Endostatin's Luster Dims, EntreMed Slides

Folkman Urges Doctors, Learn from Scientists

by JACQUELINE STRAX

Patient receiving a trial drug at U of Wisconsin Comprehensive Cancer Center, one of the clinics where endostatin has been tested in a Phase I trial.

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. Baltimore Sun, Nov 7, 2002.

Early Endostatin Results Show Promise NCI 11/09/2000

Angiogenesis Inhibitors in Clinical Trials NCI Chart, link reverified 12/27/2005

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 hemorrhage 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 endostatin 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 inhibitorsand 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.

Update: [Cancer Research 63, 8890-8898, December 15, 2003] Combined Therapy with Direct and Indirect Angiogenesis Inhibition Results in Enhanced Antiangiogenic and Antitumor Effects

Peter Huber et al.

Diagram adapted from Angiogenesis Research: Guidelines for Translation to Clinical ApplicationJudah Folkman, Timothy Browder, Jan Palmblad reprinted online at Clinica Y Laboratorio Biotrechnologico, Uruguay

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 Antiangiogenesis 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 Marlene Oliver on November 16, 2002.

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This page last updated September 30, 2005, by J. Strax

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