FT Surveys: Life Sciences (15 July 1999)

by Clive Cookson, 1999 Science Writer of the Year.

Of all the new biotech approaches to cancer treatment, the one that has caused most media excitement over the past year or two is anti-angiogenesis - starving a growing tumour by cutting off its blood supply. More than 40 drugs that work by this mechanism are undergoing clinical trials, with several dozen more in preclinical research.

The approach contrasts with others that attack cancer cells head-on, whether by traditional cytotoxic drugs or new techniques such as monoclonal antibodies. The aim is to prevent the growth of new blood vessels (angiogenesis) that deliver the oxygen and nutrients required by cells to proliferate.

A worldwide wave of publicity for angiogenesis inhibitors followed an over-enthusiastic article in the New York Times in May last year, which focused on two proteins being developed by EntreMed, a small US company based in Maryland. Although the two molecules, endostatin and angiostatin, are not due even to begin clinical trials until late this year, the article described spectacular results in mice experiments and contained a quote from James Watson, co-discoverer of the DNA double helix, about a "cure for cancer within two years". (Dr Watson later denied using those words.)

EntreMed has the benefit of a research and licensing agreement with Judah Folkman of Boston Children's Hospital, who is generally regarded as the father of anti-angiogenesis. Dr Folkman first proposed in 1972 that a tumour could be starved by cutting off its blood supply and he discovered the first angiogenesis inhibitor in 1975.

Today, more than 300 molecules are known to have this effect, according to the Angiogenesis Foundation, a non-profit organisation that promotes research in the area. And EntreMed is just one of 140 pharmaceutical and biotech companies in the US, Europe and Australia with angiogenesis-based drug development programmes.

Although cancer is the main application, there are some other diseases that could benefit from inhibition of angiogenesis; for example, some forms of blindness are caused by new blood vessels forming behind or in front of the retina. Conversely, drugs that encourage angiogenesis may help to treat conditions where new blood vessels are needed, such as cardiovascular disease and wound healing.

Estimating the future size of the angiogenesis-based drug market is hard, since it does not exist yet. No product designed to inhibit or stimulate angiogenesis has been approved for any clinical application. But Biophoenix, a UK biomedical consultancy, makes an attempt in an FT Pharmaceutical Industry Report*.

Biophoenix says sales of anti-angiogenesis cancer drugs could be worth $3bn a year by 2005, assuming successful launches for several products now in development. Ophthalmology and cardiology products could bring in another $800m a year.

Many different types of angiogenesis inhibitors are in development, including small molecule drugs, proteins, monoclonal antibodies, oligonucleotides, ribozymes and gene therapy products. But Biophoenix authors Streten Bogdanovic and Beata Langlands identify several "waves" of anti-angiogenic product moving through the industry's research and development pipeline.

The first wave consists of matrix metalloproteinase (MMP) inhibitors. They block enzymes secreted by cancer cells, which help blood vessels to spread by breaking down the surrounding tissues. British Biotech has staked its future on MMP inhibitors - marimastat, which is in Phase 3 clinical trials, and follow-up compounds BB-3644 and BB-10153 - but several other companies are developing drugs with a similar mode of action.

The broader second wave includes inhibitors of growth factors, such as vascular epithelial growth factor (VEGF), which stimulate blood vessel formation. A third wave, now in early development, consists of inhibitors of other proteins that trigger angiogenesis, plus various recently discovered anti-angiogenic proteins. Finally - still in pre- clinical research - is a fourth wave of gene therapy products.

But angiogenesis prevention is not just about newly discovered molecules. As scientists investigate the action of old drugs, they are finding that some have an anti-angiogenic effect.

For example, recent research suggests that tamoxifen, AstraZeneca's widely prescribed breast cancer treatment, works not only by adjusting hormone levels but also by blocking angiogenesis. Several cytotoxic drugs (including Taxol and 5-fluorouracil) have anti- angiogenesis as a secondary mode of action. And thalidomide, the notorious sedative that caused birth defects before its withdrawal in the early 1960s, is beginning to redeem its dreadful reputation in a new role as a cancer drug. It has a strong anti-angiogenic effect, which may explain why it damaged the developing foetus (by restricting blood supply to the growing limbs).

No wonder some experts are enthusiastic about angiogenesis research. The Angiogenesis Foundation goes so far as to predict that "angiogenesis therapies promise to become the 'antibiotics of the 21st century'."

"Just as medicine was revolutionised in the 1940s by the realisation that the great diseases of that time were linked by micro-organism growth (infections) which could be conquered through antibiotics, so too do we believe that our understanding of angiogenesis as a common denominator will reshape the way we triumph over the disease of our time," says Shawna Cornelius, the foundation's director.

*Angiogenesis Players, published by FT Pharmaceuticals, costs £375/$590. Tel: +44 (0)20 7896 2184.