Updated Data with Oral Proteasome Inhibitor MLN9708 Reported in Newly Diagnosed Multiple Myeloma Patients

NEW ORLEANS & OSAKA, Japan

Takeda Pharmaceutical Company Limited (TSE:4502) today announced final Phase 1 and preliminary Phase 2 results of a study combining oral investigational MLN9708 administered twice a week with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (MM). The investigators reported a combined complete response and very good partial response (CR+VGPR) rate of 76 percent (46/62) and a 94 percent overall response rate (ORR; 58/62 ≥ partial response). Stringent complete response (sCR) was reached in 75 percent of patients that attained CR. Overall, drug-related serious adverse events (SAEs) were reported in 28 percent of patients (18/64), and drug-related grade 3 adverse events (AEs) in 58 percent of patients (37/64). There were no drug-related grade 4 AEs. These data were presented today at the 55^th American Society of Hematology (ASH) annual meeting held December 7-10 in New Orleans, LA.

“This all-oral MLN9708, lenalidomide and dexamethasone study generated high response rates and increased depth of response with extended treatment duration in newly diagnosed multiple myeloma patients,” said lead investigator, Paul G. Richardson, MD, Dana-Farber Cancer Institute, Boston, MA. “This is the first all-oral proteasome inhibitor, IMiD combination under investigation in this setting to date, and the data support its feasibility and activity.”

“The safety profile and encouraging response rates presented at ASH for the twice-a-week oral MLN9708 combination supplement our clinical understanding of this all-oral triplet regimen in newly diagnosed multiple myeloma patients,” said Michael Vasconcelles, MD, Head, Oncology Therapeutic Area Unit. ”Bringing new therapies to patients is an important goal, and the oral MLN9708 combination has the potential to become yet another way to extend proteasome inhibition. Based on data from this and another Phase 1/2 study, we are further exploring oral MLN9708 in our TOURMALINE Phase 3 development program using a once-a-week dosing schedule.”

MLN9708 is an investigational, oral proteasome inhibitor being developed for the treatment of patients with MM and Amyloid Light-chain (AL) Amyloidosis. It is the first oral proteasome inhibitor to enter Phase 3 clinical trials.

Twice-Weekly Oral MLN9708, an Investigational Proteasome Inhibitor, in Combination with Lenalidomide (Len) and Dexamethasone (Dex) in Patients (Pts) with Newly Diagnosed Multiple Myeloma (MM): Final Phase 1 Results and Phase 2 Data (Abstract #535)

This oral presentation provides final Phase 1 results and Phase 2 data of a Phase 1/2 study. The primary objective of Phase 1 was to determine the safety, tolerability, maximum tolerated dose (MTD) and recommended Phase 2 dose; the primary objective of Phase 2 was to determine response rates (CR+VGPR) and further evaluate safety and tolerability. In this Phase 1/2 study, patients received MLN9708, lenalidomide and dexamethasone for up to 16, 21-day cycles, followed by MLN9708 maintenance until disease progression or unacceptable toxicity. Transplant-eligible patients could undergo stem cell collection after at least four cycles, and discontinue for autologous stem cell transplant (ASCT) after at least eight cycles. Key findings from the study, which were presented by Paul G. Richardson, MD, include:

• Phase 1:
  • Patients received MLN9708 3.0 mg (n=7) and 3.7 mg (n=7).
  • No adverse events met dose-limiting toxicity (DLT) criteria in cycle 1 at either dose of MLN9708.
  • Based on overall tolerability, including incidence of rash at 3.7 mg, a 3.0 mg fixed dose was recommended for Phase 2.
  • The most common drug-related AEs included rash-related (71 percent; 10/14), peripheral neuropathies and fatigue (64 percent each; 9/14) and peripheral edema (50 percent; 7/14).
• Results from patients receiving recommended Phase 2 dose (RP2D):
  • Fifty-seven patients were enrolled at the 3.0 mg dose of MLN9708.
  • At data cut-off, the median number of cycles of therapy was nine (range 1–30).
    • Seventy-nine percent (45/57) received at least eight cycles and 16 percent (9/57) received at least 16 cycles of treatment.
  • Based on 56 response-evaluable patients treated at the RP2D, preliminary data showed deepening responses over the course of treatment, with 93 percent ORR after four cycles (≥61% VGPR) and 95 percent ORR overall (≥ 71% VGPR).
  • 26 percent of patients that received RP2D (15/57) remained on therapy at data cut-off.
  • Among the 11 evaluable patients who achieved a sCR + CR, an assessment of minimal residual disease (MRD) was conducted, and nine patients were MRD negative.
  • Grade 3 drug-related AEs at the RP2D were reported in 56 percent of patients (32/57), with AEs leading to dose reduction in 56 percent (32/57) and discontinuation in 12 percent (7/57) of patients reporting AEs.
    • Grade 3 drug-related AEs (≥5% total) included rash-related AEs (11 percent; 6/57), hyperglycemia (9 percent; 5/57), pneumonia (7 percent; 4/57), thrombocytopenia, decreased lymphocyte count, hyponatremia, neutropenia and peripheral neuropathies (5 percent each; 3/57).
    • All grade drug-related adverse events (≥20 percent) included peripheral neuropathies (53 percent, 30/57), fatigue (47 percent, 27/57) and rash-related AEs (44 percent, 25/57).
    • There was one on-study death due to cardio-respiratory arrest, likely a pulmonary embolism. The investigator reported this event as probably related to lenalidomide, and not to MLN9708 or dexamethasone.

At data cut-off, 33 percent (21/64) of patients overall discontinued to undergo ASCT, a further 17 percent (11/64) discontinued due to AEs, 9 percent (6/64) due to progressive disease and 16 percent (10/64) for other reasons.

About Multiple Myeloma

Multiple myeloma is the second most common hematologic malignancy. In the U.S., more than 77,000 individuals have MM¹ and over 22,000 new cases are diagnosed each year.² Worldwide there are approximately 86,000 new cases and more than 63,000 deaths annually.³

About MLN9708

MLN9708 is an investigational oral, proteasome inhibitor, which is being studied in multiple myeloma and other malignancies. It is the first oral proteasome inhibitor to enter Phase 3 clinical trials. Three global Phase 3 trials are ongoing; TOURMALINE-MM1, investigating MLN9708 in combination with lenalidomide and dexamethasone in relapsed and/or refractory MM, TOURMALINE-MM2, investigating MLN9708 in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM who are not eligible for transplantation, and TOURMALINE-AL1, investigating MLN9708 plus dexamethasone in patients with relapsed or refractory light chain amyloidosis (AL). For additional information on the ongoing Phase 3 studies please visit www.tourmalinetrials.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 people worldwide through leading innovation in medicine. Additional information about Takeda is available through its corporate website, www.takeda.com.

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

¹ “SEER Stat Fact Sheets: Myeloma.” National Cancer Institute. http://seer.cancer.gov/statfacts/html/mulmy.html Last accessed November 21, 2013.
² “Cancer Facts & Figures 2013.” American Cancer Society. 2013. http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-036845.pdf. Last accessed November 20,2013. Page 4.
³ Becker N. (2011). Epidemiology of Multiple Myeloma. In T. Moehler, H. Goldschmidt (Eds.), Multiple Myeloma. (p. 25). New York: Springer-Verlag Berlin Heidelberg. (Available online: http://rd.springer.com/chapter/10.1007%2F978-3-540-85772-3_2#page-1)