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ASX and Media release
7 May 2015
OPT-302 DATA PRESENTED AT TWO MAJOR OPHTHALMOLOGY
CONFERENCES
Circadian Technologies Limited (ASX:CIR, OTCQX:CKDXY) reports that Dr Kameran Lashkari of
Schepens Eye Research Institute/Massachusetts Eye & Ear at Harvard Medical School presented
preclinical data overnight at the annual ARVO conference in Denver demonstrating efficacy with
Circadian’s targeted therapy OPT-302 (VGX-300). The data demonstrates OPT-302 reduced blood
vessel growth and vessel leakage in a mouse model of wet age-related macular degeneration (AMD),
either as monotherapy or in combination with the VEGF-A inhibitor aflibercept (Eylea®).
The podium presentation entitled “VGX-300, a ‘Trap’ for VEGF-C and VEGF-D, inhibits choroidal
neovascularization and vascular leakage in a mouse model of Wet AMD” was part of the AMD Novel
Therapies session. The presentation focussed on preclinical data that underpinned the Company’s
decision to progress its lead molecule OPT-302 into the clinic for the treatment of wet AMD.
The Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO) is the
largest gathering of eye and vision researchers in the world, attracting over 11,000 attendees from
more than 75 countries.
Wet AMD is the leading cause of blindness in developed countries in individuals over the age of 50.
Circadian is developing its lead clinical product candidate OPT-302 and remains on-track to initiate a
Phase 1 clinical study under an IND at US clinical sites in the first half of 2015.
A copy of the presentation is available at www.circadian.com.au and www.opthea.com.
Dr Lashkari will also present preclinical data describing the activity of OPT-302 in a poster presentation
at the 33rd Annual Meeting of the American Society of Retina Specialists (ASRS) to be held 11-14 July
in Vienna.
Company and media enquiries
Megan Baldwin, PhD
CEO & Managing Director
Circadian Technologies
Tel: +61 (0) 3 9826 0399 or
[email protected]
Rudi Michelson
Monsoon Communications
Tel: +61 (0) 3 9620 3333
Join our email database to
receive program updates:
Tel: +61 (0) 3 9826 0399
[email protected]
www.circadian.com.au
About Circadian Technologies Limited
Circadian (ASX:CIR; OTCQX:CKDXY) is a biologics drug developer focusing on ophthalmic disease 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 primarily focused on
developing OPT-302 (formerly VGX-300, soluble VEGFR-3) for ‘back of the eye’ disease such as wet age-related
macular degeneration (wet AMD). 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.
About Wet AMD
Wet (neovascular) age-related macular degeneration, or wet AMD, is a disease characterised by the loss of vision in
the middle of the visual field caused by degeneration of the central portion of the retina (the macula). Abnormal growth
of blood vessels below the retina, and the leakage of fluid and protein from the vessels, causes retinal degeneration
and leads to severe and rapid loss of vision.
Wet AMD typically affects individuals aged 50 years or older, and is the leading cause of blindness in the developed
world. The prevalence of AMD is increasing annually as the population ages. Sales of the drug Lucentis®
(Roche/Novartis), which targets VEGF-A but not VEGF-C, were over $US4BN in 2014. Sales of EYLEA™
(Regeneron/Bayer), which also targets VEGF-A but not VEGF-C first marketed in November 2011 for the treatment of
wet AMD, were over $US1.8BN in 2014. Approximately half of the people receiving Lucentis ®/Eylea® are classified as
non-responders or ‘poor’ responders and experience no significant gain in vision and/or have persistent retinal vascular
leakage. There is great opportunity to improve patient responses by targeting more than one factor involved in disease
progression. Existing therapies, such as Lucentis ®/Eylea®, target VEGF-A that promotes blood vessel growth and
leakage through its receptor VEGFR-2. VEGF-C can also induce angiogenesis and vessel leakage through the same
receptor. Combined inhibition of VEGF-A and VEGF-C, has the potential to improve patient response by more effective
inhibition of the pathways involved in disease progression.
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.
Suite 0403 Level 4, 650 Chapel Street, South Yarra, Victoria 3141 Australia T +61 (3) 9826 0399 F +61 (3) 9824 0083
www.circadian.com.au ABN 32 006 340 567
VGX-300: a ‘Trap’ for VEGF-C and VEGF-D
Inhibits Choroidal Neovascularization in a
Mouse Model of Wet AMD
Kameran Lashkari, M.D.
Schepens Eye Research Institute
Mass Eye & Ear, HMS, Boston, MA
Co-authors: Jie Ma 1, Yu Sun, 1, Gianna Teague 1, Megan E Baldwin 2
1.
2.
Schepens Eye Research Institute, Mass Eye & Ear, Boston, MA
Circadian Technologies Ltd, Opthea Pty Ltd, South Yarra, Victoria, Australia
Financial Disclosures
Kameran Lashkari, M.D.: F (Financial Support from Opthea Pty Ltd, Victoria, Australia;
P (Patent Application –Schepens Eye Research Institute /Mass Eye & Ear & Opthea
Ltd); S (Scientific Advisory Committee, Opthea Ltd)
Jie MA, Ph.D., P (Patent Application –Schepens Eye Research Institute/Mass Eye & Ear
& Opthea Ltd)
Yu Sun, M.S., N (No financial disclosure)
Gianna Teague, B.A., N (No financial disclosure)
Megan E Baldwin, Ph.D., E (CEO, Opthea Pty Ltd), P (Patent Application –Schepens Eye
Research Institute/Mass Eye & Ear & Opthea Pty Ltd)
Resistance to anti-VEGF-A monotherapy
•
At least 45% of subjects with wet AMD
exhibit some degree of resistance to antiVEGF-A monotherapy
– Sub-optimal improvements in VA (<15-line gain)
– Persistent fluid on OCT
• Resistance to VEGF-A monotherapy may
be related to other proangiogenic factors
such as VEGF-C and VEGF-D
• VEGF-C and VEGF-D can bind and activate
VEGFR-2 and VEGFR-3 receptors
• Complete blockade of VEGFR-2 requires
blockade of all ligands
• VEGFR-3 also stimulates angiogenesis via a
VEGF-A independent pathway
VEGF-A
VEGF-C and VEGF-D
• Critical mediators of angiogenesis and vascular permeability
– via independent & overlapping pathways with VEGF-A
• VEGF-C and VEGF-D are not blocked by existing therapies
• Sub-responsiveness to anti-VEGF-A therapy is associated with
up-regulation of VEGF-C and VEGF-D expression
– Signaling through VEGFR-2 can occur by VEGF-C and VEGF-D even in the
presence of a VEGF-A inhibitor
– VEGFR-3 mediated activities are not blocked by VEGF-A inhibitors
VEGF-C can stimulate angiogenesis and vascular permeability
VEGF-C is required for retinal vascular development
Tammela et al., Nature Cell Biology, 2011.
VEGF-C is a potent inducer of vascular leakage
Cao et al,. Circ Res., 2004
VEGF-C can stimulate angiogenesis via VEGFR-3:
A VEGF-A independent pathway
VEGFR-3 +/+
VEGF-A
VEGFR-3 -/VEGF-A
VEGF-C
VEGFR-1 VEGFR-2 VEGFR-3
VEGF-C
VEGFR-1 VEGFR-2 VEGFR-3
Abnormal vasculogenesis & hematopoiesis
Hamada et al. Blood 2000, 96:3799
VEGF-C can stimulate angiogenesis via VEGFR-2 and VEGFR-3
Additive effects of complete VEGFR-2 & VEGFR-3 inhibition
Tammela et al. Nature., 2008
VGX-300: A ‘Trap’ for VEGF-C and VEGF-D
• VGX-300 (OPT-302): soluble form of VEGFR-3
• Consists of first three extracellular domains of VEGFR-3 joined to hIgG1 Fc
• Potent inhibitor of VEGF-C and VEGF-D (<nM)
ELISA
VEGFR-2 Bioassay
VGX-300: Mouse laser-induced CNV
Laser perforates Bruch’s membrane
•
VGX-300 Aflibercept
IgG
Vascular leakage of the retina
(angiography and flourescent tracer – RHS)
“The mouse model of laser-induced choroidal
neovascularization (CNV) has been used
extensively in studies of AMD … and has
served as the backbone for testing antiantigenic therapies” … Lambert et al. (2013)
Comparable activity of VGX-300 & aflibercept in mouse AMD
Laser Injury & IVT on day 0; FA on day 14
Reduction of vascular leakage
Reduction of CNV lesion area
CNV Area (x103 uM2)
Fluorescence (x103 AU)
** P < 0.05
IgG
Aflibercept
VGX-300
IgG
Aflibercept
VGX-300
Established mouse AMD lesions regress and have less leakage
following treatment with VGX-300
Laser Injury on day 0; FA on day 7 & 14
Treatment day 7
IgG Isotype
Aflibercept
VGX-300
*
*
*
*
Significant additive activity of VGX-300 + aflibercept in mouse AMD
*, ** P < 0.05
**
*
*
*
CNV Area X 103 μM2 ± SE
Combined inhibition of VEGF-A (Aflibercept), VEGF-C and VEGF-D
(VGX-300/OPT-302) is more effective than inhibition of VEGF-A alone
600
70%
78%
91%
400
200
*
* Pairwise comparison VGX-300 vs Aflibercept + VGX-300 (p<0.02)
Aflibercept vs Aflibercept + VGX-300 (p<0.05)
Expression of VEGF-C and VEGFR-3 after laser injury
F
IgG
VEGF-A
VEGF-C
VEGF-D
VEGFR-2
VEGFR-3
CD11b
MFG-E8
MCP-1
TNF-α
IL-1β
IP-10
Normalized mRNA Expression
Effect of VGX-300 on expression of biomarkers after laser injury
100
50
0
Summary
• VEGF-C and VEGF-D bind and activate VEGFR-2 and VEGFR-3 and
stimulate angiogenesis through both receptors
• VEGF-C is a potent inducer of vascular permeability. Persistent
leakage/fluid on OCT may be more effectively managed by
combined VEGF-A/VEGF-C inhibition
• VGX-300 was effective in inhibiting laser-induced CNV and vascular
leakage to a comparable extent as aflibercept (Eylea)
• Combination of VGX-300 and aflibercept demonstrated superior
inhibition compare to either agent alone
• Treatment with VGX-300 alone or in combination with other antiVEGF-A agents may be an effective wet AMD therapy, particularly in
clinically resistant cases of wet AMD