Takeda Provides Update on EU Marketing Authorization Application for NINLARO® (ixazomib) in Relapsed/Refractory Multiple Myeloma

OREANDA-NEWS. May 30, 2016. Takeda Pharmaceutical Company Limited (TSE: 4502) today announced that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a negative opinion, recommending against the authorization of NINLARO^® (ixazomib) capsules, an oral proteasome inhibitor for the treatment of patients with relapsed and/or refractory multiple myeloma. Takeda intends to appeal this opinion and request a re-examination by the CHMP.

“We are disappointed by the CHMP’s opinion. With the support of European key medical experts, we will continue our efforts working closely with the CHMP to make NINLARO – the first oral proteasome inhibitor – available for patients in Europe,” said Christophe Bianchi, M.D., President, Takeda Oncology. “Despite recent progress, myeloma remains an intractable disease, and patients suffering from multiple myeloma and their treating physicians need more options to improve outcomes. We stand behind the TOURMALINE-MM1 trial data, which were recently published in the New England Journal of Medicine and demonstrated a significant extension in progression-free survival for NINLARO + lenalidomide and dexamethasone vs. placebo + lenalidomide and dexamethasone and a favorable benefit-risk profile.”

“After years of treating patients, I have yet to see two people whose diseases are exactly alike. The diversity of patients with multiple myeloma demands a wide range of innovative treatment options that offer efficacy, tolerable safety profiles and convenience, which are especially important benefits for elderly populations,” said Philippe Moreau, M.D., University of Nantes, France. “In Europe, where no oral proteasome inhibitor is available, NINLARO would fill a noticeable void and enable the first all-oral triplet combination therapy for patients with relapsed or refractory multiple myeloma.”

NINLARO was approved by the U.S. Food and Drug Administration (FDA) in November 2015 following a priority review. In the U.S., 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. The FDA approval of NINLARO marked the first global regulatory approval of ixazomib. Takeda also has submitted applications for approval of ixazomib to additional regulatory authorities around the world. In addition to the TOURMALINE-MM1 trial that is forming the basis of these global regulatory submissions in relapsed and refractory multiple myeloma, ixazomib is being investigated in a number of other multiple myeloma treatment settings.

There will be no significant impact to Takeda’s fiscal year 2016 financials due to the CHMP opinion.

About NINLARO^® (ixazomib)
NINLARO^® (ixazomib) is an investigational 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.

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, a large number of investigator initiated studies are evaluating ixazomib for patients globally.

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.

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.

ADVERSE REACTIONS