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Prolonged Progression-Free Survival Demonstrated by VELCADE(R) (Bortezomib) for Injection Based Induction Regimens in Transplant-Eligible Previously Untreated Multiple Myeloma Patients

Tuesday, December 9, 2008 General News J E 4
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SAN FRANCISCO, Dec. 8 Millennium: The Takeda OncologyCompany today reported updated results from two large, multi-center,randomized Phase III clinical trials of VELCADE based combinations for theinduction treatment of transplant-eligible patients with previously untreatedmultiple myeloma (MM). Prolonged progression-free survival (PFS) was observedin one study comparing VELCADE and dexamethasone (VcD) with vincristine,adriamycin and dexamethasone (VAD), as well as in another study comparingVELCADE, thalidomide and dexamethasone (VcTD) with thalidomide anddexamethasone (TD). These data were presented at the 50th Annual Meeting ofthe American Society of Hematology (ASH), held December 5-9, 2008 in SanFrancisco, California.

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

"VELCADE based combinations continue to deliver high response rates,including complete responses," said Nancy Simonian, M.D., Chief MedicalOfficer, Millennium. "It is impressive to see that this already translates toimproved progression-free survival when VELCADE regimens are used inconjunction with high dose therapy and stem cell transplantation."

VELCADE-Dexamethasone versus VAD as Induction Treatment Prior to ASCT inNewly Diagnosed Multiple Myeloma: Updated Results of the IFM2005/01 Trial(ASH/ASCO Joint Symposium)

This 482-patient Phase III trial was conducted by the IntergroupeFrancophone du Myelome (IFM) cooperative group and Nantes University Hospital(France). The updated results, which were presented by Professor Harousseau,showed:

"The data from patients treated with VELCADE and dexamethasone prior totransplantation showed significantly longer progression-free survival," saidJean-Luc Harousseau, M.D., Hospital Hotel-Dieu and Principal Investigator ofthe trial. "We are interested in whether this will translate into extendedoverall survival for these patients with previously untreated multiple myelomawhen the follow-up duration is sufficient."

Patients in the VcD arm received VELCADE at 1.3 mg/m(2) on days 1, 4, 8and 11 and dexamethasone at 40 mg on days 1 through 4 during cycles 1 through4 and days 9 through 12 during only the first and second cycles. Patients inthe VAD arm received vincristine at 0.4 mg/m(2) and doxorubicin at 9 mg/m(2)on days 1 through 4, and dexamethasone at 40 mg on days 1 through 4 duringcycles 1 through 4 and on days 9 through 12 and 17 through 20 during only thefirst and second cycles.

Superior Complete Response Rate and Progression-Free Survival AfterAutologous Transplantation with Up-Front VELCADE-Thalidomide-DexamethasoneCompared with Thalidomide-Dexamethasone in Newly Diagnosed Multiple Myeloma(Abstract #158)

In a Phase III study conducted by the Italian Myeloma Network GIMEMA,researchers compared VcTD with TD as induction therapy in preparation for andas consolidation after melphalan-based double ASCT in 460 patients withsymptomatic MM. The median follow-up was 15 months.

The updated results, which were presented by Michele Cavo, M.D., SeragnoliInstitute of Hematology and Medical Oncology, showed:

-- The two-year PFS was 90 percent in the VcTD arm, compared with 80percent in the TD arm (p=0.009).

-- After three cycles of induction, CR/nCR rates were 32 percent in theVcTD arm, compared with 12 percent in the TD arm (p<0.001).

-- After the first ASCT, CR/nCR rates were 55 percent in the VcTD arm,compared with 32 percent in the TD arm (p<0.001).

-- After the first ASCT, VGPR or better rates were 76 percent in the VcTDarm, compared with 58 percent in the TD arm (p<0.001).

-- Serious adverse events were recorded in 15 percent of patients in theVcTD arm, compared with 12 percent of those in the TD arm.

Patients in the VcTD arm received 1.3 mg/m(2) of VELCADE on days 1, 4, 8and 11; 200 mg of thalidomide daily and 40 mg of dexamethasone on days 1, 2,4, 5, 8, 9, 11 and 12. Patients in the TD arm received 200 mg of thalidomidedaily and 40 mg of dexamethasone on days 1 through 4 and 9 through 12 forthree 21-day cycles.

About Multiple Myeloma

Multiple myeloma is the second most common hematologic malignancy andalthough the disease is predominantly a cancer of the elderly (the median ageof onset is 70 years), recent statistics indicate both increasing incidenceand younger age of onset. In the U.S., more than 50,000 individuals have MMand 20,000 new cases are diagnosed each year. Worldwide there areapproximately 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 isresponsible for commercialization of VELCADE in the U.S., Janssen-Cilag isresponsible for commercialization in Europe and the rest of the world. JanssenPharmaceutical K.K. is responsible for commercialization in Japan. VELCADE isapproved in more than 87 countries worldwide.

Important Safety Information

In the U.S., VELCADE is indicated for the treatment of patients withmultiple myeloma. VELCADE also is indicated for the treatment of patients withmantle cell lymphoma who have received at least one prior therapy. VELCADE iscontraindicated in patients with hypersensitivity to bortezomib, boron ormannitol. VELCADE should be administered under the supervision of a physicianexperienced in the use of antineoplastic therapy.

Risks associated with VELCADE therapy include new or worsening peripheralneuropathy, hypotension throughout therapy, cardiac and pulmonary disorders,reversible posterior leukoencephalopathy syndrome, gastrointestinal adverseevents, thrombocytopenia, neutropenia, tumor lysis syndrome and hepaticevents. Women of childbearing potential should avoid becoming pregnant whilebeing treated with VELCADE. Nursing mothers are advised not to breastfeedwhile receiving VELCADE. Cases of severe sensory and motor peripheralneuropathy have been reported. The long-term outcome of peripheral neuropathyhas not been studied in mantle cell lymphoma. Acute development orexacerbation of congestive heart failure, and new onset of decreased leftventricular ejection fraction has been reported, including reports in patientswith no risk factors for decreased left ventricular ejection fraction. Therehave been reports of acute diffuse infiltrative pulmonary disease of unknownetiology such as pneumonitis, interstitial pneumonia, lung infiltration andAcute Respiratory Distress Syndrome in patients receiving VELCADE. Some ofthese events have been fatal. There have been reports of Reversible PosteriorLeukoencephalopathy Syndrome (RPLS) in patients receiving VELCADE. RPLS is arare, reversible, neurological disorder which can present with seizure,hypertension, headache, lethargy, confusion, blindness, and other visual andneurological disturbances. VELCADE is associated with thrombocytopenia andneutropenia. There have been reports of gastrointestinal and intracerebralhemorrhage in association with VELCADE. Transfusions may be considered.Complete blood counts (CBC) should be frequently monitored during treatmentwith VELCADE. Cases of acute liver failure have been reported in patientsreceiving multiple concomitant medications and with serious underlying medicalconditions. Patients who are concomitantly receiving VELCADE and drugs thatare inhibitors or inducers of cytochrome P450 3A4 should be closely monitoredfor either toxicities or reduced efficacy. Patients on oral antidiabeticmedication while receiving VELCADE should check blood sugar levels frequently.

Adverse Reaction Data

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

In the integrated analysis, the most commonly reported adverse events wereasthenic 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) (each36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache,paresthesia and dysesthesia and headache (each 22%), dyspnea (21%), cough andinsomnia (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 >/= Grade 4toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of50% 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 andthrombocytopenia (each 3%).

In the Phase III VELCADE + melphalan and prednisone study, the safetyprofile of VELCADE in combination with melphalan/prednisone is consistent withthe known safety profiles of both VELCADE and melphalan/prednisone. The mostcommonly 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% vs10%), 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 inextremity (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% vs10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

About Millennium

Millennium: The Takeda Oncology Company, a leading biopharmaceuticalcompany 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 CompanyLtd. ("Takeda", TSE: 4502) in May, 2008. The Company's research, developmentand commercialization activities are focused in oncology. Additionalinformation about Millennium is available through its website,http://www.millennium.com.

Editors' Note: This press release is also available under the Mediasection of the Company's website at: http://www.millennium.com.-- The two year PFS was 69 percent in the VcD arm, compared with 60 percent in the VAD arm (p=0.0115). -- Post-induction complete response (CR)/near complete response (nCR) rates were 15 percent in the VcD arm, compared with 7 percent in the VAD arm (p=0.0035). -- After the first performed ASCT, CR/nCR rates were 40 percent in the VcD arm, compared with 22 percent in the VAD arm (p=0.0001). -- After the first performed ASCT, very good partial response (VGPR) or better rates were 61 percent in the VcD arm, compared with 44 percent in the VAD arm (p=0.0007). -- Thirty-four percent of patients in the VcD arm required a second ASCT, compared with 47 percent of patients in the VAD arm. -- Serious adverse events were reported in 27 percent of the VcD patients, compared with 34 percent of the VAD patients.

SOURCE Millennium: The Takeda Oncology Company
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