By Nancy Volkers

Special to BioWorld Financial Watch

Gaining control over angiogenesis the growth of new blood vessels would be a major breakthrough for biotechnology. For many, the word "angiogenesis" brings to mind the use of anti-angiogenic therapies to stop tumors from growing new blood vessels. An effective anti-angiogenic would cut off a tumor's blood supply, strangling it and stopping it in its tracks. But these compounds might also help treat other conditions, such as macular degeneration, arthritis and Crohn's disease.

Perhaps, the better-known compounds on the anti-angiogenic stage are endostatin and angiostatin, which EntreMed Inc. licensed from Boston Children's Hospital in 1996 and 1994, respectively. In April the Rockville, Md., company presented preclinical results on both compounds, as well as progress in the manufacturing of endostatin in sufficient quantities for clinical trials. In late September, endostatin began Phase I trials.

But many more compounds are in development, some in Phase III trials and one already on the market. As of December 1, the National Cancer Institute's clinical trials database displayed 37 clinical trials of anti-angiogenesis therapies, including thalidomide, aplidine, COL-3, combretastatin A4-phosphate, squalamine, IM-862, SU5416, PTK787/ZK222584, marimastat, CT-2584, a monoclonal vascular endothelial growth factor (VEGF) antibody, SU-5416 and AG3340. Preclinically, more than 30 other compounds have shown anti-angiogenic capabilities.

Of the compounds being researched, some are examples of the latest in biologics technology, while others are natural products or older drugs revitalized.

The old abandoned drug and the one already on the market is thalidomide, branded Thalomid by Celgene Corp., of Warren, N.J. Thalomid is in clinical trials for multiple tumors, including Kaposi's sarcoma (Phase III) and small-cell lung cancer (Phase I).

The compound is on the market already for treating cutaneous manifestations of erythema nodosum leprosum (ENL), a condition associated with leprosy, but off-label uses include several cancers and Crohn's disease. The drug has orphan designations for Crohn's and multiple myeloma. Last month, reports from a chemotherapy symposium in New York showed the drug had promise in treating androgen-independent prostate cancer, glioblastoma and multiple myeloma.

"Thalomid clearly appears to have anti-angiogenic properties, although the exact mechanism is unknown," said Mike King, senior analyst at BancBoston Robertson Stephens Inc. in New York.

The drug may have an advantage in the burgeoning anti-angiogenesis market, because "it's already out there [on the market]," King said. "There was tremendous interest in Thalomid at the ASH [American Society of Hematology] meeting. I think [oncologists] will be motivated to use it in lymphoma and leukemia patients, and I see it being used in solid tumors as well. That's why the market is so large you can use anti-angiogenics in almost any cancer."

As for non-cancer indications, King said, "The evidence isn't in yet on rheumatoid arthritis, but I am excited by its activity in Crohn's. If you look at the alternatives, 50 or 100 mg of thalidomide at bedtime is a lot more appealing than an IV infusion [of Remicade]. Also, the researchers doing the work are the same ones who did the work on Remicade, so the credibility is very high. Gastroenterologists don't have to worry if the researchers are well respected."

Besides Thalomid, Celgene is developing thalidomide analogues immunomodulatory drugs, or IMiDs, and selective cytokine inhibitory drugs, or SelCIDs that the company says are more potent than Thalomid.

Thalomid sales hit $3.5 million in the first quarter of 1999, $5.3 million in the second quarter, and $6.3 million in the third quarter.

Anti-angiogenic natural products include squalamine, a compound isolated from the dogfish shark (Squalus acanthiasis). Magainin Pharmaceuticals Inc., of Plymouth Meeting, Pa., has squalamine in Phase II trials for non-small-cell lung cancer in combination with chemotherapy. According to Michael Dougherty, Magainin's president and CEO, multiple additional studies are planned, including trials in ovarian cancer, pediatric tumors, and other adult solid tumors.

"We should start to have clinical results in mid-2000," Dougherty said, "and with success we would begin pivotal testing, which we expect would take up to about two years."

Squalamine was originally discovered as part of an antimicrobial screening effort in 1992.

"We're enthusiastic about this drug and have had excellent preclinical results," Dougherty said. "A number of collaborators have worked with it and published on it multiple times; that gives us good reason to be enthusiastic."

AE-941 (Neovastat), Aeterna Laboratories' entry in the anti-angiogenesis race, is also derived from shark, but that compound comes from shark cartilage. Neovastat was found safe and tolerable in Phase I trials for macular degeneration, and should soon enter NCI-sponsored Phase III trials in non-small-cell lung cancer. The Quebec-based company also plans pivotal trials in renal cell cancer, and recently said trials would begin soon for macular degeneration (MD).

Sugen Inc. considers anti-angiogenics to be one of its major programs and "probably the most advanced," said Kevin Kwok, director of new product planning at the Redwood City, Calif., company.

The company's SU5416 targets the FLK1/KDR receptor, which has shown to be important in VEGF signaling. SU5416 is just entering Phase III trials for colorectal cancer, Kwok said, and will also begin Phase III trials for NSCLC in the first quarter of 2000. In addition, he said, "NCI is sponsoring 20 Phase II trials [involving SU5416] in a variety of cancers. [The institute] has taken a real interest in this product."

Besides SU5416, Sugen is researching SU6668, which has multiple targets, including FLK1/KDR, PDGF and FGF receptors. Trials of this molecule are in Phase I.

There are almost as many mechanisms of anti-angiogenic action as there are anti-angiogenics. Squalamine "gets into endothelial cells and binds to calmodulin," explained Ken Holroyd, director of clinical affairs at Magainin. "It affects the ability of the cells to join together and form new blood vessels, and blocks their response to multiple growth factors."

This mechanism makes squalamine an ideal partner for certain chemotherapy drugs, such as cisplatin or Taxol, because "the chemotherapy destroys the cancer cells, and when they try to regrow, [squalamine is] there to stop the cells from performing angiogenic rescue," said Greg Miliotes, an associate with BancBoston Robertson Stephens Inc.

For many anti-angiogenics, the exact mechanism is still unknown. However, it's thought that some work by inhibiting endothelial cells directly. Some inhibit matrix metalloproteases (MMPs); others block activators of angiogenesis, such as growth factor receptors. Some have more than one proposed mechanism of action; for example, Neovastat apparently inhibits both MMPs and vascular endothelial growth factor receptors.

The market for anti-angiogenics is wide. Many of the 1.2 million people diagnosed with cancer each year could benefit from the therapy, as could people with MD, the leading cause of blindness in people over 65. A new case of MD is diagnosed every three minutes in the U.S..

Many anti-angiogenics also have anti-inflammatory properties, which could make them ideal for treating arthritis and autoimmune diseases such as Crohn's, which affects about 200,000 people in the U.S.

More than a dozen other companies have anti-angiogenics in their pipelines, including Agouron Pharmaceuticals Inc., of La Jolla, Calif.; Alza Corp., of Palo Alto, Calif.; Angstrom Pharmaceuticals, of San Diego; Boston Life Sciences Inc., of Boston; British Biotech plc, of Oxford, England; CollaGenex Inc., of Newtown, Pa.; Cytran Inc., of Kirkland, Wash.; Genzyme Molecular Oncology, of Framingham, Mass.; Ilex Oncology Inc., of San Antonio, Texas; ImClone Systems Inc., of New York; Oxigene Inc., of Boston; Progen Industries Ltd., of Melbourne, Australia; Ribozyme Pharmaceuticals, of Boulder, Colo.; and TAP Pharmaceuticals, of Deerfield, Ill. Big pharma investments in the field include those from Bristol Myers-Squibb Co., of New York; Merck KgaA, of Darmstadt, Germany; Novartis AG, of Basel, Switzerland; and Schering-Plough Corp., of Madison, N.J.

The market for these therapies is still uncertain, but the potential is great. "As with anything, we need double-blind, placebo-controlled trials and [to know] what indications and what populations we're talking about," Miliotes said. "That will either narrow or expand the market, depending. It's a tough thing to get your arms around."

However, he continued, "It might be that this isn't a zero-sum game there might be multiple compounds on the market, increasing the visibility of the whole therapeutic category. If [anti-angiogenics] come to fruition, the result could be similar to that for protease inhibitors a lot of physician calls, a lot of presentations at medical meetings. *