Press Release

Millennium: The Takeda Oncology Company with its parent company Takeda Pharmaceutical Company Limited (TSE:4502) today reported Phase I and Phase I/II results from three studies evaluating the safety, tolerability and dosing of MLN9708, the first oral proteasome inhibitor in clinical trials. The studies evaluated once or twice weekly oral dosing of MLN9708, alone or in combination, in patients with relapsed and/or refractory or previously untreated multiple myeloma (MM). These data were announced during a series of oral presentations at the 53rd annual meeting of the American Society of Hematology (ASH), held December 10th – 13th in San Diego, California.

“These data reveal a promising profile for this therapy and clearly support further investigation of MLN9708 in patients with multiple myeloma, including as a single agent in heavily pre-treated patients as well as in combination therapy for those who have received no prior treatment for their disease,” said Karen Ferrante, M.D., Chief Medical Officer, Millennium.

Investigational Agent MLN9708, An Oral Proteasome Inhibitor, in Patients with Relapsed and/or Refractory Multiple Myeloma: Results From the Expansion Cohorts of a Phase 1 Dose-Escalation Study (Abstract #301)

The primary objectives of this study were to determine the safety, tolerability and maximum tolerated dose (MTD) of oral MLN9708 in patients with relapsed and/or refractory MM. To date, 36 of the 56 patients in the study have been enrolled to expansion cohorts. Results, which were presented by Paul G. Richardson, M.D., Dana-Farber Cancer Institute, showed:

• MTD has been determined as 2.0 mg/m2 for the twice-weekly dosing schedule used in this trial
• Of the 36 patients at MTD, 81 percent had prior bortezomib treatment and 32 percent were bortezomib-refractory
• Of 46 patients evaluable for response, 1 patient achieved a complete response and 5 patients achieved a partial response
• Twenty-eight patients have achieved stable disease and seven have achieved minimal response or better
  • Duration of disease control was up to 15.9 months
• The most common adverse events were fatigue (46 percent), thrombocytopenia (39 percent), nausea (30 percent), diarrhea and vomiting (each 23 percent), and rash (21 percent)
• Six patients (11 percent) had drug-related peripheral neuropathy (four grade 1, two grade 2), no grade =3 peripheral neuropathy was reported

Patients with measurable disease and no grade =2 peripheral neuropathy were eligible. For the dose escalation phase patients required two or more prior therapies, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids. At MTD patients were enrolled to four expansion cohorts: relapsed and refractory, bortezomib-relapsed, proteasome inhibitor-naĂŻve, and prior carfilzomib exposure. MLN9708 was administered orally on a twice-weekly basis in 21 day cycles.

Weekly Dosing of the Investigational Oral Proteasome Inhibitor MLN9708 in Patients with Relapsed and/or Refractory Multiple Myeloma: Results From a Phase 1 Dose-Escalation Study (Abstract #816)

This study evaluated MLN9708 in 32 patients who had received two or more prior therapies. The primary objectives of this ongoing study were to determine the safety, tolerability and MTD of weekly MLN9708. Results presented by Shaji K. Kumar, M.D., showed:

• The MTD has been determined at 2.97 mg/m2 for the weekly dosing schedule in this patient population
• 97 percent of patients had prior bortezomib exposure and 28 percent were bortezomib refractory
• Three dose limiting toxicities (DLT) have been observed among 27 DLT-evaluable patients
  • One grade 3 rash, one grade 3 nausea, vomiting and diarrhea at 3.95 mg/m2
  • One grade 3 nausea, vomiting and diarrhea at 2.97 mg/m2
• Three patients (9 percent) had drug-related peripheral neuropathy (all grade 2); all had grade 1 peripheral neuropathy at baseline
• No grade =3 peripheral neuropathy was reported
• The most common adverse events were fatigue and thrombocytopenia (31 percent), nausea (28 percent), diarrhea (25 percent), vomiting (19 percent), and neutropenia (13 percent)
• Of 18 evaluable patients one achieved very good partial response and one achieved a partial response
  • Both had prior bortezomib exposure
• Eight patients achieved stable disease

Patients with MM who had received =2 prior therapies, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids, and no grade =2 peripheral neuropathy were eligible. MLN9708 was orally administered weekly on a 28 day cycle. Dose escalation proceeded from 0.24 mg/m2 following a 3+3 scheme based on the occurrence of DLTs in cycle 1.

Phase 1/2 Dose-Escalation Study of Oral MLN9708, A Novel, Investigational Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients with Previously Untreated Multiple Myeloma (Abstract #479)

This study evaluated MLN9708 in 15 patients with previously untreated multiple myeloma. The primary objectives of this ongoing study were to determine the safety, tolerability, MTD and recommended Phase II dose, of weekly MLN9708 in combination with lenalidomide and dexamethasone. Results presented by Jesus G. Berdeja, M.D., Sarah Cannon Research Institute, showed:

• The MTD has been determined at 2.97 mg/m2, in combination with lenalidomide or dexamethasone, for the weekly dosing schedule in this patient population and the recommended weekly Phase II dose has been established at 2.23 mg/m2
• DLTs included one grade 3 rash at 2.97 mg/m2 and three grade 3 nausea and vomiting at 3.95 mg/m2
• The most common adverse events were fatigue (60 percent), rash (60 percent) and vomiting (53 percent), anemia (40 percent), nausea and diarrhea (33 percent) insomnia, peripheral edema and thrombocytopenia (27 percent)
• No grade =3 peripheral neuropathy was reported
• 100 percent of 15 evaluable patients achieved a partial response or better, including four complete responses, five very good partial responses and six partial responses
  • 14 of 15 achieved partial response or better after cycle 1, 100 percent achieved partial response or better by cycle 2
• No patient has progressed to date

Patients with previously untreated MM, an ECOG score of 0-2 and adequate hepatic, renal and hematological function and no grade =2 peripheral neuropathy were eligible. Patients received oral MLN9708 weekly, lenalidomide 25 mg on days 1-21, and dexamethasone 40 mg weekly, for up to twelve 28-day cycles. Dose escalation of MLN9708 proceeded from 1.68 mg/m2 following a 3+3 scheme based on the occurrence of DLTs in cycle 1.

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.

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Last updated on: 13/12/2011 16:00:09