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Novel VELCADE(R) (Bortezomib) for Injection Based Four-Drug Combination Was Well Tolerated In Previously Untreated Multiple Myeloma Patients
Date:12/7/2008

SAN FRANCISCO, Dec. 7 /PRNewswire/ -- Millennium: The Takeda Oncology Company today reported the Phase I results from a randomized, multi-center, Company-sponsored Phase I/II study of VELCADE, dexamethasone, cyclophosphamide and lenalidomide (VcDCR) in patients with previously untreated multiple myeloma (MM). The preliminary analysis of the safety data showed that the combination of four drugs was generally well tolerated in patients who had received no prior therapies and response rates were encouraging. These data were presented at the 50th Annual Meeting of the American Society of Hematology (ASH), held December 5-9, 2008 in San Francisco, California.

(Logo: http://www.newscom.com/cgi-bin/prnh/20080827/NEW076LOGO )

This trial, called EVOLUTION(1), builds on positive results from previous studies of VELCADE based combinations in this setting. The presentation reported the first clinical data with the novel four-drug combination. The safety results allow the trial to proceed to Phase II, which will randomize patients to receive VcDR, VcDC or VcDCR.

Results from the 25 patients treated in this trial with VcDCR for a median of four cycles (range: 2-11 cycles), which were presented by Shaji Kumar, M.D., Mayo Clinic, showed:

-- The maximum tolerated dose of cyclophosphamide in the VcDCR regimen was not reached. The recommended doses for the Phase II portion of the trial include 500 mg/m(2) of cyclophosphamide, the highest planned dose, 1.3 mg/m(2) of VELCADE, 40 mg of dexamethasone and 15 mg of lenalidomide.

-- The only two dose-limiting toxicities reported were febrile neutropenia and reactivation of the Herpes Zoster virus infection.

-- The overall rate of serious adverse events (AEs) was 40 percent. The most common treatment-emergent AEs were constipation (64 percent), fatigue (60 percent) and nausea (52 percent).

-- There were no reports of deep-vein thrombosis or pulmonary embolism.

-- As initial therapy, all patients had a partial response or better, with 36% of patients achieveing a CR.

"We are committed to advancing multiple myeloma treatment that delivers the best patient outcomes," said Nancy Simonian, M.D., Chief Medical Officer, Millennium. "The tolerability of this novel four-drug combination allows us to study its efficacy relative to two of the most active three-drug regimens for previously untreated multiple myeloma patients."

During Phase I, patients received VELCADE at 1.3 mg/m(2) on days 1, 4, 8 and 11 on a 21-day cycle for up to eight cycles; dexamethasone at 40 mg on days 1, 8 and 15; lenalidomide at 15 mg on days 1 through 14; and cyclophosphamide at 100, 200, 300, 400 or 500 mg/m(2) on days 1 and 8 for up to eight 21-day cycles. This was followed by VELCADE at 1.3 mg/m(2) on days 1, 8, 15 and 22 for four 42-day maintenance cycles. The primary endpoint of this Phase I trial was the determination of the maximum tolerated dose of cyclophosphamide in combination with VcDR. The primary endpoints of the ongoing Phase II portion of the trial are complete response and very good partial response rates, while the secondary endpoints include progression-free survival, overall survival, safety and tolerability.

About Multiple Myeloma

Multiple myeloma is the second most common hematologic malignancy and although the disease is predominantly a cancer of the elderly (the median age of onset is 70 years), recent statistics indicate both increasing incidence and younger age of onset. In the U.S., more than 50,000 individuals have MM and 20,000 new cases are diagnosed each year. Worldwide there are approximately 74,000 new cases and over 45,000 deaths annually.

About VELCADE

VELCADE is 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. VELCADE is approved in more than 87 countries worldwide.

Important Safety Information

In the U.S., VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE also is indicated for the treatment of patients with mantle cell lymphoma 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 throughout therapy, cardiac and pulmonary disorders, reversible posterior leukoencephalopathy syndrome, gastrointestinal adverse events, thrombocytopenia, neutropenia, tumor lysis syndrome and hepatic events. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Nursing mothers are advised not to breastfeed while receiving 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 new onset of decreased left ventricular ejection fraction has been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome in patients receiving VELCADE. Some of these events have been fatal. There have been reports of Reversible Posterior Leukoencephalopathy Syndrome (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. Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy. Patients on oral antidiabetic medication while receiving VELCADE should check blood sugar levels frequently.

Adverse Reaction Data

Safety data from Phase II and III studies of single-agent VELCADE 1.3 mg/m(2)/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the Phase III, VELCADE plus DOXIL(R) [doxorubicin HCl liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise and weakness) (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated) (39%), thrombocytopenia and appetite decreased (including anorexia) (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia and headache (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo) (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of greater than or equal to Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the Phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events for VELCADE in combination with MP vs MP, respectively, were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

About Millennium

Millennium: The Takeda Oncology Company, a leading biopharmaceutical company based in Cambridge, Mass., markets VELCADE, a novel cancer product, and has a robust clinical development pipeline of product candidates. Millennium Pharmaceuticals, Inc. was acquired by Takeda Pharmaceutical Company Ltd. ("Takeda", TSE: 4502) in May, 2008. The Company's research, development and commercialization activities are focused in oncology. Additional information about Millennium is available through its website, www.millennium.com.

(1) Evaluation of VELCADE, dexamethasOne, and Lenalidomide with or without cyclophosphamide Using Targeted Innovative ONcology strategies in the treatment of front-line multiple myeloma

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

    Contacts:
    Manisha Pai                   Karen Gobler
    (617) 551-7877                (617) 444-1392
    Manisha.Pai@mpi.com           Karen.Gobler@mpi.com


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SOURCE Millennium: The Takeda Oncology Company
Copyright©2008 PR Newswire.
All rights reserved

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