In Clinical Trials VELCADE (Bortezomib) for Injection as a Foundation of Therapy Continues to Deliver Significant Response Rates in Previously Untreated Multiple Myeloma Patients

ORLANDO, Fla.--(BUSINESS WIRE)--May 31, 2009 - Millennium: The Takeda Oncology Company today reported the presentation of results from two clinical trials of VELCADE based combinations for the treatment of patients with previously untreated multiple myeloma (MM). An overall response rate (ORR) of 84 percent was observed in one study of VELCADE, cyclophosphamide and dexamethasone (VcCD) as induction therapy, and an ORR of 97 percent was observed in a study of VELCADE, lenalidomide, doxorubicin and dexamethasone (VcRDD). These data were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting held in Orlando, Florida, May 29 – June 2, 2009.

“These presentations validate that researchers are attempting to build on VELCADE as a foundation of therapy, based on VELCADE's mechanism of action, strong activity and combinability with other therapies in both low- and high-risk patients,” said Nancy Simonian, M.D., Chief Medical Officer, Millennium.

Lenalidomide, Bortezomib, pegylated liposomal doxorubicin hydrochloride, and dexamethasone in newly diagnosed multiple myeloma: Initial results of the Phase I/II Multiple Myeloma Research Consortium Trial

Andrzej Jakubowiak, M.D., Ph.D., Associate Professor, University of Michigan Comprehensive Cancer Center, presented a Phase I/II study in which researchers investigated the maximum tolerated dose, safety and efficacy of a novel four-drug combination of VELCADE, lenalidomide, doxorubicin and dexamethasone after a median of 13.5 weeks of treatment. The study enrolled a total of 40 patients with a median age of 59 years. The maximum tolerated dose was not reached; therefore, the highest dose level, level 4, has been recommended as the Phase II dose (1.3 mg/m2 of VELCADE on days 1, 4, 8 and 11; 20 mg of dexamethasone for cycles 1 through 4 and 10 mg for cycles 5 through 8 on the days of and immediately following VELCADE dosing; and 30 mg/m2 of pegylated liposomal doxorubicin and 25 mg of lenalidomide).

Jakubowiak presented the following results:


  • ORR was 97 percent, with 22 percent of patients achieving a complete response (CR)/near complete response (nCR).
     
  • Grade 3 and 4 toxicities included pneumonia/infections (7 patients), neutropenia (4 patients), thrombocytopenia (3 patients), fatigue (2 patients), deep vein thrombosis/pulmonary embolism (2 patients) and sensory neuropathy (1 patient).
     

“In this study, the data show that this four-drug combination was well tolerated in patients with newly diagnosed multiple myeloma, and appeared to be highly active,” said Jakubowiak. “We are hopeful that these initial results will translate into better outcomes for patients with more follow-up.”

Bortezomib, IV cyclophosphamide, and dexamethasone (VelCD) as induction therapy in newly diagnosed multiple myeloma: Results of an interim analysis of the German DSMM XIa trial

In a Phase I/II study, researchers explored the effectiveness of VELCADE, cyclophosphamide and dexamethasone as induction therapy in preparation for autologous stem cell transplant (ASCT) in 200 patients with a mean age of 52.4 years. The maximum tolerated dose of cyclophosphamide was 900 mg/m2, and patients in the Phase II portion of the trial received three cycles of induction with 1.3 mg/m2 of VELCADE on days 1, 4, 8 and 11; 40 mg/d of dexamethasone on days 1, 2, 4, 5, 8, 9, 11 and 12; and 900 mg/m2 of IV cyclophosphamide on day 1.

Stefan Knop, M.D., University Hospital of Wuerzberg, Germany, presented the following results:


  • ORR was 84 percent, and 12.5 percent of patients achieved CR.
     
  • ORRs in cytogenetic subgroups were as follows:

    • 81.8 percent in patients with 13q-deletion
       
    • 93.8 percent in patients with t(4;14)
       
    • 70 percent in patients with 17p-deletion.
       


     
  • Adverse events included grade 3 or higher neutropenia in 6.5 percent of patients and grade 3 neuropathy in 3.5 percent, and mortality rate during induction was 1 percent.
     

“These preliminary results suggest that this is an effective induction regimen for younger patients, regardless of their cytogenetic risk factors,” said Knop.

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/m2/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® [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 ‰¥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 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: www.millennium.com.

Contact: Millennium: The Takeda Oncology Company
Manisha Pai, 617-510-9193
Manisha.Pai@mpi.com
or
Lisa Adler, 617-413-1296
Lisa.Adler@mpi.com

Posted: June 2009

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