Firms in cancer-starving drug race
Boston Business Journal - by Allison Connolly Journal Staff
Since Boston's Dr. Judah Folkman earned international attention three years ago for his work on a cancer-fighting therapy called Endostatin, others have followed with their own versions of angiogenesis inhibitors. But while some would see it as competition, Folkman sees it as opportunity.
"Angiogenesis inhibitors are emerging as a new class of drug, but they can be added to others," said Folkman, a researcher at Children's Hospital Boston. Angiogenesis inhibitors stop the growth of new blood vessels that feed tumors--a process known as angiogenesis.
In fact, Folkman could one day see Endostatin being used with one of its rival angiogenesis inhibitors for the maximum effect on tumors. While it is believed the inhibitors will work well in conjunction with chemotherapy and radiation treatments, the ultimate goal is to replace the toxic therapies with anti-angiogenesis drugs, for a relatively safe, lifetime treatment. And there are a number of them in the making.
While Endostatin is a conventional angiogenesis inhibitor, there are others that use different mechanisms to starve tumors. One such promising drug is Combretastatin A4 Prodrug, a vascular targeting agent (VTA) that is being developed locally by Watertown-based Oxigene Inc.
"It's a totally different approach to angiogenesis," said Oxigene's chairman and chief executive officer, Dr. Bjorn Nordenvall.
Angiogenesis inhibitors, like Endostatin, stop new blood vessels from forming inside a tumor, preventing it from growing further. However, Combretastatin attacks existing blood vessels within the tumor, starving tumor cells until they eventually die.
With Combretastatin, Nordenvall said, the blood vessels inside the tumor collapse within 15 minutes of injection, and within an hour, he said, one can see the tumor dying due to the lack of blood supply. With angiogenesis inhibitors, according to Nordenvall, patients would have to take the drug every day for the rest of their lives, because new vessels would grow without it.
Combretastatin, which is derived from tree bark, was discovered by Bob Pettit of Arizona State University. Oxigene licensed it, and is developing the drug with Princeton, N.J.-based Bristol-Myers Squibb Co. Combretastatin has shown to be safe in Phase I trials, and the company is looking to begin Phase II trials. But more importantly, Nordenvall said, Phase I showed that the drug was effective, and another study showed it worked even better when used along with chemotherapy and radiation. Efficacy usually is not seen until Phase II, he said.
"The industry is getting excited about what we're doing because we're killing the tumor from the inside out," Nordenvall said. "The core of the tumor is impossible to attack."
Folkman said he has been impressed by what he has seen of Combretastatin, adding that it works faster than Endostatin. But he will not venture to say it is better than Endostatin.
"It's too early to say what angiogenesis inhibitor is going to make it and what isn't," Folkman said. "I think the fact that it (Combretastatin) passed Phase I is good."
Angiogenesis inhibitors made the public's radar screen when an article in the Sunday edition of the New York Times on May 3, 1998, proclaimed Folkman's work would cure cancer. Folkman was caught off guard by the newfound notoriety, because he and his colleagues had been studying angiogenesis for some time, and inhibitors had not yet been proven to work in humans.
But it didn't take long for other companies to follow the angiogenesis idea, albeit with different approaches.
According to Dr. William Li, president of the Boston-based Angiogenesis Foundation, there are 64 anti-angiogenesis agents in cancer-related clinical trials. The foundation estimates the public and private investment in angiogenesis research is $4 billion as of 1998, the most recent data available. Though it is very difficult to evaluate the worth of the cancer market for anti-angiogenesis drugs, estimates have ranged from $1 billion per year to $8.4 billion, based on a number of reports. Li said the market will likely be worth between $400 million to $1.8 billion by 2003, when the first products are expected to become available.
While Endostatin is only in Phase I/II trials, there are as many as 12 angiogenesis inhibitors in Phase III, the last phase a company must complete before applying for market approval from the U.S. Food and Drug Administration. Among the front-runners are SU5416, made by San Francisco-based Sugen, and Neovastat, from Quebec-based Aeterna.
Scientists have been studying angiogenesis for nearly 30 years, since Folkman made the initial observation that it may be involved in the progression of cancer. But advances in the field are taking place only now, thanks to high-throughput screening capabilities and a better understanding of how cancer spreads.
"They've really honed in on what makes the cancer cells tick," said Mary Lynn Carver, a spokeswoman for London-based AstraZeneca PLC, which is best known for its breakthrough cancer drug Tamoxifen, but also is developing compounds that act like angiogenesis inhibitors. Much of that research is being done at AstraZeneca's Waltham facility. The company is in preclinical trials with a VTA called ZD6126, which causes blood vessels to hemorrhage and block, preventing the blood supply from reaching malignant cells. It also has an anti-angiogenesis candidate in trials called ZD6474.
Last month, French-owned Aventis SA licensed a compound called AVE8062 that attacks the blood supply to tumors. Aventis, which sells the chemotherapy drug called Taxotere, will begin early Phase I trials on AVE6082 in the United States and Europe later this year, and in Japan early next year. Jason Ford, a spokesman for Aventis' oncology division, said the compound acts more like Combretatstatin than Endostatin, in that it attacks existing blood vessels within the tumor.
"We think this is promising because, if you had a choice, you'd want a compound that goes after what already exists," Ford said.
Yet, Folkman believes Endostatin, which is being developed by Rockville, Md.-based EntreMed Inc., will show good results since it is made from a naturally-occurring protein in the blood.
"It's very hard in Phase I to know whether it's working," Folkman said. "But with angiogenesis inhibitors, we have begun to see efficacy. You really have to wait until Phase II."
Nordenvall said he wants to develop a second-generation Combretastatin drug that would negate the need for a complimentary dosage of chemotherapy or radiation. The company already is developing a drug called Declopramide, which makes cancer cells more sensitive to chemotherapy and radiation. The company saw positive results from Phase I trials and is in Phase II.
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