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

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 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 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.