Cambridge, MA and Osaka, Japan (Press Release) – Takeda Pharma­ceu­tical Company Limited (TSE: 4502) today announced that the ran­dom­ized, Phase 3 TOURMALINE-MM3 study met its pri­mary end­point, demonstrating single-agent oral NINLARO® (ixazomib) as a main­te­nance ther­apy resulted in a statistically sig­nif­i­cant im­prove­ment in pro­gres­sion-free survival (PFS) versus placebo. The trial eval­u­ated the effect of NINLARO as a main­te­nance ther­apy in adult patients diag­nosed with multiple myeloma who responded to high-dose ther­apy (HDT) and au­tol­o­gous stem cell trans­plant (ASCT). Takeda plans to submit data from the trial to regu­la­tory agencies around the world. NINLARO is cur­rently not approved as a main­te­nance ther­apy for multiple myeloma fol­low­ing ASCT.

“Within the main­te­nance setting, it is critical that we find agents that are efficacious, tolerable and convenient,” said Jesús Gomez Navarro, M.D., Vice Pres­i­dent, Head of Oncology Clinical Research and Development, Takeda. “The results of the TOURMALINE-MM3 trial rep­re­sent an im­por­tant step to­ward the goal of expanding the use of NINLARO as a main­te­nance ther­apy. This is the first and only Phase 3 placebo-controlled study eval­u­ating a pro­te­a­some inhibitor in this setting and we look forward to discussions with Health Authorities around the world.”

There were no new safety signals found in TOURMALINE-MM3. The safety profile of NINLARO in the main­te­nance setting is con­sis­tent with pre­vi­ously reported results of single-agent NINLARO use.

Full data results will be submitted for presentation at the 60th American Society of Hematology Annual Meeting in December.

About the TOURMALINE-MM3 Trial

TOURMALINE-MM3 is a ran­dom­ized, placebo-controlled, double-blind Phase 3 study of 656 patients, designed to determine the effect of NINLARO® (ixazomib) main­te­nance ther­apy on pro­gres­sion-free survival (PFS), compared to placebo, in par­tic­i­pants with multiple myeloma who have had a response (complete response [CR], very good partial response [VGPR], or partial response [PR]) to induction ther­apy followed by high-dose ther­apy (HDT) and au­tol­o­gous stem cell trans­plant (ASCT). The pri­mary end­point is pro­gres­sion-free survival (PFS). A key sec­ond­ary end­point in­cludes over­all survival (OS). For addi­tional in­­for­ma­tion: https://www.clinicaltrials.gov/ct2/show/NCT02181413.

About NINLARO® (ixazomib) capsules

NINLARO® (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 and by the European Com­mis­sion in November 2016. In the U.S. and Europe, 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. NINLARO has received market­ing authori­za­tion by regu­la­tory author­i­ties in more than 55 countries.

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 Japanese Ministry of Health, Labour and Welfare granted Orphan Drug desig­na­tion to ixazomib in 2016.

The com­pre­hen­sive ixazomib clin­i­cal devel­op­ment pro­gram, TOURMALINE, in­cludes a total of six ongoing pivotal trials – five, 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-MM5, investigating ixazomib plus dexamethasone vs. poma­lido­mide plus dexa­metha­sone in patients with relapsed and/or refractory multiple myeloma who have become resistant to lena­lido­mide
• 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

For more in­­for­ma­tion about actively enrolling Phase 3 studies please visit: https://www.tourmalinetrials.com/

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

NINLARO® (ixazomib) capsules: 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 European Union Summary of Product Characteristics: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003844/WC500217620.pdf
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 (TSE: 4502) 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 neuroscience thera­peutic areas plus vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of inno­va­t. Innovative prod­ucts, especially in on­col­ogy and gastroenterology, as well as Takeda’s presence in emerging markets, are cur­rently fueling the growth of Takeda. Approximately 30,000 Takeda employees are committed to im­prov­ing quality of life for patients, work­ing with Takeda’s partners in health care in more than 70 countries.

For more in­­for­ma­tion, visit https://www.takeda.com/newsroom/.

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.