− Oral Data Presentation to be Featured in “Highlights of ASH” −

New Orleans, LA & Osaka, Japan (Press Release) - 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 55th 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 inno­va­t 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)

Source: Takeda Pharma­ceu­tical Company.