Opthea Ltd — Investor Presentation 2013

Jun 3, 2013

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ASX and Media release

4 June 2013

VGX-100 Phase 1 oncology clinical trial in progress presented at ASCO 2013 Annual Meeting

Circadian Technologies Limited (ASX: CIR, OTCQX:CKDXY), through its 100% owned subsidiary Ceres Oncology Pty Ltd, reported overnight the study design and progress of the phase 1 clinical trial in advanced cancer patients of its anti-VEGF-C monoclonal antibody, VGX-100 at the 49[th] Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

Gerald Falchook, M.D., Assistant Professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, and a principal investigator on the study presented "Phase I study of VGX-100, an anti-VEGF-C monoclonal antibody, with or without bevacizumab, in patients with advanced solid tumours.” in the “Trials in Progress” Developmental Therapeutics - Clinical Pharmacology and Experimental Therapeutics Poster Session (Abstract TPS2619, Monday, June 3).

The Trials in Progress Session at ASCO highlights the transition of emerging biologic pathways and new agents into the clinic - providing "coming attractions" for oncologists in clinical practice.

Dr Falchook presented a scientific background / rationale for VGX-100 in oncology together with an overview of the accelerated Phase 1a / 1b trial design and an interim clinical update. The Phase 1 clinical trial is being conducted under an Investigational New Drug (IND) application (ClinTrials.gov study # NCT01514123) at two clinical sites in the USA in patients with advanced or metastatic solid tumours. The study has an accelerated two arm dose escalation design consisting of Arm A: VGX-100 mono-therapy and Arm B: VGX-100 in combination with bevacizumab (Avastin®). The objectives of the clinical trial are to establish the safety and toxicity, pharmacokinetic and biomarker profiles, as well as preliminary anti-tumour activity of VGX-100 in refractory patients. To date more than 35 patients have received weekly VGX-100 at doses ranging from 1 to 30 mg/kg.

Key updates presented included the following:

• Arm A cohorts A1 to A5, of single agent VGX-100 at weekly doses up to 20 mg/kg have completed accrual without any investigator reported Dose Limiting Toxicities (DLTs). In addition, Arm B cohorts B1 to B4, of VGX-100 at weekly doses of 2.5, 5 or 10 mg/kg in combination with bevacizumab given every 2 weeks at doses of 5 or 10 mg/kg have completed accrual with one reported protocol specified DLT in the lowest dose level cohort B1.

• The combination of inhibiting the VEGF-A and VEGF-C signalling pathways with VGX-100 + bevacizumab appears promising.

• Patient accrual for remaining cohorts A6 (single agent VGX-100 at weekly doses of 30 mg/kg) and B5 (combination of VGX-100 at weekly doses of 20 mg/kg + bevacizumab 10 mg/kg every 2 weeks) are near completion.

A copy of the ASCO poster presentation is attached in the Appendix.

Company enquiries Media enquiries – international Robert Klupacs Lauren Glaser CEO & Managing Director – The Trout Group LLC Circadian 251 Post Street, Suite 412 Tel: +61 (0) 3 9826 0399 or San Francisco, CA 94108 robert.klupacs@circadian.com.au 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 Ceres Oncology Pty Ltd

Ceres Oncology Pty Ltd is a 100% owned subsidiary of Circadian Technologies Limited based in Melbourne, Australia. Ceres is developing VGX-100, which is a fully human monoclonal antibody that specifically and potently blocks the activity of vascular endothelial growth factor C (VEGF-C) which is involved in tumour angiogenesis (blood vessel growth), lymphangiogenesis (lymphatic vessel growth) and vascular leakage. By targeting and inhibiting the effects of VEGF-C, VGX-100 may have a broad utility in a range of oncology related disease states characterised by aberrant blood and/or lymphatic vessel growth, vascular leakage or edema, and/or inflammation, including solid tumours and lymphedema.

About Circadian Technologies Limited

Circadian (ASX:CIR; OTCQX:CKDXY)) is a biologics drug developer focusing on cancer, cancer related and ophthalmic disease therapies. It controls exclusive worldwide rights to a significant intellectual property portfolio around Vascular Endothelial Growth Factor (VEGF)-C and –D and VEGFR-3. 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 primarily focused on developing VGX-100 (a human antibody against VEGF-C) as a treatment for lymphedema resulting from breast cancer treatment and solid tumours, in particular glioblastoma and colorectal cancer through its subsidiary Ceres Oncology, as well as developing VGX-300 (soluble VEGFR-3) for ‘back of the eye’ disease such as “wet” Age Related Macular Degeneration through its subsidiary Opthea. 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 anti-lymphatic antibody-based drug IMC-3C5 targeting VEGFR-3.

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 statements

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 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 endeavour 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

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Abstract #TPS2619

Phase 1 Study of VGX-100, an anti-VEGF-C monoclonal antibody, with or without Bevacizumab in Patients with Advanced Solid Tumors G.S Falchook[1] , J. Desai[2] , I.M. Leitch[3] , J.W.Goldman[4] , J.J. Wheler[1] , S. Fu[1] , R. Kurzrok[1] , M.E. Baldwin[3] , L.S. Rosen[4 ] 1University of Texas MD Anderson Cancer Center, Houston, TX; 2Royal Melbourne Hospital, Melbourne, Australia; 3Ceres Oncology Pty Ltd, Melbourne, Australia; 4UCLA Hematology-Oncology, Santa Monica, CA PHASE 1 STUDY DESIGN

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INTRODUCTION / BACKGROUND

• VGX-100 is an investigational, novel fully human IgG1λ neutralizing monoclonal antibody that selectively targets vascular endothelial growth factor C (VEGF-C), inhibiting its signaling through VEGFR-2 & VEGFR-3 receptor pathways.

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Efficacy of VGX-100 alone or in combination with anti-angiogenic agents +/-
chemotherapy in murine models of cancer
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U87MG Glioblastoma Colo205 Colorectal
VGX-100 + bevacizumab (anti-VEGF-A) VGX-100 + TKI’s
• VGX-100 has the potential to inhibit not only primary tumor growth through its anti-
Negative Isotype Control
VGX-100
angiogenic and anti-lymphangiogenic activities, but to also inhibit metastasis via the
Bev
lymphatic vessels. Lymphatic metastasis is associated with poor prognosis that is
VGX-100 + bev
not effectively blocked by anti-VEGF-A or anti-VEGFR-2 therapeutics.
. Get similar data with VGX-100 +
VGX-100 Inhibition of VEGF-C Signaling In Tumors
sorafenib or sunitinib
VGX-100
Metastatic PC3 prostate cancer model
VEGF-B VEGF-C OVCAR-8 Ovarian Cancer VGX-100 single agent
VGX-100 + bevacizumab & docetaxel
PIGF
VEGF-A VEGF-D
Isotype Control
Docetaxel
Bev+docetaxel
VGX-100 + bev+ docetaxel
In several murine models of human cancer, VGX 100 enhanced the efficacy of :
(1) standard chemotherapy and/or bevacizumab (in U87 glioblastoma & OVCAR-8 ovarian xenograft tumors), and
(2) small molecule TKIs including pazopanib, sorafenib and sunitinib (in Colo205 colorectal xenograft tumors). [8-9]
In addition, VGX-100 monotherapy reduced lymph node metastasis in an orthotopic PC3 prostate tumor model. [[7]]
VEGF C is a member of the VEGF family of secreted glycoproteins that are critical mediators of
angiogenesis and lymphangiogenesis. VEGF C induces angiogenesis via activation of both VEGFR-2 and
•
VEGFR-3, and lymphangiogenesis via activation of VEGFR -3. VGX-100 is a fully human neutralizing
The combination of VGX-100 with bevacizumab may result in synergistic
monoclonal antibody directed against human VEGF C.
antitumor effects by targeting multiple VEGF signaling pathways that mediate
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• VGX-100 has the potential to inhibit not only primary tumor growth through its antiangiogenic and anti-lymphangiogenic activities, but to also inhibit metastasis via the lymphatic vessels. Lymphatic metastasis is associated with poor prognosis that is not effectively blocked by anti-VEGF-A or anti-VEGFR-2 therapeutics.

In addition, VGX-100 monotherapy reduced lymph node metastasis in an orthotopic PC3 prostate tumor model.[[7]] • The combination of VGX-100 with bevacizumab may result in synergistic antitumor effects by targeting multiple VEGF signaling pathways that mediate

tumor angiogenesis and lymphangiogenesis.

• Over-expression of VEGF-C has been shown in human tumors, including cancers of the colon, stomach, breast, ovary and prostate. Elevated levels of intra-tumoral and circulating VEGF-C often correlate with poor outcomes and features associated with tumor aggression (e.g. tumor depth, size, lymphatic invasion and lymph node metastasis).[1-4 ]

• Here we describe the ongoing first-in-human, Phase I clinical study design of the anti-VEGF-C human monoclonal antibody VGX-100 administered alone and in combination with bevacizumab in adult patients with advanced or metastatic solid tumors.

• Tumoral escape and relapse following VEGF-A inhibition with bevacizumab (a humanized monoclonal antibody that binds to and inhibits the biologic activity of human VEGF-A), may in part be due to increased VEGF-C that signals through VEGFR-2 and VEGFR-3.[5-6 ]

PHASE 1 STUDY OBJECTIVES

Primary Objectives

• To evaluate the safety and establish the recommended dose of VGX-100 alone and in combination with bevacizumab.

• Previous published results in several mouse xenograft models of human cancer with VGX-100 have demonstrated efficacy when used as a monotherapy and in combination with approved cancer therapeutics.

Secondary Objectives

• To assess: o the pharmacokinetic profile of VGX-100 alone and co-administered with bevacizumab

• In an orthotopic PC3 prostate cancer model, single agent VGX-100 effectively reduced lymph node metastasis.[7 ]

• the incidence of anti-VGX-100 antibody formation

• In addition, enhanced efficacy has been demonstrated pre-clinically in models of human xenograft tumor growth using: o VGX-100 in combination with bevacizumab (Avastin[®] ) and/or standard chemotherapy.[8 ]

• o VGX-100 in combination with pazopanib, sorafenib or sunitinib which are small molecule tyrosine kinase inhibitors (TKIs) of the receptors for VEGF ligands.[9]

• potential biomarkers of VGX-100 alone and co-administered with

• bevacizumab

• o preliminary tumor response to VGX-100 alone and co-administered with

• bevacizumab

Study Design

• Ongoing, open label, phase 1a / 1b dose escalation study (NCT01514123)

with a standard “3+3” design.

• The study has an accelerated two arm design:

• Arm A: VGX-100 mono-therapy

• Arm B: VGX-100 in combination with bevacizumab

Phase 1 Study Schema

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A6
VGX-100
30 mg/kg, QW
Arm A:
A5
VGX-100 (QW) single agent
Dose escalation
Bev + VGX-100
VGX-100
10 + 20 mg/kg
20 mg/kg
A4
B5
Bev + VGX-100
VGX-100
10 + 10 mg/kg
10 mg/kg
A3
B4
Bev + VGX-100
VGX-100
10 + 5 mg/kg
5 mg/kg
A2
B3
Bev + VGX-100
VGX-100
10 + 2.5 mg/kg
2.5 mg/kg
Arm B:
A1 B2
VGX-100 (QW) + Bevacizumab (Q2W)
Bev + VGX-100 Dose escalation
VGX-100
5 + 2.5 mg/kg
1 mg/kg
B1
• Dose escalation occurs if none of the initial 3 patients enrolled experience dose-
limiting toxicities (DLTs) per protocol definition during the first 28 days of the study.
• 28 day DLT / safety data from Arm A will be available prior to starting the equivalent
dose level in Arm B.
• Arm A (VGX-100 mono-therapy)
o
28 day treatment cycle of 4 administrations of VGX 100 by IV infusion at D1,
D8, D15 & D22.
• Arm B (VGX-100 plus bevacizumab)
o
At each administration, treatment with bevacizumab will be administered first,
followed by VGX-100. For each subject, the 28 day treatment cycle will consist
of:
•
Screening
Enrolment
DLT window 28 d
Safety Follow Up Visit / End of Study
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Two administrations of bevacizumab, IV infusion at D1 and D15.

Four administrations of VGX 100, given as an IV infusion over approximately 60 minutes 7 days apart at D1, D8, D15 and D22.

•

• Patients received treatment until disease progression or intolerable toxicity.

• The safety follow-up period was 28 days after the last dose.

Key Eligibility Criteria

• Adult (≥ 18 years) patients with advanced solid tumors refractory to standard treatment or for which no curative therapy is available.

• Adequate hematologic, renal and hepatic function.

• • Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 and life expectancy > 3 months.

• • Evaluable OR measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

• • Patients are excluded with central nervous system or cerebrovascular haemorrhage, myocardial infarction or reversible posterior leukoencephalopathy syndrome associated with prior anti-VEGF/anti-VEGFR therapy.

Endpoints Primary endpoint:

• Safety will be assessed by incidence and severity of adverse events (including

DLTs) and clinically significant changes in vitals, EKGs and clinical lab tests. • The recommended dose of VGX-100 alone and in combination with bevacizumab will be determined by the observed safety profile and incidence of DLTs during the 28 day DLT period from Arm A and Arm B, respectively.

Secondary endpoints:

• Serum concentrations of VGX 100 and bevacizumab including Cmax, Cmin AUC, and half life (t1/2).

• The development of serum anti-VGX-100 antibodies

• Selected biomarkers including VEGF-A, VEGF-C, VEGF-D, sVEGFR-2, and sVEGFR-3, will be determined from serum and other tissue samples.

• • .

• Tumor response measured by CT or MRI and using RECIST 1.1 criteria

• PHASE 1 INTERIM STATUS

• Cohorts A1 to A5 of VGX-100 alone and cohorts B1 to B4 of VGX-100 in

. combination with bevacizumab have completed accrual

•	Cohorts A1 to A5 of VGX-100 alone and cohorts B1 to B4 of VGX-100 in combination with bevacizumab have completed accrual.
	Patient Disposition
Cohort Patients Enrolled & Receiving VGX-100 N Arm A: VGX-100 Single agent (A1)VGX-100: 1 mg/kg,QW 4a (A2)VGX-100: 2.5 mg/kg,QW 3 (A3)VGX-100: 5 mg/kg,QW 3 (A4)VGX-100: 10 mg/kg,QW 3 (A5)VGX-100: 20 mg/kg,QW 3 Arm B: Bevacizumab + VGX-100 (B1)Bev: 5 mg/kg,Q2W + VGX-100: 2.5 mg/kg,QW 6 (B2)Bev: 10 mg/kg,Q2W + VGX-100: 2.5 mg/kg,QW 3 (B3)Bev: 10 mg/kg,Q2W + VGX-100: 5 mg/kg,QW 6 (B4)Bev: 10 mg/kg,Q2W + VGX-100: 10 mg/kg,QW 3 Accrual has completed in cohorts A1-A5 and B1-B4.aOne patient in cohort A1 withdrew consent @ Day 18 after 2 doses of VGX-100 and was replaced per protocol. Cohort B3 was expanded to 6 patients to get more data at this dose level.

SUMMARY

• Cohorts A1 to A5 of VGX-100 at weekly doses up to 20 mg/kg alone have completed accrual without any DLTs. In addition, cohorts B1 to B4 of VGX-100 at weekly doses of 2.5, 5 or 10 mg/kg in combination with bevacizumab given every 2 weeks at doses of 5 or 10 mg/kg have completed with 1 DLT observed in cohort B1. • The combination of inhibiting the VEGF-A and VEGF-C signaling pathways with VGX-100 + bevacizumab appears promising.

• Patient accrual for remaining cohorts A6 and B5 is near completion and further evaluation of VGX-100 alone or in combination with bevacizumab is on-going.

References

1. Joukov, EMBO J, 15, 290, 1996 5. Shojaei, F. et al., Nat Biotech., 25(8):911-20, 2007. 2. Adams and Alitalo, Cell Biol, 8, 464. 2007. 6. Lieu, C. et al., J Clin Oncol 29: (suppl; abstr 3533) 2011. 3. Jubb, A. et al., Clin Can Res., 17(2):372-81, 2011 7. Baldwin et al., AACR (Abstract # LB-284), 2011. 4. Li, X. et al., J Gastrointest Surg 15, 2011. 8. Tester et al., AACR (Abstract # 2442), 2010. 5. Grau, S. et al., J Neuro-Oncol., Aug, 103-112, 2011. 9. Tester et al, EORTC (Abstract #36), 2012.