Latest Developments in Shark Cartilage Technology

Liquid Shark Cartilage Extracts Show Encouraging Results Without Serious Side Effects Related To Oral Administration.

On March 26, 2001, Æterna Laboratories, a leading Canadian biotechnology company, reported that phase I/II data indicate that a high dose of the company's oral antiangiogenesis product Neovastat doubles the median survival time for patients with refractory metastatic kidney cancer. This press release, as published on The Huntsman Cancer Institute at the University of Utah Web Site (as reported by Reuters Health Information) follows:

Phase I/II data show shark Cartilage extract effective against kidney cancer.
NEW YORK (Reuters Health) - Canadian biopharmaceutical firm Æterna Laboratories reported on Monday that phase I/II data indicate that a high dose of the company's oral antiangiogenesis product Neovastat doubles the median survival time for patients with refractory metastatic kidney cancer.
In the trial, 22 such patients received either a 30-mL or 120-mL dose of Neovastat, a shark Cartilage extract, twice daily. The median survival time of patients on the lower dose was 7.1 months, versus 16.3 months with the higher dose.
The average survival time of a refractory metastatic kidney cancer patient without treatment is 8 months, according to Æterna.
In light of these and earlier clinical results, patients in the treatment arm of an ongoing phase III placebo-controlled trial of Neovastat for refractory metastatic kidney cancer will receive the daily 240 mL dose, a company spokesman told Reuters Health.
This trial, expected to conclude in late 2002, will enroll about 250 patients, the spokesman said. If the data from this trial are positive, he said, an application for marketing approval for the drug will be filed concurrently with US, Canadian and European regulators.

Neovastat is also under phase III and phase II investigation for lung cancer and multiple myeloma, respectively. The myeloma trial is expected to conclude in late 2002, with the lung cancer trial ending around 2005.

Æterna’s Liquid Shark Cartilage Extracrt (Neovastat) Shows Ability To Increase The Angiostatin Level In Mice With Implanted Human Brain Cancer Cells.

On May 14, 2001, Æterna Laboratories issued the following press release:

San Francisco, California – Today, Æterna Laboratories Inc. presented new data showing that Neovastat/Æ-941 is able to increase the level of angiostatin in mice with implanted human glioblastoma, a form of brain cancer. Results on this additional mechanism of action of Neovastat were presented in San Francisco at the American Society of Clinical Oncology (ASCO) Annual Meeting on “New Drugs in Cancer Therapy” by Professor François Berger, MD, PhD, neuro-oncologist and investigator of this study at the Institut national de la santé et de la recherche médicale (INSERM), in Grenoble, France.
The study consisted in injecting human glioblastoma cells (cancer cells) into the brain of nude mice. The mice were then given Neovastat in order to test its antitumoral activity. Not only did results show an antitumoral activity in Neovastat, but it also uncovered a new element of its activity which increases tissue type Plasminogen activator (tPA), an enzyme involved in the production of angiostatin. This increased tPA activity resulted in an increase in endogenous (produced by the body) angiostatin at the tumor site.
“These results are significant since this model is very aggressive and few agents are capable of improving survival time,” declared Dr. Berger. “Neovastat’s activation of tPA translates into a multifunctional impact including inhibition of angiogenesis and tumor infiltration. These two effects might have an important contribution in improving survival in this model.”
“Glioblastomas are one of the most vascularized tumor and are VEGF-dependent. The use of an antiangiogenic agent containing several mechanisms of action, such as Neovastat, may prove effective in increasing survival time in glioblastoma patients,” added Dr. Berger.

“Neovastat does not contain angiostatin, but rather agents which induce the production of endogenous angiostatin at the tumor site,” said Dr. Pierre Falardeau, Æterna’s Vice President of Scientific Affairs. “This particular mechanism of action further strengthens Neovastat’s position as a unique angiogenesis inhibitor with multiple mechanisms of action since it has been previously shown to block the VEGF (Vascular Endothelial Growth Factor) signaling pathway, selectively inhibit matrix metalloproteinases (MMPs 2, 9 and 12) and induce endothelial cell apoptosis (programmed cell death). Therefore, instead of blocking only one of the multistep process of angiogenesis, Neovastat’s several mechanisms of action could act together in a synergistic fashion to induce a more complete inhibition of angiogenesis,” concluded Dr. Falardeau.
About Æterna and Neovastat/Æ-941
Æterna Laboratories Inc. is a Canadian biopharmaceutical company and a frontrunner in the field of antiangiogenesis. Its lead product, Neovastat/Æ-941, is being investigated in three major therapeutic areas: oncology, dermatology and ophthalmology.
Neovastat is a novel antiangiogenic product with multiple mechanisms of action that block angiogenesis — the process involved in the formation of new blood vessels which are needed in order for cancer tumors and other pathological conditions to develop.
Neovastat is currently used in two Phase III pivotal clinical trials for the treatment of lung and kidney cancer as well as in a Phase II pivotal trial for the treatment of multiple myeloma, a form of blood cancer. These trials are currently held in more than 125 clinical institutions in Canada, the U.S. and in several European countries.

Æterna has completed patient recruitment for its international Phase III clinical trial in kidney cancer.

On December 18, 2001 – Æterna Laboratories Inc., issued the following press release:

Quebec City, December 18, 2001 – Æterna Laboratories Inc., has completed patient recruitment for its international Phase III clinical trial in renal cell carcinoma. Some 280 patients are taking part in this trial at 50 investigative centres in 10 different countries in America and Europe. Conducted by an international team of oncology experts, the study aims to determine whether Neovastat can increase survival time in patients who have failed to respond to standard immunotherapy treatments. Trial results are expected in early 2003.

The announcement was made by Dr. Claude Hariton, Vice President, Clinical and Regulatory Affairs at Æterna during the company's Scientific Advisory Board meeting in Quebec City.

"We have reached a crucial milestone in Neovastat's clinical development program. It was of the utmost importance to complete patient recruitment within the set timelines in order to avoid any delays of this international study," said Dr. Hearten. "Neovastat is part of a late-stage clinical development program in oncology, which has already yielded encouraging safety and efficacy data in Phase II clinical trials, mainly in improving survival."
The lead investigators for this study are Dr. Gerald Batist, Director of the McGill Centre for Translational Research in Cancer and Professor at the Department of Oncology and Medicine at McGill University, Montreal, in Canada, Dr. Ronald Bukowski, Director of Experimental Therapeutics Program at the Cleveland Clinic Cancer Center in the United States, and Dr. Bernard Escudier, Head of Immunotherapy and Innovative Therapy Unit at the Institut Gustave Roussy in Villejuif, France, in Europe. All three of them expressed their satisfaction in the successful recruitment. "We wish to thank the oncologists on both continents for their remarkable work in recruiting patients at such a fast pace. Such a commitment from the international medical community is very encouraging. We are very much aware that this study allows us all the opportunity to participate in the development of a unique drug in a new and exciting therapeutic class of anticancer agents."

Dr. Hariton also presented the conclusions of the Data Safety Monitoring Board, an independent body of oncologists, which is responsible for evaluating patient safety and ensuring the integrity of this international Phase III trial in renal cell carcinoma. The Board stated that the safety profile of the study drug is acceptable to allow the trial to continue without adjustment.

According to Gilles Gagnon, Vice President and Chief Operating Officer at Æterna, "Our ability to conduct the clinical development program as scheduled, reinforces Æterna's status as possibly one of the first companies to bring an angiogenesis inhibitor to market."
About renal cell carcinoma and Neovastat ongoing trial Renal cell carcinoma is the most common type of kidney cancer in adults. There are about 34,000 new cases of renal cell carcinoma in North America each year and about 38,000 new cases in Europe. The five-year mortality rate for this disease is approximately 90%. The therapies currently available are effective in less than 20% of the cases and are associated with a large number of serious side effects.
Æterna's Phase III renal cell carcinoma cancer trial involves some 280 patients who have failed to respond to standard immunotherapy treatments. Patients will fall into one of two groups: one will be given Neovastat, while the second group will be given a placebo. Results of the trial which is currently conducted in 10 countries in America and Europe, are expected in early 2003.

About Æterna and Neovastat

Æterna Laboratories Inc. is a Canadian biopharmaceutical company and a leader in the field of angiogenesis inhibitors. The Company's efforts are mainly focused on developing new cancer therapies. Æterna's lead compound, Neovastat, is currently undergoing two Phase III clinical trials for the treatment of lung and kidney cancer, and one Phase II trial for treatment of multiple myeloma, a form of blood cancer. These clinical trials are currently being held in more than 140 clinical institutions in America and Europe. Covance has been selected as the Contract Research Organization for ensuring the world-wide monitoring of the renal cell carcinoma and multiple myeloma trials.

Two Significant Patents Dealing with the Anti-Tumoral Activities of Shark Cartilage Extracts Were Issued by The US Patent Office in February of 2000

In February of 2000, US Patent No. 6,025,334 (Dupont, et. al,; Extracts of shark Cartilage having anti-collagenolytic, anti-inflammatory, anti-angiogenic and anti-tumoral activities; process of making, methods of using and compositions thereof; February 15, 2000) and US Patent No. 6,028,118 (Dupont, et. al; Methods of using extracts of shark Cartilage ; February 22, 2000) were issued by US Patent Office. (Click on the Patent No. to view the full text of the Patents)

These patents, which were originally filed in 1995 and 1996, seem to provide further evidence of the anti-tumoral activities of shark Cartilage extracts. Concerning the Anti-Angiogenic effect of the shark Cartilage extract which was the subject of the patents, the abstract of the patents included the following encouraging observations:

ANTI-ANGIOGENIC EFFECT

The concentrated permeate was used for treating angiogenesis-dependent diseases. Three different types representative of angiogenesis-dependent diseases were tested in practice in human; the first type being cancer (prostate cancer), the second type being dermatological disorders (psoriasis), and the third type being arthritis. The examples below will illustrate and indicate at least the antiangiogenic activity of the liquid extract.

Among dermatological diseases, psoriasis cases were selected. Among the psoriasis cases tested, it is worthwhile noting a difference between psoriasis cases complicated by hyperkeratosis and non-complicated ones. The keratosis component is the formation of cornified envelope in the form of a plaque. Such a plaque is a physical barrier which impedes the efficient penetration of the active ingredients towards the blood vessels.
A patient suffering of a prostate cancer has voluntary tried a 10 fold-concentrated Cartilage permeate. This patient underwent a series of successive conventional therapies that were temporarily successful. He recently began to consume the Cartilage extract after his cancer showed recidivism. Other volunteers suffering of arthritis and having previously taken medication (prednisone) or not started consuming a concentrated Cartilage extract. Their condition improved as verified by the reduction of pain and stiffness in the joints.

The results shown herein below are very encouraging and are deemed predictive of the usefulness of the crude permeate and fractions thereof in the treatment of all angiogenesis-dependent diseases, and not only to the ones specifically tested. Insofar as a disease has an angiogenic component, it is deemed that the Cartilage extract of the present invention will be effective in this respect provided that it enters a composition containing an effective amount thereof and that this composition is in a suitable form for proper administration.

Traponin I identified as an Anti-Tumor Compound

In late 1999, researchers, Marcia Moses, Robert Langer and their colleagues at children's Hospital in Boston and at the Massachusetts Institute of Technology, reported that that when purified, a protein in Cartilage makes it a powerful anti-tumor compound placing it on a long list of angiogenesis inhibitors under investigation for treating cancer because they starve cancerous tumors by eliminating the tumors's ability to form a vascular system. The newest discovery involves an inhibitory protein that was identified by peptide microsequencing and protein database analysis as Traponin I. The researchers tested the purified substance and found it worked in "a very profound way," Langer said. For example in mice infected with lung cancer, the compound worked against nearly all of the tumors.

The research results have been patented and licensed to Boston Life Sciences, a biotechnology company. "The whole popular notion of there being something in shark Cartilage originated with this work," which began in the 1980s said company founder Marc Langer. Human trials on Troponin I could come this year Lancer also said.

The researcher's findings were published in the Proceedings of the National Academy of Science.

BioTherapies, Inc. Announces Development of Oral Shark Cartilage Extract

BioTherapies Inc. of Fairfield New Jersey, makers of Cartilade Brand Shark Cartilage rejoiced at the recent confirmation by researchers at the Massachusetts Institute of Technology that shark Cartilage contains active anti-cancer principles. BioTherapies Inc. (formerly Cartilage Technologies Inc.) has manufactured and sold Cartilade in the retail market for the past seven years. Cartilade was the first shark Cartilage product ever sold with consistent proprietary manufacturing and is the world's leading brand of shark Cartilage .

BioTherapies Inc. and Cartilage Technologies Inc., have, for several years, held the patent rights for shark Cartilage as an inhibitor of angiogenesis, a process of unwanted blood vessel growth in several diseases including cancer. Cartilade, a 100% pure shark Cartilage product, was used in clinical trials for cancer in Cuba. These trials using Cartilade fueled widespread interest in shark Cartilage as a potential cancer cure after they were reported by Mike Wallace on the TV show "60 Minutes" in 1994.

In keeping with their continued research and development of innovative Shark Cartilage technologies, BioTherapies has recently announced the development of Cartilade LED, a liquid shark Cartilage extract for which there currently is a patent pending. Cartilade LED is a hydrosoluble extract of Cartilage (100% Cartilade shark Cartilage ) containing Cartilage proteins and complex polysaccharides from shark Cartilage . Available as a dietary supplement, Cartilade LED is available in a 10 fluid ounce bottle. The suggested dosage is one third fluid ounce per day, meaning that one 10-ounce bottle will constitute a 30-day supply. The retail price of the Cartilade LED is $99.

According to Stephen Holt, M.D., the author of The Power of Cartilage : "For many years shark Cartilage has been known to contain antiangiogenic proteins, but there has been an issue about the ability of these proteins to enter the body when shark Cartilage is administered by the oral route." Dr. Holt believes that the inconsistent response to the oral administration of powdered shark Cartilage in some cancer clinical trials may have been related to unpredictable and variable absorption of the active, anti-cancer principles that are present in powdered shark Cartilage . BioTherapies Inc., developed their Cartilade LED to enhance the oral delivery of Cartilade to help ensure better absorption of active constituents.

BioTherapies is planning new clinical trials with oral Cartilade LED in a format that may help enhance absorption and they are approaching the pharmaceutical industry and the biotechnology industry for assistance in further researching the potential benefits of Cartilade LED. Mr. Richard McNall, Vice President of Sales and Marketing at BioTherapies/Cartilage Technologies Inc. stated: "Our company is delighted by the news that Cartilage protein may form the basis of a credible cancer cure. The reports in the Proceedings of the National Academy of Sciences by Harvard researchers have given people new hope and the involvement of the company Boston Life Sciences and others is a real boost to natural health care."

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