Phase 3 Trial Results for First Oral Proteasome Inhibitor NINLARO (ixazomib) Published in The New England Journal of Medicine

Takeda Pharmaceutical Company Limited (TSE: 4502) today announced that results from the international, randomized, double-blind, placebo-controlled TOURMALINE-MM1 Phase 3 clinical study, evaluating once-weekly oral NINLARO^® (ixazomib) capsules plus lenalidomide and dexamethasone versus placebo plus lenalidomide-dexamethasone in patients with relapsed and/or refractory multiple myeloma, have been published in the prestigious New England Journal of Medicine (NEJM). NINLARO was recently approved by the U.S. Food and Drug Administration (FDA), based on the pivotal TOURMALINE-MM1 data, in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.

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“NEJM has published the results of the first Phase 3 study supporting an all-oral triplet regimen containing a proteasome inhibitor in multiple myeloma. With the emergence of long-term treatment as a preferred approach for multiple myeloma, it is crucial that we investigate more ways to improve treatment sustainability for patients,” said study co-author and lead investigator Philippe Moreau, M.D., University of Nantes, France. “The TOURMALINE-MM1 results demonstrated that ixazomib in combination with lenalidomide and dexamethasone is an effective and tolerable oral regimen with a manageable safety profile for patients with relapsed and/or refractory multiple myeloma.”

“The publication of the Phase 3 TOURMALINE-MM1 trial results is another important milestone for patients and physicians. This reflects invaluable efforts from our researchers, the study investigators, the patients and their families,” said Dixie-Lee Esseltine, MD, FRCPC, Vice President, Oncology Clinical Research, Takeda. “The publication concluded that the addition of ixazomib to lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. We look forward to sharing additional ixazomib data from our ongoing TOURMALINE studies over the next few years.”

TOURMALINE-MM1, a double-blind, placebo-controlled trial including 722 patients, is the first Phase 3 study with an oral proteasome inhibitor. As reported in NEJM, the trial results demonstrated a statistically significant and clinically meaningful (35%) extension of PFS (HR 0.74; p = 0.01; median PFS: 20.6 months vs. 14.7 months in control group; median follow-up 14.7 months). A benefit in PFS was observed with the ixazomib regimen across pre-specified patient subgroups, including patients with poor prognosis, such as elderly patients, those who have received two or three prior therapies, those with advanced stage disease, and those with high-risk cytogenetic abnormalities. Overall response rates were 78% in the ixazomib arm versus 72% in the placebo group and at least very good partial response rates were 48% versus 39%. The median time to response was 1.1 months in the ixazomib arm versus 1.9 months in the placebo group, and median duration of response was 20.5 versus 15.0 months, respectively. In the ixazomib and placebo groups, frequencies of serious adverse events (47% vs. 49%) and on-study deaths (4% vs. 6%) were similar; 74% and 69% of patients experienced grade ≥3 adverse events. Grade 3 and 4 thrombocytopenia was more frequent in the ixazomib (12 and 7%) vs. placebo group (5 and 4%). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group, and no grade 4 events were reported). Please see below for the full U.S. prescribing information of NINLARO (ixazomib) capsules.

Data from TOURMALINE-MM1 were previously presented at the 57^th Annual Meeting of the American Society of Hematology (ASH) in Orlando, Florida.

NINLARO is currently under review by the European Medicines Agency (EMA). Takeda has also submitted applications for approval of ixazomib to additional health authorities around the world.

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 4 mg fixed dose on days 1, 8, and 15 of a 28-day treatment cycle. 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 comprehensive ixazomib clinical development program, TOURMALINE, further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with multiple myeloma worldwide and the healthcare professionals who treat them. TOURMALINE includes a total of five ongoing pivotal trials – four investigating every major multiple myeloma patient population and one in light-chain amyloidosis:

• TOURMALINE-MM1, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. This trial is currently ongoing, and patients continue to be treated to progression and will be evaluated for long-term outcomes.
• 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 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. Manage thrombocytopenia with dose modifications and platelet transfusions as per standard medical guidelines. 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. Diarrhea resulted in the discontinuation of one or more of the three drugs in 1% of patients in the NINLARO regimen and < 1% of patients in the placebo regimen. Adjust dosing for severe symptoms.
• Peripheral Neuropathy (predominantly sensory) was reported with NINLARO. The most commonly reported reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO and placebo regimens, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (< 1%). Peripheral neuropathy resulted in discontinuation of one or more of the three drugs in 1% of patients in both regimens. 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 of dexamethasone per its prescribing information or NINLARO for Grade 3 or 4 symptoms.
• Cutaneous Reactions: Rash, most commonly maculo-papular and macular rash, was reported with NINLARO. Rash resulted in discontinuation of one or more of the three drugs in < 1% of patients in both regimens. Manage rash with supportive care or with dose modification.
• Hepatotoxicity has been reported with NINLARO. Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in
  < 1% of patients treated with NINLARO. Events of liver impairment have been reported (6% in the NINLARO regimen and 5% in the placebo regimen). 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 (≥ 20%) in the NINLARO regimen and greater than the placebo regimen, respectively, were diarrhea (42%, 36%), constipation (34%, 25%), thrombocytopenia (78%, 54%; pooled from adverse events and laboratory data), peripheral neuropathy (28%, 21%), nausea (26%, 21%), peripheral edema (25%, 18%), vomiting (22%, 11%), and back pain (21%, 16%). Serious adverse reactions reported in ≥ 2% of patients included thrombocytopenia (2%) and diarrhea (2%).

SPECIAL POPULATIONS

• Hepatic Impairment: Reduce the NINLARO starting dose to 3 mg 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.

Please see the accompanying NINLARO full Prescribing Information.

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 monoclonal plasma cells, or myeloma cells, becomes cancerous and multiplies. These malignant plasma cells 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 Pharmaceutical Company
Takeda Pharmaceutical Company Limited is a global, R&D-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its research efforts on oncology, gastroenterology and central nervous system therapeutic areas. It also has specific development programs in specialty cardiovascular diseases as well as late-stage candidates for vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. New innovative products, especially in oncology and gastroenterology, as well as its presence in emerging markets, fuel the growth of Takeda. More than 30,000 Takeda employees are committed to improving quality of life for patients, working with our partners in health care in more than 70 countries. For more information, visit http://www.takeda.com/news.

Additional information about Takeda is available through its corporate website, www.takeda.com, and additional information about Takeda Oncology, the brand for the global oncology business unit of Takeda Pharmaceutical Company Limited, is available through its website, www.takedaoncology.com.

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Contact information

Takeda Pharmaceutical Company Limited
Japanese Media
Tsuyoshi Tada, +81 (0) 3-3278-2417
tsuyoshi.tada@takeda.com
or
Media outside Japan
Amy Atwood, +1-617-444-2147
amy.atwood@takeda.com