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Takeda Presents Data from Phase 1/2 Studies for NINLARO™ (ixazomib) in Newly Diagnosed Multiple Myeloma Patients and in the Maintenance Setting

Takeda Pharmaceutical Company Limited (TSE: 4502 ) today announced that data from two Phase 1/2 clinical trials evaluating NINLARO™ (ixazomib) in patients with newly diagnosed multiple myeloma will be presented during oral sessions at the 2017 European Hematology Association (EHA) annual meeting on Saturday, June 24, 11:45 a.m. – 12 p.m. CEST and Sunday, June 25, 8:15 a.m. – 8:30 a.m. CEST. Both studies evaluated NINLARO plus lenalidomide and dexamethasone in newly diagnosed patients with multiple myeloma who did not undergo stem cell transplant (SCT), followed by maintenance with single-agent ixazomib. NINLARO is currently not approved for the treatment of newly diagnosed multiple myeloma or in the maintenance setting.

“Despite recent progress, multiple myeloma remains a rare, devastating and incurable hematologic cancer. Data being presented at EHA demonstrate Takeda’s ongoing commitment to exploring new ways to provide effective and sustainable treatment for patients with multiple myeloma, both at the time of diagnosis and for long-term use,” said Jesus Gomez Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda. “These Phase 1/2 data demonstrate the potential use of ixazomib in combination with lenalidomide-dexamethasone in newly diagnosed multiple myeloma and as a single-agent maintenance therapy, which resulted in patients achieving deepening responses with continual use of the treatment. Ixazomib’s efficacy and safety profile – coupled with its administration as a completely oral regimen – potentially can reduce some logistical burdens, and help patients be able to sustain a multiple myeloma therapy.”

Deep and Durable Responses with Weekly Ixazomib, Lenalidomide and Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma: Long-Term Follow-up of Patients who did not Undergo SCT (Abstract S408, oral presentation at 11:45 a.m. CEST on June 24, 2017 at IFEMA Madrid, Hall A)

In this Phase 1/2 study, patients with newly diagnosed multiple myeloma received weekly oral ixazomib (1.68 - 3.95 mg/m2 in Phase 1 and 4.0 mg in Phase 2) plus lenalidomide and dexamethasone for up to twelve, 28-day induction cycles. Of the 65 enrolled patients, 42 continued on study treatment without withdrawing early for SCT. After initial therapy, 25 patients went on to receive weekly, single-agent ixazomib at the last tolerated dose given during induction until disease progression or unacceptable toxicity.

Key findings, which will be presented by Dr. Shaji Kumar of the Mayo Clinic, Rochester, Minnesota, include:

  • Patients who did not undergo SCT and were treated with ixazomib plus lenalidomide and dexamethasone at induction achieved high response rates, demonstrate the activity of this regimen
    • At a median follow-up of 55.2 months, the confirmed overall response rate (ORR) was 80%, complete plus very good partial response (CR+VGPR) rate was 63% and CR rate was 32%
    • Of the patients who achieved sCR/CR and were evaluated for minimal residual disease (MRD), 6 of 7 (86%) were MRD-negative.
    • Median progression-free survival (PFS) was 29.4 months
    • Median overall survival (OS) was not reached at a median follow-up of 55.2 months; four-year landmark OS estimate was 82%
    • A total of 86% of patients had grade ≥ 3 adverse events (AEs) and 52% of patients had serious AEs. The most common grade ≥ 3 AEs were neutropenia, thrombocytopenia, diarrhea, back pain, vomiting, rashes, eruptions and exanthems, peripheral neuropathy and nausea. Of the two patients who died on study, one was considered to be treatment-related and was due to respiratory syncytial viral pneumonia
  • After completing 12 cycles of induction therapy with lenalidomide and dexamethasone, 25 patients went on to receive maintenance single-agent ixazomib
    • Increased depth of response occurred in a number of patients who received maintenance therapy with single-agent ixazomib; 32% of patients improved their response during maintenance
    • The occurrence of the most common grade ≥ 3 AEs and adverse drug reactions (ADRs), which included neutropenia, thrombocytopenia, back pain and rashes, eruptions and exanthems, was confined almost exclusively to the induction period
      • Less toxicity was reported during the maintenance versus induction periods

“Based on an increasing body of evidence that long-term therapy may improve clinical outcomes, this Phase 1/2 trial focused on continuous treatment of patients with newly diagnosed multiple myeloma,” said lead investigator Shaji Kumar, M.D., Mayo Clinic, Rochester, Minn. “The trial evaluated patients who received weekly ixazomib plus lenalidomide and dexamethasone as an induction regimen followed by maintenance with single-agent ixazomib. Data showed that patients had deep responses on single-agent therapy and median progression-free survival of more than two years. We remain committed to gathering additional data of ixazomib in this investigational, maintenance setting.”

Twice Weekly Ixazomib Plus Lenalidomide-Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma: Long-Term Follow-up Data for Patients who did not Undergo Stem Cell Transplant (SCT) (Abstract S780, oral presentation at 8:15 a.m. CEST on June 25, 2017 at IFEMA Madrid, Hall D)

This Phase 1/2 study evaluated twice-weekly oral ixazomib (3.0 or 3.7 mg) plus lenalidomide and dexamethasone for up to sixteen, 21-day cycles followed by maintenance therapy with single-agent twice weekly ixazomib (at last tolerated dose). Of the 64 patients enrolled, 41 continued on study treatment without early withdrawal for SCT.

Key findings, which will be presented by Deborah Berg, Senior Scientific Director, Oncology Clinical Research, Takeda, on behalf of Dr. Paul Richardson, Dana-Farber Cancer Institute, Boston, Mass., include:

  • In patients who did not undergo SCT, initial treatment with twice-weekly ixazomib plus lenalidomide and dexamethasone was associated with deep responses
    • At median follow-up of 47 months, the ORR was 92%, the CR + VGPR rate was 69% and the CR rate was 31%
    • Of the patients who achieved sCR/CR and were evaluated for minimal residual disease (MRD), 8 of 9 (89%) were MRD-negative
    • Median PFS for patients was 24.9 months and median OS was not estimable; three-year landmark OS estimate was 86%
    • A total of 85% of patients had grade ≥ 3 AEs and 54% of patients had serious AEs. The most common grade ≥3 AEs included rash, eruptions and exanthems, hyperglycemia, peripheral neuropathy, peripheral edema, thrombocytopenia and neutropenia. There was one on-study treatment-related death due to cardio respiratory arrest.
  • After completing induction therapy, 18 patients went on to receive maintenance with twice-weekly single-agent ixazomib
    • Patients on maintenance therapy received a median of 31.5 treatment cycles
    • 22% patients improved their responses during maintenance
    • 44% of patients who received maintenance therapy had an onset of a grade ≥ 3 AE and ADRs in cycle 17 or beyond. The most common grade ≥ 3 AEs and ADRs were hyperglycemia, rashes, eruptions and exanthems, diarrhea, vomiting, peripheral neuropathy, nausea and neutropenia.

“The addition of ixazomib – a first in class oral proteasome inhibitor – to doublet therapy has been shown to substantially improve efficacy in newly diagnosed multiple myeloma patients,” said lead investigator Paul Richardson, M.D., Dana-Farber Cancer Institute. “In this Phase 1/2 trial in newly diagnosed multiple myeloma, ixazomib plus lenalidomide and dexamethasone resulted not only in high quality of responses using a twice a week schedule but also in an encouraging deepening of responses over time in patients who did not receive a stem cell transplant. In addition, impressive durable clinical benefit was seen as patients went on to receive maintenance therapy with single-agent ixazomib after successful induction/remission therapy using this all oral approach.”

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 114,000 new cases globally per year.

About NINLARO TM  (ixazomib) capsules

NINLAROTM  (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.

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 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, 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-AL1, investigating ixazomib plus dexamethasone vs. physician choice of selected regimens in patients with relapsed or refractory AL amyloidosis; 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-MM6, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in patients with multiple myeloma transitioning from a bortezomib-based triplet induction regimen

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

NINLARO TM  (ixazomib): 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

Takeda Pharmaceutical Company Limited 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 central nervous system therapeutic areas plus vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. New innovative products, especially in oncology and gastroenterology, as well as our 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 .

Contact:

Takeda Pharmaceutical Company Limited
Japanese Media
Tsuyoshi Tada, +81 (0) 3-3278-2417
tsuyoshi.tada@takeda.com
or
European Media
Kate Burd, +44 7974 151510
kate.burd@takeda.com
or
Media outside Japan/EU
Sara Noonan, +1-508-566-2408
sara.noonan@takeda.com

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