By David N. Leff

An experimental drug now in Phase II clinical trials against solid tumors has just won new spurs as a potent, potential contraceptive.

It goes by the name fumagillol and specifically arrests the spread of unwanted new blood vessels. This ability to inhibit angiogenesis makes fumagillol a natural anti-tumor agent.

TAP Pharmaceuticals, a joint venture between Takeda Chemical Industries Ltd., of Osaka, Japan, and Abbott Pharmaceuticals, of Abbott Park, Ill., is testing a fumagillol analogue clinically under the proprietary name AGM-1470.

"One of these big trials," said research ophthalmologist Robert D'Amato, of Harvard Medical School, "is under way at the Dana-Farber Cancer Institute," in Boston. "I've heard that a few patients with metastases have responded," he told BioWorld Today, "but I don't think there's a lot of data out of this study yet."

D'Amato is principal author of an article in the April issue of Nature Medicine titled: "Critical components of the female reproductive pathway are suppressed by the angiogenesis inhibitor AGM-1470."

That is to say, it worked to prevent pregnancy, albeit in mice.

But D'Amato sees AGM-1470 first as a means of zapping fibroids * a major problem in obstetrics and gynecology * and other benign tumors of the uterus. "Our next step," he observed, "is to determine in animal models how effective such anti-angiogenesis agents are in treating endometriosis and other female reproductive disorders."

OB/GYN Ills First; Contraception Soon

"To make mice that model endometriosis," D'Amato observed, "we take endometrial cells [which line the uterine wall], grow them in culture and inject them into the abdomen. There they form little islands of ectopic endometrial tissue."

Once such preclinical experiments have been done, he foresees that "it would be possible to do clinical trials, because the drug is already in studies of human cancer. Fibroids," he pointed out, "are on the same spectrum as cancer, except that they're benign. So it's not that large a deviation from the current clinical trials."

He added: "Our paper in Nature Medicine is the first demonstration that these drugs are useful for many different disorders of the female reproductive system. This work was funded by EntreMed Inc., of Rockville, Md., which supports the Folkman laboratory, of which I'm a part.

"EntreMed has a big program on angiogenesis," D'Amato went on. "They have licenses to Angiostatin and Endostatin, the two very potent inhibitors that Folkman discovered. These are licensed from Children's Hospital, here in Boston, the Harvard teaching hospital where his laboratory is located."

Judah Folkman is the acknowledged pathfinder of anti-angiogenesis tactics, strategies and logistics. (See BioWorld Today, Aug. 24, 1995, p. 1.)

"Going in the other direction," D'Amato continued, "we want to see how effective angiogenesis inhibitors are as contraceptives in humans. What's the half-life? How delivered? How often would one have to take it? Would once in the ovulation cycle be sufficient to block ovulation? Things like that."

EntreMed also has clinical trials of another angiogenesis inhibitor, thalidomide, under way * to treat macular degeneration and cancer.

It was thalidomide, despite its horrendous past, that led D'Amato from the ophthalmological aspects of angiogenesis to the gynecological.

"I'm the person who discovered thalidomide as an angiogenesis inhibitor," he said. "I was looking for drugs that stopped the menstrual cycle, as an in vivo model of blood-vessel sprouting. From the literature I learned that those women who took thalidomide years ago as a sedative stopped menstruating. So I started looking for drugs that stopped menstruation as a way to find angiogenesis inhibitors.

"From there," he observed, "it was an obvious leap to say that these drugs that caused amenorrhea might be used to contraceptive advantage."

In the female mice he used to prove this principle, D'Amato and his co-authors administered their AGM-1470 anti-angiogenesis agent by systemic injection. Assuming such a drug would work as well in women, he would, of course, prefer oral, transdermal or intrauterine administration. "I picture a dissolvable implant something like an IUD," he suggested. "Just pop in the implant and it would dissolve away and release an angiogenesis inhibitor that would prevent the uterus from cycling."

How Mice Modeled Birth-Control Agent

As reported in Nature Medicine, when the team injected AGM-1470 into one-day-pregnant mice, all embryos had been resorbed by the time the pregnancy reached term. In contrast, when administered at 14 days, two-thirds through the gestational period, the murine mothers delivered normal litters.

To prove uterine recovery, the investigators mated the first group of mice again, six weeks after the first experiment in which they had lost their litters. This second pregnancy yielded normal litters in all the animals.

To determine the effect of the drug on their estrus cycles, sexually mature mice received AGM-1470 injections every other day for 16 days. This chronic regimen produced physical changes in their vaginal openings and uteruses (comparable to less drastic amenorrhea in humans) which rendered the animals unable to copulate. But after a seven-week recovery period, they were all successfully mated and produced normal litters.

D'Amato made the point: "Now that we know angiogenesis inhibitors might be useful as a contraceptive, I am not using AGM-1470 for its own sake, but as a way of modeling it as an angiogenesis inhibitor. I expect that this effect will be generalizable to all or most such agents."

He concluded: "Right now, we're just trying to find out if these things work as contraceptives, and which inhibitors might work best. So we've got a lot of that kind of work to do."

EntreMed has not embarked on that pathway.

The firm's vice president of regulatory and clinical development, Edward Gubish, told BioWorld Today: "Our focus is not reproduction; our focus is angiogenesis. The company has not really made a decision to actively pursue any further work in contraception." *