Osaka, Japan, July 4, 2016 – Takeda Pharmaceutical Company Limited (TSE: 4502) today announced that it has submitted a New Drug Application ("NDA") to the Ministry of Health, Labour and Welfare in Japan for ixazomib, the first oral proteasome inhibitor for the treatment of relapsed or refractory multiple myeloma.
The NDA was filed based on the results of TOURMALINE-MM1, a global Phase 3 trial published in the New England Journal of Medicine in April. The trial demonstrated that the all-oral triplet regimen containing ixazomib, lenalidomide and dexamethasone significantly extended the progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma, with a manageable safety profile and the convenience and practicality of oral dosing.
"Multiple myeloma remains a devastating, relapsing and incurable rare cancer. We designed our extensive global Phase 3 clinical trial program, which includes TOURMALINE-MM1, to address the unmet need for an effective, tolerable and conveniently dosed therapy that may reduce some of the burdens that patients currently face," said Andrew Plump, M.D., Ph.D., Takeda Chief Medical and Scientific Officer. "Should it be approved, the NDA submission of ixazomib will enable the first all-oral, proteasome inhibitor-containing triplet regimen in Japan. We thank the patients and investigators who have contributed to the development of ixazomib and look forward to the opportunity of offering this innovative drug to patients in Japan."
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 114,000 new cases globally per year. It is reported that there are approximately 14,000 patients with multiple myeloma in Japan.
Ixazomib is a novel oral proteasome inhibitor which is being studied in multiple myeloma and systemic light-chain (AL) amyloidosis, and other malignancies. Ixazomib was granted orphan drug designation for the treatment of patients with relapsed or refractory multiple myeloma by the Ministry of Health, Labour and Welfare in February 2016. In the United States, an NDA was submitted based on the data of TOURMALINE-MM1 trial in July 2015, and the U.S. Food and Drug Administration (FDA) approval was obtained as a drug for treatment of patients with multiple myeloma who have received at least one prior therapy in November 2015, four months prior to its Priority Review PDUFA date. Ixazomib then became available in the U.S. in December, 2015 under the trade name "NINLARO®".
About TOURMALINE Trials
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, a large number of investigator initiated studies are evaluating ixazomib for patients globally.
About Orphan Drug Designation
Ixazomib was granted orphan drug designation for the treatment of patients with relapsed or refractory multiple myeloma by the Minister of Health, Labour and Welfare in February 2016. For additional information on Orphan Drug Designation, please visit the following press release dated February 26, 2016.
Important Safety Information (U.S.)
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.
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%).
- 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 NINLARO full U.S. Prescribing Information: https://www.ninlarohcp.com/safety.
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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