Millennium's LDP(PS)-341 inhibits growth and induces death of cancer cells, appears to overcome chemotherapy resistance

December 04, 2000

LDP-341 Press release and fact sheet on multiple myeloma:

-Clinical and preclinical data presented at American Society for Hematology Meeting-

-Additional clinical trials planned with National Cancer Institute -

San Francisco, Dec. 4, 2000 -- Millennium Pharmaceuticals, Inc. (Nasdaq: MLNM) today announced the presentation of preclinical and clinical study results demonstrating that an investigational proteasome inhibitor, LDP-341 (formerly PS-341), the first in a new class of anti-cancer agents, is active against multiple myeloma. The latest findings were presented at the 42nd Annual Meeting of the American Society of Hematology (ASH) meeting in San Francisco.

The first presentation, entitled "The Proteasome Inhibitor PS-341 Inhibits Growth, Induces Apoptosis and Overcomes Drug Resistance in Human Multiple Myeloma (MM) Cells," was based on research conducted by Teru Hideshima, M.D., Ph.D., and colleagues at Dana-Farber Cancer Institute and Harvard Medical School in collaboration with Millennium. In the preclinical study, LDP-341, a proprietary small molecule compound, showed in vitro activity against multiple myeloma cells, resulting in the inhibition of cancer cell growth and reproduction, and the inducement of cell suicide (apoptosis), in animals. The potent anti-tumor action of LDP-341 on multiple myeloma cells in these preclinical studies appears to involve both direct (apoptosis) and indirect inhibition of growth factors that promote tumor growth. In addition, in animals LDP-341 appears to increase the effectiveness of other anti-cancer drugs by overcoming cellular resistance, which in humans is a major cause of chemotherapy failure.

Clinical research was presented at the meeting by Thomas Stinchcombe, M.D., and principal investigator Robert Orlowski, M.D., Ph.D., in a report entitled "PS-341 is Active in Multiple Myeloma: Preliminary Report of a Phase I Trial of the Proteasome Inhibitor PS-341 in Patients with Hematologic Malignancies." Drs. Stinchcombe and Orlowski are affiliated with the University of North Carolina at Chapel Hill and performed the research in collaboration with colleagues and Millennium. The study presents data from a recent Phase I clinical trial. In the study of nine heavily pretreated patients with advanced hematological malignancies, three patients with multiple myeloma were treated with LDP-341 over a four-out-of-six week cycle. LDP-341 reduced serum myeloma protein levels and myeloma cell numbers in bone marrow in two of these three patients with advanced multiple myeloma. The drug was well-tolerated by these patients and in addition appears to have induced a complete response in one patient and a reduction in bone marrow plasma cells in another.

"The results are encouraging because clinically significant responses are rare in advanced stage, heavily pretreated patients. Preliminary findings support more advanced clinical studies to explore LDP-341's use in refractory treatment for multiple myeloma and other blood-borne cancers," said Dr. Orlowski.

According to Julian Adams, Ph.D., senior vice president, research and development of Millennium, LDP-341's novel mechanism of action and its role in the metabolism of a variety of proteins with critical cell function make it a promising candidate for the treatment of cancer. "Proteasome inhibition is a prime strategy for developing new therapeutic agents to combat solid tumor and hematologic cancers, such as multiple myeloma," says Dr. Adams. "Based on our findings, we will further explore the safety and efficacy of LDP-341 in numerous clinical trials as both a single agent and in combination with other chemotherapeutic agents. Millennium is committed to initiating additional studies in multiple myeloma in the coming months."

In addition to the studies discussed at the ASH meeting, the National Cancer Institute (NCI) is conducting an extensive program of LDP-341 clinical trials under a Cooperative Research and Development Agreement with Millennium. A number of Phase I trials of LDP-341 in combination with other chemotherapeutic agents are planned as well as Phase II studies. The first combination study, LDP-341 with 5-FU and leucovorin, was initiated at the University of Southern California, Norris Comprehensive Cancer Center, directed by principal investigator Heinz-Josef Lenz, M.D.

"Through its oncology franchise, Millennium is committed to developing safe, more effective cancer therapies," said Lee Brettman, M.D., senior vice president, clinical development and medical affairs, Millennium. According to Brettman, Millennium will examine the pharmacogenomic information derived from clinical studies with LDP-341 in the hopes of revealing the genetic controls for cancer cell responsivity or resistance to therapy. "Millennium may then use this data to develop DiagnomicÔ and pharmacogenomic tests to predict which patients will most likely respond to specific therapies," Dr. Brettman explained.

Multiple Myeloma

Multiple myeloma is a type of cancer characterized by the excessive growth of the immune system's plasma cells. More than 36,000 Americans have multiple myeloma and about 13,000 develop the cancer each year, according to the NCI. The disease is difficult to cure-the disease is associated with a 28 percent five-year survival rate and a 3 percent 10-year survival rate. (source: the Leukemia and Lymphoma Society and NCI.)

Multiple myeloma occurs when the immune system's plasma cells undergo abnormal uncontrolled growth and reproduction. Multiple myeloma cells prevent the marrow from forming normal plasma cells and other white blood cells important to the immune system. Patients with multiple myeloma may not be able to fight infection and disease and often have anemia, bone pain or fractures and numbness or weakness of limbs.

Many multiple myeloma patients pursue chemotherapy treatment to improve the quality of life by controlling symptoms and limiting disease complications. Multiple myeloma usually is treated by a combination of drug therapies, but some patients may receive radiation therapy, bone marrow transplants or surgery.

Proteasome Inhibition

In normal cells, the ubiquitin-proteasome pathway is responsible for the orderly breakdown of multiple proteins and thereby helps to define protein turnover rates. Proteasomes, large complexes of proteolytic enzymes, break down these intracellular proteins, recognizing them by their ubiquitin molecular tags. In addition to degrading unwanted proteins, the proteasome is involved in the generation of antigens and the regulation of cellular signals that govern growth and differentiation. In addition, proteasomes help generate antigens, which stimulate the production of antibodies.

Selective inhibition of proteasome activity has numerous effects, including attenuating the activity of NF-kB, the transcription factor that controls cellular inflammatory response. In tumor cells, proteasome inhibition produces overwhelming cellular stress by stabilizing cell cycle regulatory proteins and disrupting cell proliferation, ultimately leading to apoptosis.

Millennium's Oncology Franchise

Millennium's approach to personalized medicine is demonstrated through the development of a portfolio of breakthrough products comprised of both therapeutic (both small molecule and antibody) and predictive programs. Inflammation, oncology and metabolic disease comprise Millennium's three key research and development franchise areas. In addition to LDP-341, the Company has a number of oncology-based targets and compounds in various stages of development that span from discovery research to advanced clinical trials. These programs include the CAMPATHâ monoclonal antibody, a therapeutic owned by a joint venture of Millennium that is currently being evaluated by the Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia, the most prevalent adult form of leukemia. A Millennium alliance partner and licensee is in the process of developing and commercializing Melastatinä, a melastatin detection product developed through our predictive medicine efforts.

Millennium Predictive Medicine, Inc. (MPMx), a wholly owned subsidiary of Millennium, focuses on the development of Diagnomicä and pharmacogenomic products and services. Diagnomics are molecular diagnostics that describe a patient's current medical condition and provide prognostic and therapeutic information. Pharmacogenomic tests determine a patient's response to a specific therapeutic based on their genetic information. To identify the genetic markers that are key to these tests, MPMx leverages Millennium's integrated science and technology platform, including state-of-the-art transcriptional profiling and proteomics expertise.

Millennium, a leading biopharmaceutical company, applies its comprehensive and integrated science and technology platform for the discovery and development of breakthrough therapeutic and predictive medicine products, with a goal of delivering personalized medicine. Through the industrialization of this gene-to-patient platform, Millennium is also striving to accelerate the process of drug discovery and development. Headquartered in Cambridge, Mass., Millennium currently employs more than 1,200 people.

This press release contains "forward-looking statements," including Millennium's expectations of future industry conditions, strategic plans and forecasts of operational results. Various risks may cause Millennium's actual results to differ materially, including: uncertainties about its drug discovery and clinical development processes, uncertainties about obtaining patent protection for its discoveries and about the commercial limitations imposed by patents owned or controlled by third parties; Millennium's dependence upon strategic alliance partners to develop and commercialize products and services based on its work; uncertainties about obtaining regulatory approvals to market products and services resulting from its development efforts; and the requirement for substantial funding to conduct research and development and to expand commercialization activities. For a further list and description of such risks and uncertainties, see the reports filed by Millennium with the Securities and Exchange Commission. Millennium disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.
-end-
Editor's Note: This release is available on Millennium's Web site at:
www.mlnm.com

MULTIPLE MYELOMA FACT SHEET

The Multiple Myeloma Research Foundation estimates that approximately 50,000 Americans have multiple myeloma and about 13,000 develop the cancer each year. Multiple myeloma is the second most prevalent blood cancer and represents approximately 1 percent of all cancers (source: Multiple Myeloma Research Foundation). There is no known cure for multiple myeloma and the disease is associated with a five-year survival rate of 28 percent and a 10-year survival rate of 3 percent (sources: Leukemia and Lymphoma Society and the National Cancer Institute). According to the American Cancer Society, the average age of most multiple myeloma patients is 70 years. Multiple myeloma patients are more often African American and male than white or female (source: National Cancer Institute).

Explanation of Multiple Myeloma

Multiple myeloma is a cancer of the plasma cells. Plasma cells normally produce proteins called immunoglobulins or antibodies that destroy foreign bodies and disease-causing germs. When there is uncontrolled growth of plasma cells, a tumor can be produced. These tumors tend to collect in the bone's interior marrow, but when they occur in multiple parts of the body, the condition is referred to as multiple myeloma (source: American Cancer Society). Multiple myeloma cells prevent the marrow from forming normal plasma cells and other white blood cells important to the immune system.

Unfortunately, in many patients, multiple myeloma may not cause symptoms until after it has reached an advanced stage, and in other patients, it may cause vague symptoms that at first appear to be due to other diseases.

Symptoms of multiple myeloma can include:Treatments for Multiple Myeloma

The main treatment to improve the quality of a multiple myeloma patient's life is chemotherapy, although side effects are frequent because healthy cells are damaged by the therapy. Multiple myeloma is usually treated by a combination of drug therapies, such as melphalan and prednisone (source: American Cancer Society). Other chemotherapeutic drugs such as vincristine, cyclophosphamide, dexamethasone, and doxorubicin are also often used. The choice and dose of drug therapy depends on many factors including the stage, age, and kidney function of the patient.

Multidrug resistance of cancer is one major cause of failure of chemotherapy. An alternative treatment for multiple myeloma is radiation therapy, which is often given as a treatment for areas of bone damaged by myeloma that have not responded to chemotherapy and are causing serious symptoms. Newer approaches to treatment in clinical trials and in other research include:Contacts:
Gina Brazier (investor) 617-551-3611
Lynn Smiledge (media) 617-761-4700
Millennium Pharmaceuticals, Inc.

Porter Novelli

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