Takeda to Present Positive Data from TOURMALINE-MM3, First Pivotal Phase 3 Placebo Controlled Trial Evaluating Proteasome Inhibitor Treatment in Maintenance Setting

CAMBRIDGE, Mass. & OSAKA, Japan--(BUSINESS WIRE)-- Takeda Pharmaceutical Company Limited (TSE:4502) today announced that data from the Phase 3 randomized, TOURMALINE-MM3 study evaluating the effect of single-agent oral NINLARO^™ (ixazomib) as a maintenance therapy in adult patients diagnosed with multiple myeloma who previously responded to high-dose therapy (HDT) and autologous stem cell transplant (ASCT) will be presented at the 60^th American Society of Hematology (ASH) annual meeting on Sunday, December 2, 2018 in San Diego, California. NINLARO is currently not approved as a maintenance therapy for multiple myeloma following ASCT.

The trial achieved its primary endpoint with NINLARO resulting in a statistically significant improvement in progression-free survival (PFS) versus placebo in adult patients diagnosed with multiple myeloma who responded to HDT and ASCT as assessed by an Independent Review Committee (IRC) (HR 0.72; p-value=0.002). This corresponds to a 28 percent reduction in risk of progression or death and a 39 percent improvement in PFS with NINLARO compared with placebo. The safety profile of NINLARO in the maintenance setting is consistent with previously reported results of single-agent NINLARO use.

“A growing body of evidence has shown that maintenance therapy in multiple myeloma may prolong the duration of disease control,” said Meletios Dimopoulos, MD, Professor and Chairman of the Department of Clinical Therapeutics at the University Athens School of Medicine, Athens, Greece. “As currently approved options are limited and do not include a proteasome inhibitor, there is a need for additional maintenance treatments that can sustain response and have a tolerable safety profile. Data from the TOURMALINE-MM3 clinical trial supports single-agent NINLARO as a potential oral proteasome inhibitor maintenance therapy option post-ASCT.”

“The positive results from this pivotal study – the first and only Phase 3 placebo controlled study evaluating a proteasome inhibitor in this setting – support NINLARO as a potential maintenance therapy for patients who have undergone a stem cell transplant,” said Jesús Gómez Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda. “It is crucial that we continue to support patients by developing treatment options aimed to maintain or deepen response and delay disease progression. According to the findings, patients treated with NINLARO had improved progression-free survival over those in the control arm, which corresponds to a reduced risk of progression or death of nearly one-third.”

“As a result of continued research, the multiple myeloma treatment landscape is constantly evolving. While this is encouraging news for the multiple myeloma community, there is still work to be done to further our goal of addressing the unmet needs of patients,” said Brian GM Durie, M.D., Chairman of the Board, International Myeloma Foundation. “To that end, the development of additional safe and effective maintenance therapies is essential.”

Maintenance Therapy With the Oral Proteasome Inhibitor (PI) Ixazomib Significantly Prolongs Progression-Free Survival (PFS) Following Autologous Stem Cell Transplantation (ASCT) in Patients With Newly Diagnosed Multiple Myeloma (NDMM): Phase 3 TOURMALINE-MM3 Trial Sunday, December 2, 2018, 7:30 – 9:00 a.m., Marriott Marquis San Diego Marina, Grand Ballroom 7

Key findings, which will be presented by Dr. Meletios Dimopoulos, include:

• The trial achieved its primary endpoint with NINLARO resulting in a statistically significant improvement in PFS versus placebo in adult patients diagnosed with multiple myeloma who responded to HDT and ASCT as assessed by an Independent Review Committee (IRC) (HR 0.72; 95% CI: 0.582, 0.890; p-value=0.002). This corresponds to a 28 percent reduction in risk of progression or death and a 39 percent improvement in PFS with NINLARO.
• Per IRC assessment, median PFS for patients in the NINLARO arm was 26.5 months compared to 21.3 months in the placebo arm.
• Conversion from documented minimal residual disease (MRD) positivity at study entry to MRD negativity occurred at a higher rate among patients treated with NINLARO compared with placebo (12 percent versus 7 percent, respectively).
• NINLARO maintenance led to higher rates of deepened response compared with placebo (relative risk 1.41; 95 percent CI: 1.10, 1.80; p=0.0042).
• PFS benefit was seen broadly across subgroups, including ISS III (HR 0.661), PI-exposed (HR 0.750), PI-naïve (HR 0.497), and patients with high-risk cytogenetics (HR 0.625).
• Secondary endpoints including median PFS2 and OS have not yet been reached in either arm. Median follow-up was 31 months.
• Global Quality of Life scores (EORTC QLQ-C30) for patients on NINLARO were similar to those on placebo.
• The safety profile of NINLARO in the maintenance setting is consistent with previously reported results of single-agent NINLARO use.
  • Discontinuation of treatment due to adverse events (AE) was low, at 7 percent in the NINLARO arm compared to 5 percent in the placebo arm.
  • Grade ≥3 AEs were experienced by 42 percent of patients receiving NINLARO versus 26 percent receiving placebo.
  • Patients in the NINLARO arm experienced serious AEs at a rate of 27 percent versus 20 percent in the placebo arm.
  • Common grade ≥3 AEs in both the NINLARO and placebo arms included infections (15 and 8 percent, respectively) including pneumonia (6 and 4 percent, respectively), gastrointestinal disorders (6 and 1 percent, respectively), neutropenia (5 and 3 percent, respectively) and thrombocytopenia (5 and <1 percent, respectively).
  • On the NINLARO arm, peripheral neuropathy events were observed in 19 percent of patients versus 15 percent on the placebo arm. In the NINLARO arm, <1 percent of peripheral neuropathy events were Grade 3 compared with 0 in the placebo arm.
  • The rate of second primary malignancies was 3 percent in both arms.
  • One patient in the NINLARO arm died on study while no patients in the placebo arm did. The single study death was considered to be treatment-related and was due to pneumonia.

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 60 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 versus placebo in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma
• TOURMALINE-MM2, investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
• TOURMALINE-MM3, investigating ixazomib versus placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant (ASCT)
• TOURMALINE-MM4, investigating ixazomib versus placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone ASCT
• TOURMALINE-AL1, investigating ixazomib plus dexamethasone versus physician choice of selected regimens in patients with relapsed or refractory AL amyloidosis; this study is currently enrolling
• TOURMALINE-MM5, investigating ixazomib plus dexamethasone versus pomalidomide plus dexamethasone in patients with relapsed and/or refractory multiple myeloma who have become resistant to lenalidomide; 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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