Seven-year study matches the longest
duration of follow-up for any CML treatment, including
imatinib, based on approved prescribing information
Bristol-Myers Squibb Company (NYSE:BMY) and Otsuka America
Pharmaceutical, Inc. today announced that the U.S. Food and Drug
Administration (FDA) has approved an update to
the Sprycel® (dasatinib) product labeling. The labeling
now includes five-year efficacy and safety data in adult patients
with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic
myeloid leukemia (CML) in chronic phase (CP) and seven-year data in
CP Ph+ CML patients who are resistant1 or intolerant2 to prior
therapy, including Gleevec®3 (imatinib mesylate).
“The five- and seven-year data now included in the Sprycel U.S.
label offer valuable insight into its long-term efficacy and safety
profile in both first- and second-line patients,” said Neil Shah,
MD, PhD, Associate Professor, Division of Hematology/Oncology,
University of California, San Francisco. “CML requires ongoing
treatment and assessment of treatment milestones in order to manage
the disease properly. Given the chronic nature of CML, these
long-term data are particularly important for patient care.”
Sprycel is associated with the following warnings and
precautions: myelosuppression, bleeding-related events, fluid
retention, cardiovascular events, pulmonary arterial hypertension,
QT prolongation, severe dermatologic reactions, tumor lysis
syndrome, and embryo-fetal toxicity. Please see detailed Important
Safety Information below.
“Treating CML across the spectrum of the disease has been an
important focus for Bristol-Myers Squibb and Otsuka, and we remain
committed to helping newly diagnosed and imatinib-resistant or
intolerant CP Ph+ CML patients through treatment with Sprycel,
a convenient once-daily treatment option,” said Laura Bessen, MD,
Vice President, head of U.S. Medical, Bristol-Myers Squibb. “We are
proud to have generated this important five- and seven-year data in
the first- and second-line treatment of CP Ph+ CML, as the findings
further support the overall efficacy and safety profile of Sprycel
over the long-term.”
About the DASISION Study (CA180-056)
DASISION is an open-label, randomized, Phase 3 international
trial of Sprycel 100 mg tablet taken once-daily (n=259)
vs. imatinib 400 mg taken once-daily (n=260) in the treatment of
newly-diagnosed CP Ph+ CML. The primary study endpoint was
confirmed CCyR4 by 12 months and secondary endpoints included
MMR5 at any time, time to MMR, and time to confirmed
CCyR. With a minimum of five years follow-up, 61%
of Sprycel patients and 62% of imatinib patients were
still on treatment at the time of final analysis.
In DASISION, 77% [95% CI,6 71% - 82%] of patients treated
with Sprycel vs. 66% [95%, CI, 60% - 72%] of patients treated
with imatinib achieved the primary endpoint of confirmed CCyR
(defined as two consecutive assessments of CCyR at least 28 days
apart) by 12 months (p=0.007). After five years of follow-up,
median time to confirmed CCyR was 3.1 months in 215
Sprycel responders and 5.8 months in 204 imatinib responders7.
In the long-term (by 5 years), confirmed CCyR rates were
83% Sprycel vs. 79% imatinib.
Sprycel patients were more likely than imatinib patients to
achieve MMR, a measure of deeper treatment response, by year one
(52% [95% CI, 46% - 58%] vs. 34% [95% CI, 28% - 40%], respectively;
p<0.0001). In the long-term (by year 5), MMR at any time
was higher for Sprycel than imatinib (76% [95% CI, 71% -
82%] vs 64% [95% CI, 58% - 70%], respectively). At 60 months
follow-up, in the Sprycel arm, the rate of MMR at any time in each
risk group determined by Hasford score (a prognostic scoring
system) was 90% (low risk), 71% (intermediate risk) and 67% (high
risk). In the imatinib arm, the rate of MMR at any time in each
risk group determined by Hasford score was 69% (low risk), 65%
(intermediate risk) and 54% (high risk). The five-year data for
confirmed CCyR and MMR demonstrate the long-lasting efficacy of
Sprycel.
At five years, eight patients (3%) in the Sprycel arm progressed
to either accelerated phase or blast crisis while 15 patients (6%)
in the imatinib arm progressed to either accelerated phase or blast
crisis. Sprycel does not appear to be active against the T315I
mutation, based on in vitro data. The estimated five-year survival
rates for Sprycel- and imatinib-treated patients were 91% (CI:
87%–94%) and 90% (CI: 85%–93%), respectively.
In newly diagnosed chronic phase CML patients, drug-related
serious adverse events (SAEs) were reported for 17% of
Sprycel-treated patients. Serious adverse reactions reported in ≥5%
of patients included pleural effusion (5%). Most common adverse
reactions (≥5%) included myelosuppression, fluid retention and
diarrhea.
About Dose Optimization Study (CA180-034)
The dose optimization study (CA180-034) is an open-label,
randomized study designed to assess the efficacy and safety
of Sprycel in CP Ph+ CML patients with resistance (n=497)
or intolerance (n=173) to imatinib. The trial enrolled 670 CML
patients who were randomized to one of four treatment arms: 100 mg
once-daily (n=167), 50 mg twice-daily (n=168), 140 mg once-daily
(n=167) and 70 mg twice-daily (n=168). Efficacy was achieved across
all Sprycel treatment groups, with the once-daily
schedule demonstrating comparable efficacy (non-inferiority) to the
twice-daily schedule on the primary efficacy endpoint (difference
in MCyR 2%; 95% CI [-7% – 11%]); however, the 100 mg once-daily
regimen demonstrated improved safety and tolerability.
Based on data seven years after the last patient was enrolled,
44% of patients on the trial were known to be alive, with an
additional 25% having unknown survival data (the remaining 31% of
patients were known to have died). In patients treated with the 100
mg once-daily dose of Sprycel, nine patients transformed to
accelerated or blast phase CML by seven years while on treatment.
The primary endpoint was major cytogenetic response (MCyR) in
imatinib-resistant patients; 63% of imatinib-resistant or
-intolerant patients taking Sprycel 100 mg once-daily achieved
MCyR at two years [95% CI: 56% - 71%].
In patients resistant or intolerant to prior imatinib therapy
who were treated with the 100 mg once-daily dose of Sprycel, 26%
reported drug-related SAEs. Serious adverse reactions reported in
≥5% of patients included pleural effusion (10%). Most common
adverse reactions (≥15%) included myelosuppression, fluid retention
events, diarrhea, headache, fatigue, dyspnea, skin rash, nausea,
hemorrhage and musculoskeletal pain.
About Sprycel Assist
As part of its commitment to the CML community, Bristol-Myers
Squibb recently launched Sprycel Assist, which offers a single
point of contact and live support and assistance for oncologists,
healthcare professionals in their practice, patients and their
caregivers. Accessible through www.Sprycel.com or 1-855-SPRYCEL,
the services include:
- Dedicated patient support
coordinators
- One-month free for new, eligible
Medicare, Medicaid or cash patients*
- $0 copay for eligible commercially
insured patients*
- Support throughout the reimbursement
process
- Educational resources for adults with
Ph+ CML
*Subject to terms and conditions of program, which are available
through 1-855-SPRYCEL or visiting www.Sprycel.com.
About Chronic Myeloid Leukemia
CML is a type of leukemia in which the body produces an
uncontrolled number of abnormal white blood cells. According
to the most recent statistics, about 33,990 people are living with
the disease in the United States. An estimated 6,660 new cases were
diagnosed in 2014. CML occurs when pieces of two different
chromosomes (chromosomes 9, 22) break off and attach to each other.
The newly formed chromosome is called the Philadelphia chromosome,
which contains an abnormal gene called the
BCR-ABL gene. This gene produces the BCR-ABL protein that
signals cells to make too many white blood cells. There is no known
cause for the genetic change that results in CML.
About Sprycel® (dasatinib)
Sprycel was first approved by the FDA in 2006 for the
treatment of adults with CP Ph+ CML who are resistant or intolerant
to prior therapy including imatinib. At that
time, Sprycel was also approved for adults with Ph+ ALL
who are resistant or intolerant to prior therapy. It is the first
and only BCR-ABL kinase inhibitor with survival data in its label
for CP Ph+ CML patients who are resistant or intolerant to
imatinib. Sprycel is approved and marketed worldwide for these
indications in more than 60 countries.
Sprycel is also an FDA-approved treatment for adults with
newly diagnosed CP Ph+ CML (since October
2010). Sprycel received accelerated FDA approval for this
indication. Additional country approvals for this indication total
more than 50.
SPRYCEL® (dasatinib) INDICATIONS &
IMPORTANT SAFETY INFORMATION
INDICATIONS
SPRYCEL® (dasatinib) is indicated for the treatment of adults
with:
- Newly diagnosed Philadelphia
chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic
phase
- Chronic, accelerated, or myeloid or
lymphoid blast phase Ph+ CML with resistance or intolerance to
prior therapy including imatinib
- Philadelphia chromosome-positive acute
lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to
prior therapy
IMPORTANT SAFETY INFORMATION
Myelosuppression:
Treatment with SPRYCEL is associated with severe (NCI CTC Grade
3/4) thrombocytopenia, neutropenia, and anemia, which occur earlier
and more frequently in patients with advanced phase CML or Ph+ ALL
than in patients with chronic phase CML.
- In patients with chronic phase CML,
perform complete blood counts (CBCs) every 2 weeks for 12 weeks,
then every 3 months thereafter, or as clinically indicated.
- In patients with advanced phase CML or
Ph+ ALL, perform CBCs weekly for the first 2 months and then
monthly thereafter, or as clinically indicated.
- Myelosuppression is generally
reversible and usually managed by withholding SPRYCEL temporarily
and/or dose reduction.
- In clinical studies, myelosuppression
may have also been managed by discontinuation of study
therapy.
- Hematopoietic growth factor has been
used in patients with resistant myelosuppression.
Bleeding-Related Events:
SPRYCEL caused thrombocytopenia in human subjects. In addition,
dasatinib caused platelet dysfunction in vitro. In all CML or Ph+
ALL clinical studies, ≥grade 3 central nervous system (CNS)
hemorrhages, including fatalities, occurred in <1% of patients
receiving SPRYCEL. Grade 3 or greater gastrointestinal hemorrhage,
including fatalities, occurred in 4% of patients and generally
required treatment interruptions and transfusions. Other cases of
≥grade 3 hemorrhage occurred in 2% of patients.
- Most bleeding events in clinical
studies were associated with severe thrombocytopenia.
- Concomitant medications that inhibit
platelet function or anticoagulants may increase the risk of
hemorrhage.
Fluid Retention:
SPRYCEL may cause fluid retention. After 5 years of follow-up in
the randomized newly diagnosed chronic phase CML study (n=258),
grade 3/4 fluid retention was reported in 5% of patients, including
3% of patients with grade 3/4 pleural effusion. In patients with
newly diagnosed or imatinib resistant or intolerant chronic phase
CML, grade 3/4 fluid retention occurred in 6% of patients treated
with SPRYCEL at the recommended dose (n=548). In patients with
advanced phase CML or Ph+ ALL treated with SPRYCEL at the
recommended dose (n=304), grade 3/4 fluid retention was reported in
8% of patients, including grade 3/4 pleural effusion reported in 7%
of patients.
- Patients who develop symptoms of
pleural effusion or other fluid retention, such as new or worsened
dyspnea on exertion or at rest, pleuritic chest pain, or dry cough
should be evaluated promptly with a chest x-ray or additional
diagnostic imaging as appropriate.
- Fluid retention events were typically
managed by supportive care measures that may include diuretics or
short courses of steroids.
- Severe pleural effusion may require
thoracentesis and oxygen therapy.
- Consider dose reduction or treatment
interruption.
Cardiovascular Events:
After 5 years of follow-up in the randomized newly diagnosed
chronic phase CML trial (n=258), the following cardiac adverse
events occurred:
- Cardiac ischemic events (3.9% dasatinib
vs 1.6% imatinib), cardiac related fluid retention (8.5% dasatinib
vs 3.9% imatinib), and conduction system abnormalities, most
commonly arrhythmia and palpitations (7.0% dasatinib vs 5.0%
imatinib). Two cases (0.8%) of peripheral arterial occlusive
disease occurred with imatinib and 2 (0.8%) transient ischemic
attacks occurred with dasatinib.
Monitor patients for signs or symptoms consistent with cardiac
dysfunction and treat appropriately.
Pulmonary Arterial Hypertension (PAH):
SPRYCEL may increase the risk of developing PAH, which may occur
any time after initiation, including after more than 1 year of
treatment. Manifestations include dyspnea, fatigue, hypoxia, and
fluid retention. PAH may be reversible on discontinuation of
SPRYCEL.
- Evaluate patients for signs and
symptoms of underlying cardiopulmonary disease prior to initiating
SPRYCEL and during treatment. If PAH is confirmed, SPRYCEL should
be permanently discontinued.
QT Prolongation:
In vitro data suggest that dasatinib has the potential to
prolong cardiac ventricular repolarization (QT interval).
- In clinical trials of patients treated
with SPRYCEL at all doses (n=2440), 16 patients (<1%) had
QTc prolongation reported as an adverse reaction. Twenty-two
patients (1%) experienced a QTcF >500 ms.
- In 865 patients with leukemia treated
with SPRYCEL in five Phase 2 single-arm studies, the maximum mean
changes in QTcF (90% upper bound CI) from baseline ranged from 7.0
to 13.4 ms.
- SPRYCEL may increase the risk of
prolongation of QTc in patients including those with hypokalemia or
hypomagnesemia, patients with congenital long QT syndrome, patients
taking antiarrhythmic medicines or other medicinal products that
lead to QT prolongation, and cumulative high-dose anthracycline
therapy.
- Correct hypokalemia or hypomagnesemia
prior to and during SPRYCEL administration.
Severe Dermatologic Reactions:
Cases of severe mucocutaneous dermatologic reactions, including
Stevens-Johnson syndrome and erythema multiforme, have been
reported in patients treated with SPRYCEL.
- Discontinue permanently in patients who
experience a severe mucocutaneous reaction during treatment if no
other etiology can be identified.
Tumor Lysis Syndrome (TLS):
TLS has been reported in patients with resistance to prior
imatinib therapy, primarily in advanced phase disease.
- Due to potential for TLS, maintain
adequate hydration, correct uric acid levels prior to initiating
therapy with SPRYCEL, and monitor electrolyte levels.
- Patients with advanced stage disease
and/or high tumor burden may be at increased risk and should be
monitored more frequently.
Embryo-Fetal Toxicity:
Based on limited human data, SPRYCEL can cause fetal harm when
administered to a pregnant woman. Hydrops fetalis, fetal leukopenia
and fetal thrombocytopenia have been reported with maternal
exposure to SPRYCEL. Transplacental transfer of dasatinib has been
measured in fetal plasma and amniotic fluid at concentrations
comparable to those in maternal plasma.
- Advise females of reproductive
potential to avoid pregnancy, which may include the use of
effective contraception, during treatment with SPRYCEL and for 30
days after the final dose.
Lactation:
No data are available regarding the presence of dasatinib in
human milk, the effects of the drug on the breastfed infant or the
effects of the drug on milk production. However, dasatinib is
present in the milk of lactating rats.
- Because of the potential for serious
adverse reactions in nursing infants from SPRYCEL, breastfeeding is
not recommended during treatment with SPRYCEL and for 2 weeks after
the final dose.
Drug Interactions:
SPRYCEL is a CYP3A4 substrate and a weak time-dependent
inhibitor of CYP3A4.
- Drugs that may increase SPRYCEL plasma
concentrations are:
- CYP3A4 inhibitors: Concomitant
use of SPRYCEL and drugs that inhibit CYP3A4 should be avoided. If
administration of a potent CYP3A4 inhibitor cannot be avoided,
close monitoring for toxicity and a SPRYCEL dose reduction should
be considered
- Strong CYP3A4 inhibitors (eg,
ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir,
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin,
voriconazole). If SPRYCEL must be administered with a strong CYP3A4
inhibitor, a dose decrease or temporary discontinuation should be
considered
- Grapefruit juice may also
increase plasma concentrations of SPRYCEL and should be
avoided
- Drugs that may decrease SPRYCEL plasma
concentrations are:
- CYP3A4 inducers: If SPRYCEL must
be administered with a CYP3A4 inducer, a dose increase in SPRYCEL
should be considered
- Strong CYP3A4 inducers (eg,
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin,
phenobarbital) should be avoided. Alternative agents with less
enzyme induction potential should be considered. If the dose of
SPRYCEL is increased, the patient should be monitored carefully for
toxicity
- St John’s Wort may decrease
SPRYCEL plasma concentrations unpredictably and should be
avoided
- Antacids may decrease SPRYCEL
drug levels. Simultaneous administration of SPRYCEL and antacids
should be avoided. If antacid therapy is needed, the antacid dose
should be administered at least 2 hours prior to or 2 hours after
the dose of SPRYCEL
- H2 antagonists/proton pump
inhibitors (eg, famotidine and omeprazole): Long-term
suppression of gastric acid secretion by use of H2 antagonists or
proton pump inhibitors is likely to reduce SPRYCEL exposure.
Therefore, concomitant use of H2 antagonists or proton pump
inhibitors with SPRYCEL is not recommended
- Drugs that may have their plasma
concentration altered by SPRYCEL are:
- CYP3A4 substrates (eg,
simvastatin) with a narrow therapeutic index should be administered
with caution in patients receiving SPRYCEL
Adverse Reactions:
- In newly diagnosed chronic phase CML
patients:
- Drug-related serious adverse events
(SAEs) were reported for 16.7% of SPRYCEL-treated patients. Serious
adverse reactions reported in ≥5% of patients included pleural
effusion (5%).
- Most common adverse reactions (≥15%)
included myelosuppression, fluid retention, and diarrhea.
- In patients resistant or intolerant to
prior imatinib therapy:
- Drug-related SAEs were reported for
26.1% of Sprycel-treated patients treated at the recommended dose
of 100 mg once daily in the randomized dose-optimization trial of
patients with chronic phase CML resistant or intolerant to prior
imatinib therapy. Serious adverse reactions reported in ≥5% of
patients included pleural effusion (10%).
- Most common adverse reactions (≥15%)
included myelosuppression, fluid retention events, diarrhea,
headache, fatigue, dyspnea, skin rash, nausea, hemorrhage and
musculoskeletal pain.
Please see full Prescribing Information
here.
Sprycel is a registered trademark of Bristol-Myers Squibb
Company.
About Bristol-Myers Squibb and Otsuka Pharmaceutical Co.,
Ltd.
Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd. are
collaborative partners in the commercialization of Sprycel in the
United States, Japan, and major European countries. Sprycel was
discovered and developed by Bristol-Myers Squibb.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global pharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail over serious diseases. For more
information about Bristol-Myers Squibb, visit www.bms.com, or
follow us on Twitter at http://twitter.com/bmsnews.
About Otsuka
Otsuka Pharmaceutical, headquartered in Japan, is a leading firm
in the challenging area of mental health and also has products and
research programs for several under-addressed diseases including
tuberculosis, a significant global public health issue. These
commitments illustrate more powerfully than words how Otsuka is a
“big venture” company at heart, applying a youthful spirit of
creativity in everything it does.
In the U.S., Otsuka America Pharmaceutical, Inc. commercializes
Otsuka-discovered and in-licensed products, with a focus on
neuroscience, oncology, cardio-renal, and medical devices.
Otsuka welcomes you to visit its global website at:
http://www.otsuka.co.jp/en/index.php and its U.S. website at
www.otsuka-us.com.
Bristol-Myers Squibb Forward Looking Statement
This press release contains "forward-looking statements" as that
term is defined in the Private Securities Litigation Reform Act of
1995 regarding the research, development and commercialization of
pharmaceutical products. Such forward-looking statements are based
on current expectations and involve inherent risks and
uncertainties, including factors that could delay, divert or change
any of them, and could cause actual outcomes and results to differ
materially from current expectations. No forward-looking statement
can be guaranteed. Forward-looking statements in this press release
should be evaluated together with the many uncertainties that
affect Bristol-Myers Squibb's business, particularly those
identified in the cautionary factors discussion in Bristol-Myers
Squibb's Annual Report on Form 10-K for the year ended December 31,
2014 in our Quarterly Reports on Form 10-Q and our Current Reports
on Form 8-K. Bristol-Myers Squibb undertakes no obligation to
publicly update any forward-looking statement, whether as a result
of new information, future events or otherwise.
Endnotes: 1. Resistance to imatinib was defined as
failure to achieve a complete hematologic response (CHR; after 3
months), major cytogenetic response (MCyR; after 6 months), or
complete cytogenetic response (CCyR; after 12 months); or loss of a
previous molecular response (with concurrent ≥10% increase in Ph+
metaphases), cytogenetic response, or hematologic response. 2.
Imatinib intolerance was defined as inability to tolerate 400 mg or
more of imatinib per day or discontinuation of imatinib because of
toxicity. 3. Gleevec is a registered trademark of Novartis AG. 4.
Complete cytogenetic response (CCyR) is defined as the absence of
Philadelphia chromosome-positive metaphases on cytogenetic
assessment of bone marrow cells. 5. Major molecular response (MMR)
is defined as a BCR-ABL transcript level of ≤0.1% (3 log reduction)
as measured by real-time quantitative polymerase chain reaction
(RQ-PCR) of peripheral blood. These are cumulative rates
representing minimum follow-up for the timeframe specified. 6.
CI=confidence interval 7. Formal statistical comparison of cCCyR
and MMR rates was only performed at the time of the primary
endpoint (cCCyR within 12 months).
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Bristol-Myers SquibbMedia:Shelly Mittendorf,
609-897-2055cell:
609-480-2951shelly.mittendorf@bms.comorInvestors:Ranya
Dajani, 609-252-5330cell: 215-666-1515ranya.dajani@bms.comorWilliam
Szablewski, 609-252-5894cell:
215-801-0906william.szablewski@bms.comorOtsukaMedia:Kimberly
Whitefield, 609-535-9259cell:
201-738-7130kimberly.whitefield@otsuka-us.com
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