Takeda Provides Update on TOURMALINE-AL1 Phase 3 Trial in AL Amyloidosis

CAMBRIDGE, Mass. & OSAKA, Japan–(BUSINESS WIRE)–Takeda Pharmaceutical Company Limited (TSE:
4502/NYSE: TAK)
today announced that the Phase 3 TOURMALINE-AL1
clinical trial in patients with relapsed or refractory systemic
light-chain (AL) amyloidosis did not meet the first of two primary
endpoints. Treatment with NINLAROTM (ixazomib) in combination
with dexamethasone did not demonstrate a significant improvement in
overall hematologic response compared to physician’s choice of standard
of care regimens. As a result of this analysis, Takeda has decided to
discontinue the trial.

“While we are disappointed with this outcome, we aim to maximize our
learnings from this trial and share findings with the community in hopes
of helping to improve care for patients living with this devastating
disease,” said Phil Rowlands, Ph.D., Head, Oncology Therapeutic Area
Unit, Takeda. “This has been one of the largest studies ever conducted
in systemic light-chain AL amyloidosis and we are proud to have led it.
This study demonstrated our dedication to this rare and traditionally
difficult-to-enroll patient population and we thank the patients and
investigators for their engagement and participation. We remain
optimistic about NINLARO and continue to investigate NINLARO in patient
populations across the continuum of multiple myeloma care.”

An Independent Data Monitoring Committee (IDMC) did not raise any
concerns about the safety profile of NINLARO in this setting. Patients
are encouraged to consult their study investigators to address any

About the TOURMALINE-AL1 Trial

TOURMALINE-AL1 (NCT01659658) is an international, randomized,
controlled, open-label, multicenter, Phase 3 study, designed to
determine whether NINLAROTM (ixazomib) in combination with
dexamethasone improves hematologic response, 2-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. Patients were randomly
selected to receive either NINLARO plus dexamethasone, or physician’s
choice of dexamethasone plus melphalan; dexamethasone plus
cyclophosphamide; dexamethasone plus thalidomide; dexamethasone plus
lenalidomide; or dexamethasone alone. 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™ (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 four 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
  • 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

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

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

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

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.

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.

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

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
US Prescribing Information:
Canada Product Monograph:

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, Gastroenterology (GI), Neuroscience and
Rare Diseases. 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 and regions.

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

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Japanese Media
Kazumi Kobayashi
[email protected]
(0) 3-3278-2095

Media outside Japan
Sara Noonan
sara.noona[email protected]


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