EXECUTIVE SUMMARY
Mounting evidence indicates that excessive or inadequate growth of new
blood vessels (angiogenesis) plays a key role in many diseases.
Antiangiogenic therapies are being developed to halt excessive angiogenesis
associated with cancer, age-related macular degeneration, diabetic
retinopathy, psoriasis and rheumatoid arthritis. Therapeutic angiogenesis
is being developed to stimulate angiogenesis in ischaemic conditions such
as coronary artery disease and peripheral vascular disease, and to
facilitate wound healing.
Although few agents for inhibition or stimulation of angiogenesis have been
approved as yet, many are in clinical trials. According to the Angiogenesis
Foundation, an estimated $4 billion has been invested in the R&D of
angiogenesis-based medicines, making this one of the most heavily funded
areas of medical research in human history. This clearly is an area, which
no decision-maker in the pharmaceutical industry can afford to ignore.
The first angiogenesis-targeted pharmaceutical product to reach the market
was Johnson & Johnson's treatment for diabetic foot ulcers, Regranex
(becaplermin). We believe that the commercial performance of this product,
which we examine in detail, models most of the factors likely to influence
sales of newly approved angiogenesis-targeted drugs over the next few
years. Based on this case study, we forecast that such drugs could capture
some 3% of the potential market for such drugs, ie $2.2 billion worldwide
at constant 2001 manufacturers' selling prices, within 5 years (ie 2007).
Cancer is the major area under investigation. Studies have demonstrated the
profound dependence of tumour growth and metastasis on the generation of
new blood vessels. In 1999, the US National Cancer Institute designated the
development of antiangiogenic therapies for cancer a national priority.
This report reviews 170 antiangiogenic agents under commercial
investigation, 60 of which are in clinical trials, including 13 in Phase
III trials. They are discussed under 10 separate category headings, to
which they have been assigned based on their known mode of action or their
origin. Where available, recent results of clinical trials of individual
agents are also discussed as they provide some indication as to how
successful the particular approach to inhibition is likely to be.
First-generation angiogenic inhibitors affect the endothelial cells
involved in angiogenesis indirectly by interfering with the production of a
tumour cell product or its receptor. In the last 2 years, a few of those
inhibitors produced disappointing results in Phase III trials. At the same
time, a number of second-generation inhibitors, many of which work by
exerting their effects directly on the vascular endothelial cells, produced
positive results in early clinical trials. Typically, this has meant
disease stabilisation and increased patient survival time, although in some
cases reduction in tumour size was also observed. The second-generation
agents include naturally occurring compounds of human and non-human origin,
antimicrobials and products already approved for other indications; many
are characterised by multimodality of action.
One particularly promising group, inhibitors of the epidermal growth factor
receptor, inhibit angiogenesis and retard tumour invasion and metastasis.
The report also includes the development of vascular targeting agents,
which are being designed to destroy vessels formed by angiogenesis rather
than prevent their formation. Vascular targeting agents appear able to
induce blood flow shutdown to the tumour.
As cytostatics, antiangiogenic agents promise to change cancer from a
lethal disease to a manageable condition. There are also indications that
antiangiogenic agents are non-toxic and give synergistic effects when
combined with each other, or with current cytotoxic therapies, a strategy
that offers significant market opportunities.
There has been considerable interest in the development of methods to
maximise the body's ability to develop collateral vessels in ischaemic
tissues associated with coronary artery disease and peripheral vascular
disease. This report reviews 39 angiogenic products under commercial
investigation, 19 of them in clinical trials. Positive results have began
to emerge from early stage trials of recombinant growth factors, involving
mainly symptomatic improvements such as reduction in angina in coronary
artery disease.
Although initial trials involved administration of individual recombinant
growth factors or other angiogenic factors, new protocols favour a
multi-drug approach. It may indeed prove essential to use combinations of
angiogenic factors in order to obtain stable and mature blood vessels. Gene
therapy offers the possibility of achieving sustained, localised production
of several angiogenic factors and its development is continuing. In the
near future, angiogenic agents are most likely to find use in association
with new angiogenesis-inducing procedures such as transmyocardial
revascularisation.
As the process of arteriogenesis, or vessel maturation, is becoming better
understood, new information regarding the control of vessel remodelling is
being incorporated into approaches such as stem cell therapy and tissue
engineering for the design of products to improve cardiac function.
Outside of cancer and cardiovascular disease, two areas that are receiving
most attention are vascular eye diseases, in particular age-related macular
degeneration, and dermatology. In 1997, Johnson & Johnson's Regranex wound
healing gel became the first US FDA-approved angiogenesis-stimulating
medicine, and in 2001, Visudyne became the first FDA-approved
antiangiogenic therapy for age-related macular degeneration patients.
However, it is believed that inappropriate angiogenesis plays a key role in
approximately 80 diseases, and the report attempts to assess the
opportunities for angiogenesis-based intervention in some of the less
intensively studied applications.
There are indications that various marketed drugs may include in their
mechanism of action either an inhibitory or stimulatory effect on
angiogenesis. While a few drugs are currently being evaluated for use
specifically as angiogenesis modulators, for example thalidomide and
paclitaxel, many more could be investigated.
Sources of information used in compiling this report
Product pipeline and company information was obtained directly from sources
such as annual reports, press releases, briefing materials provided to
analysts, corporate websites and personal communications. Drug and company
data was also obtained indirectly from two databases, which rely
predominantly on the same sources. These are PJB Publications'
Pharmaprojects database of drugs in development and Biophoenix's
PharmaPlayers database of biotechnology companies. A retrospective search
of PJB Publications' newsletters (Scrip, Clinica, and Genomica) provided
additional information.
