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 60th 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 RD efforts on
oncology, gastroenterology and neuroscience therapeutic areas plus
vaccines. Takeda conducts RD 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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