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Preclinical Study Published in Today's Issue of Science Cites Potency of aaATIII Discovered by Folkman, O'ReillyGenzyme Molecular Oncology Announces Previously Undisclosed Antiangiogenic CompoundSept. 16,1999 -- Genzyme /WiredBird/ Genzyme Molecular Oncology (Nasdaq: GZMO) announced today that preclinical data on the antiangiogenic activity of aaATIII - an antiangiogenic conformation of antithrombin III - to treat cancer in mice has been published in today's issue of Science. aaATIII is the previously undisclosed antiangiogenesis protein exclusively licensed by Genzyme Molecular Oncology from Children's Hospital Medical Center in Boston in February of this year. Development of aaATIII is the basis of a planned collaboration between Genzyme Molecular Oncology and the ATIII LLC, the joint venture between Genzyme Transgenics (Nasdaq: GZTC) and Genzyme General (Nasdaq: GENZ), (see companion press release). Antithrombin III (ATIII) is a protein normally found in human plasma that helps regulate blood clotting. A change in the shape of ATIII, induced by contact with heat or enzymes, has been shown by Dr. Michael S. O'Reilly, M.D., research fellow in Dr. Judah Folkman's laboratory at Children's Hospital, Dr. Folkman, director of the Surgical Research Laboratories, and their team of scientists, to cause the protein to become an angiogenesis inhibitor. Their paper, entitled "Antiangiogenesis: A novel activity for the cleaved conformation of the serpin antithrombin III," states results of Drs. Folkman and O'Reilly,s preclinical studies of aaATIII, which showed that the protein produced a potent and sustained inhibition of angiogenesis in mice and subsequent tumor regression. Results also showed that in the animal models and cell cultures described, aaATIII produced no toxic side effects or inflammatory reaction at any dose. Drs. Folkman and O'Reilly found that aaATIII "significantly and specifically inhibits capillary endothelial cell growth in cell culture in a dose-dependent manner." Endothelial cells are the cells that line all blood vessels and that are required for new blood vessel formation to occur. The efficacy of aaATIII was tested in two animal models - SK-NAS neuroblastoma and Lewis lung carcinoma. Mice with these tumors were treated with daily injections of the different conformations of ATIII. Data show that the aaATIII conformation substantially inhibited tumor growth in a dose dependent manner - that is, the higher dose produced greater tumor regression. Tumors regressed to small subcutaneous nodules without evidence of bleeding or toxicity. In contrast, tumors in the control groups were highly vascularized and tumor growth was not significantly affected. These animal studies suggest that the potency of aaATIII is at least comparable to that of angiostatin and endostatin, two other naturally occurring protein inhibitors of tumor angiogenesis previously described by Drs. Folkman and O'Reilly. Indeed, in characterizing the tumor regression achieved with aaATIII in the SK-NAS neuroblastoma animal model, the paper states, "This same pattern of regression of established tumors has been demonstrated previously for human angiostatin and endostatin but required substantially higher and more frequent dosing." However, the optimal dosing regimens of all three compounds have not yet been determined in humans.Mark Goldberg, Genzyme vice president, medical affairs for oncology, said, "The data provided by Drs. Folkman and O'Reilly show exciting promise for the development of aaATIII as a novel therapy to treat cancer. Access to the expertise of Drs. Folkman and O'Reilly, coupled with the ATIII LLC's ability to rapidly produce large quantities of the protein, allows us to contemplate an innovative trial design for aaATIII. Pending successful completion of replication and preclinical studies, we could file our IND for aaATIII clinical trials as early as 2000.". Genzyme Molecular Oncology is pursuing multiple approaches to promote antiangiogenesis, including the use of proteins, small molecules, and gene therapies. It believes that multiple antiangiogenic compounds will likely be used together to elicit the most potent antiangiogenic response. Genzyme Molecular Oncology has assembled a product development platform that includes integrated technologies, academic and commercial collaborations, and access to the expertise of Genzyme Corporation in clinical development, regulatory affairs, manufacturing, and marketing. Genzyme Molecular Oncology is developing a new generation of cancer products, focusing on cancer vaccines and angiogenesis inhibitors. It has completed two phase I cancer vaccine trials in melanoma, initiated a phase I/II melanoma cancer vaccine trial and a phase I breast cancer vaccine trial, and plans to begin an ovarian cancer vaccine trial in the next year. Genzyme Molecular Oncology is developing novel cancer products through the integration of its gene discovery, gene therapy, small-molecule drug discovery, protein therapeutic and genetic diagnostic efforts. A division of Genzyme Corporation, Genzyme Molecular Oncology has its own common stock intended to reflect its economic value and track its performance. This press release contains forward-looking statements, including statements concerning expectations for the formation of an aaATIII research collaboration, scale-up of production of aaATIII and the adequacy of supplies of aaATIII for development efforts, the anticipated filing of an IND for aaATIII, the planned initiation of clinical trials of aaATIII and an ovarian cancer vaccine, and the ability of aaATIII to successfully treat cancer. Actual results may materially differ due to numerous factors, including the ability of the companies to negotiate and execute a definitive collaboration agreement, successfully replicate Dr. Folkman's experiments and complete preclinical studies, and to produce adequate quantities of aaATIII for development activities, the timing and content of submissions to and decisions by the FDA and other regulatory authorities, and the enrollment rate of clinical trials and other results of those trials. Genzyme Molecular Oncology will broadcast live over the Internet a conference call discussing this announcement at 9:00 a.m. ET tomorrow, September 17. To access the call you need RealPlayer , a computer equipped with speakers, and a sound card. If you miss the live call, the broadcast will be archived through midnight ET on September 30. Investors may also listen to a replay of the conference call by calling 1-800-633-8284 in the United States or 1-619-812-6440 outside the United States from 11:00 a.m. ET tomorrow through midnight ET on September 30. Please refer to reservation #13131298.
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