Endostatin's Luster Dims, EntreMed Slides
Folkman Urges Doctors, Learn from Scientists
by
JACQUELINE STRAX
PSA Rising, New York, November 14, 2002 -- Dr. Judah Folkman used to
stress that endostatin and angiostatin, anti-angiogenesis
compounds which he discovered and spent decades developing at Harvard,
work on tumors implanted in mice. Almost anything works
in mice but the effects of Folkman's drugs on implanted tumors looked
spectacular. When Folkman's colleague Michael O'Reilly M. D. showed
slides of the mice at chemotherapy conferences, oncologists gasped.
But published results from a trio of Phase I trials of endostatin at
leading cancer centers are modest. Today in its Third Quarter Report
, EntredMed, Inc, the Rockville, Md. biopharmaceutical company that
owns rights to manufacture endostatin and angiostatin, assured cancer
patients in or about to enter those clinical trials that the drug will
still be available. "EntreMed will maintain its ongoing clinical
trials with its two protein drug candidates, Endostatin and Angiostatin,"
the reports says, "but will not initiate new trials with these
two proteins."
|
CLINICAL
TRANSLATION OF ANGIOGENESIS INHIBITORS Robert Kerbel &
Judah Folkman Nature Reviews Cancer 2, 727-739 (2002) Requires
registration
Figure
1 Direct
and indirect angiogenesis inhibitors
Table
1 Direct inhibitors
Table
2 Indirect inhibitors
Table
3 Pro-angiogenic oncogenes
EntreMed
Inc. Third Quarter Report November 14 2002
"EntreMed
will maintain its ongoing clinical trials with its two protein
drug candidates, Endostatin and Angiostatin, but will not initiate
new trials with these two proteins. "
EntreMed Refocuses Executive Team Sep
26, 2002
FDA
Awards EntreMed Orphan Drug Grant For Endostatin Trial Grant Covers
Costs of Ongoing Trial
EntreMed
to de-emphasize two marquee cancer drugs
To save cash, company puts angiostatin and endostatin on back
burner, pushes Pamzen, report says. Sunspot, The Baltimore Sun,
Nov 7, 2002.
Early
Endostatin Results Show Promise NCI 11/09/2000
Angiogenesis
Inhibitors in Clinical Trials NCI Chart, Updated: 06/19/2002
Online
Medical Dictionary
Menu
of articles on
this site about anti-angiogenic treatments and trials.
|
EntreMed has stocks of endostatin but plans to make no more this year.
The company cannot afford to make the drug and watch it limp through
trials with no signs of miracle cure. EntreMed sold its rights to thalidomide
to a Swiss company for $22.4 million and this summer in further efforts
to stem financial hemorrage halved its workforce. A headline last week
in the Washington Post said, "After
Rocketing to Fame, EntreMed Is in Dire Straits." The company's
stock has stock fallen from an all-time high of $98.50 in spring 2000
to just over a dollar last week.
On the street, doubts began in 1999, when the Wall Street Journal reported
that National Cancer Institute (NCI) scientists had failed to replicate
Folkman's mouse results. NCI
officials replied that this was "incorrect." "Given
the reports of antitumor activity of human endostatin in mice and its
documented lack of toxicity," a spokesperson said, "NCI believes
that the only way to begin to rigorously evaluate this unique compound
in people with cancer is to move it into clinical trials."
Early results of these trials showed recombinant endostatin ( rh-Endo)
to be safe and non-toxic in humans at the doses given. The only side
effects reported were skin rash at the infusion site and, for one person,
a bacterial infection of a central line port. Some tumors showed measurably
reduced blood flow -- just what an angiogenesis
inhibitor is supposed to do so as to inhibit cancer cells' ability to
sprout new blood vessels and find nourishment beyond their original
site in the body.
At an "Era
of Hope" meeting run by the Department of Defense Breast Cancer
Research Program two years ago, Elieser Gorelik M.D., Ph.D of the University
of Pittsburgh, said high expectations attended the discover of endosatin
and angiostatin "but their promise is yet to be demonstrated in
human studies." Gorelik, a professor of pathology, said "Used
alone, they destroy new blood vessels but not all tumor cells that lurk
around established blood vessels. When treatment stops, even tumors
that shrink resume growth."
Dr.
Folkman and the Dana Farber team reported this fall that in endostatin
Phase I trials "one patient with a pancreatic neuroendocrine tumor
had a minor response and two patients showed disease stabilization."
At M.. D. Anderson, a team including Folkman's close colleague Michael
O'Reilly M.D. gave endostatin to 25 patients with advanced cancer.
Escalating doses produced "measurable effects on tumor blood flow
and metabolism." In two patients, "there was evidence of antitumor
activity, but no responses were seen."
Until today's announcement from EntreMed it looked as though this picture
might brighten as trials moved forward into Phase II where more patients
could receive an optimum or at least a ballpark dose. Researchers have
already found that adding angiogenesis inhibitors increases the efficacy
of some standard treatments (although this is liable to add side effects).
For patients dealing with non-symptomatic cancer, stable disease from
a non-toxic drug can be a tremendous benefit.
Folkman and tumor biologist Robert Kerbel Ph.D. defend the value of
"stable disease" in an
article published this week in Nature Reviews Cancer (NRC). Folkman
says that "clinical end points" that apply to conventional
drugs (such as old-fashioned chemotherapies) "do not always apply
to anti-angiogenic therapy." A chemotherapy drug that gives stable
disease is a relative failure, Folkman and Kerbal say, because tumors
eventually become drug-resistant to it and to all similar drugs; then
exponential growth resumes. With anti-angiogenesis drugs, acquired resistance,
Folkman says, might not arise. If so, patients could stay in remission
for extended periods of time.
But this puts angiogenesis inhibitors in a less glamorous category
for investors. This September, the FDA awarded
EntreMed Inc.an orphan drug grant of $300,000 per year for three
consecutive years to cover clinical and administrative costs associated
with the Phase II endostatin trial in patients with neuroendocrine tumors.
This trial was to be conducted at Dana-Farber/Partners CancerCare in
Boston and University of California at San Francisco (UCSF). The FDA
had already granted orphan drug status for the treatment of patients
with malignant metastatic melanoma (MM). FDA money does not cover the
cost of manufacturing endostatin. The company has promised that ongoing
tests of angiostatin and endostatin will be completed and cancer patients
who have been promised supplies of the drug will continue to receive
them for as long as they need.
Dr. Edward Gubish, EntreMed's President and Chief Operating Officer,
announced four days before the FDA award that he would step down. Dr.
John W. Holaday Ph.D., CEO and Chief Scientific Officer, emphasized
the plans to cut costs but said the company would stay "on schedule
for the development of our clinical drug candidates -- endostatin, angiostatin
and Panzem(TM)." He said that due to "strategic manufacturing
measures taken late last year, we have ample supply of clinical drug
material on-hand to support current and planned trials through 2003
and anticipate no significant associated cash expenditures for the remainder
of this year. These actions reflect our continued commitment to bring
these candidates to market and increase shareholder value."
In early November the company announced that it would appeal to stop
Nasdaq delisting its common stock. The company's secure worth had dropped
in market value to below the necessary $50 million. Holaday relinquished
his title as CEO. EntreMed's stock continues
to fall and the company is considered to be at high risk.
As the biopharmaceutical company entrusted with his discoveries fights
for its own survival, Dr. Judah Folkman maintains faith in the science
behind the drugs. To test angiogenesis inhibitors properly on humans,
Folkman and Kerbel say, clinicians need to learn from the scientists.
Success depends on "transfer of expertise from scientists who are
familiar with the biology of angiogenesis." Folkman calls for application
of these principles:
- Differentiate between direct and indirect angiogenesis inhibitors.
[View Figure
1 Direct
and indirect angiogenesis inhibitors and Tables
1:DIRECT
and 2:INDIRECT]
- Realize that the microvascular endothelial cell is a genetically
stable target of anti-angiogenic therapy.
- Understand that slowly growing tumors, which are more difficult
to treat by chemotherapy, respond well to anti-angiogenic therapy.
- Appreciate that rapidly growing tumors require higher doses of
an angiogenesis inhibitor.
- Angiogenesis inhibitors are most effective when administered on
a dose-schedule that maintains a constant concentration in the circulation
instead of a schedule in which therapy is periodically discontinued.
Animal studies reveal that many angiogenesis inhibitors are most effective
when administered by a dose and schedule that maintains a constant
concentration of the inhibitor in the circulation, rather than a once-daily
therapy.
- A current unsolved problem in anti-angiogenic therapy is the lack
of surrogate markers for therapeutic efficacy. Whether quantification
of circulating progenitor endothelial
cells will become an indicator of efficacy remains to be shown.
- When various angiogenesis inhibitors become available for clinical
use in cancer patients, these new therapeutic agents might be added
to chemotherapy or to radiotherapy
or used in combination with immunotherapy or vaccine therapy.
Read the article: Nature Reviews Cancer
2, 727-739 (2002): CLINICAL
TRANSLATION OF ANGIOGENESIS INHIBITORS Robert Kerbel &
Judah Folkman, Nature Reviews Cancer 2, 727-739 (2002). To access articles
at this site you register e-mail address and password.
Dr. Robert Kerbel is a tumor biologist who has been studying aspects
of cancer metastasis, drug resistance and tumor angiogenesis for more
than 25 years. He received his Ph.D. in 1972 and currently holds a Canada
Research Chair in Molecular Medicine at the University of Toronto, Department
of Medical Biophysics, and Sunnybrook and Women's College Health Sciences
Center, Molecular and Cell Biology Research. His main interests in tumor
angiogenesis include defining the role of oncogenes, and the anti-angiogenic
effects of various oncogene targeting signal-transduction inhibitor
drugs, and the use of conventional chemotherapeutic drugs as anti-angiogenic
agents, especially when administered frequently at low dose  that is,
'metronomically.'
Judah Folkman M.D. is the founder of the field of angiogenesis
research. He received his M.D. from Harvard Medical School in 1957 and
served as Surgeon-in-Chief of the Children's Hospital in Boston from
1967 to 1981, when he stepped down to devote his full time to research.
He is currently Director of the Surgical Research Laboratory at Children's
Hospital, and he is the Andrus Professor of Pediatric Surgery and Professor
of Cell Biology at Harvard Medical School. At present, he is studying
the angiogenic mechanisms of persistent dormancy in human tumors, the
endogenous inhibitors of angiogenesis and the molecular regulation of
lymphangiogenesis.
Comments:
In Europe,
physicians are now being discouraged from prescribing chemotherapy.
Medical isotopes, short-lived, short-acting forms of radiation, are
placed within or adjacent to the cancer, or bonded to immune system
carriers, like peptides (portions of proteins) or monoclonal antibodies
that target cancer cell surface receptor sites. Healthy tissue is
spared. Many patients who have failed other therapies respond. Metastatic
prostate cancer, liver, pancreatic, neuroendocrine, and other cancers
respond best with combination therapies - perhaps antiangiogensis
to shrink tumors, and targeted medical isotopes to "zap" remaining
cancer cells.
I am
the NW Chair, National Assoc. of Cancer Patients (and National Cancer
Institute Consumer Advocate for Research and Related Activities).
Contributed by [email protected]
(Marlene Oliver) on November 16, 2002.
Add/View
More Comments to this page. Or visit FORUM
E-mail
[email protected] 
