By Randall Osborne

Editor

It sounded almost like magic.

The idea that blood vessels might be encouraged with drugs to grow around a diseased heart, or might be thwarted to starve an advancing tumor, seemed when it first hit the public consciousness, anyway a concept from the realm of science fiction.

Investors perked up.

The twin approach had (to non-scientific ears) an exotic ring, with plenty of syllables: Angiogenesis means making the blood vessels grow. Anti-angiogenesis, of course, means stopping them.

Maybe the very reason why money soon followed the concept was that the notion was so strange, so far out and at the same time so eagerly embraced by respected scientists and journalists.

In any case, still strong in the memories of many is the Monday in 1998 when shares of EntreMed Inc. soared from $12 to $51, after reports about preclinical mouse data related to the company's anti-angiogenesis proteins, Angiostatin and Endostatin.

The National Cancer Institute and Nobel Laureate James Watson cheered scientist Judah Folkman, professor of surgery at the Harvard University-affiliated Children's Hospital in Boston. Folkman pioneered the research carried on by EntreMed.

Media hype powered the EntreMed stock surge. But, less than a year later, the firm's shares plummeted with the disclosure that partner Bristol-Myers Squibb Co. was returning development of Angiostatin to EntreMed.

Never convinced anyway was Michael Simons, director of the Angiogenesis Research Center at Beth Israel Deaconess Medical Center in Boston.

"I don't believe in that stuff, personally," said Simons, about the protein research. "It requires very large amounts, and nobody can figure out how it works. There could be all sorts of funny effects. I was never convinced that was promising."

The Beth Israel center, on the side of what is often called "pro-angiogenesis," is conducting research with its own peptide.

"It is not far along," Simons said.

"Nothing is far along," he added.

Simons, with both feet in the academic-medical research realm, but his eyes on private biotech and its investigations, has his own ideas as do many industry watchers about what's worthwhile and what's not. And there's no shortage of what's worthwhile, although the field still has challenges aplenty, Simons said.

Researchers in pro-angiogenesis and anti-angiogenesis, wary of overshooting their claims, dare not ballyhoo their discoveries with wild abandon. All realize the time is too early to speak of a cancer cure, or to trumpet a sure fix for coronary illness. Nevertheless, many speak of their blood vessel work with gleams in their eyes.

"I think there's promise on both sides, but anti-angiogenesis [advances] will come faster," Simons said.

"There are no clear leaders in the pro-angiogenesis area," he added. "It turned out to be a lot more difficult than we imagined. There is a major delivery problem. You need to be able to deliver effective amounts of growth factor to the places where they are needed, in the heart or limbs, and the frontal assault was not a resounding success. You could argue Chiron [Corp.] has had positive results, but hasn't solved the problem."

Eyed as potential angiogenesis drugs are vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2). VEGF has been regarded as the more direct route, and FGF-2 seems to function by way of VEGF receptors.

Chiron has done research with FGF-2. Genentech Inc. has worked with VEGF.

The dilemma "may well require devices," Simons said which may call for biotech firms to team up with device companies.

"They speak different languages, and that's a big hindrance," he said. "Biotech companies are not used to this at all. It's a curious cultural problem."

Overall, Simons said, evaluating pro-angiogenesis firms will be fairly simple for investors that is, once it becomes clear which has the best way deal, delivery-wise.

"There are a number of growth factors that work as molecules, if you can figure out how to get them in," he said. "If I were an investor in pro-angiogenesis, I'd go for small companies with the best delivery potential. That's what it's going to ride on."

Genentech, Simons said, having met with unimpressive results with VEGF, is "back at the starting line" with its cardiovascular studies, and Chiron is "not announcing what its intentions are."

Chiron's FGF-2 failed to meet its primary endpoint this spring in a Phase II trial in symptomatic coronary artery patients, but seemed to have value in reducing chest pain.

A promising player in the pro-angiogenesis field, he said, is Collateral Therapeutics Inc. The company's angiogenic gene-therapy approach for alleviating ischemia, called GENERX, met with positive results in a Phase I/II study, sending the firm's stock soaring 56 percent in March. Delivery of the adenoviral gene therapy vector, containing human fibroblast growth factor-4, is accomplished during standard heart catheterization.

The anti-angiogenesis scenario, in Simon's view, is much more distinct.

"It's systemic administration," with leaders easy to identify, he said.

"Genentech has the strongest science," Simons said. "You understand how it works, and there's beautiful animal data."

Last December, Genentech said it was entering Phase III trials with its recombinant humanized monoclonal antibody to vascular endothelial growth factor (rhuMAb-VEGF) in combination with chemotherapy in metastatic colorectal cancer and metastatic non-small-cell lung cancer.

Genentech is the smartest choice for anti-angiogenesis investors, Simons said, "but there are other companies pushing hard. One of them is Regeneron [Pharmaceuticals Inc.] and the other is Immunex [Corp.]"

Regeneron "has been largely a one-man show, and it's getting a little old," Simons said. "Nobody can spell his name."

The firm's research is promising, albeit early. Led by senior vice president of research and chief scientific officer George Yancopoulos, Regeneron's VEGF work was outlined in an article last year in the journal Science.

Immunex Corp. has a "nice portfolio," Simons said, and has been beefing up the staff with scientific heavyweights. "I like Immunex."

The company is best known for its arthritis drug Enbrel and the multiple sclerosis drug Novantrone, but the well-chosen staff of researchers at Immunex is impressive enough, Simons said, to bear watching in other areas.

Immunex discovered Tek (tunica interna endothelial cell kinase), a member of the receptor tyrosine kinase superfamily, a large family of receptor molecules involved in cellular inflammation, growth, activation, differentiation and survival. When engaged with its cognate ligands, the angiopoietins, Tek promotes angiogenesis, the spouting of new blood vessels from the existing vasculature which plays a major role not only in tumors' growth and spread, but rheumatoid arthritis and retinopathy.

Overall, however, Simons said investment players in angiogenesis, "pro" or "anti," would be well served to expect no abundance of miracles anytime soon. They also would be wise to examine all research carefully, sifting claims and (because so much of the research is in the first stages) becoming educated about the complex field.

Simons said money pledged to one of biotech's bigger names would be money wisely directed, meanwhile.

"I would go for Genentech," he said, adding that Sugen Inc. [bought by Pharmacia] has "very nice" potential, but "it's hard to tell [between other companies which one might be the strongest]. Immunex and Sugen have fairly similar things, but both are way behind Genentech." *

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