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Millennium acquires rights to proteasome inhibitors and related synthesis techonology - agreement to augment company's proteasome inhibitor program-.

Millennium Pharmaceuticals, Inc. (Cambridge, MA) today announced it has signed a research agreement with Harvard University and Professor E.J. Corey for a family of proteasome inhibitors and a related chemical synthesis process. Millennium intends to utilize the agreement to enhance the Company's ongoing efforts to develop next-generation proteasome inhibitors, building upon the success of its first-in-class proteasome inhibitor, VELCADE(R) (bortezomib) for Injection.

"As the world leader in the field of proteasome inhibition, this collaboration represents an exciting opportunity for us to enhance our unparalleled knowledge base and further explore the biology and chemistry surrounding the proteasome," said Robert Tepper, M.D., president, research and development at Millennium. "Following the extraordinary success of VELCADE, which is being used to treat relapsed and refractory multiple myeloma patients and is being explored as a potential treatment for non-Hodgkin's lymphoma, lung cancer and other malignancies, Millennium is committed to expanding its second-generation proteasome inhibitor program."

Under the terms of the agreement, Harvard grants Millennium certain rights to intellectual property and inventions for development of proteasome inhibitors utilizing a chemical synthesis process developed by E.J. Corey, Sheldon Emery Professor of Chemistry, Harvard University, the 1990 Nobel laureate in chemistry and the recipient of the 2004 Priestley Medal. Millennium will pay milestone fees and royalties to Harvard on net sales of products resulting from the agreement. Additional financial terms were not disclosed.

Professor Corey's synthetic process now enables the production, in substantial quantities, of a wide variety of novel chemical analogues related to known proteasome inhibitors. Prior to the development of Professor Corey's flexible chemical synthesis process, the ability to easily make analogues of certain classes of known proteasome inhibitors for drug discovery and development was constrained by reliance on fermentation-based production or less effective synthetic processes.

"It is my hope that the researchers at Millennium will succeed in translating the fundamental scientific advances made by my group at Harvard into new medicines for people in need, in continuation of their pioneering development of proteasome-inhibiting therapeutics," said Professor Corey.

The collaboration will marry the synthetic chemistry expertise of the Corey laboratory at Harvard University with the extensive knowledge of the biology, pharmacology and clinical features of proteasome inhibition that is resident at Millennium. Ideally, the combined research efforts will yield new proteasome inhibitors with highly desirable properties for drug development such as oral bioavailability, enhanced efficacy and improved safety.

Millennium is a world leader in the development of proteasome inhibition, a new and potentially significant strategy in cancer treatment. The proteasome is an enzyme complex found within the cytoplasm of cells. Evidence suggests that it serves both as a disposal system for damaged cellular proteins and as a mechanism for degrading short-lived regulatory proteins that govern cellular functions such as the cell cycle, cell growth, and differentiation. Because these processes or their dysregulation are crucial steps in tumor formation, the proteasome pathway is a logical target for therapeutic intervention. In laboratory studies, proteasome inhibition appears to: impede cancer cell proliferation by preventing the breakdown of certain valuable proteins and transcription factors that are known to hinder cancer cell growth; reduce the survivability of cancer cells by inactivating certain genes and proteins that help cancer cells survive chemotherapy; and cause cancer cell death by producing extreme cellular stress in tumor cells through disruption of cell proliferation.

VELCADE, the first of a new class of medicines called proteasome inhibitors, is the first treatment in more than a decade to be approved for patients with multiple myeloma -- a cancer of the blood. Millennium received approval from the U.S. Food and Drug Administration (FDA) on May 13, 2003 to market VELCADE for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. The effectiveness of VELCADE is based on response rates. There are no controlled trials demonstrating a clinical benefit such as an improvement in survival. On April, 27, 2004, the European Commission granted marketing

authorization for VELCADE for the treatment of patients with multiple myeloma who have received at least two prior therapies and have demonstrated disease progression on their last therapy.

VELCADE is being co-developed by Millennium and Johnson & Johnson Pharmaceutical Research & Development; Millennium is responsible for commercialization of VELCADE in the U.S.; Ortho Biotech and Janssen-Cilag are responsible for commercialization in Europe and the rest of the world. Janssen Pharmaceutical K.K. will be responsible for Japan upon approval.

VELCADE(R) (bortezomib) for Injection has a generally predictable, manageable safety profile (with appropriate monitoring and, if necessary, dose modification). VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

Risks associated with VELCADE therapy include new or worsening peripheral neuropathy, orthostatic hypotension, congestive heart failure, gastrointestinal adverse events, thrombocytopenia, and tumor lysis syndrome. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Complete blood counts should be frequently monitored during VELCADE treatment.

In 228 patients who were treated with VELCADE 1.3 mg/m(2)/dose in phase II studies, the most commonly reported adverse events were asthenic conditions (65 percent), nausea (64 percent), diarrhea (51 percent), decreased appetite including anorexia (43 percent), constipation (43 percent), thrombocytopenia (43 percent), peripheral neuropathy (37 percent), pyrexia (36 percent), vomiting (36 percent), and anemia (32 percent). Fourteen percent of patients experienced at least one episode of Grade 4 toxicity, with the most common toxicities being thrombocytopenia (3 percent) and neutropenia (3 percent). A total of 113 (50 percent) of the 228 patients experienced Serious Adverse

Events (SAEs) during studies. The most commonly reported SAEs included pyrexia (7 percent), pneumonia (7 percent), diarrhea (6 percent), vomiting (5 percent), dehydration (5 percent), and nausea (4 percent).

Millennium markets VELCADE(R) (bortezomib) for Injection, a novel cancer product, co-promotes INTEGRILIN(R) (eptifibatide) Injection, a market-leading cardiovascular product, and has a robust clinical development pipeline of product candidates. The Company's research, development and commercialization activities are focused in three therapeutic areas: oncology, cardiovascular, and inflammation. By applying its knowledge of the human genome, its understanding of disease mechanisms, and its industrialized drug discovery platform, Millennium is seeking to develop breakthrough products.

Millennium Pharmaceuticals, Inc.

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Title Annotation:Millennium Pharmaceuticals Inc.
Publication:BIOTECH Patent News
Geographic Code:1USA
Date:May 1, 2004
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