Angiocol™

Discovery of Angiocol™

Cancer tumors secrete molecules that stimulate surrounding tissues to develop new blood vessels, providing additional blood flow to the tumor. The process of capillary growth and development from pre-existing blood vessels is referred to as angiogenesis. Without an increased blood supply, the growth of a tumor would be substantially limited. A key step in the angiogenesis process is the synthesis of new vascular basal lamina, which is required to support and direct the growth and development of new capillaries.

The process of angiogenesis begins with the activation
of vascular endothelial cells and their degradation of the vascular basement membrane and blood vessel wall. These activated cells then migrate outside the blood vessel where they proliferate and begin to form tube-like structures.
As a new capillary begins to take shape, the cells begin
to secrete basal lamina components, and a new basal lamina begins to form around the developing capillary.
The completion of a viable capillary depends on the synthesis and assembly of a biologically active basal lamina. Without a basal lamina, a viable capillary wall
will not form, and the cells will not engage in binding interaction with the basal lamina that directs the cells
to a stable cell phenotype of the vascular lining.

An important focus of basal lamina research is the study
of how Type IV collagen and laminin components assemble into a functional, biologically active membrane structure. In conducting such studies, BioStratum scientists discovered that the introduction of a portion of the type IV collagen molecule, referred to as the non-collaganeous domain, or NC1 domain, interrupted basal lamina assembly. Realizing the requirement for an organized and functionally active basal lamina in the angiogenesis process, we examined the NC1 domain for possible anti-angiogenesis activity.
We found three of the six known Type IV collagen NC1 domains to exhibit potent anti-angiogenesis activity. The name Angiocol™ has been assigned to our lead drug candidate in this field.

Preclinical Studies

We have evaluated Angiocol™ in a number of angiogenesis models systems, including a chimera tumor model that uses grafted human skin on NUDE mice, followed by
the implantation of human melanoma tumors. In these systems, Angiocol™ exhibits a 50 to 80 percent inhibition of both angiogenesis and tumor growth. Tumors studied to date include CS-1 melanoma, B-16 melanoma, M21 human melanoma and HT1080 human fibrosarcoma.

Clinical Development

The Company has initiated preclinical toxicology and we expect to file an investigational new drug application (IND) in 2001. Phase I trials should commence soon thereafter.

Phase I trials will examine the safety of increasing intravenous doses of Angiocol™ in cancer patients who have previously received various modalities of anticancer treatment, but have not been cured. We will also monitor these patients for tumor shrinkage over a period of 6 to 8 weeks. We expect to enroll approximately 30 to 40 patients in the Phase I trial.

Because Angiocol™ is an endogenous substance, it is expected that patients will experience little if any toxicity. This is in contrast to traditional cytotoxic drugs that have been used as cancer chemotherapeutics for decades, and which generally cause severe morbidity. This anticipated lack of toxicity makes Angiocol™ an ideal drug to combine with cytotoxic agents to treat cancer. The Company believes such combination regimens have the best chance of demonstrating anticancer activity in relatively healthy patients. Therefore, we expect that the planned Phase II clinical trial of Angiocol™ will be conducted in combination with other drugs in patients who are undergoing chemotherapy for the first time.

Market Analysis and Projections

We anticipate that Angiocol™ will be administered will be administered intravenously as an adjunct therapy in combination with other chemotherapeutic agents. Initial disease targets for Phase II clinical trials are colorectal and melanoma.

According to the most recent statistics reported by the American Cancer Society, 129,400 cases of colorectal cancer were diagnosed in 1999. Colorectal cancer is currently the third most common cancer in American
men and women, and in 1999 approximately 56,600
deaths will have been attributed to colorectal cancer.

Approximately 44,200 melanoma cases were diagnosed in the United States in 1999. The American Cancer Society estimates that approximately 7,300 deaths were associated with this disease in 1999. Due to the high
failure rate associated with surgical treatment, adjunct radiation therapy, chemotherapy and biological therapy
are often administered to these patients.

We anticipate that Angiocol™ will be administered on an intermittent schedule in association with chemotherapy or radiotherapy. The product will most likely be administered once or twice a week over the course of the treatment period, which is estimated to be six to twelve months. Given these assumptions, we expect the average treatment costs for Angiocol™ to be approximately $15,000 per patient per year.

Because Angiocol™ is an anti-angiogenesis agent whose mechanism of action is not specific for a particular type of cancer, if proven to be efficacious against melanoma and colorectal cancers, it is likely that it would be prescribed for most cancers. The Company believes that Angiocol's™ unique basal lamina-based mode of action will make it more effective than other drug candidates that are currently undergoing development in this area. Whereas most drug candidates target only one mode of action, Angiocol™, via its basal lamina-based mechanism, attacks several molecular processes involved in new blood vessel growth.