Here is the WSJ's article.
February 10, 1999
Bristol-Myers Squibb Ends Research
On EntreMed's Anticancer Drug
By RALPH T. KING JR. and MICHAEL WALDHOLZ
Staff Reporters of THE WALL STREET JOURNAL
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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