Opthea Ltd — Investor Presentation 2011

Sep 6, 2011

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Ci rca di an ec T h l i Li i d no og es m te (ASX:CIR , OTCQX:CKDXY) C orpora e resen a t P t ti on September 2011

Robert Klupacs , CEO & Managing Director

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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.

Thi s presentat on i i s not an o ff er or i nv tat on i i f or su b scr pt on or purc i i h ase o f or a recommen d at on o i f secur t es. i i I t d oes 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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Developer of biological therapies targeted to block angiogenesis AND lymphangiogenesis to treat cancer and eye disease

• Novel Vascular Endothelial Growth Factors (VEGF) 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 or as a .

• single agent in eye disease

CORPORATE SNAPSHOT

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Lead Internal Therapeutics program: VGX 100 Fully human, high affinity, 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 may be a predictive biomarker of Avastin[®] resistance in CRC – ASCO 2011

IND Fili Q4 2011 ng

• Glioblastoma and mCRC first indications

• Expanding development to also include treatment of front-of-eye-diseases

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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

• :

• Diagnostics Cancer of Unknown Primaries (CUP) molecular diagnostic  Development partnership with Healthscope  Launch in Asia expected H2 2011

: 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

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VGX-100 - VEGF C I n hibiti on: a R ti ona e l

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

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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 p athwa y s,

"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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VE G F- C i s a m e m be r o f t h e VE G F f a mil t h at b in ds y VEGFR-2 and VEGFR-3

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Angiogenesis ANGIOGENESIS ANGIOGENESIS Monocyte Migration LYMPHANGIOGENESIS Hematopoiesis

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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 g rowth due to factors other than VEGF; and/or

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

• VEGF C i s a lik e y can l did a e me t di a ti ng th e umora t l grow th ‘ escape ’ i n anti-VEGF -resistant tumors.

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

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Circulatin VEGF-C levels are elevated in Avastin[®] /FOLFIRI g 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)“ , 12 J.Clin.Oncol. 29:2011 (suppl; Abstract #3533).

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VEGF-C –well recognised survival prognostic factor in a number of tumour types Some examples

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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. 14

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VGX-100 Efficacy in Mouse M o d e s o l f H uman ancer C

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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
) +/- SE
Burden (mg
Mean Tumor
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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 sin le-a in PC-3 g g ent & combination therap y 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
+/- SE
rden (mg)
n Tumor Bu
Mea
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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
VGX-100
VGX - 100 + Avastin
Docetaxel
Avastin + Docetaxel
VGX-100 + Avastin + Doc etaxel
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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
en (mg) +/- SE
n Tumor Burd
Mea
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VGX-100 reduces metastasis in an orthotopic prostate cancer model

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VGX-100 ONCOLOGY CLINICAL DEVELOPMENT

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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

• Phase I trials expected to commence in USA Q4 2011

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Oncology Milestones Achieved to Date

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• Extensive proof of concept studies in animal models

• GMP manufacturing process & drug product

• Yield > 2g/L

• Stable formulation

• Clinical trial drug made

• GLP toxicology studies in two species completed

• Safe & well-tolerated

• Pre-IND with FDA successful

• Phase I trial sites selected

• Phase 2 indications – Glioblastoma, Colorectal cancer

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Glioblastoma

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• I n th e US i n 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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Metastatic colorectal cancer

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• In the US[1]

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

• Estimated dia g nosed in 2010: 142 , 570

• Estimated fatalities in 2010: 51,370

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

• 39% locali z ed (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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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 Glio-
colorectal cancer cancer cancer blastoma
cancer
Non- Metastatic Phase II Phase II
squamous HER2
Part B
non-small negative
cell
(with (with (with (with (with
Avastin [®] + Avastin [®] , Avastin [®] Avastin [®] Avastin [®] )
FOLFOX) pac lit axe l an d an d
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 Glio-
colorectal cancer cancer cancer blastoma
cancer
Non- Metastatic Phase II Phase II
squamous HER2
Part B
non-small negative
cell
(with (with (with (with (with
Avastin [®] Avastin [®] , Avastin [®] Avastin [®] Avastin [®] )
+ pac lit axe l an d an d
FOLFOX) and carbo.) paclitaxel) interferon
alpha)
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Avastin[®] Registrational Study in Glioblastoma

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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
	IND Filing	Q4 2011
	First-in-human Clinical Study Initiation	Q4 2011
	(monotherapy and in combination)
	Phase I trial complete	Q4 2012
	Phase II studies start (Multiple Indications)	Q1 2013	28
	Clinical proof-of-concept in Glio (Basis for registration?)	2H 2014

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- VGX 100 OCULAR DEVELOPMENT OPPORTUNITY

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

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• Opportunity to leverage VGX-100 oncology program

• Scientific rationale

• Existing supportive preclinical data

• Relationship with Key Opinion Leader

• • Mechanism of Action differentiation from VEGF-A inhibitors

• • D e fi ne d c li n ca en i l d po n s us ng va i t i lid a e t d proce d ures

• Short timeframe to clinical POC

• Large market opportunity (>$1B p.a)

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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)

• 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 d rug “R es as s t i se ll s > $1B/ yr wor ld w id e

  • • 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 Preclin cai l Data:

VGX-100 improves Corneal Trans lant Survival p

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Re j ected corneas are infiltrated b y blood and l y mphatic - - vesse s an l d over-express VEGF C an d VEGFR 3

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Transplanted Corneas: 3 wks Post-Transplant

ACCEPTED REJECTED

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Photomicrographs

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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/D99533

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

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- -
C on ro t l VGX 100 C on ro t l VGX 100
Blood Vessels Lymphatic Vessels
Control VGX-100 Control VGX-100
l (%) l (%)
e e
overed by vess overed by vess
c c
Area Area
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Day 7 post-transplant

ARVO Annual Meeting 2010. Program#/Poster#1554/D99534

- VGX 100 P romo es ornea t C l T ransp an l t S urv va i l

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ARVO Annual Meeting 2010. Program#/Poster#1554/D99535

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Current Activities and Value Adding Events

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	ACTIVITY TIMELINE Further efficacy data in preclinical CNV & Corneal 4Q’11 – 2H’12	ACTIVITY TIMELINE Further efficacy data in preclinical CNV & Corneal 4Q’11 – 2H’12	ACTIVITY TIMELINE Further efficacy data in preclinical CNV & Corneal 4Q’11 – 2H’12
	ACTIVITY	TIMELINE
	Further efficacy data in preclinical CNV & Corneal	4Q’11 – 2H’12
	Transplant & Dry Eye models
	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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C orpora e e a t D t il s

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A s rong nanc a pos t fi i l iti on & s h are h o ld er ase b

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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 Fund)	2.70
National Nominees	2.30
CitigroupNominees	2.23
JFF Steven Pty Ltd	1 76 .
Total 10 shareholders own	55.6%
Total 20 shareholders own	63.0%

Financial ummary S @ 30 August 2011 (unaudited)

Stock code:	CIR
Share price: Shares issued + deferred issue:	60c (AUD) 46,396,928
Market cap: Cash holdings: Listed investments: (ASX: ANP, OIL)	~ A$27 mill ~ A$21 mill A$2.0M

Cash Burn estimate 2011/12 $10-12m Institutions/Funds: ~ 43% Retail investors: ~ 30% Professional investors: ~ 27%

K ey eve opmen D l t Mil es ones t

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	A i i ct v ty	Ti li me ne
	CUP Test Launch	H2 2011
	VGX-100 publication of results in dry eye disease	Q3 2011
	VGX-100 IND Filing	Q4 2011
	VGX-100 First-in-human cancer patients Clinical Study commenced	Q4 2011
	VGX-100 & Avastin Phase 1 trials commenced	Q2 2012
	VGX-100 Phase 1 studies completed	H2 2012
	IMC-3C5 Phase 1 trials reported	H1 2013
	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	2H 2014

K R t I t ey easons o nves

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• Clin cai l Stage sseA ts

• 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 currently in development

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K R t I t ey easons o nves

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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

• 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

• “ ”

• – OIL culmination of strategic review

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K R t I t ey easons o nves

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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 – A pp rox $ 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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