Takeda Presents Data from Phase 3 TOURMALINE-MM1 Study for NINLARO® (ixazomib), First and Only Once-Weekly Oral Proteasome Inhibitor Recently Approved for Multiple Myeloma

- Additional Presentation: Phase 2 Results From an Investigational study of Ixazomib plus Cyclophosphamide and Low-Dose Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma

Orlando, Fla., December 6, 2015 – Takeda Pharmaceutical Company Limited (TSE: 4502) today announced results from the TOURMALINE-MM1 trial presented at the 57th Annual Meeting and Exposition of the American Society of Hematology (ASH), showing that treatment with NINLARO® (ixazomib) capsules is effective in extending progression free survival (PFS) with a manageable tolerability profile in patients with relapsed and/or refractory multiple myeloma. The TOURMALINE-MM1 trial is an international, randomized, double-blind, placebo-controlled Phase 3 clinical trial designed to evaluate once-weekly oral ixazomib plus lenalidomide and dexamethasone compared to placebo plus lenalidomide and dexamethasone.

NINLARO was recently approved by the U.S. Food and Drug Administration (FDA) in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. The approval was based on the Phase 3 TOURMALINE-MM1 data, which were highlighted at today’s ASH press briefing. Ixazomib data will be featured in 18 presentations at this year’s ASH meeting, including an oral presentation on Phase 2 data from an investigational study evaluating the all-oral combination of ixazomib plus cyclophosphamide and low-dose dexamethasone (ICd) in newly diagnosed multiple myeloma patients.

“The data presented at ASH this year are the first major output from the comprehensive ixazomib clinical trial program, TOURMALINE, demonstrating Takeda’s ongoing commitment to providing effective and convenient treatment options for patients with multiple myeloma,” said Andy Plump, M.D., Ph.D, Takeda Chief Medical and Scientific Officer. “The breadth and depth of the TOURMALINE program allows us to gather important data across a broad range of patients that live with multiple myeloma and to expand on the efficacy and safety profile of our oral proteasome inhibitor, ixazomib. We will continue this and other important clinical trials and look forward to sharing results over the next few years.”

The comprehensive ixazomib clinical development program, TOURMALINE, includes a total of five pivotal trials – four investigating every major multiple myeloma patient population and one in light-chain amyloidosis.

Ixazomib, an Investigational Oral Proteasome Inhibitor (PI), in Combination with Lenalidomide and Dexamethasone (IRd), Significantly Extends Progression-Free Survival (PFS) for Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): The Phase 3 Tourmaline-MM1 Study (Abstract #727)
TOURMALINE-MM1 (n= 722) is the first double-blind, placebo-controlled trial with a proteasome inhibitor and has met the primary endpoint at the first interim analysis. Trial results demonstrate a statistically significant (35%) improvement in PFS, with patients treated in the ixazomib arm living for a significantly longer time without their disease worsening compared to patients in the control arm (20.6 months vs. 14.7 months in control group; Hazard Ratio [HR] 0.742; p = 0.012). Overall response rate (ORR) was 78.3% in the ixazomib arm and median duration of response was 20.5 months, vs. 71.5% and 15 months in the control group. Median PFS in high-risk patients (HR 0.543; HR 0.596 in patients with del(17p)) was similar to that in the overall patient population and in standard-risk patients. Adverse events observed with IRd were consistent with reported safety profiles for the individual agents. The most common gr ≥3 adverse events included neutropenia, anemia, thrombocytopenia, and pneumonia. Gastrointestinal events included diarrhea, nausea, and vomiting. Peripheral neuropathy (PN) rates were 28% in the IRd arm vs. 21% in the control arm, 35% vs. 21% had rash events, 8% vs. 10% had acute renal failure, and 4% vs. 3% had heart failure.

“The TOURMALINE-MM1 trial evaluated ixazomib plus lenalidomide and dexamethasone in some of the most common patient types in the relapsed/refractory multiple myeloma setting who are in urgent need of new treatment options due to the complex nature of this disease. This trial enabled us to gather efficacy and safety data across a large variety of patients such as older patients, patients with moderate renal impairment, light chain disease, and high risk cytogenetics,” said lead investigator and presenter Philippe Moreau, M.D., University of Nantes, France.”

The TOURMALINE-MM1 trial is currently ongoing. Patients continue to be treated to progression in this trial and will be evaluated for long-term outcomes.

Takeda has submitted additional review applications for ixazomib to regulatory authorities around the world, including the European Medicines Agency (EMA), based on the TOURMALINE-MM1 data.

Randomized Phase 2 Study of the All-Oral Combination of Investigational Proteasome Inhibitor (PI) Ixazomib Plus Cyclophosphamide and Low-Dose Dexamethasone (ICd) in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Who Are Transplant-Ineligible (Abstract #26)
Takeda also presented preliminary data from an open-label, multicenter, Phase 2 study that investigates the all-oral triplet combination of ixazomib plus cyclophosphamide and low-dose dexamethasone (ICd) as a first line therapy for patients not eligible for transplant. Preliminary data demonstrated comparable activity across treatment arms with a manageable toxicity profile in line with previous ixazomib studies and with manageable myelosuppression. This is the first study to assess ICd for the frontline treatment of multiple myeloma.

The Phase 2 study (n = 70) randomized patients receiving ixazomib, low-dose dexamethasone and two different doses of cyclophosphamide 300 mg/m2 (ICd-300, n = 36) or 400 mg/m2 (ICd-400, n = 34), with a mean duration follow-up of 7.0 months in both arms. Preliminary results across treatment arms demonstrated best unconfirmed complete response plus very good partial response (CR+VGPR) of 27% (ICd-300) and 23% (ICd-400), as well as early overall response rates (ORR) of 80% (ICd-300) and 73% (ICd-400). Toxicity was manageable in both the ICd-300 and ICd-400 arms, but toxicity rates appeared higher with ICd-400. Thrombocytopenia events occurred in 5 patients (no gr ≥3) in the ICd-300 arm and 4 patients (3 gr ≥3) in the ICd-400 arm. Most common adverse events (>15% all patients) included anemia, neutropenia, nausea, PN, diarrhea, vomiting, constipation, and fatigue. Most common gr ≥3 adverse events were neutropenia, anemia and pneumonia; no Grade 3 PN was observed.

“Research has shown that the combination of a proteasome inhibitor with cyclophosphamide and dexamethasone is active in patients with multiple myeloma. As treatment practices for multiple myeloma can vary across regions, it is important that we gain an understanding of the utility of ixazomib in a number of combination settings,” said lead investigator and presenter Meletios A. Dimopoulos, M.D., National and Kapodistrian University of Athens, School of Medicine. “Preliminary data suggest that this may be a viable all-oral triplet regimen. We are committed to gathering additional data of ixazomib in this investigational setting.”

About NINLARO (ixazomib) capsules
NINLARO (ixazomib) is the first and only oral proteasome inhibitor approved by the U.S. Food and Drug Administration (FDA) in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO is administered orally, once-weekly on days 1, 8, and 15 of a 28-day treatment cycle. NINLARO is currently under review by the European Medicines Agency (EMA) and was granted an accelerated assessment by the Committee for Medicinal Products for Human Use (CHMP). NINLARO also received Breakthrough Therapy status by the U.S. FDA for relapsed or refractory systemic light-chain (AL) amyloidosis, a related ultra orphan disease, in 2014.

The TOURMALINE clinical development program further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with multiple myeloma worldwide and the healthcare professionals who treat them. Five global Phase 3 trials are ongoing:

· TOURMALINE-MM1, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma
· TOURMALINE-MM2, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
· TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant (ASCT)
· TOURMALINE-MM4, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone ASCT
· TOURMALINE-AL1, investigating ixazomib plus dexamethasone vs. physician choice of selected regimens in patients with relapsed or refractory AL amyloidosis

In addition to the TOURMALINE program, a large number of investigator initiated studies are evaluating ixazomib for patients globally.

For additional information on the ongoing Phase 3 studies please visit www.clinicaltrials.gov. To learn more about NINLARO, please visit www.NINLARO.com or call 1-844-N1POINT (1-844-617-6468).

Important Safety Information

WARNINGS AND PRECAUTIONS
· Thrombocytopenia has been reported with NINLARO. During treatment, monitor platelet counts at least monthly, and consider more frequent monitoring during the first three cycles. Adjust dosing as needed. Platelet nadirs occurred between Days 14-21 of each 28-day cycle and recovered to baseline by the start of the next cycle.
· Gastrointestinal Toxicities, including diarrhea, constipation, nausea and vomiting, were reported with NINLARO and may occasionally require the use of antidiarrheal and antiemetic medications, and supportive care. Adjust dosing for severe symptoms.
· Peripheral Neuropathy (predominantly sensory) was reported with NINLARO. Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed.
· Peripheral Edema was reported with NINLARO. Monitor for fluid retention. Investigate for underlying causes when appropriate and provide supportive care as necessary. Adjust dosing as needed.
· Cutaneous Reactions: Rash, most commonly maculo-papular and macular rash, was reported with NINLARO. Manage rash with supportive care or with dose modification.
· Hepatotoxicity has been reported with NINLARO. Monitor hepatic enzymes regularly during treatment and adjust dosing as needed
· Embryo-fetal Toxicity: NINLARO can cause fetal harm. Women should be advised of the potential risk to a fetus, to avoid becoming pregnant, and to use contraception during treatment and for an additional 90 days after the final dose of NINLARO.

ADVERSE REACTIONS
The most common adverse reactions occurring in greater than or equal to 20% of patients treated with NINLARO were diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting and back pain.

SPECIAL POPULATIONS
· Hepatic Impairment: Reduce the NINLARO starting dose to 3mg in patients with moderate or severe hepatic impairment
· Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease requiring dialysis. NINLARO is not dialyzable.
· Lactation: Advise women to discontinue nursing while on NINLARO.

DRUG INTERACTIONS: Avoid concomitant administration of NINLARO with strong CYP3A inducers.

INDICATION
NINLARO (ixazomib) is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.

Please see the accompanying full Prescribing Information for NINLARO.

About Multiple Myeloma
Multiple myeloma is a cancer of the plasma cells, which are found in the bone marrow. In multiple myeloma, a group of plasma cells, or myeloma cells, becomes cancerous and multiplies, increasing the number of plasma cells to a higher than normal level. Because plasma cells circulate widely in the body, they have the potential to affect many bones in the body, possibly resulting in compression fractures, lytic bone lesions and related pain. Multiple myeloma can cause a number of serious health problems affecting the bones, immune system, kidneys and red blood cell count, with some of the more common symptoms including bone pain and fatigue, a symptom of anemia. Multiple myeloma is a rare form of cancer, with more than 26,000 new cases in the U.S. and 114,000 new cases globally per year.

About Takeda
Located in Osaka, Japan, Takeda (TSE: 4502) 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. 

Contacts:

Japanese Media
Tsuyoshi Tada
tsuyoshi.tada@takeda.com
+81 (0) 3-3278-2417

Media outside Japan
Amy Atwood
amy.atwood@takeda.com
+1-617-444-2147