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Supplemental New Drug Application Filed for Bortezomib as Treatment of Patients with Second-Line Multiple Myeloma

CAMBRIDGE, Mass., Sept. 29 /PRNewswire-FirstCall/ -- Millennium Pharmaceuticals, Inc. (Nasdaq: MLNM) today announced the submission of the Company's supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for VELCADE for the treatment of patients with multiple myeloma who have received at least one prior therapy, a patient population of approximately 22,000 in the U.S. The submission is based on data from the phase III APEX study that compared VELCADE to high-dose dexamethasone which demonstrated a survival benefit for patients receiving VELCADE.

A regulatory decision on acceptance of the filing, and whether the filing receives priority review status, is expected within 60 days. Should the filing receive priority review status, a regulatory decision on the approval of the filing would be expected within six months. A regulatory decision would be expected within 10 months through a standard review.

"We believe the submission of the sNDA for VELCADE as a second-line treatment in multiple myeloma will further validate the important role VELCADE has in the entire multiple myeloma treatment paradigm," said David Schenkein, M.D., vice president, clinical oncology development, Millennium. "We anticipate this submission will fulfill our regulatory obligations, and based on the data from the APEX study, are requesting priority review as well as full approval for VELCADE."

The submission of this supplementary filing comes after the approval of VELCADE for the treatment of relapsed and refractory multiple myeloma in the U.S. by the FDA approximately 16 months ago, and in the European Union states by the EMEA approximately five months ago. 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.

APEX Results
The sNDA submission was based primarily upon the results of the phase III APEX confirmatory study that compared VELCADE® (bortezomib) for Injection to high-dose dexamethasone. The APEX trial was halted one year early after an independent data monitoring committee concluded the findings of a pre- specified interim analysis showed a statistically significant improvement in time-to-disease progression in favor of VELCADE.

The APEX trial enrolled 669 patients with relapsed or refractory multiple myeloma (patients had received one to three prior therapies) at 94 centers in North America, Europe and Israel. Preliminary results presented at ASCO 2004 included:

*A statistically significant survival advantage (p<.01 in="" patients="" treated="" the="" velcade="" alone="" arm.="" importantly="" statistical="" significance="" was="" maintained="" even="" though="" approximately="" percent="" of="" crossed="" over="" to="" receive="" after="" experiencing="" progressive="" disease="" on="" dexamethasone="" arm=""> During the first year, there was an estimated 30 percent reduction in risk of death in patients receiving VELCADE compared to those receiving dexamethasone.

*Data from the interim analysis showed a 58 percent improvement in time to progression (p<.0001 in="" patients="" receiving="" velcade="" months="" compared="" to="" high-dose="" dexamethasone=""> The incidence of adverse events was similar between the two groups. Importantly, the overall grade 4 adverse events rates were 11 percent in the VELCADE arm and 13 percent in the dexamethasone arm. Millennium anticipates the final APEX data will be presented at the December American Society of Hematology (ASH) 46th annual meeting in San Diego, Calif.

Millennium and Johnson & Johnson Pharmaceutical Research and Development continue to investigate VELCADE globally in both hematologic and solid tumors and currently have approximately 80 ongoing clinical trials.

VELCADE is approved 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 improvement in survival. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

VELCADE is currently approved in the United States, 27 European Union states, Argentina and Korea. VELCADE is being co-developed by Millennium and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. 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.

Risks associated with VELCADE® (bortezomib) for Injection 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.

In 228 patients who were treated with VELCADE 1.3 mg/m2/dose in phase II studies, the most commonly reported adverse events were asthenic conditions (65%), nausea (64%), diarrhea (51%), decreased appetite including anorexia (43%), constipation (43%), thrombocytopenia (43%), peripheral neuropathy (37%), pyrexia (36%), vomiting (36%), and anemia (32%). Fourteen percent of patients experienced at least one episode of Grade 4 toxicity, with the most common toxicities being thrombocytopenia (3%) and neutropenia (3%). A total of 113 (50%) of the 228 patients experienced Serious Adverse Events (SAEs) during studies. The most commonly reported SAEs included pyrexia (7%), pneumonia (7%), diarrhea (6%), vomiting (5%), dehydration (5%), and nausea (4%).

For more information about VELCADE clinical trials, patients and physicians can contact the Millennium Medical Product Information Department at 1-(866)-VELCADE.

Source: Millenium Pharmaceuticals

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