• If authorized, NINLARO will provide a new treat­ment option for European patients with multiple myeloma who have received at least one prior ther­apy
• Opinion based on TOURMALINE-MM1 trial, in which NINLARO plus lena­lido­mide and dexa­meth­a­sone dem­onstrated 6 month im­prove­ment in pro­gres­sion-free survival versus the placebo regi­men

Cambridge, MA, and Osaka, Japan (Press Release) – Takeda Pharma­ceu­tical Company Limited (TSE: 4502) announced today that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending the con­di­tional approval of NINLARO^TM (ixazomib) capsules in com­bi­na­tion with lena­lido­mide and dexa­meth­a­sone for the treat­ment of adult patients with multiple myeloma who have received at least one prior ther­apy. If the European Com­mis­sion ratifies the CHMP’s opinion and authori­za­tion is granted, NINLARO will be the first and only oral pro­te­a­some inhibitor approved for use across the Euro­pean Economic Area, which in­cludes the 28 member states of the European Union as well as Norway, Liechtenstein and Iceland.

“This is great news and a very positive devel­op­ment for myeloma patients in Europe,” said Eric Low, Chief Executive, Myeloma UK, and Board Member, Myeloma Patients Europe. “The im­prove­ment in pro­gres­sion free survival in this dif­fi­cult-to-treat stage of myeloma is sig­nif­i­cant. In addi­tion to ixazomib’s efficacy in this re­lapsed and/or refractory group of patients, its man­ageable safety profile and oral admin­istra­tion makes ixazomib a very welcome new treat­ment option for this serious and complex cancer. It is im­por­tant that attention is now turned in earnest to the Health Technology Assessment bodies to ensure their approval of ixazomib.”

Data from the pivotal Phase 3 trial TOURMALINE-MM1 dem­onstrate that the addi­tion of NINLARO to lena­lido­mide and dexa­meth­a­sone provides a sig­nif­i­cant im­prove­ment in pro­gres­sion-free survival when com­pared to placebo plus lena­lido­mide and dexa­meth­a­sone in this patient pop­u­la­tion. Patients con­tinue to be treated to pro­gres­sion in the trial, with addi­tional evaluations planned for long-term out­comes such as over­all survival.

“The heterogeneity of multiple myeloma means that it is very im­por­tant for patients and physicians to have access to a variety of treat­ment options, and many physicians are now looking forward to the possibility of adding NINLARO to our treat­ment armamentarium,” said Philippe Moreau, MD, Head of the Hematology Department at the University Hospital of Nantes, France. “The clin­i­cal data strongly sup­port the use of NINLARO in re­lapsed and/or refractory patients, while also delivering the advantages of an all-oral triplet regi­men. In the TOURMALINE-MM1 trial, the NINLARO regi­men showed a sig­nif­i­cant im­prove­ment in pro­gres­sion-free survival of 35 per­cent when compared to the placebo regi­men.”

“Today’s positive CHMP opinion for the con­di­tional approval of NINLARO is an im­por­tant first step to bringing this treat­ment to a re­lapsed and/or refractory patient pop­u­la­tion where there is a sig­nif­i­cant unmet need,” said Christophe Bianchi, M.D., Pres­i­dent, Takeda Oncology. “Currently approved pro­te­a­some inhibitors are only avail­able through twice-weekly injections and infusions, which can place addi­tional logistical burdens on patients and their care­givers, who already are dealing with a dif­fi­cult disease. We hope that the efficacy, convenience and man­ageable safety profile of this inno­va­tive treat­ment may allow for extended duration of treat­ment, which has the poten­tial to im­prove patient out­comes. Thank you to the patients and investigators for their par­tic­i­pa­tion in the TOURMALINE-MM1 trial to further our under­stand­ing of NINLARO’s benefits.”

For a con­di­tional approval, Takeda is required to provide post-approval updates on safety and efficacy analyses for TOURMALINE-MM1 and some other already ongoing studies to dem­onstrate the treat­ment's long-term effects.

NINLARO received its first approval from the U.S. Food and Drug Admin­istra­tion in November 2015 fol­low­ing priority review. In the U.S., it is indicated for use in com­bi­na­tion with lena­lido­mide and dexa­meth­a­sone for the treat­ment of patients with multiple myeloma who have received at least one prior ther­apy. Currently licensed for use in the U.S., Canada, Israel and Venezuela, NINLARO is also under review for approval by a number of regu­la­tory author­i­ties around the world. The CHMP’s positive opinion for the con­di­tional approval of NINLARO will now be reviewed by the European Com­mis­sion.

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 NINLARO^TM (ixazomib)

NINLARO^TM (ixazomib) is an oral pro­te­a­some inhibitor, which is being studied in multiple myeloma and systemic light-chain (AL) amyloidosis. It was the first oral pro­te­a­some inhibitor to enter Phase 3 clin­i­cal trials and to receive approval in the countries listed above.

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, 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
• 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, Takeda sup­ports a number of investigator ini­ti­ated studies evalu­at­ing the use of ixazomib in various com­bi­na­tions in on­col­ogy settings for patients 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 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.