[April 27, 2016] |
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Phase 3 Trial Results for First Oral Proteasome Inhibitor NINLARO (ixazomib) Published in The New England Journal of Medicine
Takeda Pharmaceutical Company Limited (TSE:
4502) today announced that results from the international,
randomized, double-blind, placebo-controlled TOURMALINE-MM1 Phase 3
clinical study, evaluating once-weekly oral NINLARO®
(ixazomib) capsules plus lenalidomide and dexamethasone versus placebo
plus lenalidomide-dexamethasone in patients with relapsed and/or
refractory multiple myeloma, have been published in the prestigious New
England Journal of Medicine (NEJM). NINLARO was recently
approved by the U.S. Food and Drug Administration (FDA), based on the
pivotal TOURMALINE-MM1 data, in combination with lenalidomide and
dexamethasone for the treatment of patients with multiple myeloma who
have received at least one prior therapy.
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"NEJM has published the results of the first Phase 3 study
supporting an all-oral triplet regimen containing a proteasome inhibitor
in multiple myeloma. With the emergence of long-term treatment as a
preferred approach for multiple myeloma, it is crucial that we
investigate more ways to improve treatment sustainability for patients,"
said study co-author and lead investigator Philippe Moreau, M.D.,
University of Nantes, France. "The TOURMALINE-MM1 results demonstrated
that ixazomib in combination with lenalidomide and dexamethasone is an
effective and tolerable oral regimen with a manageable safety profile
for patients with relapsed and/or refractory multiple myeloma."
"The publication of the Phase 3 TOURMALINE-MM1 trial results is another
important milestone for patients and physicians. This reflects
invaluable efforts from our researchers, the study investigators, the
patients and their families," said Dixie-Lee Esseltine, MD, FRCPC, Vice
President, Oncology Clinical Research, Takeda. "The publication
concluded that the addition of ixazomib to lenalidomide and
dexamethasone was associated with significantly longer progression-free
survival; the additional toxic effects with this all-oral regimen were
limited. We look forward to sharing additional ixazomib data from our
ongoing TOURMALINE studies over the next few years."
TOURMALINE-MM1, a double-blind, placebo-controlled trial including 722
patients, is the first Phase 3 study with an oral proteasome inhibitor.
As reported in NEJM, the trial results demonstrated a
statistically significant and clinically meaningful (35%) extension of
PFS (HR 0.74; p = 0.01; median PFS: 20.6 months vs. 14.7 months in
control group; median follow-up 14.7 months). A benefit in PFS was
observed with the ixazomib regimen across pre-specified patient
subgroups, including patients with poor prognosis, such as elderly
patients, those who have received two or three prior therapies, those
with advanced stage disease, and those with high-risk cytogenetic
abnormalities. Overall response rates were 78% in the ixazomib arm
versus 72% in the placebo group and at least very good partial response
rates were 48% versus 39%. The median time to response was 1.1 months in
the ixazomib arm versus 1.9 months in the placebo group, and median
duration of response was 20.5 versus 15.0 months, respectively. In the
ixazomib and placebo groups, frequencies of serious adverse events (47%
vs. 49%) and on-study deaths (4% vs. 6%) were similar; 74% and 69% of
patients experienced grade =3 adverse events. Grade 3 and 4
thrombocytopenia was more frequent in the ixazomib (12 and 7%) vs.
placebo group (5 and 4%). Rash occurred more frequently in the ixazomib
group than in the placebo group (36% vs. 23% of the patients), as did
gastrointestinal adverse events, which were predominantly low grade. The
incidence of peripheral neuropathy was 27% in the ixazomib group and 22%
in the placebo group (grade 3 events occurred in 2% of the patients in
each study group, and no grade 4 events were reported). Please see below
for the full U.S. prescribing
information of NINLARO (ixazomib)
capsules.
Data from TOURMALINE-MM1 were previously presented at the 57th
Annual Meeting of the American Society of Hematology (ASH) in Orlando,
Florida.
NINLARO is currently under review by the European Medicines Agency
(EMA (News - Alert)). Takeda has also submitted applications for approval of ixazomib
to additional health authorities around the world.
About NINLARO (ixazomib) capsules NINLAR (ixazomib) is the
first and only oral proteasome inhibitor approved by the U.S. Food and
Drug Administration (FDA) in combination with lenalidomide and
dexamethasone for the treatment of patients with multiple myeloma who
have received at least one prior therapy. NINLARO is administered
orally, once-weekly 4 mg fixed dose on days 1, 8, and 15 of a 28-day
treatment cycle. NINLARO also 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 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 investigating every major multiple
myeloma patient population and one in light-chain amyloidosis:
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TOURMALINE-MM1, investigating ixazomib vs. placebo, in combination
with lenalidomide and dexamethasone in relapsed and/or refractory
multiple myeloma. This trial is currently ongoing, and patients
continue to be treated to progression and will be evaluated for
long-term outcomes.
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TOURMALINE-MM2, investigating ixazomib vs. placebo, in combination
with lenalidomide and dexamethasone in patients with newly diagnosed
multiple myeloma
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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)
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TOURMALINE-MM4, investigating ixazomib vs. placebo as maintenance
therapy in patients with newly diagnosed multiple myeloma who have not
undergone ASCT
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TOURMALINE-AL1, investigating ixazomib plus dexamethasone vs.
physician choice of selected regimens in patients with relapsed or
refractory AL amyloidosis
In addition to the TOURMALINE program, a large number of investigator
initiated studies are evaluating ixazomib for patients globally.
For additional information on the studies please visit www.clinicaltrials.gov.
To learn more about NINLARO, please visit www.NINLARO.com
or call 1-844-N1POINT (1-844-617-6468).
Important Safety Information
WARNINGS AND PRECAUTIONS
-
Thrombocytopenia has been reported with NINLARO. During
treatment, monitor platelet counts at least monthly, and consider more
frequent monitoring during the first three cycles. Manage
thrombocytopenia with dose modifications and platelet transfusions as
per standard medical guidelines. Adjust dosing as needed. Platelet
nadirs occurred between Days 14-21 of each 28-day cycle and recovered
to baseline by the start of the next cycle.
-
Gastrointestinal Toxicities, including diarrhea,
constipation, nausea and vomiting, were reported with NINLARO and may
occasionally require the use of antidiarrheal and antiemetic
medications, and supportive care. Diarrhea resulted in the
discontinuation of one or more of the three drugs in 1% of patients in
the NINLARO regimen and < 1% of patients in the placebo regimen.
Adjust dosing for severe symptoms.
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Peripheral Neuropathy (predominantly sensory) was reported with
NINLARO. 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%). Peripheral neuropathy resulted in
discontinuation of one or more of the three drugs in 1% of patients in
both regimens. Monitor patients for symptoms of peripheral neuropathy
and adjust dosing as needed.
-
Peripheral Edema was reported with NINLARO. Monitor for fluid
retention. Investigate for underlying causes when appropriate and
provide supportive care as necessary. Adjust dosing of dexamethasone
per its prescribing information or NINLARO for Grade 3 or 4 symptoms.
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Cutaneous Reactions: Rash, most commonly maculo-papular and
macular rash, was reported with NINLARO. Rash resulted in
discontinuation of one or more of the three drugs in < 1% of patients
in both regimens. Manage rash with supportive care or with dose
modification.
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Hepatotoxicity has been reported with NINLARO. Drug-induced
liver injury, hepatocellular injury, hepatic steatosis, hepatitis
cholestatic and hepatotoxicity have each been reported in
< 1% of
patients treated with NINLARO. Events of liver impairment have been
reported (6% in the NINLARO regimen and 5% in the placebo regimen).
Monitor hepatic enzymes regularly during treatment and adjust dosing
as needed.
-
Embryo-fetal Toxicity: NINLARO can cause fetal harm. Women
should be advised of the potential risk to a fetus, to avoid becoming
pregnant, and to use contraception during treatment and for an
additional 90 days after the final dose of NINLARO.
ADVERSE REACTIONS The most common adverse reactions (= 20%)
in the NINLARO regimen and greater than the placebo regimen,
respectively, were diarrhea (42%, 36%), constipation (34%, 25%),
thrombocytopenia (78%, 54%; pooled from adverse events and laboratory
data), peripheral neuropathy (28%, 21%), nausea (26%, 21%), peripheral
edema (25%, 18%), vomiting (22%, 11%), and back pain (21%, 16%). Serious
adverse reactions reported in = 2% of patients included thrombocytopenia
(2%) and diarrhea (2%).
SPECIAL 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
requiring dialysis. NINLARO is not dialyzable.
-
Lactation: Advise women to discontinue nursing while on NINLARO.
DRUG INTERACTIONS: Avoid concomitant administration of NINLARO
with strong CYP3A inducers.
Please see the accompanying NINLARO full Prescribing
Information.
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 more than 26,000 new cases in the
U.S. and 114,000 new cases globally per year.
About Takeda Pharmaceutical Company Takeda Pharmaceutical
Company Limited is a global, R&D-driven pharmaceutical company committed
to bringing better health and a brighter future to patients by
translating science into life-changing medicines. Takeda focuses its
research efforts on oncology, gastroenterology and central nervous
system therapeutic areas. It also has specific development programs in
specialty cardiovascular diseases as well as late-stage candidates for
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 its 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.
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