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Oral Presentations Showcase Impressive Results of VELCADE (bortezomib) Based Therapy in Multiple Myeloma

CHICAGO - (BUSINESS WIRE) - Millennium: The Takeda Oncology Company today reported on data from oral presentations of VELCADE (bortezomib) for Injection based therapy in multiple myeloma presented at the 2010 Annual Meeting of the American Society of Clinical Oncology (ASCO). These data highlight VELCADE based therapy in both transplant and non-transplant eligible previously untreated multiple myeloma patients, as well as VELCADE used as induction and/or maintenance therapy.

"We are seeing increasing interest from physicians to explore ways to optimize multiple myeloma treatment combinations using VELCADE as a foundation of myeloma therapy, across a broad spectrum of patients," said Nancy Simonian, M.D., Chief Medical Officer, Millennium.

VELCADE, Lenalidomide and Dexamethasone

This is an open-label Phase I/II, single-arm, multi-center study evaluating the safety and efficacy of VELCADE in combination with lenalidomide and dexamethasone (VRD) in patients with previously untreated multiple myeloma. This clinical trial was the first prospective study of the three-drug combination in this setting.

Sixty-six patients were enrolled in the trial (35 in Phase II). Thirty-one (47%) patients proceeded to autologous stem cell transplantation (ASCT). The following final results were reported by Paul Richardson, M.D. of the Dana-Farber Cancer Institute on behalf of the study investigators:

• All patients (100%) achieved a partial response (PR) or better
• Complete response (CR) or nCR was achieved in 57% of Phase II patients
• With a median follow-up of 27.3 months, the estimated 24-month progression free survival (PFS) and overall survival (OS) rates among all patients both with and without ASCT were 68% and 95%, respectively
• Median PFS and OS were not reached

"We are very encouraged to see these unprecedented response rates in patients with previously untreated multiple myeloma, and these data support the synergy seen with VELCADE and other agents preclinically," said Dr. Richardson. "The combination, which was generally well tolerated, provided durable benefit even in patients with adverse cytogenetics, as well as in both younger and older patients. It may also delay the need for transplant in some patients, although larger randomized trials are needed to confirm these findings."

During the study, patients received a median 10 cycles of therapy. The most common adverse events were sensory peripheral neuropathy, fatigue and constipation. Other Grade 3/4 toxicities were lymphopenia, neutropenia and thrombocytopenia. The rate of thrombosis was 6%.

VELCADE, Melphalan, Prednisone and Thalidomide

An open-label, multi-center, randomized Phase III study examined the use of VELCADE, melphalan, prednisone and thalidomide (VMPT) followed by VELCADE and thalidomide (VT) maintenance compared to VELCADE, melphalan and prednisone (VMP), the current standard of care, in 511 previously untreated multiple myeloma patients ineligible for transplant. Antonio Palumbo, M.D., presented the following results on behalf of GIMEMA: Italian Multiple Myeloma Network:

• After a median follow-up of 26.5 months, the three-year PFS was 54% in VMPT/VT and 40% in VMP (p=0.006)
• Response rates were superior with VMPT/VT compared to VMP: ≥PR (89% vs. 81%, p=0.01); ≥VGPR (59% vs. 50%, p=0.03); and CR (38% vs. 24%, p=0.0008)
• Sixty-nine (69) percent of patients in the VMPT/VT arm did not need second-line therapy at three years vs. 55% in the VMP arm (p=0.006)

Patients were randomized to receive either induction therapy of VMPT followed by VT maintenance or VMP induction with no maintenance. Patients in the VMPT arm received nine six-week cycles of VELCADE at 1.3 mg/m² twice-weekly in cycles 1-4 and once-weekly in cycles 5-9, melphalan at 9 mg/m² daily, prednisone at 60 mg/m² on days 1-4 and thalidomide at 50 mg on days 1-42 followed by maintenance with VELCADE at 1.3 mg/m² on days 1 and 15 and thalidomide at 50 mg daily every 3 weeks. Patients in the VMP arm received the same doses and schedule for the first 9 cycles without maintenance. In March 2007, both VMPT and VMP schedules were changed to once-weekly VELCADE infusion. VMPT resulted in a higher incidence of Grade 3/4 neutropenia and cardiac complications. The incidence of Grade 3/4 peripheral neuropathy was 8% in VMPT/VT and 5% in VMP (p=0.19).

About VELCADE

VELCADE is co-developed by Millennium and Ortho Biotech Oncology Research & Development, a unit of 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. Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. entered into a co-promote agreement in May 2010 for VELCADE in Japan. VELCADE is approved in more than 90 countries and has been used to treat more than 160,000 patients worldwide.

Important Safety Information

CONTRAINDICATION

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

WARNINGS AND PRECAUTIONS

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE.

Pregnancy and Nursing: Women should avoid breastfeeding or becoming pregnant while being treated with VELCADE.

Peripheral neuropathy, including severe cases, may occur - manage with dose modification or discontinuation. Patients with pre-existing symptoms may experience worsening peripheral neuropathy (including ≥ Grade 3). Patients should be monitored for symptoms of peripheral neuropathy.

Hypotension can occur. Caution should be used when treating patients receiving antihypertensives, those with a history of syncope and those who are dehydrated.

Cardiac Disorders including acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported. Isolated cases of QT-interval prolongation have been reported. Patients with risk factors for, or existing heart disease should be closely monitored.

Pulmonary Disorders, some fatal, including pneumonitis interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS), have been reported. Pulmonary hypertension in the absence of left heart failure or significant pulmonary disease has also been reported.

Gastrointestinal Adverse Events including nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement.

Thrombocytopenia/Neutropenia can occur - manage with dose and/or schedule modifications. Platelets should be monitored prior to each dose of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage. Transfusions may be considered.

Patients with Hepatic Impairment: VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be started at a lower dose of VELCADE, which can be adjusted after cycle 1 depending on tolerability.

Patients with Diabetes: Hypoglycermia and hyperglycemia have been reported with VELCADE use. Patients may require close monitoring and adjustment of the antidiabetic medications.

Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome (RPLS) and acute hepatic failure have been reported.

Adverse Reactions

Previously Untreated MM: In the phase 3 VELCADE with melphalan and prednisone study, the most commonly reported adverse events 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%).

Relapsed MM and MCL: In the integrated analysis of 1163 patients in phase 2 and 3 studies, 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%).

In the integrated analysis, a total of 50% of patients experienced serious adverse events (SAEs). The most commonly reported SAEs included 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: The Takeda Oncology Company, a leading biopharmaceutical company based in Cambridge, Mass., markets VELCADE, a first-in-class proteasome inhibitor, and has a robust clinical development pipeline of product candidates. Millennium Pharmaceuticals, Inc. was acquired by Takeda Pharmaceutical Company Ltd. 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.

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

Millennium: The Takeda Oncology Company
Manisha Pai, 617-551-7877
Manisha.Pai@mpi.com
or
Lauren Musto, 617-551-7848
Lauren.Musto@mpi.com