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Millennium Pharmaceuticals, Inc. (Cambridge, Massachusetts) Release: Positive Results From Combination Trials Build On VELCADE(R) (Bortezomib) For Injection Proven Single-Agent Strength In Relapsed Multiple Myeloma

Published: Dec 11, 2006

ORLANDO, Fla., Dec. 11 /PRNewswire-FirstCall/ -- Millennium Pharmaceuticals, Inc. today reported presentation of results from several clinical trials of VELCADE(R) (bortezomib) for Injection combination therapies for treatment of relapsed multiple myeloma (MM). The results of these trials showed overall response rates (ORR) as high as 93 percent and complete and near complete response (CR/nCR) rates as high as 43 percent. Based on an interim analysis of a randomized Phase III trial announced by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD), VELCADE in combination with DOXIL(R) (pegylated liposomal doxorubicin) achieved a statistically significant improvement in time to disease progression (TTP), the primary endpoint of the study, compared to VELCADE alone. These data were presented at the 48th Annual Meeting of the American Society of Hematology (ASH) being held December 9-12, 2006, in Orlando, Fla.

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"VELCADE is the market leader in relapsed multiple myeloma with the strongest single-agent activity," said Nancy Simonian, M.D., Senior Vice President and Chief Medical Officer, Millennium. "Our strategy is to build on the strength of these data by adding novel and conventional therapies to further increase the clinical benefit to patients."

The Combination of Pegylated Liposomal Doxorubicin and VELCADE (Bortezomib) Significantly Improves Time to Progression of Patients with Relapsed/Refractory Multiple Myeloma Compared with VELCADE (Bortezomib) Alone: Results from a Planned Interim Analysis of a Randomized Phase III Study (Abstract #404)

The randomized, multicenter Phase III trial is evaluating the efficacy and safety of VELCADE in combination with DOXIL in 646 relapsed MM patients who had received at least one prior therapy. The primary endpoint of the study is TTP as defined by the interval between the date of randomization and the date of disease progression, including relapse after CR or death due to disease progression. Patients were randomized in a one-to-one ratio. Three hundred twenty-two patients received VELCADE at 1.3 mg/m2 on days 1, 4, 8, and 11 of the 21-day cycle. Three hundred twenty-four patients received the same dose and schedule of VELCADE with the addition of DOXIL at 30 mg/m2 given on day four of each cycle. Patients were treated for up to eight cycles. Responses were assessed by European Group for Blood and Marrow Transplantation (EBMT) criteria.

Based on the results of a planned interim analysis, an independent data monitoring board determined that the pre-specified criterion of TTP was met. As a result, patients receiving VELCADE in the study were offered the opportunity to add DOXIL to their regimen. The trial is ongoing. The oral presentation was given by Robert Orlowski, M.D., Ph.D., of the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill. Interim results showed:

* A statistically significant improvement in median TTP of 9.3 months was achieved for patients receiving the combination compared to 6.5 months for patients randomized to VELCADE alone (p= < 0.0001) * The overall survival analysis showed a trend favoring the combination therapy group (a secondary endpoint of the study), but results had not reached statistical significance at interim analysis, performed after 230 progression events * ORR (CR and PR) was 48 percent for patients who received the combination compared to 43 percent for patients who received VELCADE alone * The most common adverse events were anemia, neutropenia and thrombocytopenia For full information please see: http://www.orthobiotech.com/releaseDetail.jsp?releaseID=300001.

A Phase I/II Trial of VELCADE (Bortezomib) Plus Oral Cyclophosphamide and Prednisone for Relapsed/Refractory Multiple Myeloma (Abstract #3536)

The Phase I/II clinical trial evaluated the addition of VELCADE to cyclophosphamide (CY) and prednisone (P) in 27 evaluable relapsed MM patients who had received a median of two prior regimens and who had previously undergone autologous stem cell transplantation. VELCADE was administered at 1.5 mg/m2 on a weekly schedule on days 1, 8 and 15 of a 28-day cycle in combination with full dose oral CY + P for up to eight cycles. The data were presented by Donna Reece, M.D., Princess Margaret Hospital, University Health Network, Toronto, Canada. Results showed:

* Of the 14 evaluable patients enrolled in the Phase I stage of the trial, ORR was 93 percent, with a CR/nCR rate of 43 percent and median progression-free survival (PFS) of 11 months * Of the seven patients enrolled in the Phase II stage of the trial, ORR was 75 percent with two patients achieving a CR * Toxicities were generally mild and manageable; the most common adverse events were infection and febrile neutropenia

"The substantial response rates seen with this combination are some of the highest recorded to date in this underserved patient group," said Dr. Reece. "Building on previously reported studies, these data show that VELCADE may have synergistic activity with alkalating agents like cyclophosphamide and encourage the exploration of additional VELCADE based combinations with these agents that could provide even deeper responses that are durable."

Combination of VELCADE (Bortezomib), Melphalan, Prednisone and Thalidomide (VMPT) for Relapsed Multiple Myeloma: Results of a Phase I/II Clinical Trial (Abstract #407)

The open-label, multicenter Phase I/II clinical trial evaluated the safety and efficacy, as defined by ORR, duration of PFS and survival, of the four-drug combination -- VELCADE, melphalan, prednisone and thalidomide (VMPT) -- in 30 patients with relapsed/refractory MM. Response was assessed using International Myeloma Working Group criteria. VELCADE was administered on days 1, 4, 15 and 22 at three dose levels: 1.0 mg/m2 in the first cohort of 10 patients; 1.3 mg/m2 in the second cohort of 10 patients; and 1.6 mg/m2 in the third cohort of 10 patients. Oral melphalan was administered at 6 mg/m2 and oral prednisone at 60 mg/m2 on days one through five. Thalidomide was delivered at 50 mg on days one through 35. The data were presented by Antonio Palumbo, M.D., Azienda Ospedaliera San Giovanni Battista, Torino, Italy. Initial results showed:

* Of all 30 patients, the CR and VGPR rate was 43 percent with a 17 percent CR rate * Of the 14 second-line patients, the CR and VGPR rate was 57 percent with a 36 percent CR rate * One-year PFS rate was 61 percent; one-year survival from study entry was 84 percent * Therapy was well tolerated; the most common adverse events for the combination included infections, fatigue and vasculitis; incidence of neurotoxicity was low

VELCADE (Bortezomib) Plus Lenalidomide in Relapsed and/or Refractory Multiple Myeloma: Final Results of a Multicenter Phase I Trial (Abstract #405)

The multicenter Phase I dose-escalation study was designed to determine the maximum tolerated dose (MTD) and activity of VELCADE plus lenalidomide with and without dexamethasone in 36 evaluable patients with relapsed and/or refractory MM. Patients had been heavily pretreated with a median of five prior therapies, including: VELCADE, thalidomide, lenalidomide and stem cell transplantation. Response was assessed by modified EBMT criteria. Patients were treated with VELCADE at 1.0 or 1.3 mg/m2 on days 1, 4, 8 and 11 and lenalidomide at 5, 10, 15, or 20 mg on days one through 14 in 21-day cycles. Patients with progressive disease were able to receive dexamethasone 40 mg on day of and day after each VELCADE dose. The data were presented by Paul Richardson, M.D., of the Dana-Farber Cancer Institute in Boston, Mass. Final results showed:

* MTD was defined with VELCADE at 1.0 mg/m2 and lenalidomide at 15 mg for relapsed MM patients; this dose was taken into a Phase II trial in this treatment setting * ORR was 39 percent, with a median duration of response of eight months and 11 patients remaining on therapy beyond one year * The most common adverse events with the combination were neutropenia and thrombocytopenia; there was no significant grade 3 or greater peripheral neuropathy; there was no deep vein thrombosis in the combination arm * A Phase I/II study of VELCADE, lenalidomide and dexamethasone in front- line MM is also ongoing About Multiple Myeloma

MM is the second most common hematologic malignancy and although the disease is predominantly a cancer of the elderly (the average age of onset is 65 to 70 years of age), recent statistics indicate both increasing incidence and younger age of onset. In the U.S., more than 50,000 individuals have MM and over 15,000 new cases are diagnosed each year. Worldwide there are approximately 74,000 new cases and over 45,000 deaths annually.(1)

About VELCADE

VELCADE is being co-developed by Millennium Pharmaceuticals, Inc. and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Millennium is responsible for commercialization of VELCADE in the U.S.; Janssen-Cilag is responsible for commercialization in Europe and the rest of the world. Janssen Pharmaceutical K.K. is responsible for commercialization in Japan. For a limited period of time, Millennium and Ortho Biotech Inc. will co-promote VELCADE in the U.S. VELCADE also is approved in the European Union after first relapse.

VELCADE is indicated for the treatment of patients with multiple myeloma who have received at least one prior therapy. VELCADE is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron or mannitol. VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy.

Risks associated with VELCADE therapy include new or worsening peripheral neuropathy, hypotension observed throughout therapy, cardiac and pulmonary disorders, gastrointestinal adverse events, thrombocytopenia, neutropenia and tumor lysis syndrome. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Cases of severe sensory and motor peripheral neuropathy have been reported. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction has been reported, including reports in patients with few or no risk factors for decreased left ventricular ejection fraction. There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. A higher proportion of these events have been reported in Japan. There have been rare reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. VELCADE is associated with thrombocytopenia and neutropenia. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. Complete blood counts (CBC) should be frequently monitored during treatment with VELCADE. Rare cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions.

Safety Data: In 1163 patients in MM and MCL studies, the most commonly reported adverse events were asthenic conditions (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy (39%), thrombocytopenia (36%), appetite decreased, including reports of anorexia (36%), pyrexia (34%), vomiting (33%) and anemia (29%). Twenty percent of patients reported at least one episode of grade 4 toxicity; the most common grade 4 toxicities were thrombocytopenia (5%) and neutropenia (3%). Fifty percent of patients reported serious adverse events (SAEs). The most commonly reported SAEs were pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

For more information about VELCADE clinical trials, patients and physicians can contact the Millennium Medical Product Information Department at 1-866-VELCADE (1-866-835-2233).

About Millennium

Millennium Pharmaceuticals, Inc., a leading biopharmaceutical company based in Cambridge, Mass., markets VELCADE, a novel cancer product, and has a robust clinical development pipeline of product candidates. The Company's research, development and commercialization activities are focused in two therapeutic areas: oncology and inflammation. By applying its knowledge of the human genome, understanding of disease mechanisms and industrialized drug discovery platform, Millennium is developing an exciting pipeline of innovative product candidates. The Company's website is www.millennium.com.

This press release contains "forward-looking statements," including statements about the Company's growth and development of products. Various important risks may cause the Company's actual results to differ materially from the results indicated by these forward-looking statements, including: adverse results in its drug discovery and clinical development programs; failure to obtain patent protection for its discoveries; commercial limitations imposed by patents owned or controlled by third parties; the Company's dependence upon strategic alliance partners to develop and commercialize products and services based on its work; difficulties or delays in obtaining regulatory approvals to market products and services resulting from its development efforts; product withdrawals; competitive factors; difficulties or delays in manufacturing the Company's products; government and third party reimbursement rates; the commercial success of VELCADE and INTEGRILIN(R) (eptifibatide) Injection; achieving revenue consistent with internal forecasts; and the requirement for substantial funding to conduct research and development and to expand commercialization activities. For a further list and description of the risks and uncertainties the Company faces, see the reports it has filed with the Securities and Exchange Commission. The Company disclaims any intention or obligation to update or revise any forward- looking statements, whether as a result of new information, future events or otherwise.

Editors' Note: This press release is also available under the Media section of the Company's website at: www.millennium.com.

1. American Cancer Society, Overview: Multiple Myeloma, 2005, http://www.cancer.org Contacts: Jennifer Snyder (media) Kyle Kuvalanka (investors) (617) 448-0281 (857) 498-0818

Photo: http://www.newscom.com/cgi-bin/prnh/19991220/MLNMLOGOMillennium Pharmaceuticals, Inc.

CONTACT: Media, Jennifer Snyder, +1-617-448-0281, or Investors, KyleKuvalanka +1-857-498-0818, for Millennium Pharmaceuticals, Inc.

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