OSAKA, Japan, May 27, 2021 – Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) ("Takeda") today announced that it has received approval from the Japanese Ministry of Health, Labour and Welfare for a partial amendment to the manufacturing and marketing approval of NINLARO® (ixazomib citrate; "NINLARO") to expand the eligible patient population for this medicine to those requiring a maintenance therapy after first-line treatment for multiple myeloma without prior stem cell transplant.
The approval is based primarily on the results of the TOURMALINE-MM4 study, a randomized and placebo-controlled double-blind multicenter international Phase III clinical trial. The study achieved its primary endpoint, demonstrating a statistically significant improvement in progression-free survival (PFS) in adult patients with multiple myeloma receiving NINLARO maintenance who had not undergone stem cell transplantation. The safety profile of NINLARO as a maintenance therapy is similar to its established safety profile in the monotherapy setting, and, notably, no new concerns were identified in the TOURMALINE-MM4 study.
"The TOURMALINE-MM4 study demonstrated that maintenance therapy with the oral proteasome inhibitor NINLARO reduces the risk of progression and death by 34% in patients with multiple myeloma who are not candidates for transplantation. Maintenance therapy with NINLARO is well tolerated by older patients, has not been associated with an increased risk of secondary cancers, and therefore may be a treatment option that can be expected to delay relapse regardless of clinical stage or type of first-line remission-induction therapy," said Dr. Shinsuke Iida of the Department of Hematology and Oncology, Nagoya City University Hospital, the principal investigator in the TOURMALINE-MM4 study.
"I am pleased that in addition to the existing indication for NINLARO as a maintenance therapy after autologous hematopoietic stem cell transplantation, it is now indicated as a maintenance therapy after initial treatment in patients without prior stem cell transplantation, meaning that we can now offer this medicine to a wider range of patients. We will continue to work to bring this new therapy to patients who need it by informing the medical community," said Takashi Horii, Head of Japan Oncology Business Unit.
NINLARO received manufacturing and marketing approval from the Japanese Ministry of Health, Labour and Welfare in March 2017 for the treatment of relapsed or refractory multiple myeloma, indicated in combination with lenalidomide and dexamethasone, and was launched on May 24, 2017. On March 25, 2020, Takeda received approval for a partial amendment to the drug's prior manufacturing and marketing approval as a maintenance therapy after autologous hematopoietic stem cell transplantation in multiple myeloma.
About the TOURMALINE-MM4 Trial
TOURMALINE-MM4 is a randomized, double-blind, placebo-controlled, multicenter international Phase 3 study of 706 patients, designed to evaluate the effect of single-agent oral NINLARO as a maintenance therapy following primary therapy in adult patients diagnosed with multiple myeloma who have not received a stem cell transplant. This is the first company-led Phase III trial to evaluate switch maintenance, in which maintenance therapy is given to patients who did not receive initial induction therapy. The primary endpoint was progression-free survival (PFS), and the study demonstrated a statistically significant improvement in this metric. The safety profile of NINLARO as a maintenance therapy is similar to the known safety profile of monotherapy, and no new concerns were identified in the TOURMALINE-MM4 study.
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NINLAROTM (ixazomib): GLOBAL 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 typically 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.
- Thrombotic Microangiopathy: Cases, sometimes fatal, of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received NINLARO. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop NINLARO and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting NINLARO. The safety of reinitiating NINLARO therapy in patients previously experiencing TTP/HUS is not known.
- 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: Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with NINLARO and for 90 days following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with NINLARO and for 90 days following the final dose. Ninlaro can cause fetal harm.
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%).
DRUG INTERACTIONS: Avoid concomitant administration of NINLARO with strong CYP3A inducers.
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 not to breastfeed during treatment with NINLARO and for 90 days after the last dose.
For European Union Summary of Product Characteristics: http://www.ema.europa.eu/docs/enGB/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 Limited
Takeda Pharmaceutical Company Limited (TSE: 4502/NYSE: TAK) is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to discover and deliver life-transforming treatments, guided by our commitment to patients, our people and the planet. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Rare Genetics and Hematology, Neuroscience, and Gastroenterology (GI). We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people’s lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries. For more information, visit https://www.takeda.com.
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