Pivotal TOURMALINE-MM1 Results Demonstrated that the Addition of Oral Ixazomib to Lena­lido­mide and Dexamethasone Significantly Extended Progression-Free Survival, with Limited Additional Toxicity in Patients with Relapsed/Refractory Multiple Myeloma

Cambridge, MA and Osaka, Japan (Press Release) – 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.

“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 57th 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 inno­va­t. 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.

Source: Takeda.