Phase 3 Trial of NINLARO® (ixazomib) as Maintenance Therapy Met Primary Endpoint Demonstrating Statistically Significant Improvement in Progression-Free Survival in Patients with Multiple Myeloma Post-Transplant

Takeda Pharmaceutical Company Limited (TSE: 4502) today announced that the randomized, Phase 3 TOURMALINE-MM3 study met its primary endpoint, demonstrating single-agent oral NINLARO^® (ixazomib) as a maintenance therapy resulted in a statistically significant improvement in progression-free survival (PFS) versus placebo. The trial evaluated the effect of NINLARO as a maintenance therapy in adult patients diagnosed with multiple myeloma who responded to high-dose therapy (HDT) and autologous stem cell transplant (ASCT). Takeda plans to submit data from the trial to regulatory agencies around the world. NINLARO is currently not approved as a maintenance therapy for multiple myeloma following ASCT.

“Within the maintenance setting, it is critical that we find agents that are efficacious, tolerable and convenient,” said Jesús Gomez Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda. “The results of the TOURMALINE-MM3 trial represent an important step toward the goal of expanding the use of NINLARO as a maintenance therapy. This is the first and only Phase 3 placebo-controlled study evaluating a proteasome inhibitor in this setting and we look forward to discussions with Health Authorities around the world.”

There were no new safety signals found in TOURMALINE-MM3. The safety profile of NINLARO in the maintenance setting is consistent with previously reported results of single-agent NINLARO use.

Full data results will be submitted for presentation at the 60th American Society of Hematology Annual Meeting in December.

About the TOURMALINE-MM3 Trial

TOURMALINE-MM3 is a randomized, placebo-controlled, double-blind Phase 3 study of 656 patients, designed to determine the effect of NINLARO^® (ixazomib) maintenance therapy on progression-free survival (PFS), compared to placebo, in participants with multiple myeloma who have had a response (complete response [CR], very good partial response [VGPR], or partial response [PR]) to induction therapy followed by high-dose therapy (HDT) and autologous stem cell transplant (ASCT). The primary endpoint is progression-free survival (PFS). A key secondary endpoint includes overall survival (OS). For additional information: https://www.clinicaltrials.gov/ct2/show/NCT02181413.

About NINLARO ^® (ixazomib) capsules

NINLARO^® (ixazomib) is an oral proteasome inhibitor which is also being studied across the continuum of multiple myeloma treatment settings as well as systemic light-chain (AL) amyloidosis. It was the first oral proteasome inhibitor to enter Phase 3 clinical trials and to receive approval. NINLARO was approved by the U.S. Food and Drug Administration (FDA) in November 2015 following a priority review and by the European Commission in November 2016. In the U.S. and Europe, 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. NINLARO has received marketing authorization by regulatory authorities in more than 55 countries.

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 Japanese Ministry of Health, Labour and Welfare granted Orphan Drug designation to ixazomib in 2016.

The comprehensive ixazomib clinical development program, TOURMALINE, includes a total of six ongoing pivotal trials – five, which together are 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; this study is currently enrolling
• TOURMALINE-MM5, investigating ixazomib plus dexamethasone vs. pomalidomide plus dexamethasone in patients with relapsed and/or refractory multiple myeloma who have become resistant to lenalidomide
• TOURMALINE-AL1, investigating ixazomib plus dexamethasone vs. physician choice of selected regimens in patients with relapsed or refractory AL amyloidosis; this study is currently enrolling

For more information about actively enrolling Phase 3 studies please visit: https://www.tourmalinetrials.com/

In addition to the TOURMALINE program, ixazomib is being evaluated in multiple therapeutic combinations for various patient populations in investigator initiated studies globally.

NINLARO ^® (ixazomib) capsules: Global Important Safety Information

SPECIAL WARNINGS AND PRECAUTIONS
Thrombocytopenia has been reported with NINLARO (28% vs. 14% in the NINLARO and placebo regimens, respectively) with platelet nadirs typically occurring between Days 14-21 of each 28-day cycle and recovery to baseline by the start of the next cycle. It did not result in an increase in hemorrhagic events or platelet transfusions. Monitor platelet counts at least monthly during treatment with NINLARO and consider more frequent monitoring during the first three cycles. Manage with dose modifications and platelet transfusions as per standard medical guidelines.

Gastrointestinal toxicities have been reported in the NINLARO and placebo regimens respectively, such as diarrhea (42% vs. 36%), constipation (34% vs. 25%), nausea (26% vs. 21%), and vomiting (22% vs. 11%), occasionally requiring use of antiemetic and anti-diarrheal medications, and supportive care.

Peripheral neuropathy was reported with NINLARO (28% vs. 21% in the NINLARO and placebo regimens, respectively). 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%). Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed.

Peripheral edema was reported with NINLARO (25% vs. 18% in the NINLARO and placebo regimens, respectively). Evaluate patients for underlying causes and provide supportive care, as necessary. Adjust the dose of dexamethasone per its prescribing information or the dose of NINLARO for severe symptoms.

Cutaneous reactions occurred in 19% of patients in the NINLARO regimen compared to 11% of patients in the placebo regimen. The most common type of rash reported in both regimens was maculo-papular and macular rash. Manage rash with supportive care, dose modification or discontinuation.

Hepatotoxicity, drug-induced liver injury, hepatocellular injury, hepatic steatosis, and hepatitis cholestatic have been uncommonly reported with NINLARO. Monitor hepatic enzymes regularly and adjust dose for Grade 3 or 4 symptoms.

Pregnancy- NINLARO can cause fetal harm. Advise male and females patients of reproductive potential to use contraceptive measures during treatment and for an additional 90 days after the final dose of NINLARO. Women of childbearing potential should avoid becoming pregnant while taking NINLARO due to potential hazard to the fetus. Women using hormonal contraceptives should use an additional barrier method of contraception.

Lactation- It is not known whether NINLARO or its metabolites are excreted in human milk. There could be potential adverse events in nursing infants and therefore breastfeeding should be discontinued.

SPECIAL PATIENT 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 (ESRD) requiring dialysis. NINLARO is not dialyzable and, therefore, can be administered without regard to the timing of dialysis.

DRUG INTERACTIONS
Co-administration of strong CYP3A inducers with NINLARO is not recommended.

ADVERSE REACTIONS
The most frequently reported adverse reactions (≥ 20%) in the NINLARO regimen, and greater than in the placebo regimen, were diarrhea (42% vs. 36%), constipation (34% vs. 25%), thrombocytopenia (28% vs. 14%), peripheral neuropathy (28% vs. 21%), nausea (26% vs. 21%), peripheral edema (25% vs. 18%), vomiting (22% vs. 11%), and back pain (21% vs. 16%). Serious adverse reactions reported in ≥ 2% of patients included thrombocytopenia (2%) and diarrhea (2%). For each adverse reaction, one or more of the three drugs was discontinued in ≤ 1% of patients in the NINLARO regimen.

For European Union Summary of Product Characteristics: http://www.ema.europa.eu/docs/en_GB/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
Takeda Pharmaceutical Company Limited (TSE: 4502) is a global, research and development-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its R&D efforts on oncology, gastroenterology and neuroscience therapeutic areas plus vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. Innovative products, especially in oncology and gastroenterology, as well as Takeda’s presence in emerging markets, are currently fueling the growth of Takeda. Approximately 30,000 Takeda employees are committed to improving quality of life for patients, working with Takeda’s partners in health care in more than 70 countries.

For more information, visit https://www.takeda.com/newsroom/.

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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Contact information

Takeda Pharmaceutical Company Limited
Japanese Media
Kazumi Kobayashi, +81 (0) 3-3278-2095
kazumi.kobayashi@takeda.com
or
European Media
Kate Burd, +41 79 514 9533
kate.burd@takeda.com
or
Media outside Japan/EU
Victoria von Rinteln, +1-617-444-4391
Victoria.vonRinteln@takeda.com