Bristol-Myers Squibb Co. said it is halting development of its high-profile cancer drug angiostatin, dealing a blow to the efforts of tiny biotech company EntreMed Inc. and Harvard scientist Judah Folkman.
The drug received world-wide publicity last year after Dr. Folkman reported he had eradicated tumors in laboratory mice when angiostatin was combined with a second agent, endostatin. The agents, if they ever work in humans, will represent a new way to fight cancer by blocking the flow of blood to tumors.
EntreMed, based in Rockville, Md., owns the rights to develop both angiostatin and endostatin -- and had licensed angiostatin to Bristol-Myers, New York.
Now, however, by modifying its collaboration with EntreMed, Bristol-Myers is effectively acknowledging that it has been unable to duplicate Dr. Folkman's results in lab mice. "At this time, angiostatin protein in its present form does not meet our criteria for molecules that advance to clinical trials," said Robert A. Kramer, a Bristol-Myers senior scientist.
In an interview, Dr. Kramer said Bristol-Myers still believes angiostatin is an exciting target. But the company has decided that developing the molecule would take at least several more years. In a recent review of its 40 to 60 drug projects, the company decided to put its emphasis on other drug candidates with more immediate promise.
'Complicated Protein'
Dr. Kramer said Bristol-Myers had trouble consistently producing angiostatin in large enough amounts to test. "It's a very complicated protein," he said, noting that the company was able to get anticancer activity only from several of numerous batches of the drug it produced. The company said if EntreMed can show that angiostatin works in prehuman lab tests, it still retains the right to develop and market the agent.
For Dr. Folkman, Bristol-Myers's action could deal a blow to his life's work. The highly respected Harvard researcher has pioneered the field of antiangiogenesis, and his discoveries have encouraged the development of numerous experimental drugs designed to squelch blood flow to tumors.
Dr. Folkman was not available Tuesday to comment, according to Children's Hospital, where he works. In a statement, the Boston hospital called such research "high risk," but noted that earlier this week it struck a separate deal related to his research with Genzyme Corp., Cambridge, Mass.
Last year, EntreMed's stock soared to $85 in one morning on news that it owned the rights to both agents. Soon after, however, the stock settled in the mid $30s, and Tuesday it closed at $24.50, down 81.25 cents on the Nasdaq Stock Market. The joint announcement by EntreMed and Bristol-Myers , which came after the close of trading, is likely to be perceived as negative news for EntreMed and, to a much lesser extent, Bristol-Myers, which is a diversified and successful pharmaceutical giant.
John W. Holaday, EntreMed's chairman, indicated the company will continue working on angiostatin and endostatin. In an interview, he stressed the company will seek government approval to begin safety trials of both agents before year's end. "We think they will provide a one-two punch" against cancer, he said.
For Bristol-Myers, this marks a costly chapter in its vaunted cancer-fighting history that began with an unusual personal commitment on the part of the company's former research chief. The company spent about three years and millions of dollars on angiostatin.
Emerging Doubts
Doubts about the compounds began to emerge several months ago. A number of prominent researchers, including collaborators at the National Cancer Institute, said they were unable to reproduce the lab results. Bristol-Myers officials cited some progress with angiostatin but indicated it was painfully slow.
The angiostatin setback shows how frustrating and unpredictable cancer research can be, and how long it can take to determine whether one avenue is worth pursuing. Usually pharmaceutical companies pick their shots with great care because of the extraordinary costs involved, building consensus and support among its scientific staff.
The decision to pursue angiostatin was based largely on the conviction of Leon Rosenberg, then head of research at Bristol-Myers, that angiostatin was a winner despite his staff's earlier decision not to pursue it. (Dr. Rosenberg has not been in charge of research since January 1997. He remained with the company until last March when he joined Princeton University.)
He first learned of angiostatin from Dr. Folkman. The occasion was an April 1995 awards dinner at Bristol-Myers honoring Dr. Folkman for several decades of cancer work. In a private conversation, Dr. Folkman, a mesmerizing speaker, shared his excitement about angiostatin, citing data published six months earlier in the journal Cell.
At the end of the evening, Dr. Rosenberg told staffers he wanted to find out more. "It took me about 15 minutes to become interested," Dr. Rosenberg said in a recent interview. "I believed that the opportunity for Bristol was too enormous to pass it by."
Aware that competitors were also interested, Dr. Rosenberg personally handled the matter. He had spent much of his career in academia, serving as dean of Yale University's medical school before taking over research at Bristol-Myers in 1991. Several former colleagues say he wanted to put his own stamp on a major new initiative in the company's labs.
Within a few weeks, Dr. Rosenberg traveled by helicopter and limousine to EntreMed headquarters in Maryland from the Bristol-Myers research operations in New Jersey. "We were very impressed that anyone would helicopter in to our small company," said Carol Nacy, then EntreMed's executive vice president and chief scientific officer who has since left the company. "We thought it was great fun."
'I'm a Scientist Too'
Initially, says Dr. Rosenberg, he didn't know that cancer experts on his team had previously looked into angiostatin and were not interested. He says he did take into account the opinions of some staffers but continued to believe that angiostatin was a potential winner. "I believe I am entitled to my own scientific judgment," says Dr. Rosenberg. "I'm a scientist, too."
Eight months later, the Bristol-Myers licensing deal with EntreMed was announced. The deal enabled EntreMed to raise about $50 million in a public offering in early 1996. Dr. Folkman's employer, Children's Hospital in Boston, got hefty EntreMed stock options, and Dr. Rosenberg joined EntreMed's board until he left Bristol. But the deal would probably not have been struck without Dr. Rosenberg's strong personal backing, people close to the situation say. There was some internal resistance to the project, these people say, and that was compounded by problems Bristol-Myers had in dealing with EntreMed right from the start.
For a long time, EntreMed refused to allow direct contact between Dr. Folkman and Bristol scientists, according to Drs. Nacy and Rosenberg. Dr. Nacy says EntreMed worried that Bristol-Myers would horn in on other parts of Dr. Folkman's research beyond the narrow licensing deal.
"EntreMed depended entirely on Dr. Folkman for its public persona so it was not easy for us to relinquish control," Dr. Nacy says. "If Bristol had its way, it would have had that direct relationship with Folkman."
As a result, Bristol scientists couldn't run experiments necessary to make angiostatin. By last November, Bristol officials were saying that they had succeeded in making small batches of the protein, but they still faced big practical hurdles in testing it on human beings.
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