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Anp1204elixir211.doc
I N V E S T M E N T INTERSUISSE R E S E A R C H Antisense Therapeutics Ltd
(ASX CODE: ANP) www.antisense.com.auDecember 2004 www.elixir-secs.com Victoria-based Antisense Therapeutics is one of the leading players in the discovery and development of second-generation antisense therapeutics. It has an important 5-year collaboration with the leading antisense company, Isis Pharmaceuticals. This collaboration has given the company access to Isis' proprietary drug discovery technology and intellectual property.
Antisense Therapeutics has begun a Phase IIa clinical
study in multiple sclerosis on its most advanced drug
candidate (ATL 1102). This drug targets VLA-4, a
VALUATION
strategy that may be validated by the FDA approval of
Antegren, a monoclonal antibody that inhibits a sub-set
of VLA-4 receptors. A second molecule has recently
EPS (Cents)
entered proof-of-concept clinical trials in patients for the
EV/EBITDA
The financial markets' image of antisense-based
Elixir FCF
therapeutics has been tarnished by a number of recent
high profile clinical trial disappointments (Affinitak,
Genasense). Despite addressing many of the failings of
the first generation molecules with a series of
EPS (Cents)
improvements in the second generation, we doubt that
the market is sufficiently well informed to discriminate
EV/EBITDA
between the two. Consequently, the financial markets are
Elixir FCF
unlikely to give the technology credit until it sees positive
Clearly the most telling impact on the valuation will be the
clinical trial results of the company's own products,
EPS (Cents)
however it may also benefit from positive clinical
progress of Isis' own second generation molecules.
EV/EBITDA
Furthermore, the company will also have to compete with
Elixir FCF
emerging competition in the field of RNA interference
(RNAi). The prospect of RNA based therapeutics has
already generated a great deal of interest (and drawn
52-Week High
parallels with antisense), but the technology still faces
52-Week Low
similar technological challenges to those faced by
Percentage Change 1yr Percentage Change YTD Percentage Change 6m
In the absence of clinical trial results and meaningful
Percentage Change 3m Relative Index
revenues, the market is likely to focus on the cash
1Yr Rel. Performance
position of the company: As of June 2004 it had
3mo Rel. Performance
AU$14.4m. At the current estimated rate of cash burn,
6mo Rel. Performance
there is a strong possibility that the company will need to return to the market in the near future if it is to move forward with its 3 development projects as planned.
Elixir Securities Ltd is an independent investment research company specialising in the biopharmaceutical sector and regulated by the Financial Services Authority in the United Kingdom. In November 2004, Elixir and Intersuisse Limited co-hosted the first Australian Life Sciences Forum in London, presenting ten leading Australian Life Sciences companies. Elixir was commissioned by Antisense Therapeutics to prepare this report for which it received a fee.
_________________________________________________________________________________________________________________________
Melbourne - Level 7, 530 Collins Street, Melbourne, Vic, Australia 3000
ASX Market Participant. AFS Licence 246827
Telephone: (+613) 9629 8288 Facsimile (+613) 9629 8882
Sydney - Level 7, 5 Elizabeth Street, Sydney, NSW, Australia 2000
Telephone: (+612) 92332100 Facsimile (+612) 9233 2117
Antisense Therapeutics (ASX: ANP) is a drug discovery
The company has a sensible strategy for the
and development company that focuses on the creation,
development of antisense therapeutics. It has and
development and commercialisation of novel antisense
intends to gain access to leading antisense technologies
therapeutics. It was founded on a strategic collaboration
by partnering with key leaders in the field. It is seeking to
with Isis Pharmaceuticals. Nasdaq listed and Californian
develop therapeutics in markets that are largely and
based Isis Pharmaceuticals Inc is a world leader in the
poorly served by current therapeutics. It conducts its pre-
field of antisense drug discovery and development.
clinical early stage clinical research through seasoned
Antisense Therapeutics listed on the Australian Stock
third party contractors. Like many biotechnology
Exchange in December 2001, raising AU$13m in the
companies in a similar fi nancial situation, it intends to
partner its products to larger pharmaceutical companies.
Antisense Therapeutics has access to a broad range of
Antisense Therapeutics plans to license certain of its
intellectual property through its strategic partnership with
products at an early stage of development to generate
Isis Pharmaceuticals. Isis has granted Antisense
income progress other projects into later stage clinical
Therapeutics rights to use Isis technology to
development. When commercialised, Antisense
commercialise antisense drugs to a number of drug
Therapeutics' drugs will compete head-on with a number
targets. This partnership provides Antisense
of conventional drugs, biologics and other nucleic acid
Therapeutics the opportunity to create and progress a
portfolio of second generation (MOE) antisense drugs in its development pipeline.
Table 2: Key inflexions
The company has several antisense drug development projects at various stages of completion. The two most
advanced of these are potential drugs against multiple
sclerosis (ATL1102) and psoriasis (ATL1101), two
ATL1101 Psoriasis cream trials commenced
conditions for which there are large, unmet needs for
Key Shareholders Source: Company, Elixir Securities
Its key shareholders include PolyChip Pharmaceuticals (20.4%, a 100% subsidiary of Circadian Technologies
Limited - a leading Australian biotechnology commercilisation firm), Syngene (15.3%, of which
Antisense Therapeutics has sufficient cash to cover its
Circadian controls 42%), Isis Pharmaceuticals (11.4%)
current projected outflows until the middle of 2005. At 30
and Queensland Investment Corporation (4.5%).
June 2004 it had cash reserves of AU$14.4m.
Syngene is focused on commerically exploiting
During the financial year 2004, Antisense raised
inventions and patents in the area of hybridisation
AU$10.4m through the issue of new shares, of which
histochemistry (DNA therapeutics and diagnostics).
AU$5m was raised in a private share placement to
Polychip is controlled by Circadian, a listed vehicle on the
Australian institutions and professional investors. The
Australian Stock Exchange that provides management
balance of AU$5.4m was raised through an issue of
and funding for the development and commercialisation
41.5m shares to eligible shareholders at AU$0.13 per
of Australian biomedical research which includes
share, pursuant to the Company's Share Purchase Plan.
maintaining its own research and development programmes.
In October 2004 the company announced that it had accepted a proposal from the Bank of New York to
In addition to private and institutional investors, Antisense
establish a Level 1 American Depository Receipt
Therapeutics has received funding from Australian
program. The aim of the ADR programme is to promote
Government programmes (Start Grant and R&D tax
diversity in the shareholder base and give access to a far
concession). The company operates on a virtual
larger capital market, with the prospect of increasing
infras tructure principal which minimises overheads. It out-
sources much of the discovery and development work to experienced third party contractors. Whilst we consider
We estimate that Antisense Therapeutics' current burn
this structure appropriate for a drug discovery company
rate is some AU$10.5m per annum, approximately the
with limited funds, the discovery and development
same amount as its estimated cash reserve of around
programmes are exposed to third-party risks.
AU$11m. Therefore, it is highly probable that Antisense will need to raise more funds in the near future. Further
Table 1: Key Shareholders
capital will be required to accelerate current programmes and exploit new opportunities, as and when they arise.
%Holding
Consequently, investors should expect considerable
differences between forecast cash outflows and actual
results. However, the volatility created by material
differences in the financial results is likely to be less
important than that caused by the progress of its clinical
trial programmes. Although it is possible that milestone payments and other one-offs will push the company
towards breakeven in 2006, Antisense Therapeutics is
likely to reinvest these revenues into the future
development of the pipeline. Consequently, sustainable more predictable profitability may not occur until
significant royalty income flows in. We would expect
Drawbacks of Antisense
sustainable profitability late in the decade, when
The development of antisense therapeutics has been
Antisense Therapeutics' first molecule is expected to be
dogged by several concerns; particularly the efficient
delivery of the antisense therapeutic and the presence of
Phosphorothioate oligonulcleotides can, in certain
Antisense Therapeutics licensed ISIS 107248 (it is now
cirucumstances, induce immune system elevations and
known as ATL1102; a second generation antisense
other effects that are not associated with the mRNA the
inhibitor of VLA-4 in development for MS), from Isis
antisense is designed to knock out. In certain
before the company was listed. In addition to the
circumstances, these ancilliary effects may be beneficial
licensing agreement, Antisense Therapeutics and Isis
- such as in the case of Vitravene which exhibits
have a five-year antisense drug discovery and
antisense and non-antisense effects. Isis has spent a
development collaboration that gives Antisense
considerable amount of money (estimated at US$1bn) on
Therapeutics access to Isis' proprietary antisense
the development of antisense oligonucleotides. It
intellectual property. Antisense Therapeutics pays Isis for
believes that its second generation molecules can be
access to its expertise, and for research and
designed to include or exclude non-antisense effects. Isis
manufacturing services associated with the collaboration.
believes that second generation antisense molecules
This collaboration provides Antisense Therapeutics with
have sufficient oral bioavailability to permit oral dosing of
access to the rapid generation of second generation
its antisense drugs. In this respect, Isis Pharmaceuticals is planning to test an oral TNF-a antisense in Phase II
antisense lead compounds to its therapeutic targets. Antisense Therapeutics has agreed a list of research
targets with Isis and can, during the research and
Market perception of Antisense technology
development phase, select those with the most commercial potential to exclusively market and sell.
There is a pervasive view, in financial markets, that
Antisense Therapeutics is also obliged to pay royalties on
antisense technology is a high risk strategy for drug
antisense drugs discovered and developed within the
development despite the elegance of the underlying
science. There have been several late-stage clinical failures with the first generation antisense technology,
Due to its access to Isis Pharmaceuticals' proprietary
resulting in just one antisense molecule gaining approval
drug discovery process, Antisense Therapeutics believes
for human use to date. Valuations of antisense
it can quickly move candidates from drug discovery to
companies are likely to be further negatively impacted by
developing therapies. Once a therapeutic goal and gene
the decision of Sanofi-Aventis to withdraw from a
target has been identified, theoretically a lead antisense
development agreement with Genta in November. Whilst
compound can be rationally designed within hours. In
it is reasonable to argue that second generation
contrast, traditional drug discovery approaches can take
oligonucleotides appear superior to the first generation,
several years to produce lead compounds.
investor perception of the technology will be negatively
In practice, developing a lead antisense compound can
effected if antisense drugs continue to fail in the clinic.
be a little m ore complex. Optimisation of the molecule is frequently frustrated by the internal structures of the RNA
and associations with cellular proteins that cause
ATL1102 is a second generation antisense molecule that
physical barriers. Consequently, effective antisense drugs must be selected from a large pool of candidates.
targets the CD49d sub-unit of VLA4, an important immune cell protein that is responsible for trafficking of
Nevertheless, the experience and intellectual property
inflammatory white blood cells into the CNS. In multiple
position of Isis Pharmaceuticals should produce
sclerosis excessive amounts of VLA4 are thought to
meaningful advantages in the discovery and
promote the inappropriate migration of autoreactive
development of antisense based therapies.
lympocytes into the CNS which contributes to the
Isis Pharmaceuticals
progression of the disease. ATL1102 was licensed from Isis Pharmaceuticals in 2001, where it was known as
Isis Pharmaceuticals is a leading drug discovery and
ISIS107248. Isis has a right of first refusal on this
development company focused on the development of
molecule, when Antisense Therapeutics proposes to out-
RNA based therapeutics, primarily antisense, and it has
12 antisense products in development to treat metabolic, cardiovascular, inflammatory and viral diseases, and
Clinical Status
cancer. A key achievement since its inception is the
In August 2003, Antisense Therapeutics began testing
approval of the world's first antisense drug, Vitravene, for
ATL1102 in Phase I clinical trials. The 54 member
the treatment of eye infections caused by HIV-associated
healthy volunteer study was designed as a randomised
cytomegalovirus. The drug is approved in the US and Europe, where it is marketed by Novartis. Isis
double-blind, dose escalation, placebo-controlled trial. Preliminary data was presented in January 2004 at the
Pharmaceuticals has a number of alliances with global
Australian Neuroscience Conference Meeting where the
pharmaceutical companies including Amgen, Pfizer,
company reported that the data indicated a favourable
GlaxoSmithKline, Novartis, Eli Lilly and Chiron.
safety and pharmacokinetic profile. The final results were
It is our understanding that the alliance with Isis will give
revealed in June 2004, when Antisense Therapeutics
Antisense Therapeutics access to all the key intellectual
announced its intention to proceed into Phase II testing
property that relates to the commercialisation of second
with the 6mg/kg/week dose. The most frequently reported
generation antisense molecules. Previously, Isis secured
adverse events in the Phase I clinical study were mild
certain IP for developing second generation antisense by
'flu'-like symptoms and occasional injection site reactions
licensing certain patents from Hybridon.
("ISRs"). ISRs which were generally mild, increased in incidence and severity with increasing doses, particularly
A Phase IIa trial was initiated in December 2004 at the
negative or have shown only very modest benefit. Also,
University of Essen in Germany following approval by the
those DMTs that are effective in both the very early and
Ethics Committee of the University and authorisation by
relapsing-remitting stages of MS, tend to lose efficacy as
the Bundesinstitut für Arzneimittel und Medizinprodukte
the disease becomes more progressive and
in Germany. Antisense Therapeutics already had
degenerative. However, these patients still benefit from
experience dealing with international regulators: its
DMTs that help suppress any superimposed relapses.
Phase I clinical studies were conducted at Charterhouse
The only DMT approved for secondary progressive MS in
Clinical Research Unit of the Ravenscourt Park Hospital
the US is Serono's immunosuppressor Novantrone.
Because of concerns about cardiotoxicity, this drug can
The multi-centre, randomized, double-blinded, placebo-
only be used up to a lifetime maximum of 140 mg/m2
controlled eight-week clinical trial, over 60 patients with
(about 11 doses). Around 30% of all cases of MS can be
relapsing-remitting multiple sclerosis, will seek
categorized as having progressive disease - a very large
preliminary evidence of the drug's effectiveness. The
patient population whose current needs are essentially
company expects the treatment and patient monitoring
stages will be complete by early 2006-subject to the
Antegren
rate of recruitment-with results reported by mid-2006.
The treatment of multiple sclerosis is likely to be
Multiple Sclerosis
revolutionized in the near future by the launch of
Multiple sclerosis ("MS") is the most common acquired
Antegren, the first in a new generation of therapeutics.
neurological disease of young adults with most patients
Antegren, an antibody directed against VLA-4, has
diagnosed between the ages of 20 to 50. It affects
recently been approved by the FDA for marketing in the
around 2.5m people worldwide and around 350,000
US, based on one-year interim data from two-year Phase
people in the US. The typical patient is a young woman
III trials. Clinical evidence suggests that administration of
of childbearing age, although men make up 25% to 30%
Antegren leads to a reduction in the number of MRI
of all cases. A large opportunity lies in the chronic
lesions, which is thought to be indicative of efficacy.
progressive MS patient population, which constitutes
In the next six months, the two-year clinical data
around one third of the total MS patient population and
assessing the impact of Antegren on the disability of MS
lacks specifically approved treatments. The global market
patients will become available. We believe that
for MS is around USD$3bn, of which USD$1.5bn is
Antegren's approval, likely to be endorsed by such
generated in the US. We estimate that in the US the market is projected to grow to USD$3.3bn by 2008.
further data, effectively validates the therapeutic approach selected by Antisense Therapeutics in MS, i.e.
MS is a chronic inflammatory disease of the central
targeting VLA-4. It is conceivable that the Antisense
nervous system that is thought to be caused when the
Therapeutics drug ATL1102, may have efficacy, dosing
body's immune system attacks the myelin sheath that
route and cost advantages over the antibody product. At
insulates the brains nerve fibres slowing the transmission
the same time however, the hurdle will be raised.
Furthermore, amongst a whole raft of different therapeutic strategies being pursued by many companies
The areas where demyelination occurs are called
Biogen, one of the developing partners in Antegren, is
plaques (scleroses), or lesions, and cause the debilitating
known to be developing oral small molecule inhibitors of
neurological symptoms which characterise the disease.
VLA-4. ATL 1102 will target all types of VL A-4 and unlike
Although initially it presents as an inflammatory disorder,
Antegren will not produce neutralising antibodies, which
the disease develops in time into a degenerative disorder
leading to more serious abnormalities that leave the patients chronically disabled.
In addition to the VLA4 target, there is a whole raft of development drugs that target other mechanisms, with
Although the exact causes are unknown, evidence
which ATL 1102 may have to compete once it is
suggests an autoimmune reaction in which the body's T-
lymphocytes mount an attack on the myelin sheath. It is thought that the initial attack on the myelin may explain
Table 3 Selected clinical stage MS development drugs
the occurrence of sporadic exacerbations that often characterise the early, relapsing remitting, nature of the
disease. Once the myelin has been stripped-back, it is
thought that the neuron fibres themselves become irreversibly damaged and cease to transmit signals at all
resulting in the unrelenting decline seen in progressive
Treatment of MS
Until the 1990s there was no treatment for MS. Since 1993, five disease-modifying therapies ("DMTs") have
immunomodulators: Interferon-ßs (or IFN-b ) (Avonex,
Rebif, Betaseron) and glatiramer acetate (GA /
Copaxone) as well as mitoxantrone (Novantrone), an
immunosuppressant. All of the DMTs produce multiple
effects on the immune system that benefit MS.
Although the efficacy of the immunomodulators in
relapsing-remitting MS has been firmly established, the
results of studies examining their efficacy for patients with secondary progressive MS have either been
Source: Companies, Elixir Securities
There is no cure for the disease and treatment is focused on reducing the severity of the disease and minimizing its
ATL1101 is designed to inhibit skin cell division, which is
effect on the patient's life. The disease occurs in various
a key characteristic of hyperproliferative skindisorders
forms and is divided into three degrees of severity. Plaque psoriasis is the most common form and around
such as Psoriasis. It consists of an antisense sequence directed against the IGF-1R gene which encodes a
80% of patients have this form. In moderate to severe
protein called Insulin-like Growth Factor-I Receptor,
psoriasis, between 2% and greater than 10% of a
which is thought to play a pivotal role in the regulation of
patients body surface area is covered with the disease.
The disease affects 5-7m Americans with an annual incidence of between 150,000 and 260,000 new cases.
Insulin-like Growth Factor ("IGF")
However, no more than 1.5m of them seek therapy. This
IGF plays an important role in a number of disease states
is often because the efficacy of therapy is disappointing
through its potential to modulate cell proliferation,
and treatment has considerable inconveniences.
attachment and migration. It has been implicated in the
Estimates of annual outpatient costs range between
pathophysiology of psoriasis. The topical application and
US$1.6 and US$3.2bn (National Psoriasis Foundation,
subsequent penetration of large olignucleotides is
2000). It is thought that 300,000 patients are currently
problematic in normal skin. However, the structure and
receiving systemic psoriasis treatments. We estimate that
integrity of the skin's barrier function is compromised in
the current market for psoriasis therapies, which is
psoriatic lesions. It is thought that this permits the uptake
presently dominated by topical preparations (c.80% of
sales), is currently around US$550m, and is growing at 10%.
Pre-clinical studies have shown that the intra-dermal injection of antisense molecules into samples of human
Current and Future Psoriasis Therapy
psoriatic skin grafted onto mice inhibits the production of IGF-1R and normalises the skin architecture of the
Current psoriatic therapy can be grouped in four broad
grafted psoriatic tissue. The technology was licensed by
categories: topical, phototherapy, systemic treatments, and biologics. Many patients receive a combination of
Antisense Therapeutics, on a worldwide exclusive basis, from the laboratory of Professor George Werther and Dr
treatments as well as rotational therapy. Only around
Christopher Wraight at Melbourne's Murdoch Childrens'
20% of patients have severe enough psoriasis to be
Research Institute ("MCRI"). Antisense Therapeutics
treated with systemic treatments. Physicians tend to
intends to develop the antisense technology as a topical
prescribe psoriasis treatments in relationship to a ladder of disease severity and a patients response to treatment:
cream. The development of ATL1101 has been supported, in part, by a Commonwealth Government
Initial therapies often include topical applications of tar,
R&D Start grant of AU$1.1m; most of which has been
corticosteroids, and emollients as well as topical
retinoids, vitamin D, and anthralin. Additionally, the skin can become resistant to treatment in the longer term, the
Clinical Status
preparations tend to be messy an require frequent application, and patient responses vary widely.
In July 2003 Antisense Therapeutics announced plans to conduct a proof of concept study in humans suffering
There is a significant amount of research activity being
from Psoriasis. In these trials, ATL1101 will be applied to
conducted in psoriasis, which may emerge onto the
areas of psoriatic skin on a limited number of patients in
market at the same time as our projected
the study known as the small plaque or microplaque
commercialization date for ATL1101 in 2010.
assay (SPA). The SPA study will compare ATL1101 against placebo and possibly with an active comparator.
Table 4: Selected development stage psoriasis drugs
The small plaque assay will generate intrapatient data
since drugs can be applied to individual plaques in a
given patient. It will not however generate conventional PASI scores because of the nature of the assay.
Antisense Therapeutics has completed its current
programme of toxicology tests and submitted an
application for approval to begin testing in the planned
human proof of concept study-in November 2004
approval was received to conduct the study. Having
completed the manufacture of the active ingredient and formulation of the cream presentation, dosing of patients
is expected to begin in early 2005. The company intends
to partner out ATL1101 at the end of the proof-of-concept
study. Data from the study is expected in Q3 2005.
Psoriasis Source: Companies, Elixir Securities
Psoriasis is a chronic, relapsing skin disease that affects 1-3% of the world population and it is characterised by
patches of thick, red plaques on the skin. The disease remits and relapses over time and is caused by an
ATL1103 is designed to block the expression of Growth
autoimmune process leading to a chronic inflammatory
Hormone receptor. Pre-clinical studies have suggested
response directed against the skin. Although not life
that ATL1103 has utility in a number of diseases where
threatening, it leads to significant morbidity and disability
there is excessive growth hormone activity. These
as well as considerable psychological distress. Between
include a condition known as acromegaly and two
10%-40% of patients also develop psoriatic arthritis.
diseases that lead to blindness; diabetic retinopathy and wet-age related macular degeneration ("AMD"). ATL1103
has been tested by Professor Michael Waters of the
Clinical Status
University of Queensland, an international expert on
It is envisaged that sufficient bulk material can be
growth hormone receptor. The results achieved in these
purchased by the end of 2004, so that third-parties can
animal studies where comparable to those achieved with the newly approved acromegaly drug Somavert
formulate the drug for pre-clinical toxicity studies. These are likely to begin H2 2005, after which human trials will
(pegvisomant) in an equivalent animal model.
Acromegaly
Acromegaly is a rare hormonal disease that can cause enlargement of the hands, feet and part of the face. It is
Bob Moses
mainly caused by the growth of an adenoma (98%). Persons suffering from acromegaly are more likely to
Bob Moses is Chairman of the company's Board of
develop other diseases such as diabetes and heart
Directors and also Chairman of the Remuneration
disease. Symptoms appear slowly, and hence the
Committee and a member of the Audit Committee. He
diagnosis may take years to make. The symptoms are
has extensive experience in the lifescience sectors,
caused by excessive secretion of growth hormone,
having played a central role in the international
primarily from the pituitary gland. Growth hormone
development of CSL during the 90s. Prior to joining CSL
produces another hormone called insulin-like growth
in 1993, he was Managing Director of a commercial law
firm Freehills, Chairman and CEO of a NASDAQ listed medical service company and Corporate Manager of
The diagnosis of acromegaly is confirmed by
New Business Development at ICI. He has also spent 17
demonstrating elevated levels of both growth hormone
years in a variety of management positions at Eli Lilly.
and IGF-1. Once the biochemical markers of Acromegaly
Currently, he is non-executive Chairman of Amrad
have been confirmed, an MRI of the pituitary should be
Corporation, Medtech Research Limited, the National
performed to confirm the presence of a pituitary
Stem Cell Centrea, the CRC for Chronic Inflammatory
adenoma. Acromegaly is traditionally treated with
Diseases, and a commercial consultant to the MRCI.
surgery, removing the adnoma. The long-term success of surgery is estimated at around 80-85% for small tumours
Mark Diamond, Chief Executive Officer
and 50-60% in patients with large tumours. With large or
Mark Diamond has worked in the pharmaceutical and
invasive tumours, adenoma removal m ay be impractical.
biotechnology industry for 18 years, most recently with
Pharmacotherapy or radiation therapy is then considered.
Faulding. He served Faulding in a number of capacities
The goal of Pharmacotherapy is to normalise serum IGF-
within business development in Australia, Europe and the
In North America, Europe and Japan it is estimated that
Kathryn Andrews, Chief Financial Officer
there are approximately 40,000 diagnosed acromegaly patients , of whom about half require drug therapy. There
Kathryn Andrews is a Certified Practising Accountant
are approximately 3.3 new cases per million persons, per
who has over 18 years experience in accounting,
year. The market for Acromegaly is currently dominated
financial management and consulting primarily in the
by Sandostatin (octreotide) which, the published literature
mining and resources sector. She joined Antisense
states, is effective in about 60% of patients. In 2004, we
Therapeutics as Chief Financial Officer in September
estimate Sandostatin sales by Novartis of US$805m.
Pfizer's Somavert (pegvisomant) is the latest approved
Professor Graham Mitchell, Non-Executive Director
drug for acromegaly. It decreases the activity of growth hormone and levels of circulating IGF-1. It is indicated for
Professor Mitchell is a non-executive director and
treatment of acromegaly in patients that have not
member of the Remuneration Committee. He advises the
adequately responded to surgery or radiation therapy
Victorian Government on Science, Engineering and
and/or other medical therapies. ATL 1103 will be
Technology. He is one of the principals of Foursight
benchmarked directly against Sandostatin and Somavert
Associates, who jointly act as Chief Scientist for the
for acromegaly. The company believes that the profile of
Department of Primary Industries and Department of
ATL1103 may have potential cost, dosing route and
Sustainability and Environment. Graham is non-executive
lower frequency of dosing advantages over these
director of Compumedics Limited, AVS Pty Ltd and the
Geoffrey Gardner Dairy Foundation. He is also Professorial Associate of the University of Melbourne.
Diabetic Retinopathy and AMD
Previously he has acted as Director of Research for CSL and a research scientist at the Walter & Eliza Hall
Diabetic retinopathy is estimated to effect over 5m
Americans, aged 18 and older. In the US, around 12,000 to 14,000 of these patients lose their eyesight every year.
Professor George Werther, Non-Executive Director
Diabetic retinopathy is caused by new blood vessel formation in the retina or macula, which can break and
Professor Werther is a non-executive director and
bleed into the eye. This can result in scarring within the
member of the Remuneration and Audit Committees. He
eye. Similar factors are though to stimulate the formation
is a Director of the Department of Endocrinology and
of new blood vessels in the eyes of wet AMD patients,
Diabetes at the Royal Children's Hospital and Centre for
with similar results. Wet AMD is the leading cause of
Hormone Research at the MCRI. He has and does serve
blindness for people over 50 and affects most people
on many national and international scientific committees.
over the age of 80. In both indications current treatments
He is also a Professorial Fellow at Melbourne University.
are inadequate, suggesting that there is a substantial
commercial opportunity should ATL 1103 prove an effective treatment.
Dr Chris Belyea, Non-Executive Director
Chris Belyea Chairman of the Audit Committee and a
< VLA4 gains regulatory validation through approval
member of the Remuneration Committee. He holds a
PhD in physics and is a registered patent attorney. He was the founding CEO of Antisense Therapeutics in
< The product is out-licensed in Phase IIa to a major
2000, remaining in this role until shortly after it was listed
pharmaceutical company. Antisense Therapeutics
on the Australian Stock Exchange in January 2002. He is currently CEO of Metabolic Pharmaceuticals, of which he
receives upfront payments and milestones in the
was founding CEO in 1998. Prior to founding Metabolic
Pharmaceuticals, Chris was a Licensing and Projects Manager for Circadian Technologies and worked for 5
< Commercialised in major markets during 2009
years at Australian Patent firm Griffith Hack & Co.
Dr Stanley Cooke, Non-Executive Director
We estimate peak sales of AU$975m and a royalty rate of 15%.
Dr Cooke is a member of Antisense' remuneration committee. He is Founder, Chairman and CEO of Isis
< Has to compete with oral VLA4 inhibitors and other
Pharmaceuticals, a world leader in the field of antisense
oral MS drugs; in addition to incumbent interferons
therapeutics. He is also currently a member of the board of EPIX Medical and Idun Pharmaceuticals. He is a
member of the IBC Advisory Council, Current Drugs Advisory Board and the Editorial Advisory Board of
Journal of drug Target and Antisense Research and
< The product is out-licensed after Proof of Concept
Development. Prior to founding Isis, he was president of
study to a major pharmaceutical company. It
Research and Development for SmithKline Beckman and held a senior position at Bristol-Myers. Dr Crooke is also
an adjunct professor at the University of California, San
< Commercialised in major markets during 2010
Dr Jega Iswaran, Development Director
Dr Iswaran has over 20 years experience in the
< We estimate peak sales of AU$520m and a royalty
pharmaceutical industry. From 1972 to 1980, he was a
pre-clinical scientist at ICI Pharmaceuticals and later held positions of Project Manager and Pathology Section
< Has to compete with a new generation of oral
Manager at ICI Safety of Medicines. His remit extended
psoriasis agents; potentially including drugs like
through the UK, Western Europe, North America and Japan. Amongst consulting services, he has most
recently worked for CSL as Regulatory Manager for Haemostasis and as Regulatory Practices Manager.
Dr Christopher Wraight, Research Director
< Commercialised in major markets during 2011
Dr Wraight has 20 years experience in basic and applied
medical research, specialsing in the field of antisense
We estimate peak sales of AU$520m, split between
delivery and gene silencing. He joined the MCRI in 1991,
acromegaly, diabetic retinopathy and AMD. We
where he established an antisense R&D programme with
envisage that Antisense Therapeutics will receive a
Professor George Werther. In addition to directing
research at Antisense Therapeutics, Dr Wraight is an Associate Researcher at the MCRI and Head of the
< Will compete with current incumbents. Little
innovation expected in Acromegaly, although
Dr George Tachas, Director Drug Discovery &
diabetic retinopathy is likely to be an active area of
Dr Tachas has considerable experience in biomedical
< We have increased the discount rate on antisense
research and intellectual property law. Following his biological studies at the University of Melbourne, Dr
therapeutics to reflect their historical failure rate.
Tachas moved to Griffith Hack and Co, a leading
Once we have derived a value for the enterprise,
Australian intellectual property firm. He is well versed in
we add an estimate of the current balance in cash
biotechnology patent prosecution, opposition,
and debt to arrive at the market capitalisation of the
infringement and licensing, portfolio management and
The immediate valuation will be driven by the market's
Antisense is a tool that can be used to specifically inhibit
perception of Antisense technology, whether it believes
the expression of selected genes. It is underpinned by
the company will need to return to the market and
the principle that the sequence of nucleic acids in a
progress in the clinical trial programme. The latter is the
strand of antisense can bind to the sense strand of
critical component in the long-term valuation, since
messenger RNA and prevent its translation into a protein.
strong clinical science should attract investment from
After over 20 years of research, the technology gained a
strategic partners and the market. Our valuation model is
degree of commercial validation with the approval of
Vitravene for the treatment of AMD in the US during
Despite the scientific elegance of the antisense
approach, turning the science into dollars has been difficult. There are many factors which can affect delivery:
Messenger RNA
< Nucleases. Naturally occurring enzymes that
It is estimated that the human genome comprises of approximately 30,000 genes which can be transcribed
degrade nucleic acids. This leads to a short half-life
into approximately 85,000 different mRNA. Each mRNA
is used as an instruction set or template to synthesise a different protein. Genes consist of a series of functional
< Endosomes. Large macromolecules such as
unit called Exons that are separated by regions of DNA
antisense can be internalised by the cell in packets
that do not appear to play a direct role in the formation of
known as endosomes. These may be trafficked
the encoded protein. When the messenger RNA is
directly to lysosomes that degrade the contents or
copied from the DNA in the cells chromosomes, it copies
both the Exons and Introns. Special enzymes then process the mRNA, excising the Introns (splicing). The
mRNA contains the code for a specific protein that is
Non-antisense effects. The backbone of the
dependent on the order and frequency of which exons
antisense avidly binds to proteins and can induce
are spliced together. Once generated, the mRNA is then
non-antisense effects. This is particularly
exported from the nucleus to specific cell substructures
pronounced in unmethylated CpG rich sequences.
that produce the protein in a process known as translation. This takes place at a structure known as the
< Diseases are polygenic. Many diseases involve the
ribosome, which is essentially a protein factory.
dysunction of more than one gene. Antisense
The process can be disrupted at a number of stages.
agents have traditionally focused on individual
Antisense blockade can prevent the mRNA leaving the
nucleus by targeting a structure that is known as the 5' methylated guanosine cap that is involved in the
Antisense researchers have addressed these issues with
transport of the gene from the nucleus. Once out of the
a number of solutions in the second generation of
nucleus, Antisense DNA can bind to mRNA and inhibit
antisense molecules. They have replaced the backbone
protein synthesis by preventing the cells ribosomes from
of the antisense structure with one that resists nucleases
'reading' the RNA. Finally, the RNA component of a
and improves half-life. These changes also appear to
antisense/mRNA double strand can be degraded by
reduce the affinity of antisense for proteins. Different
RNase H, which is a group of naturally occurring
types of nucleotides (building blocks of nucleic acids)
enzymes in every cell. In total, at least 12 known
have been shown to improve the strength of the binding.
mechanisms can be induced once antisense binds its
A number of strategies are being adopted to improve the
delivery of antisense, at a micro and macro level. Isis has recently started large-scale human trials with the first oral
The Challenges of Antisense Table 5: Select Clinical Stage Antisense Agents Indication Source: Company, Elixir Securities Antisense Therapeutics Forecast Financials
2003A 2004A H105E 2005E H106E 2006E H107E 2007E
Profit & Loss: Top Total Revenues Operating Profit Carried Forward Cashflow Brought Forward
Non -Cash Operating/non-operating Charges
Operating FCF Elixir FCF Cashflow Net Cash & liquid assets closing Profit & Loss: Bottom Operating Profit Pre- Exceptional, Pre-tax profit Net Income Fully Diluted EPS Fully Diluted EPS Excl. Amortisation INTERSUISSE This document is for the confidential use of the recipients only and is not to be reproduced without the authority of Intersuisse Limited. The persons involved in or responsible for the preparation and publication of this report believe that the information herein is accurate but no warranty of accuracy is given. It is important to note that recommendations are of a general nature and are based on a consideration of the securities alone, and as such are conditional and must not be relied upon without advice from a securities adviser as to the appropriateness to you given your individual investment objectives, financial situation and particular needs. Whilst this document is based on information and assessments that are current at the date of publication, Intersuisse Limited has no obligation to provide revised assessments in the event of changed circumstances. Intersuisse Limited, its directors and associates disclose that they may have a relevant interest in the securities mentioned in this document.
Briefing note on Kangaroo Management - II Yorke Peninsula Natural Resource Management Group Photo: Ivan Clarke Jodie Reseigh and Geoffrey C. Bishop June 2010 Methods to assess impact of kangaroos on biodiversity and production In order to determine the methods that are required to assess the impact of kangaroos on biodiversity and production, it is important to ha
The following is a list of the most commonly prescribed drugs. It represents an abbreviatedversion of the drug list (formulary) that is at the core of your prescription-drug benefit plan. The list is not all-inclusive and does not guarantee coverage. In addition to using this list,you are encouraged to ask your doctor to prescribe generic drugs whenever appropriate. PLEASE NOTE: The symbol * nex