Approval Based on TOURMALINE-MM1 Study Results, Which Demonstrated Statistically Significant Six-Month Improvement in Progression-Free Survival

Cambridge, MA, and Osaka, Japan (Press Release) – Takeda Pharma­ceu­tical Company Limited (TSE: 4502) today announced that the European Com­mis­sion has granted con­di­tional market­ing authori­za­tion for NINLARO^TM (ixazomib) capsules, indicated in com­bi­na­tion with lena­lido­mide and dexa­meth­a­sone for adult patients with multiple myeloma who have received at least one prior ther­apy. The de­ci­sion to approve NINLARO as the first and only oral pro­te­a­some inhibitor to treat multiple myeloma follows a positive opinion by the European Medicines Agency (EMA) Committee for Medicinal Products (CHMP) for Human Use in September 2016.

“For myeloma patients living in Europe, the approval of NINLARO means we have a new and effective treat­ment option avail­able when we relapse,” said Bob Munro, a patient with multiple myeloma from the United Kingdom. “I applaud the European Com­mis­sion for recognising the addi­tional benefit that NINLARO will bring to patients, who not only want treat­ment options that are effective and tolerable, but also appreciate the convenient option of taking an oral treat­ment. I strongly hope this will be made avail­able by national health systems across Europe as soon as possible.”

The European Com­mis­sion followed the CHMP’s recom­men­da­tion to approve NINLARO based on data from the pivotal Phase 3 TOURMALINE-MM1 trial, which dem­onstrated that NINLARO plus lena­lido­mide and dexa­meth­a­sone in­­creased the length of pro­gres­sion-free survival by about six months, or 40 per­cent, in patients with re­lapsed and refractory multiple myeloma when compared with placebo, lena­lido­mide and dexa­meth­a­sone. The study also showed that the pro­gres­sion-free survival benefit observed in the NINLARO regi­men extended across pre-specified subgroups of patients. Follow-up analyses for over­all survival are planned for 2017.

“With the approval of NINLARO by the European Com­mis­sion, physicians across the region will have the option to prescribe an all-oral triplet regi­men to treat patients with multiple myeloma who have received at least one prior ther­apy,” said Philippe Moreau, MD, Head of the Hematology Department at the University Hospital of Nantes, France. “In the TOURMALINE-MM1 study, we saw a clin­i­cally meaningful six-month im­prove­ment in pro­gres­sion-free survival with NINLARO, evi­dence that has sup­ported its approval in Europe. As a hematologist, I welcome the avail­a­bil­ity of this treat­ment to address a dev­as­tat­ing disease like multiple myeloma.”

“When devel­op­ing NINLARO, Takeda Oncology’s scientists sought to formulate an efficacious and unique oral pro­te­a­some inhibitor with a man­ageable safety profile. NINLARO delivers the proven efficacy of a pro­te­a­some inhibitor in a convenient once-weekly pill that can be taken at home,” said Christophe Bianchi, M.D., Pres­i­dent, Takeda Oncology. “NINLARO has the poten­tial to help European patients with re­lapsed multiple myeloma by removing some of the barriers that can stand in the way of optimal treat­ment. With NINLARO, our hope is that many patients will be able to con­tinue ther­apy until disease pro­gres­sion. Following the European Com­mis­sion’s approval, we will con­tinue to study NINLARO in a variety of settings in the hopes that we can bring this medicine to as many of the patients who may benefit from it as possible.”

As a result of the European Com­mis­sion de­ci­sion, NINLARO is now approved for use across the European Economic Area, which in­cludes the European Union’s 28 member states as well as Norway, Liechtenstein and Iceland. In addi­tion, NINLARO is licensed for use in the U.S., Canada, Israel, Australia and Venezuela, and Takeda has submitted market­ing authori­za­tion appli­ca­tions for NINLARO to a number of addi­tional regu­la­tory author­i­ties around the world.

About NINLARO^TM (ixazomib) capsules

NINLARO^TM (ixazomib) is an oral pro­te­a­some inhibitor which is also being studied across the con­tin­uum of multiple myeloma treat­ment settings as well as systemic light-chain (AL) amyloidosis. It was the first oral pro­te­a­some inhibitor to enter Phase 3 clin­i­cal trials and to receive approval. NINLARO was approved by the U.S. Food and Drug Admin­istra­tion (FDA) in November 2015 fol­low­ing a priority review. In the U.S., NINLARO is indicated in com­bi­na­tion with lena­lido­mide and dexa­meth­a­sone for the treat­ment of patients with multiple myeloma who have received at least one prior ther­apy.

Ixazomib was granted orphan drug desig­na­tion in multiple myeloma in both the U.S. and Europe in 2011 and for AL amyloidosis in both the U.S. and Europe in 2012. Ixazomib received Break­through Therapy status by the U.S. FDA for re­lapsed or refractory systemic light-chain (AL) amyloidosis 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, which together are 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
• 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; this study is currently enrolling
• TOURMALINE-AL1, investigating ixazomib plus dexamethasone vs. physician choice of selected regimens in patients with relapsed or refractory AL amyloidosis; this study is currently enrolling

In addi­tion to the TOURMALINE pro­gram, ixazomib is being eval­u­ated in multiple thera­peutic com­bi­na­tions for various patient pop­u­la­tions in investigator ini­ti­ated studies globally.

NINLARO^TM (ixazomib): Global Important Safety Information

SPECIAL WARNINGS AND PRECAUTIONS

Thrombocytopenia has been reported with NINLARO (28％ vs. 14％ in the NINLARO and placebo regi­mens, re­spec­tive­ly) with platelet nadirs typically occurring be­tween Days 14-21 of each 28-day cycle and re­cov­ery to base­line by the start of the next cycle. It did not result in an in­­crease in hemor­rhagic events or platelet transfusions. Monitor platelet counts at least monthly during treat­ment with NINLARO and con­sider more frequent monitoring during the first three cycles. Manage with dose modifications and platelet transfusions as per standard medical guidelines.

Gastrointestinal toxicities have been reported in the NINLARO and placebo regi­mens re­spec­tive­ly, such as diarrhea (42％ vs. 36％), con­sti­pa­tion (34％ vs. 25％), nausea (26％ vs. 21％), and vomiting (22％ vs. 11％), occasionally requiring use of antiemetic and anti-diarrheal medications, and sup­port­ive care.

Peripheral neu­rop­athy was reported with NINLARO (28％ vs. 21％ in the NINLARO and placebo regi­mens, re­spec­tive­ly). 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％). Monitor patients for symp­toms of periph­eral neu­rop­athy and adjust dosing as needed.

Peripheral edema was reported with NINLARO (25％ vs. 18％ in the NINLARO and placebo regi­mens, re­spec­tive­ly). Evaluate patients for under­lying causes and provide sup­port­ive care, as nec­es­sary. Adjust the dose of dexa­meth­a­sone per its pre­scrib­ing in­­for­ma­tion or the dose of NINLARO for severe symp­toms.

Cutaneous reac­tions occurred in 19％ of patients in the NINLARO regi­men compared to 11％ of patients in the placebo regi­men. The most common type of rash reported in both regi­mens was maculo-papular and macular rash. Manage rash with sup­port­ive care, dose modification or dis­con­tinu­a­tion.

Hepatotoxicity, drug-induced liver injury, hepato­cellular injury, hepatic steatosis, and hepatitis cholestatic have been uncommonly reported with NINLARO. Monitor hepatic enzymes regularly and adjust dose for Grade 3 or 4 symp­toms.

Pregnancy - NINLARO can cause fetal harm. Advise male and females patients of reproductive poten­tial to use con­tra­­cep­tive measures during treat­ment and for an addi­tional 90 days after the final dose of NINLARO. Women of childbearing poten­tial should avoid becoming pregnant while taking NINLARO due to poten­tial hazard to the fetus. Women using hormonal con­tra­­cep­tives should use an addi­tional barrier method of con­tra­cep­tion.

Lactation - It is not known whether NINLARO or its metabolites are excreted in human milk. There could be poten­tial adverse events in nursing infants and there­fore breastfeeding should be dis­con­tinued.

SPECIAL PATIENT 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 (ESRD) requiring dialysis. NINLARO is not dialyzable and, there­fore, can be admin­istered without regard to the timing of dialysis.

DRUG INTERACTIONS

Co-administration of strong CYP3A inducers with NINLARO is not recommended.

ADVERSE REACTIONS

The most frequently reported adverse reac­tions (≥ 20％) in the NINLARO regi­men, and greater than in the placebo regi­men, were diarrhea (42％ vs. 36％), con­sti­pa­tion (34％ vs. 25％), thrombo­cytopenia (28％ vs. 14％), periph­eral neu­rop­athy (28％ vs. 21％), nausea (26％ vs. 21％), periph­eral edema (25％ vs. 18％), vomiting (22％ vs. 11％), and back pain (21％ vs. 16％). Serious adverse reac­tions reported in ≥ 2％ of patients in­cluded thrombo­cytopenia (2％) and diarrhea (2％). For each adverse reac­tion, one or more of the three drugs was dis­con­tinued in ≤ 1％ of patients in the NINLARO regi­men.

For US Prescribing Information:

https://www.ninlarohcp.com/pdf/prescribing-information.pdf

For Canada Product Monograph:

http://www.takedacanada.com/ninlaropm

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 approx­i­mately 39,000 new cases in the EU and 114,000 new cases globally per year.

About Takeda Pharma­ceu­tical Company

Takeda Pharma­ceu­tical Company Limited is a global, research and devel­op­ment-driven pharma­ceu­tical com­pany committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its R&D efforts on on­col­ogy, gastroenterology and central nervous system thera­peutic areas plus vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of inno­va­t. New inno­va­tive prod­ucts, especially in on­col­ogy and gastroenterology, as well as our 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.

Source: Takeda Pharma­ceu­tical Company.