Opthea Ltd — Investor Presentation 2011

Oct 10, 2011

Circadian Technologies Limited (ASX:CIR, OTCQX:CKDXY) Biopartnering Europe

October 10, 2011

Robert Klupacs, CEO & Managing Director

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.

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CORPORATE SNAPSHOT

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• Major IP Platform covering VEGF-C, VEGF-D and VEGFR-3

• Developing unique antibody therapies - VGX-100

• As combination therapy in chemotherapy (P1 to commence Q4 ‘11)

• As monotherapy in front of eye disease (P1 to commence Q4 ‘12/Q1 ‘13)  IMC-3C5 being developed by Eli Lilly/Imclone (P1 commenced Apr 11)

• Developing Diagnostics as early stage revenue source

• From Platform

  • VEGF-D in respiratory disease and treatment monitoring

  • VEGF-C in oncology and monitoring Avastin therapy

• Cancers of Unknown Primary – partnered with Healthscope

• Additional Revenue generating partnerships

• Ark Therapeutics – VEGF-D gene therapy

• R&D Systems Inc, Merck Millipore, Perkin Elmer – Research reagents

CORPORATE SNAPSHOT

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Our antibodies are targeted to block angiogenesis AND lymphangiogenesis to treat cancer and eye disease

• Novel Vascular Endothelial Growth Factors (VEGF-C) antibody therapy based on tumor starvation and metastasis inhibition

• Anti-VEGF therapy has gained wide acceptance on the strength of Genentech/Roche Avastin® with 2010 US Sales of $7.2 billion

• A major opportunity to be used in combination with Avastin® and/or other anti-angiogenic therapies to improve patient outcomes in oncology

• Significant potential as monotherapy in front of the eye disease.

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

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CORPORATE SNAPSHOT

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Our Lead Internal Therapeutics program: VGX-100

• Fully human neutralizing monoclonal antibody for VEGF-C

  • Pre-clinical data demonstrating anti-tumourigenic and anti-metastatic effects in animal models of human prostate, pancreatic, brain, lung and ovarian cancers presented at AACR

  • VEGF-C shown to be potential predictive biomarker of Avastin[®] resistance in Colorectal cancer – ASCO 2011

• IND Filed September 30 2011

• Phase 1 multi-dose ascending trials to commence Q4 in cancer patients

 Glioblastoma and mCRC first indications

• Also Expanding development to also include treatment of front-of-eyediseases

CORPORATE SNAPSHOT

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Partnered programs with existing and increasing royalty streams

Therapeutics: VEGFR-3 antibody (IMC-3C5) for solid tumours

• Development agreement with ImClone/Eli Lilly

• FDA Phase I trial started April 2011

• Annual Fees, Royalty on Sales

: Cancer Diagnostics Cancer of Unknown Primaries (CUP)

• Development partnership with Healthscope

• Launch in Asia expected H1 2012

: Platform Diagnostics VEGF-D diagnostic for respiratory diseases

• Development partnership with Cincinnati Children's Hospital Medical Center;

• Launched Feb 11

CORPORATE SNAPSHOT

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Dominant and protected IP position extending till at least 2025

• Acquired from Ludwig Institute/Uni Helsinki

• Exclusive worldwide licences for VEGF-C –HGS/Cogenesys/Teva Exclusive worldwide licences for VEGF-D - Chugai (Jan 2011)

Strong financial position

• Approx $A22M cash and investments

• Cash Burn 2011/12 (est) $10-12.5M

VGX-100 VEGF-C Inhibition: Rationale

Our approach is based on the widely accepted view that 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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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 signalling through VEGFR-2, despite VEGF inhibition.

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

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[ ]

Plasma VEGF-C may be a predictive biomarker for the development of resistance to Bevacizumab

C.Lieu et al., "The Association of Alternate VEGF Ligands with Resistance to Anti-VEGF Therapy in Metastatic Colorectal Cancer (mCRC)“ , 13 J.Clin.Oncol. 29:2011 (suppl; Abstract #3533).

VGX-100 Efficacy in Mouse Models of Human Cancer

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
Negative isotype Control
2000
Avastin
1800 VGX-100
1600 Docetaxel
Avastin + Docetaxel
1400
VGX-100 + Docetaxel
1200
VGX-100 + Avastin
1000 VGX-100 + Avastin + Doc e
800
600
400
200
0
0 20 40 60 80 100 120 140 160
Days Post-Tumor Implant
Mean Tumor Burden (mg) +/- SE
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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 reduces metastasis in an orthotopic prostate cancer model

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VGX-100 ONCOLOGY CLINICAL DEVELOPMENT

VGX-100 Target Product Profile in Oncology

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• Indication:

• Co-administered with anti-angiogenic agent eg (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 SOC and anti-angiogenic agent

• – In the treatment of selected Avastin[®] resistant patients plus SOC

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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

• Possibility for fast track registration based on increased PFS, OS in Phase 2b study when compared to Avastin alone

• Very strong interest from Key Opinion leaders worldwide

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

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VGX-100 OCULAR DEVELOPMENT OPPORTUNITY

Development Opportunity

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• the eye’ disease.

• Initial indications: • Corneal Neovascularisation (CNV)

  • Estimated that up to 4-5% of patients at eye clinics have CNV

• High-Risk Corneal Allograft Rejection

  • 10000 grafts/yr in USA

• Dry Eye Disease

  • Affects 5M people over 50 yrs in USA

  • 1 drug “Restasis” sells >$1B/yr worldwide

  • Preclinical POC data to be published Sept ‘11.

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

• Approx. 12 – 18 months to Phase I/II

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Existing & Supportive Preclinical Data:

VGX-100 improves Corneal Transplant Survival

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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 28

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

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Control VGX-100 Control VGX-100
Blood Vessels Lymphatic Vessels
Area covered by vessel (%) Control VGX-100 Area covered by vessel (%) Control VGX-100
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Day 7 post-transplant

ARVO Annual Meeting 2010. Program#/Poster#1554/D995 29

VGX-100 Promotes Corneal Transplant Survival

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ARVO Annual Meeting 2010. Program#/Poster#1554/D995 30

Corporate Details

STATUS AND UPCOMING VALUE ADDING EVENTS

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Activity	Timeline
VGX-100 First-in-human cancer patients Clinical Study (monotherapy)	Q4 2011
CUP Test Launch	Q1 2012
VGX-100 First-in-human cancer patients Clinical Study (Combination with Avastin/Chemotherapy)	H2 2012
VGX-100 Phase 1 trials complete	Q4 2012
IMC-3C5 Phase 1 trials reported	H1 2013
VGX-100 Phase II studies in cancer patients start (Multiple Indications)	Q1 2013
VGX-100 IND Filing Front of Eye Disease	H2 2013
Clinical proof-of-concept in cancer	32 2H 2014

A strong financial position & shareholder base

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Top 10 shareholders: 55.6%

Investor	% of issued
	shares
Packer and Co Limited	16.66
Licentia Ltd	6.79
Ludwig Institute for Cancer	6.73
Research
Select Asset Management	5.10
Leon Serry	4.53
HSBC Custody Nominees	3.45
(GSCo) (NY Fund)
Chemical Trustee Limited	3.36
&assoc
HSBC Custody Nominees (NY	2.70
Fund)
National Nominees	2.30
CitigroupNominees	2.23
JFF Steven PtyLtd	1.76
Total 10 shareholders own	55.6%
Total 20 shareholders own	63.0%

Financial Summary @ 7 October 2011 (unaudited)

Stock code:	CIR
Share price: Shares issued + deferred issue: Market cap: Cash holdings: Listed investments: (ASX: ANP, OIL)	50c (AUD) 46,396,928 ~ A$23 mill ~ A$20 mill A$2.0M

Cash Burn estimate 2011/12 $10-12m

Institutions/Funds: ~ 43% Retail investors: ~ 30%

Professional investors: ~ 27%

Key Reasons to Invest

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• Clinical Stage Assets

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

• VGX-100 by Q4 2011 in oncology

• VGX-100 by Q1 2013 in eye disease

• Major value adding clinical data from Q3 2012

• Increasing Diagnostics Portfolio generating revenues

• VEGF-D diagnostic on the market for LAM in USA; other territories next 6-12 months

• CUP test likely launch by Healthscope Q4 2011

• VEGF-C and VEGF-D diagnostics in cancer in development

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Key Reasons to Invest

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• A platform with major deal/partnering potential across a range of products over next 3-18 months

• VGX-100 in oncology

• VGX-100 in eye disease

• VEGF-C diagnostics in oncology (Avastin responders)

• VEGF-D diagnostics in oncology

• VEGF-C/D proteins in wound healing, cardiac disease, bone disease

• Investments coming up to major re-rating events

• ANP ATL1103 clinical data in Q4 2011

• OIL culmination of “strategic review” in Q4 2011

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Key Reasons to Invest

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• Re-rating of Value imminent

• Trades at cash backing

• Historical valuation based on LIC history

• Significant mispricing compared to comparables in USA, Europe and Australia

• Drivers: – clinical trial commencement and/or partnerships

• Capability to get to key value adding events

• Approx $22M in cash and investments

• Superb internal and external drug development teams

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Thank You

www.circadian.com.au

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Appendix

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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. 40

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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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 Allograft Rejection:	Corneal Allograft Rejection:
#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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Comparables

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• Market Cap Comparable

• Bioinvent, (Nasdaq OMX Stockholm: BINV SS), has been trading with a market cap in the range of $275 million

• 4 products in either FDA Phase I or II trials including TB-403

• TB-403, at Phase I, is a humanized monoclonal antibody developed to treat solid tumours in combination with Avastin and chemotherapy

• Licensing Comparable

• Astellas Pharma’s $1.3 billion milestone licensing agreement with Aveo Pharmaceutical for a FDA Stage III VEGF antibody for renal cancer

• Bioinvent/Roche Deal on PLGF Ab

• Acquisition Comparable

• Arius Research, a Canadian development stage antibody company, bought by Roche in July 2008 for $189 million

• Portfolio of pre-clinical stage antibody candidates

Competitive Landscape BIOLOGICAL ANTI-ANGIOGENIC AGENTS

Competitive Landscape BIOLOGICAL ANTI-ANGIOGENICAGENTS	Competitive Landscape BIOLOGICAL ANTI-ANGIOGENICAGENTS	Competitive Landscape BIOLOGICAL ANTI-ANGIOGENICAGENTS	Competitive Landscape BIOLOGICAL ANTI-ANGIOGENICAGENTS	Competitive Landscape BIOLOGICAL ANTI-ANGIOGENICAGENTS	Competitive Landscape BIOLOGICAL ANTI-ANGIOGENICAGENTS	Competitive Landscape BIOLOGICAL ANTI-ANGIOGENICAGENTS
Company	Molecule	Target	Partner & Partnering Stage	Clinical Stage	Indication	Relevance To CIR
Regeneron	Aflibercept (VEGF Trap)	VEGF-A PlGF	Sanofi Phase 1	P3	1stand 2ndline CRC 2ndline NSCLC 1stline hormone resistant prostate cancer	Positioned as direct competitor to Avastin, NOT as complementary agent
Regeneron	Aflibercept	VEGF-A PlGF	Bayer Phase1	P3	Wet AMD	CIR agents not for “back of eye” disease
Imclone	IMC-1121b	VEGFR-2	Eli Lilly Phase 1	P3	Breast, HCC	Positioned as direct competitor to Avastin, NOT as complementary agent
Pfizer	CVX-060	Ang-2	N/A	P2	Glioblastoma	Target outside VEGF pathway
Bioinvent	TB-403	PlGF	Roche Pre-clinical	P2	Glioblastoma	Being combined with Avastin
AVEO	AV-299	HGF	Merck (terminated) Pre-clinical	P2	Glioblastoma	Target outside VEGF
Tracon	TRC-105	Endoglin	None	P1	Ovarian	Target outside VEGF
Genentech	MNRP-1685	Neuropilin-1	None	P1	Solid Tumours	Likely to be combined with Avastin
Genentech	MEGF-0444	EGFFL7	None	P1	Solid Tumours	Likely to be combined with Avastin 45

Dominant and protected IP position

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

• Freedom to operate through deals with HGS and Chugai

• IP rights over product candidates extend beyond September 2023

• Further strategic IP filings being made to extend patent life

• Over 500 granted and pending patents worldwide

• Protection through US and European market exclusivity provisions

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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VEGF-C –well recognised survival prognostic factor in a number of tumour types One example

VEGF-C is a risk factor for colorectal cancer

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69 CRC

VEGF-C correlated with:

Low VEGF-C High VEGF-C

• 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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