Once a Week Oral Proteasome Inhibitor MLN9708-Based Therapy Showed High Response Rates in Front-Line Multiple Myeloma Phase 1 / 2 study

MLN9708: First oral proteasome inhibitor to enter clinical evaluation

in front-line multiple myeloma in combination with lenalidomide, dexamethasone

ATLANTA, GA., December 09, 2012 – Millennium: The Takeda Oncology Company with its parent company Takeda Pharmaceutical Company Limited (TSE:4502) today reported data from a phase 1 / 2 study of once a week investigational MLN9708 in combination with standard dose lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (MM). The previously reported phase 1 portion of the study was a dose escalation study to determine the safety, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of MLN9708 in combination with lenalidomide and dexamethasone. The primary objectives of the ongoing phase 2 portion of the study are to determine the combined complete and very good partial response rates (≥VGPR), safety and tolerability. Secondary objectives include overall response rate (ORR), time to response (TTR) duration of response (DOR), and progression-free survival (PFS). The data were presented at the 54th American Society of Hematology (ASH) Annual Meeting and Exposition held December 8-11, 2012 in Atlanta, GA.

In this early report, 53 newly diagnosed multiple myeloma patients have received a median of 7 cycles of therapy (range 1-19) at the RP2D of 4.0 mg. The ORR in patients who received the RP2D was of 90% and the study has already met its primary endpoint, with 58 percent of patients achieving ≥VGPR. Of the three patients who have completed 12 cycles, two achieved a CR and 1 achieved a VGPR. Among the patients who achieved a CR at the RP2D, assessment of minimal residual disease (MRD) was conducted in 8 patients; 88 percent of patients were MRD negative (n=7/8). The study is ongoing and patients will continue to be followed to further evaluate the primary and secondary endpoints.

“The MLN9708-based combination evaluated in this study of newly diagnosed myeloma patients, suggests a favorable emerging clinical profile,” said Shaji K. Kumar, M.D., Associate Professor of Hematology and Medicine, Rochester, MN. "The preliminary findings of improved depth of response with extended treatment duration warrant further investigation of this all-oral combination in front-line myeloma."

“We are excited about the once a week MLN9708 front-line myeloma evidence, the early efficacy signals observed further inform our clinical program,” said Karen Ferrante, M.D., Chief Medical Officer, Millennium. “The on-going TOURMALINE-MM1 trial in relapsed/refractory myeloma utilizes the same MLN9708 combination therapy and we plan to initiate additional studies investigating MLN9708-based therapy in front-line multiple myeloma.”

Phase 1/2 Study of Weekly MLN9708 an Investigational Oral Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients with Previously Untreated Multiple Myeloma (Abstract #332)

A total of 65 patients have been enrolled in both the phase 1 and phase 2 portions of the study. At data cut-off 52 of 53 patients treated at the RP2D were evaluable for response (received at least one cycle of treatment and had a response assessment). Results, which were presented by Shaji K. Kumar, M.D., Associate Professor of Hematology and Medicine, Rochester, MN, showed:

• The ≥VGPR rate for patients treated at the RP2D was 58 percent (n=52)

• The CR rate for patients treated at the RP2D was 23 percent

• 26 patients remain on therapy

• Treatment-emergent Peripheral neuropathy (PN) was reported in 32% of all patients (n=21)

• PN was grade 1 in the majority of patients (n=13)

• Grade 2 PN was reported in 6 patients and Grade 3 PN was reported in 2 patients

• There was one on-study death

• The most common Grade 3/4 adverse events were rash (18 percent), neutropenia (9 percent), vomiting (8 percent), back pain (7 percent), thrombocytopenia, anemia, fatigue, diarrhea and hyponatremia (6 percent) and nausea, dehydration, hypokalemia and hypophosphatemia (5 percent)

In the phase 1 portion of the study patients received escalating does of oral MLN9708 on Days 1, 8 and 15; plus 40 mg of dexamethasone orally on Days 1, 8, 15 and 22; and lenalidomide 25 mg orally on Days 1 through 21 of a 28-day cycle. In phase 2, patients received MLN9708 at the recommended phase 2 dose (4.0 mg) on Days 1, 8 and 15; plus 40 mg of dexamethasone orally on Days 1, 8, 15 and 22; and lenalidomide 25 mg orally on Days 1 through 21 of a 28-day cycle. Patients could undergo stem cell collection after three cycles and discontinue for autologous stem cell transplant after six cycles.

About MLN9708

MLN9708 is an investigational oral, potent, proteasome inhibitor, which is being studied in multiple myeloma, various hematologic malignancies and solid tumors. It is the first oral proteasome inhibitor to enter clinical trials in patients. Two global phase 3 trials, TOURMALINE-MM1, to investigate MLN9708 in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma and TOURMALINE-AL1, to investigate MLN9708 plus dexamethasone in patients with relapsed or refractory light chain AL amyloidosis were initiated in 2012. For additional information on the ongoing phase 3 studies please visit www.tourmalinetrialal1.com and www.tourmalinetrialmm1.com.

Editor’s Note: This press release is also available under the Media section of the Company’s website at: www.millennium.com/InTheNews.aspx.

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.

About Takeda Located in Osaka, Japan, Takeda is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to strive towards better health for patients worldwide through leading innovation in medicine. Additional information about Takeda is available through its corporate website, www.takeda.com.

Posted: December 2012

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