Takeda to Present Results from the Phase 3 TOURMALINE-AL1 Trial of NINLARO in Patients with Amyloidosis

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) today announced that results of the TOURMALINE-AL1 trial will be presented during an oral session at the 61^st American Society of Hematology (ASH) annual meeting on Saturday, December 7, 2019 in Orlando, Florida. TOURMALINE-AL1 is a Phase 3, randomized clinical trial evaluating the effect of NINLARO^TM (ixazomib) in combination with dexamethasone in patients with relapsed or refractory systemic light-chain (AL) amyloidosis.

The TOURMALINE-AL1 trial did not meet the first of the two primary endpoints of significant improvement in overall hematologic response, as reported in June 2019. Hematologic responses were seen in 53% versus 51% of patients receiving NINLARO plus dexamethasone versus physician’s choice (odds ratio 1.10 [95% CI 0.60-2.01], p=0.762) as assessed by an Adjudication Committee (AC). The second primary endpoint of two-year vital organ deterioration or death was not mature at the time of analysis. Other endpoints studied including vital organ progression free survival (PFS), hematologic PFS, time to treatment failure and time to subsequent therapy were numerically higher in the NINLARO plus dexamethasone arm compared to the physician’s choice arm. Takeda is committed to making data available to researchers to continue investigation of this disease. NINLARO is not approved as a treatment for AL amyloidosis.

“AL amyloidosis is a rare condition, for which prognosis and patient outcomes are poor. Current treatments are often retrofitted from therapies used for multiple myeloma,” said Angela Dispenzieri, MD, Mayo Clinic, and the trial’s principal investigator and lead author. “For a Phase 3 study that did not meet its primary endpoint, this trial provides interesting information for this community and for future studies. Ongoing research and development to investigate potential treatment options for this underserved patient population is critical.”

“We look forward to the opportunity to share the data from the TOURMALINE-AL1 trial,” said Phil Rowlands, Head of Oncology Clinical Research and Development, Takeda. “We are confident that sharing our findings with the community will help encourage conversations around the need for continued research to address the needs that remain in this patient population.”

“There are serious unmet needs for people living with amyloidosis. AL amyloidosis is a progressive and fatal disease; many patients are diagnosed late, significantly impacting life expectancy. The challenges associated with developing drugs for this disease make continued research and development for treatment critical,” said Isabelle Lousada, Founder and CEO of the Amyloidosis Research Consortium. “The data from TOURMALINE-AL1 provide valuable insights to researchers as they select endpoints for future amyloidosis studies, and knowledge that will provide context in future drug reviews and approvals, ultimately aiding in providing treatment options for patients.”

Primary Results from the Phase 3 TOURMALINE-AL1 Trial of Ixazomib-Dexamethasone Versus Physician’s Choice of Therapy in Patients (Pts) with Relapsed/Refractory Primary Systemic AL Amyloidosis (RRAL). Saturday, December 7, 9:30 a.m., Orange County Convention Center, Hall E1.

Key findings, to be presented by Dr. Angela Dispenzieri, include:

• The first of two primary endpoints was not met in TOURMALINE-AL1. Hematologic responses were seen in 53% versus 51% of patients receiving NINLARO plus dexamethasone versus physician’s choice (odds ratio 1.10 [95% CI 0.60-2.01], p=0.762).
• Complete response (CR) rate was 26% in the NINLARO plus dexamethasone arm versus 18% in the physician’s choice arm.
• The second primary endpoint, two-year vital organ deterioration or death, was not mature at the time of analysis.
• Other endpoint data as assessed by investigators includes:
  • Median duration of hematologic response was 46.5 months in the NINLARO plus dexamethasone arm and 20.2 months in the physician’s choice arm as assessed by investigators.
  • Vital organ PFS was 18.0 months in the NINLARO plus dexamethasone arm and 11.0 months in the physician’s choice arm.
  • Hematologic PFS was 20.1 months in the NINLARO plus dexamethasone arm and 16.7 months in the physician’s choice arm.
  • Time to treatment failure was 10.1 months in the NINLARO plus dexamethasone arm and 5.2 months in the physician’s choice arm.
  • Time to subsequent therapy was 26.5 months in the NINLARO plus dexamethasone arm and 12.5 months in the physician’s choice arm.
• At data cut-off, patients had received a median treatment duration of 11.7 versus 5.0 months on the NINLARO plus dexamethasone versus physician’s choice arms.
• Safety data includes:
  • Drug-related adverse events (AE) were experienced by 82% of patients receiving NINLARO plus dexamethasone compared to 81% of patients receiving physician’s choice.
  • Serious adverse events (SAE) were experienced by 47% of patients in the NINLARO plus dexamethasone arm compared to 33% in the physician’s choice arm.
  • Discontinuation of treatment due to AEs was 26% in the NINLARO plus dexamethasone arm compared to 20% in the physician’s choice arm.
  • Common any grade AEs in both the NINLARO plus dexamethasone arm and physician’s choice arm included fatigue (45% and 43%), peripheral edema (46% and 32%), diarrhea (34% and 30%), insomnia (38% and 17%), rash (33% and 20%), constipation (21% and 26%), dyspnea (24% and 19%), upper respiratory tract infection (24% versus 16%), nausea (24% versus 14%) and peripheral neuropathy (19% versus 15%).
  • Common (≥5% overall) grade ≥3 AEs were fatigue (9% versus 9%), peripheral edema (5% versus 5%), rash (4% versus 5%) and dyspnea (6% versus 4%).
  • 6% of patients in the NINLARO plus dexamethasone arm and 5% of patients in the physician’s choice arm died on study. All deaths were considered to be related to AL amyloidosis or complications thereof.

About the TOURMALINE-AL1 Trial

TOURMALINE-AL1 (NCT01659658) is an international, randomized, controlled, open-label, multicenter, Phase 3 study, designed to determine whether NINLARO^TM (ixazomib) in combination with dexamethasone improves hematologic response, two-year vital organ (heart or kidney) deterioration and mortality rate versus a physician's choice of a chemotherapy regimen in participants diagnosed with relapsed or refractory systemic light chain (AL) amyloidosis. 168 patients were enrolled and randomly selected to receive either NINLARO plus dexamethasone, or physician’s choice of the following: dexamethasone plus melphalan; dexamethasone plus cyclophosphamide; dexamethasone plus thalidomide; dexamethasone plus lenalidomide; or dexamethasone alone. The discontinuation of the TOURMALINE-AL1 trial was announced in June 2019. For more information, please visit https://clinicaltrials.gov/ct2/show/NCT01659658.

About AL Amyloidosis

Primary AL amyloidosis is a condition that falls under the umbrella of plasma cell dyscrasias. AL amyloidosis arises from a clonal plasma cell that produces abnormal immunoglobulin light-chain fragments. These misfolded light-chains form insoluble fibrils that aggregate as amyloid deposits in organs and tissues throughout the body, ultimately leading to organ dysfunction and death. The most common organs affected are the kidneys, heart, liver, and autonomic or peripheral nerves.

There are currently no treatments approved for the treatment of AL amyloidosis.

About NINLARO^TM (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 60 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.

The comprehensive ixazomib clinical development program, TOURMALINE, includes several ongoing pivotal trials, which together are investigating major multiple myeloma patient populations:

• 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

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 percent vs. 14 percent 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 percent vs. 36 percent), constipation (34 percent vs. 25 percent), nausea (26 percent vs. 21 percent), and vomiting (22 percent vs. 11 percent), occasionally requiring use of antiemetic and anti-diarrheal medications, and supportive care.

Peripheral neuropathy was reported with NINLARO (28 percent vs. 21 percent in the NINLARO and placebo regimens, respectively). The most commonly reported reaction was peripheral sensory neuropathy (19 percent and 14 percent in the NINLARO and placebo regimens, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (< 1 percent). Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed.

Peripheral edema was reported with NINLARO (25 percent vs. 18 percent 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 percent of patients in the NINLARO regimen compared to 11 percent 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 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 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 percent) in the NINLARO regimen, and greater than in the placebo regimen, were diarrhea (42 percent vs. 36 percent), constipation (34 percent vs. 25 percent), thrombocytopenia (28 percent vs. 14 percent), peripheral neuropathy (28 percent vs. 21 percent), nausea (26 percent vs. 21 percent), peripheral edema (25 percent vs. 18 percent), vomiting (22 percent vs. 11 percent), and back pain (21 percent vs. 16 percent). Serious adverse reactions reported in ≥ 2 percent of patients included thrombocytopenia (2 percent) and diarrhea (2 percent). For each adverse reaction, one or more of the three drugs was discontinued in ≤ 1percent 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/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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Contact information

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Kazumi Kobayashi
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Sara Noonan
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