Takeda Presents Positive Data from Clinical Trial Evaluating Oral NINLARO(TM) (ixazomib) in Multiple Myeloma as a First-Line Maintenance Therapy

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced it will orally present the results of two studies at the 25th Congress of the European Hematology Association (EHA). Presentations are available online starting Friday, June 12, 2020, and include positive results from TOURMALINE-MM4, a Phase 3, randomized clinical trial evaluating the effect of single-agent oral NINLARO™ (ixazomib) as a first-line maintenance therapy in adult patients diagnosed with multiple myeloma who had not been treated with stem cell transplantation. Takeda is also presenting key insights from the US MM-6 trial, which investigates the effectiveness and safety of an in-class transition to oral NINLARO in combination with lenalidomide and dexamethasone in newly diagnosed multiple myeloma patients who have previously received a parenteral bortezomib-based triplet induction therapy.

The TOURMALINE-MM4 trial achieved its primary endpoint, with treatment with NINLARO resulting in a statistically significant and clinically meaningful improvement in progression-free survival (PFS) versus placebo in adult patients diagnosed with multiple myeloma not treated with stem cell transplantation (hazard ratio [HR] 0.659; CI: 95; p <0.001). This corresponds to a 34% reduction in risk of progression or death in patients treated with NINLARO. The safety profile of NINLARO was consistent with previously reported results of single-agent NINLARO use and there were no new safety signals identified.

“There is a strong need for additional maintenance treatments for multiple myeloma, where currently approved options are limited,” said Meletios Dimopoulos, MD, University of Athens School of Medicine and principal investigator of the TOURMALINE-MM4 trial. “Data from this Phase 3 clinical trial reinforce the role of proteasome inhibition as a maintenance therapy and suggest that longer duration of therapy can improve a response, in addition to extending it. These data could be highly impactful for those who currently have limited options, which is often the case with patients not eligible for a stem cell transplant.”

Key findings of the TOURMALINE-MM4 trial, to be presented by Dr. Dimopoulos include:

• The trial achieved its primary endpoint, with treatment with NINLARO resulting in a statistically significant and clinically meaningful improvement in PFS in adult patients diagnosed with multiple myeloma not treated with stem cell transplantation (hazard ratio [HR] 0.659; CI: 95; p <0.001). Median PFS for patients in the NINLARO arm was 17.4 months compared to 9.4 months in the placebo arm. This corresponds to a 34.1% reduction in risk of progression or death in patients treated with NINLARO.
• The secondary endpoint of overall survival (OS) is not yet mature and follow-up is ongoing.
• The benefits of NINLARO maintenance were realized in the context of a well-tolerated safety profile and no adverse impact on patients’ quality of life.
• The safety profile of NINLARO is consistent with previously reported results of single-agent NINLARO use and there were no new safety signals identified.
  • The most common treatment emergent adverse events (TEAEs) (with incidence ≥5% higher with ixazomib) were nausea, vomiting, diarrhea, rash, peripheral neuropathy (PN) and pyrexia.
  • Grade ≥3 TEAEs were experienced by 36.6% of patients receiving NINLARO versus 23.2% receiving placebo.
  • The rate of new primary malignancies was 5.2% versus 6.2% in the placebo arm.
  • Discontinuation of treatment due to TEAEs was low, at 12.9% in the NINLARO arm and 8% in the placebo arm.
  • The rate of on-study deaths was 2.6% in the NINLARO arm compared to 2.2% in the placebo arm.

Updated data from US MM-6 will also be presented orally at EHA. The trial revealed the in-class transition from treatment with parenteral bortezomib to a NINLARO-based treatment, taken by patients at home, allowed for prolonged proteasome inhibitor administration and resulted in an increase in overall response rate from 62% to 70% and an increase in complete response from 4% to 26%. These data suggest promising efficacy without impacting patients’ quality of life. The safety profile of NINLARO treatment in this setting is favorable with no unexpected safety signals identified in US MM-6.

“The positive data from the Phase 3 trial evaluating NINLARO as a maintenance therapy in patients not eligible for stem cell transplantation showed significant improvement in progression-free survival,” said Christopher Arendt, Head, Oncology Therapeutic Area Unit, Takeda. “Coupled with the US MM-6 trial results of in-class transition from parenteral to oral proteasome inhibitor, these data add to the body of evidence supporting NINLARO could be an effective, tolerable and convenient medicine for patients with multiple myeloma that allows for an increased duration of treatment with proteasome inhibitors resulting in better outcomes.”

NINLARO is currently approved in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed / refractory multiple myeloma in more than 65 countries.

About the TOURMALINE-MM4 Trial

TOURMALINE-MM4 is a randomized, placebo-controlled, double-blind Phase 3 study of 706 patients, designed to determine the effect of single-agent oral NINLARO™ (ixazomib) maintenance therapy on progression-free survival (PFS), compared to placebo, in adult patients newly diagnosed with multiple myeloma not treated with stem cell transplant, who have completed 6-12 months of initial therapy and achieved a partial response or better. For additional information, please visit https://clinicaltrials.gov/ct2/show/NCT02312258.

About the US MM-6 Trial

US MM-6 is an ongoing open-label, single-arm, multicenter study evaluating the effectiveness and safety of an in-class transition to NINLARO™ (ixazomib) in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma who received bortezomib-based triplet induction. The primary endpoint is progression-free survival (PFS). Key secondary endpoints include duration of therapy and duration of response. For additional information: https://clinicaltrials.gov/ct2/show/NCT03173092

About Multiple Myeloma

Multiple myeloma is a life-threatening rare blood cancer that arises from the plasma cells, a type of white blood cell that is made in the bone marrow. These plasma cells become abnormal, multiply and release a type of antibody known as a paraprotein, which causes symptoms of the disease, including bone pain, frequent or recurring infections and fatigue, a symptom of anemia. These malignant plasma cells have the potential to affect many bones in the body and can cause a number of serious health problems affecting the bones, immune system, kidneys and red blood cell count. The typical multiple myeloma disease course includes periods of symptomatic myeloma followed by periods of remission. Nearly 230,000 people around the world live with multiple myeloma, with approximately 114,000 new cases diagnosed globally each year.

About NINLARO™(ixazomib) capsules

NINLARO™ (ixazomib) is an oral proteasome inhibitor which is being studied across the continuum of multiple myeloma treatment settings. NINLARO was first approved by the U.S. Food and Drug Administration (FDA) in November 2015 and 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 is currently approved in more than 65 countries, including the United States, Japan and in the European Union, with more than 10 regulatory filings currently under review. It was the first oral proteasome inhibitor to enter Phase 3 clinical trials and to receive approval.

NINLARO™ (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.

Thrombotic microangiopathy, sometimes fatal, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received NINLARO. Monitor for signs and symptoms of TPP/HUS and stop NINLARO if diagnosis is suspected. If the diagnosis of TPP/HUS is excluded, consider restarting NINLARO. The safety of reinitiating NINLARO therapy in patients previously experiencing TPP/HUS is not known.

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 female 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 mgin patients with moderate or severe hepatic impairment.

Renal Impairment: Reducethe 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

Takeda’s Commitment to Oncology

Our core R&D mission is to deliver novel medicines to patients with cancer worldwide through our commitment to science, breakthrough innovation and passion for improving the lives of patients. Whether it’s with our hematology therapies, our robust pipeline, or solid tumor medicines, we aim to stay both innovative and competitive to bring patients the treatments they need. For more information, visit www.takedaoncology.com.

About Takeda Pharmaceutical Company Limited

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to bringing Better Health and a Brighter Future to patients by translating science into highly-innovative medicines. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Rare Diseases, Neuroscience, and Gastroenterology (GI). We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people's lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries.

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

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