European Medicines Agency Validates Application for Bristol-Myers Squibb’s Sprycel (dasatinib) in Children with Chronic Myelogenous Leukemia

Proposal extends application to the treatment of children and
adolescents with chronic phase Philadelphia-chromosome positive chronic
myelogenous leukemia and to the powder for oral suspension

PRINCETON, N.J.–(BUSINESS WIRE)–$BMY #BMSBristol-Myers
Squibb Company
(NYSE:BMY) today announced that the European
Medicines Agency (EMA) validated its grouped Type II variation/Extension
of Application for Sprycel (dasatinib) to treat children and
adolescents aged 1 year to 18 years with chronic phase Philadelphia
chromosome positive chronic myelogenous leukemia (CML) and to include
the powder for oral suspension. Validation of the application confirms
the submission is complete and begins the EMA’s centralized review
process.

“Treatment options for pediatric patients with chronic phase CML, along
with formulations that support the unique demands of children with
cancer continue to be unmet needs,” said Murdo Gordon, executive vice
president and chief commercial officer, Bristol-Myers Squibb. “Building
on our long-standing heritage in hematology, including the use of Sprycel
for more than a decade to treat adults with certain forms of CML,
the validation of this application supports our commitment to expand
options for children and adolescents with different types of cancer.”

The application includes data from CA180-226 (NCT00777036), an ongoing
Phase 2, open-label, non-randomized trial studying Sprycel in newly
diagnosed chronic phase CML pediatric patients and in pediatric patients
resistant to or intolerant of imatinib. Data from this study will be
presented at the American Society of Clinical Oncology Annual Meeting
2017 in Chicago on Monday, June 5.

About Sprycel

Sprycel was first approved by the FDA in 2006 for the treatment
of adults with Philadelphia chromosome-positive (Ph+) chronic myeloid
leukemia (CML) in chronic phase (CP) who are resistant or intolerant to
prior therapy including imatinib. At that time, Sprycel was also
approved for adults with Ph+ acute lymphoblastic leukemia (ALL) who are
resistant or intolerant to prior therapy. 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.

U.S. FDA-APPROVED INDICATIONS FOR SPRYCEL®

SPRYCEL® (dasatinib) is indicated for the treatment of adults
with:

  • Newly diagnosed adults with 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. Myelosuppression was reported in
patients with normal baseline laboratory values as well as in patients
with pre-existing laboratory abnormalities.

  • 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
    • H 2 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

The safety data reflects exposure to SPRYCEL at all doses tested in
clinical studies including 324 patients with newly diagnosed chronic
phase CML and 2388 patients with imatinib resistant or intolerant
chronic or advanced phase CML or Ph+ ALL.

The median duration of therapy in all 2712 SPRYCEL-treated patients was
19.2 months (range 0–93.2 months). Median duration of therapy in:

  • 1618 patients with chronic phase CML was 29 months (range 0–92.9
    months)

    • Median duration for 324 patients in the newly diagnosed chronic
      phase CML trial was approximately 60 months
  • 1094 patients with advanced phase CML or Ph+ ALL was 6.2 months (range
    0–93.2 months)

In the newly diagnosed chronic phase CML trial, after a minimum of 60
months of follow-up, the cumulative discontinuation rate for 258
patients was 39%.

In the overall population of 2712 SPRYCEL-treated patients, 88% of
patients experienced adverse reactions at some time and 19% experienced
adverse reactions leading to treatment discontinuation.

Among the 1618 SPRYCEL-treated patients with chronic phase CML,
drug-related adverse events leading to discontinuation were reported in
329 (20.3%) patients.

  • In the newly diagnosed chronic phase CML trial, drug was discontinued
    for adverse reactions in 16% of SPRYCEL-treated patients with a
    minimum of 60 months of follow-up

Among the 1094 SPRYCEL-treated patients with advanced phase CML or Ph+
ALL, drug-related adverse events leading to discontinuation were
reported in 191 (17.5%) patients. Patients ≥65 years are more likely to
experience the commonly reported adverse reactions of fatigue, pleural
effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage,
and appetite disturbance, and more likely to experience the less
frequently reported adverse reactions of abdominal distention,
dizziness, pericardial effusion, congestive heart failure, hypertension,
pulmonary edema and weight decrease, and should be monitored closely.

  • 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%)
    • The most common adverse reactions (≥15%) included
      myelosuppression, fluid retention, and diarrhea
    • Grade 3/4 laboratory abnormalities included neutropenia (29%),
      thrombocytopenia (22%), anemia (13%), hypophosphatemia (7%),
      hypocalcemia (4%), elevated bilirubin (1%), and elevated
      creatinine (1%)
  • 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%)
    • The most common adverse reactions (≥15%) included
      myelosuppression, fluid retention events, diarrhea, headache,
      fatigue, dyspnea, skin rash, nausea, hemorrhage and
      musculoskeletal pain
    • Grade 3/4 hematologic laboratory abnormalities in chronic phase
      CML patients resistant or intolerant to prior imatinib therapy who
      received SPRYCEL 100 mg once daily with a minimum follow up of 60
      months included neutropenia (36%), thrombocytopenia (24%), and
      anemia (13%). Other grade 3/4 laboratory abnormalities included:
      hypophosphatemia (10%), and hypokalemia (2%)
    • Among chronic phase CML patients with resistance or intolerance to
      prior imatinib therapy, cumulative grade 3/4 cytopenias were
      similar at 2 and 5 years including: neutropenia (36% vs 36%),
      thrombocytopenia (23% vs 24%), and anemia (13% vs 13%)
  • Grade 3/4 elevations of transaminases or bilirubin and Grade 3/4
    hypocalcemia, hypokalemia, and hypophosphatemia were reported in
    patients with all phases of CML

    • Elevations in transaminases or bilirubin were usually managed with
      dose reduction or interruption
    • Patients developing Grade 3/4 hypocalcemia during the course of
      SPRYCEL therapy often had recovery with oral calcium
      supplementation

Please see the full Prescribing Information for SPRYCEL.

Please see the US full Prescribing Information here.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical 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 us at BMS.com
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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.
Among other risks, there can be no guarantee that
Sprycel will
receive regulatory approval for an additional indication described
herein.
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, 2016 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.

Contacts

Bristol-Myers Squibb
Media:
Audrey Abernathy,
919-605-4521
audrey.abernathy@bms.com
or
Investors:
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Power, 609-252-7509
timothy.power@bms.com
or
Bill
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william.szablewski@bms.com