival):

• 39% localized (90%)

• 37% regional (68%)

• 19% distant (10%)

• The median OS with Avastin[®] : 20.3 months

1 Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2008 , National Cancer Institute. seer.cancer.gov/csr/1975_2008/ based on November 2010 SEER data submission, posted to the SEER web site, 2011.

• 2 Kim G, Grothey A. Treatment Trends in Colorectal Cancer. Business Briefing: US Gastroenterology Review. 2005

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Avastin[®] Registrational Study in Metastatic Colorectal Cancer

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Oncology Product Development

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Clinical Phase I Clinical Trial Sites selected √ Biomarker Monotherapy and Combination Therapy Regulatory Toxicology Manufacture Research Cancer

Phase II Clinical Trials Glioblastoma Colorectal cancer One other

Collaborations Further indication evaluation through collaborations

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VGX-100 Lead Candidate

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Current Activities and Value Adding Events

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Activity	Timeline
Mechanism of Action Studies	Complete
PK Studies	Complete
cGMP Manufacture	Complete
Toxicology Studies	Complete (reports awaited)
IND Filing	Q4 2011
First-in-human Clinical Study (monotherapy and in combination)	Q4 2011
Phase II studies start (Multiple Indications)	Q1 2013
Clinical proof-of-concept	2H 2014

~~45~~

VGX-100 OCULAR DEVELOPMENT OPPORTUNITY

Dr Megan Baldwin Head of Preclinical R&D

The Opportunity

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Leveraging the preclinical development program results in a simplified & cost-effective development path for VGX-100 in eye disease.

Leverage oncology program investment in:

• Conducting systemic toxicology studies

• cGMP manufacture for Ph I/II clinical trials

• • Biochemical characterisation studies

• • Formulation & stability studies

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Compelling Reasons Supporting Development of VGX-100 for Eye-Disease

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• Scientific rationale

• Existing supportive preclinical data

• Relationship with Key Opinion Leader

• Mechanism of Action differentiation from VEGF-A inhibitors

• Defined clinical endpoints using validated procedures

• Short timeframe to clinical POC

• Large market opportunity (>$500m p.a)

• Opportunity to leverage VGX-100 oncology program

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Development Opportunity

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• Significant development opportunity for VGX-100 as a treatment for ‘front of the eye’ disease.

• Initial indications:

• Corneal Neovascularisation (CNV)

• Corneal Allograft Rejection

• • Dry Eye Disease

• Local ocular administration via subconjunctival injection as a single-agent.

• Approx. 18 – 24 months to Phase I/II

49

Target Product Profile in ‘Front of the Eye’ Disease

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• Indication:

• Administered as monotherapy, via subconjunctival injection for the treatment of:

• » Corneal neovascularisation of various aetiologies

• » ‘High-risk’ corneal allografts to inhibit graft rejection and prolong graft survival

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Healthy Corneas are Avascular and “Immune Privileged”

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• Healthy corneas are avascular.

• Blood AND lymphatic vessels absent.

• “Immune-privileged” state: absence of vessels hinders trafficking of immune mediators between the eye and lymphoid system.

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The cornea is the transparent front part of the eye that covers the iris, pupil and anterior chamber

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Clinical Appearance of CNV in Inflammatory Disorders

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CNV in Salzmann’s nodular degeneration

CNV due to Rosacea

Ellenberg et al., Prog.Retinal & Eye Research, 29:208-248, 2010. 53

CNV and Inflammation Associated with LSCD

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Ellenberg et al., Prog.Retinal & Eye Research, 29:208-248, 2010.

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CNV due to Limbal Stem Cell Deficiency

• CNV can be diagnosed & monitored using routine procedures: • Ocular examination

• Corneal fluorescein staining & slit-lamp

• Quantitation of vascularised corneal area, depth and stromal involvement

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VGX-100 in Eye Disease

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• o

• VGX-100 may have clinical utility in a broad range f eye diseases and

• pathologies that are characterised by:

• aberrant or increased neovascularisation

• inflammation, and

• alloimmunity.

eg. Chronic dry eye: complex immune mediated disorder characterised by lymphangiogenesis without hemangiogenesis, affecting 5 million people over 50 yrs of age in the US.

Keratitis : corneal inflammation,

Alkali/acid chemical injury,

Aphakic Bullous Keratopathy: corneal edema from cataract extraction

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Corneal Neovascularisation

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Expert Roundtable Outcome: Consensus Statements on Corneal Neovascularisation

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“[There are] several very serious unmet medical needs in the treatment of corneal neovascularisation (CN) with underlying corneal diseases.

We anticipate that the anti-angiogenic strategy will become an integral part of the treatment regimen to address the unmet medical needs in the field of CN and to avoid the dramatic complications of CN.”

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Corneal Neovascularisation

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• CNV is a common and non-specific response to a variety of ocular insults, for example:

• Infection (ocular herpes simplex)

• Trauma (surgery, burns)

• Diseases & immunological conditions (LSCD)

• Scarring, oedema, lipid deposition, persistent inflammation that affects visual acuity and may cause blindness.

• Significant risk factor for corneal allograft rejection.

• Insult upregulates growth factors leading to angiogenesis & lymphangiogenesis.

• Vessels grow into cornea from limbus.

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Common Mechanism of CNV

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• VEGF/VEGFR pathway implicated as key driver of angiogenesis and lymphangiogenesis in CNV originating from various causes.

• Rationale for VGX-100 for treatment of CNV:

• Block VEGF-C mediated activation of VEGFR-2 to reduce angiogenesis

• Block VEGF-C mediated activation of VEGFR-3 to reduce angiogenesis and lymphangiogenesis

• • Inhibit inflammation and Antigen Presenting Cells into cornea

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Need for Non-Steroid Based Treatment of CNV drives LARGE Market Opportunity

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Treatment

• Corticosteroids to control inflammation (significant risks, little direct affect on angiogenesis, infections must be resolved before treatment)

• Need for non-steroid based treatments

Market Opportunity

• Large (estimated prevalence of CNV in 4-5% of all pts presenting to eye clinics)

• Potential for concurrent use with corticosteroids

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Corneal Transplantation

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Corneal Transplantation

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• Multiple reasons/indications necessitating corneal

• transplantation.

• ~40000 corneal transplants performed per yr (US)

• ~25% are ‘high risk’ (vascularised corneal bed).

• Uncomplicated first grafts have a >90% success rate.

• Risk of graft failure increases to 50-90% if the recipient

• corneal graft ‘bed’ is vascularised.

• Graft failure involves blood and lymphatic mediated

• mechanisms.

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Existing & Supportive Preclinical Data:

VGX-100 improves Corneal Transplant Survival

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VGX-100 improves corneal transplant survival (collaboration with Harvard Uni., Schepens Eye Institute)

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• Preclinical data demonstrating efficacy of VGX-100 in extending period of corneal graft survival (ie. inhibiting corneal graft rejection).

• VGX-100 administered systemically via IP injection (20 mg/kg day prior to injection, every alternate day for 2 weeks).

• Data presented at ARVO 2010 and manuscript submitted.

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Rejected corneas are infiltrated by blood and lymphatic vessels and over-express VEGF-C and VEGFR-3

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Transplanted Corneas: 3 wks Post-Transplant

ACCEPTED REJECTED

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Photomicrographs Flat-mount IHC stained corneas: LYVE-1 (lymphatics) CD31 (blood vessels)

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VEGF-C expression increased 2-fold in rejected vs accepted allografts, and 4.8 fold over nontransplanted corneas.

ARVO Annual Meeting 2010. Program#/Poster#1554/D995 65

VGX-100 reduces blood and lymphatic vessel density in transplanted corneas

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----- Start of picture text -----

Control VGX-100 Control VGX-100
Blood Vessels Lymphatic Vessels
Area covered by vessel (%) Control VGX-100 Area covered by vessel (%) Control VGX-100
----- End of picture text -----

Day 7 post-transplant

ARVO Annual Meeting 2010. Program#/Poster#1554/D995 66

VGX-100 Promotes Corneal Transplant Survival

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ARVO Annual Meeting 2010. Program#/Poster#1554/D995 67

VGX-100 Ocular Product Development

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Clinical Regulatory

Toxicology

Manufacture Research

Cancer

Ocular

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VGX-100 Lead Candidate

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VGX-100 Ocular Product Development

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Clinical Regulatory

Lonza, UK

800L clinical grade (cGMP) √

• Yield >2g/L √

Toxicology

• Stable formulation √

Assay development √

Manufacture Research

• Clinical √

• Preclinical √

• Manufacture release √

• Research grade batch √

Cancer

Ocular

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VGX-100 Lead Candidate

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VGX-100 Ocular Product Development

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Clinical Regulatory

Toxicology

Manufacture Research

Major global toxicology laboratory

28 day, two species √

Supplemental ocular toxicology studies 14 day, dose range finding studies √ Species selection √ Pharmacokinetics in 3 species √ Biodistribution √

Cancer

Ocular

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VGX-100 Lead Candidate

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VGX-100 Ocular Product Development

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Clinical Regulatory Conduct under United States Food and Drug Administration Standards

Toxicology

Pre-IND

Manufacture Research

IND

Cancer

Ocular

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VGX-100 Lead Candidate

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VGX-100 Ocular Product Development

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Clinical Regulatory

Phase I/II Clinical Trial

Safety and initial efficacy in 1[st] trial

Toxicology

Manufacture Research

Cancer

Ocular

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VGX-100 Lead Candidate

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Clinical Studies: Likely trial design

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• Phase I/II dose escalation: safety, PK, efficacy (PhII)

• Patients with clinically stable CNV (minimum one quadrant, penetrating over limbus at least 2mm).

• One dose of 0.1cc subconjunctival VGX-100

• Ophthalmological examinations at 1 day, 1 wk, 2 wks,3 wks, 1 mo, and monthly thereafter.

• Evaluate. May undergo repeat dose at 3 mos.

• Primary Outcome Measures: Regression of CNV (Slit-lamp photographs, fluorescein angiograms.)

• Secondary Outcome Measures: Safety monitoring, visual acuity.

• • Timeframe: Phase I: 6-9 months; Phase II: 12-18 months

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Phase II: VGX-100 for Treatment of Corneal Neovascularisation

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Patients with W0 W24 Clinically Stable CNV VGX-100 N=20-40 Minimum one quadrant, penetrating limbus at least 2mm R Multicentre One dose via Subconjunct. Standard of Care (eg. Corticosteroids) N=20-40 Injection Safety, Efficacy

Ophthalmological Examinations: day 1, 1 wk, 2wks, 3 wks, 1 month, monthly thereafter. Primary Outcome Measures: Evaluation of CNV regression by fluorescein angiography. 74 Secondary Outcome Measures: Safety monitoring, visual acuity

Current Activities and Value Adding Events

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ACTIVITY	TIMELINE
Further efficacy data in preclinical CNV & CT models	4Q’11 – 2H’12
Acceptable biodistribution and PK via subconjunctival injection	2H’12
Acceptable profile in toxicology program via subconjunctival route	2H’13
IND granted	2H’13
Phase I/11 study start	2H’13
Proof of Concept Efficacy	1H’15

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Wrap Up

Robert Klupacs Chief Executive Officer

3 years on…

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• VGX-100 to achieve major milestone of IND in next few months

• VGX-100 to commence Phase 1 clinical trials Q4 2011

• VGX-100 Phase 2 data in oncology by second half of 2014

• New major opportunity for VGX-100 in front of eye disease with initial clinical data by H1 2014

• Ongoing scientific validation for role of VEGF-C in various diseases

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3 years on…

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• One product in the clinic – IMC-3C5 being developed by Eli Lilly

• A VEGF-D diagnostic on the market for LAM

• A cancer diagnostic for CUP close to being launched by Healthscope

• Superb group of internal and external scientific and development professionals

• Approx $25M in cash and investments

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Appendix

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Preliminary Market Opportunity Assessment

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CNV associated with Ocular Herpes Simplex Infection:

Incidence of New & Recurring Herpetic Keratitis Cases/Year (U.S.A.): 50,000	Incidence of New & Recurring Herpetic Keratitis Cases/Year (U.S.A.): 50,000
Annual Cost per Patient/Year (U.S.A.)	Estimated Annual Revenue (U.S.A.)
• USD 5,000	USD 250M
• USD 10,000	USD 500M
• USD 15,000	USD 750M

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Preliminary Market Opportunity Assessment

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Corneal Allograft Rejection:

#Corneal Transplants/Year(U.S.A): 40000	#Corneal Transplants/Year(U.S.A): 40000
# High-RiskCorneal Transplants/Year(U.S.A): 10000
Annual Cost per Patient/Year(U.S.A)	Estimated Annual Revenue (U.S.A.)*
• USD5000	USD50M
• USD 10000	USD 100M
• USD 15000	USD 150M

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