Opthea Ltd — Investor Presentation 2009

Mar 25, 2009

Robert Klupacs, CEO & Managing Director

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 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 forwardlooking 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.

Circadian Technologies Limited

A cashed up company developing novel antiangiogenic therapeutics for cancer and other serious diseases With a dominant IP platform And the potential for generating significant revenues in the near term.

• Developing angiogenesis-based therapies for cancer and other serious diseases

• World’s most comprehensive patent estate covering key angiogenesis targets VEGF-C, VEGF-D and VEGFR3

• Partnered programs with leading international biotechs in their fields providing existing cash flows

Ark Therapeutics plc (LSE:AKT) – Phase 3 clinical trial ImClone Systems Inc (NSDQ:IMCL) – developing anti-cancer drug Healthscope Limited (ASX:HSP) – developing cancer diagnostic test

• Strong financial position - $46 million in cash & listed investments

• Existing royalties and potential for future significant royalty income from Ark, cancer diagnostic test and ImClone (Lilly) as well as other applications of portfolio.

What is angiogenesis?

• Angiogenesis is the growth of new blood vessels

• • Tumour growth is caused by stimulation of new blood vessel growth by proteins (e.g. proteins VEGF-A, C, D)

• • Blocking these proteins blocks blood vessel growth, leading to tumour starvation

• First targeted anti-angiogenesis therapy to become drug (developed & sold by Genentech Inc and Roche)

• Antibody that blocks angiogenic protein VEGF-A

• First approved Feb 2004

• 2007 sales: in US $US2.3B, worldwide: $US6B ($10B+ 2009)

• Fastest sales growth of any drug

Avastin + chemo extends progression free survival in breast cancer Avastin + chemo extends survival in lung cancer

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

==> picture [502 x 285] intentionally omitted <==

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

VEGF-C/D
VEGF-C/D
VEGF-C/D
----- End of picture text -----

Activity of Circadian’s VEGF-C/D Inhibitors

Circadian’s approach and technology

• Developing blockers of the two other angiogenic VEGF proteins (VEGF-C & D) - involved in tumour growth as well as in tumour spread (metastasis)

• Blocking VEGF-C/D - not only starves tumours but additional major therapeutic potential for inhibiting tumour spread through lymphatic system

• Cancer first therapeutic target

• Circadian’s products capable of targeting multiple indications enabling multiple partnering and/or early revenue generating opportunities

• Product development secured by dominant IP position for VEGF family members VEGF-C/D and VEGFR3.

Our strategy

• Develop selected therapeutics to proof of efficacy in Phase II trials

• Subsequent clinical development with partners – large pharmaceutical/biotechnology companies

• Seize opportunity for earlier therapeutic partnerships if appropriate

• Selectively exploit/commercialise parts of therapeutic portfolio not in angiogenesis area at earlier stages

• Divest listed investments as soon as practicable and appropriate to liberate cash.

• Exploit clinical diagnostics and reagents for early revenues

==> picture [721 x 541] intentionally omitted <==

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

CIRCADIAN’s BUSINESS MODEL
Existing
Listed Recurrent Revenues
Cash
Investments Royalties
$41.2M
Licence Fees
$5M
Interest
Future Partnerships
Realised at R&D Projects
Reagent/Diagnostics Sales
VGX-100
appropriate
VGX-200
Ark
time
VGX-300
ImClone
Clinical Diagnostics
Healthscope
Research Reagents
Research
reagents
Additional Product
Partnerships Sales
$$$$
Existing income; royalties -
potential for significant increase
----- End of picture text -----*

Deep Product Pipeline with mechanistically distinct mechanisms

• VEGF-C, VEGF-D ligands as research reagents, therapeutic development in wound healing, cardiovascular disease, lymphedema, neurodegenerative disease

• Ownership and exclusive commercialisation rights to molecular diagnostic for Cancers of Unknown Primary (CUP) in US, Europe, Japan; partnered with Healthscope for other territories

• US incidence of CUP 60,000-100,000 per annum

• • Test to sell between $500-1500 due to significant health cost

• savings

• Commenced Phase 3 trials Jan 2009 under SPA. Expected recruitment 250 patients over 18 months.

• VEGF-D gene therapy product.

• Extends lifetime of dialysis access grafts. Phase 2 clinical trials 17 months v 4.5 months.

• Major patient impact by reduced need for repeated surgery and increased survival time of patients undergoing ongoing Collar

• dialysis.

• Market estimates > $US500M+ per annum

==> picture [271 x 149] intentionally omitted <==

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

Graft Vein
Anastamosis
----- End of picture text -----

==> picture [358 x 119] intentionally omitted <==

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

artery
vein
Step 1: Surgical isolation Step 2: Insert flexible plastic
of vein and artery tube graft to provide access for dialysis
----- End of picture text -----

• Formal internal product development candidate

• IND planned H1 2010

• Currently completing CHO cell line development and process

• Wide range of peer reviewed literature

• Confidential data in range of xenograft models

• Likely first indication head & neck cancer

• Circadian has dominant IP rights in respect of VEGF-C/D antagonists

• Granted IP rights in major territories to VEGF-C/D proteins and VEGFR-3 and blockers

• Applications in cancer and certain other diseases

• IP rights over product candidates extend beyond 2020

• Further strategic IP filings being made to extend patent life

Deal-making drug development and operational track record

• Robert Klupacs (CEO) Founder and former CEO, ES international and six other early stage companies. Entrepreneur and IP expert with extensive history of industry deals including Sanofi, Baxter, Aventis, Pharmacia, Novartis, Alexion, Pfizer.

• Dr Alex Szabo (Head, Business Development) Formerly Bionomics, Beckman-Coulter, Affymetrix, Pharmacia. Recent deals include Aventis, Eisai, Genmab, LabCorp, Merck-Serono.

• Natalie Korchev (CFO & Head of Operations) ACA Formerly Ernst & Young, global finance, risk management experience. Over 10 years experience in biotech industry.

• Product Development Advisory Committee

The nine members together bring vast experience in international drug development and oncology. Past roles have included positions with Amgen, GSK, Aventis, Schering, Affymax, Maxygen. Over 150 drug development experience.

An investment with significant upside

• Dominant IP position over key mediators of angiogenesis.

• Phase 3 product partnered and pipeline of product opportunities-multi-million royalty flow possible within 24-36 months.

• Strong financial assets to support development/deal making

• Extremely high value space for partnerships (Roche/BioInvent $500M+)

• World class drug development expertise and management

• Share price currently trading at 45% below cash with no apparent value ascribed for our IP assets or existing and future royalty flows.

APPENDICES

• •VGX-100 is a fully human, high affinity, neutralising monoclonal antibody for VEGF-C

• •Development and clinical program designed to address resistance and non-responsiveness to anti-angiogenic therapies for cancer

• •Orphan drug designations likely

• •IND expected Q1 2011.

• •Preclinical data demonstrating dose-responsive inhibition of primary tumor growth in several mouse xenograft models

• •Sound scientific rationale and pre-clinical data demonstrating potential as anti-tumorigenic and anti-metastatic agent.

• •Humanisation and affinity maturation program complete

• •Lead hIgG1 mAbs identified based on fold-improvement in KD relative to murine parental VD1 antibody

• •Formal lead identified by Nov ’09 based on in vivo efficacy

• •IND anticipated H1/2011

• •Orphan drug designation likely

• •Proof of concept model demonstrates potential as anti-tumorigenic and anti-metastatic agent.

•Soluble receptor protein consisting of the first 3 Ig-like domains of hVEGFR-3 linked to the Fc region of hIgG1

• •Neutralises both VEGF-C and VEGF-D

•Stable CHO cell line expressing levels sufficient for research grade production

• •IND anticipated H2/2011

• •Orphan drug designation likely

• •Proof of concept established using adenoviral gene delivery

•Several peer-reviewed articles demonstrating potent anti-metastatic activity

91 Gastric Adenocarcinomas

==> picture [50 x 139] intentionally omitted <==

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

VEGF-C
VEGF-D
----- End of picture text -----

VEGF-C and VEGF-D correlated with:

• LN metastases

• Decreased survival

VEGF-D and VEGFR-3 are independent prognostic markers

==> picture [104 x 12] intentionally omitted <==

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

Graphs show DFS
----- End of picture text -----

Juttner et al., JCO, 24(2): 228‐240, 2006.

180 NSCLCs

5yr survival rates for patients: VEGF-C positive: 47% VEGF-C negative: 70% VEGF-C and VEGFR-3 correlated with:

• Decreased survival

• Pts with positive staining for

• both had poorest prognosis

Arinaga et al., Cancer, 97(2): 457‐464, 2004.

117 invasive breast cancer

VEGF-C correlated with:

• LVD

• LN Metastases

• Decreased OS

Pts with high VEGF-C & VEGF levels have worst prognosis

Mohammed et al., Brit. J. Cancer, 96: 1092‐1100, 2007.

79% 78% Overall Survival Rates: High VEGF-C/VEGF-D: 28% Low VEGF-C/VEGF-D: 84% 40% 32% 69 CRC Elevated VEGF-C and VEGF-D VEGF-C correlated with:

Elevated VEGF-C and VEGF-D associated with:

• LN Metastases

• Decreased DFS

• Clinical Stage

• Decreased OS

VEGF-D correlated with:

• LN Metastases

• Depth of Tumor Invasion

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

Amo, Brit.J.Dermat., 150, 160-161, 2004 667 +/- 463 vs 273 +/- 58 HIGHin Adv vs Early vs Healthy Angiosarcoma Kaushal, Clin.Canc.Res., 11: 584-593, 2005 436 vs 332 HIGHin Adv vs Early Prostate Reference Median or Mean Level (pg/ml by ELISA) VEGF-D Indication Wojciech, Oncology Res., 16(9): 445-451, 2007 N/A HIGHvs Healthy Controls NSCLC Wojciech, Oncology Res., 16(9): 445-451, 2007 N/A HIGHvs Healthy Controls SCLC Yu et al., Surgery, 247(3): 483-89, 2008 7433 +/- 230 vs 5289 +/- 296 HIGHvs Benign PAPILLARY THYROID Yu et al., Surgery, 144: 934-41, 2008 6433 vs 5289 HIGHin Recurrent vs Benign PAPILLARY THYROID Vihinen, Acta. Oncologica, 2007 2584 vs 1643 HIGHin Adv vs Local Mets MELANOMA Wang, World J. Gastroenterol., 2007 595 +/- 201 vs 360 +/- 97.4 HIGHvs Healthy Controls GASTRIC Mathur , Gynecol Oncol., 2005 6678 vs 3505 vs 1561 HIGHin Adv vs Early vs Healthy CERVICAL Mitsuhashi et al., Cancer, 2005 11885 vs 9594 HIGHvs Healthy Controls CERVICAL Tamura, Chest, 2004 2009.2 vs 1465.5 HIGHvs non-metastatic NSCLC Tamura, Ann.Surg.Oncol., 2004 2046.7 vs 1419 HIGHvs non-metastatic NSCLC Tamura, Cancer, 2003 1726 vs 941.2 HIGHvs Healthy Controls NSCLC Duff, Int. J. Oncol., 2003. 35 U/ml vs 11.5 U/ml HIGHvs Healthy Controls CRC Reference Median or Mean Level (pg/ml by ELISA) VEGF-C Indication Circulating VEGF-C & VEGF-D levels are elevated in cancer patients

==> picture [721 x 541] intentionally omitted <==

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

LAM – Orphan Development
Opportunity for VEGF-D Antagonists
VEGF‐D is increased in Serum VEGF‐D levels distinguishable from other
serum of patients with cystic and chylous lung diseases
LAM
Young et al. NEJM., 358(2), 199‐200, 2008
VGX-200 as therapeutic?
Seyama et al. Lymphatic Res & Biol., Vol 4, #3, 143‐152, 2006
VEGF-D diagnostic?
----- End of picture text -----

 Lymphangioleiomyomatosis (LAM): cystic lung lesion, lymphatic abnormalities, abdominal tumors

 Proliferation of abnormal smooth muscle cells

 Often degenerative requiring lung transplant

 Frequently fatal

 Primarily affects women of reproductive age

 Estimated 300,000 cases worldwide

 No effective treatment

 No surrogate markers to predict severity or clinical course

• Listed on the ASX in 1985

• In 2006, Circadian acquired 50% of Vegenics Limited.

• In 2008 Circadian acquired 100% of Vegenics Limited put in place new leadership and transformed its business model to focus on the development of biologics-based therapies for cancer through inhibition of angiogenesis

• 12 person management and scientific team supported by international advisors, contracted testing agencies and relationships with leading academic researchers

• Cash at bank and listed investments at 25 March 2009 $A46.2M

• 45,241,928 shares on issue; further 1.155M to be issued Aug 10 2010 (Top 10 control approx 53.5%)

• Market Cap approx $32M @25 March 2009