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U.S. Food and Drug Administration Accepts Bristol-Myers Squibb's Application for Sprycel (dasatinib) in Pediatric Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

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Application based on results from Phase 2 CA180-372 study

Bristol-Myers
Squibb Company
(NYSE:BMY) today announced that the U.S. Food and
Drug Administration (FDA) accepted its supplemental Biologics License
Application (sBLA) for Sprycel (dasatinib) in combination with
chemotherapy for the treatment of pediatric patients with newly
diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic
leukemia (ALL). The FDA action date is December 29, 2018.

"Sprycel was first established as an important treatment option
for appropriate pediatric patients last year, when it was approved for
the treatment of children with Ph+ chronic myeloid leukemia," said
Jeffrey Jackson, Ph.D., development lead, hematology, Bristol-Myers
Squibb. "This latest milestone in Ph+ ALL reinforces our commitment to
researching the potential of Sprycel in different types of
pediatric leukemia and to providing this vulnerable population with
access to potential new therapies."

The application is based on data from CA180-372 (NCT01460160), an
ongoing Phase 2 trial evaluating the addition of Sprycel to a
chemotherapy regimen modeled on a Berlin-Frankfurt-Munster high-risk
backbone in pediatric patients with newly diagnosed Ph+ ALL.

About Sprycel

Sprycel first received FDA approval 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 also
received FDA approval for adults with Ph+ acute lymphoblastic leukemia
(ALL) who are resistant or intolerant to prior therapy. Sprycel is
approved and marketed for these indications in more than 60 countries.

Sprycel is also an FDA-approved treatment for adults with newly
diagnosed Ph+ CML-CP and is approved for this indication in more than 50
countries.

Both the FDA and the European Commission approved the expansion of Sprycel's
indication to include pediatric patients with Ph+ CML-CP in November
2017 and July 2018.

U.S. FDA-APPROVED INDICATIONS FOR SPRYCEL®

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

SPRYCEL® is indicated for the treatment of pediatric patients
with:

  • Ph+ CML in chronic phase

IMPORTANT SAFETY INFORMATION

Myelosuppression

Treatment with SPRYCEL is associated with severe (NCI CTCAE 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 can cause serious and fatal bleeding. In all CML or Ph+ ALL
clinical studies, Grade ≥3 central nervous system (CNS) hemorrhages,
including fatalities, occurred in <1% of patients receiving SPRYCEL. The
incidence of Grade 3/4 hemorrhage, occurred in 5.8% of adult patients
and generally required treatment interruptions and transfusions. The
incidence of Grade 5 hemorrhage occurred in 0.4% of adult patients. The
most frequent site of hemorrhage was gastrointestinal.

  • Most bleeding events in clinical studies were associated with severe
    thrombocytopenia
  • In addition to causing thrombocytopenia in human subjects, dasatinib
    caused platelet dysfunction in vitro
  • 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
adult 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 adult 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 adult 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. In pediatric patients with
chronic phase CML cases of Grade 1 or 2 fluid retention were reported in
10.3% 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

SPRYCEL can cause cardiac dysfunction. After 5 years of follow-up in the
randomized newly diagnosed chronic phase CML trial in adults (n=258),
the following cardiac adverse reactions 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 in adult and pediatric
patients, 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

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

Effects on Growth and Development in Pediatric Patients

In pediatric trials of SPRYCEL in chronic phase CML after at least 2
years of treatment, adverse reactions associated with bone growth and
development were reported in 5 (5.2%) patients, one of which was severe
in intensity (Growth Retardation Grade 3). These 5 cases included cases
of epiphyses delayed fusion, osteopenia, growth retardation, and
gynecomastia. Of these 5 cases, 1 case of osteopenia and 1 case of
gynecomastia resolved during treatment.

Lactation

No data are available regarding the presence of dasatinib in human milk,
the effects of the drug on the breastfed child 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
    children from SPRYCEL, breastfeeding is not recommended during
    treatment with SPRYCEL and for 2 weeks after the final dose

Drug Interactions

  • Strong CYP3A4 inhibitors: The coadministration with strong
    CYP3A inhibitors may increase dasatinib concentrations. Increased
    dasatinib concentrations may increase the risk of toxicity. Avoid
    concomitant use of strong CYP3A4 inhibitors. If concomitant
    administration of a strong CYP3A4 inhibitor cannot be avoided,
    consider a SPRYCEL dose reduction
    • Grapefruit juice may increase plasma concentrations of
      SPRYCEL and should be avoided
  • Strong CYP3A4 inducers: The coadministration of SPRYCEL
    with strong CYP3A inducers may decrease dasatinib concentrations.
    Decreased dasatinib concentrations may reduce efficacy. Consider
    alternative drugs with less enzyme induction potential. If concomitant
    administration of a strong CYP3A4 inducer cannot be avoided, consider
    a SPRYCEL dose increase
    • St. John's wort may decrease plasma concentrations of
      SPRYCEL and should be avoided
  • Gastric Acid Reducing Agents: The coadministration of
    SPRYCEL with a gastric acid reducing agent may decrease the
    concentrations of dasatinib. Decreased dasatinib concentrations may
    reduce efficacy.

    Do not administer H2 antagonists
    or proton pump inhibitors with SPRYCEL. Consider the use of antacids
    in place of H2 antagonists or proton pump inhibitors.
    Administer the antacid at least 2 hours prior to or 2 hours after the
    dose of SPRYCEL. Avoid simultaneous administration of SPRYCEL with
    antacids.

Adverse Reactions

The safety data reflects exposure to SPRYCEL at all doses tested in
clinical studies (n=2809) including 324 adult patients with newly
diagnosed chronic phase CML, 2388 adult patients with imatinib resistant
or intolerant chronic or advanced phase CML or Ph+ ALL, and 97 pediatric
patients with chronic phase CML.

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

  • 1618 adult patients with chronic phase CML was 29 months (range 0–92.9
    months)
    • Median duration for 324 adult patients in the newly diagnosed
      chronic phase CML trial was approximately 60 months
    • 1094 adult patients with advanced phase CML or Ph+ ALL was 6.2
      months (range 0–93.2 months)

In two non-randomized trials in 97 pediatric patients with chronic phase
CML (51 patients newly diagnosed and 46 patients resistant or intolerant
to previous treatment with imatinib), the median duration of therapy was
51.1 months (range 1.9 to 99.6 months).

In the newly diagnosed adult 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 adult SPRYCEL-treated patients, 88% of
patients experienced adverse reactions at some time and 19% experienced
adverse reactions leading to treatment discontinuation.

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

  • In the adult 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 reactions leading to discontinuation were
reported in 191 (17.5%) patients.

Among the 97 pediatric subjects, drug-related adverse reactions leading
to discontinuation were reported in 1 patient (1%).

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 adult newly diagnosed chronic phase CML patients:
    • Drug-related serious adverse reactions (SARs) were reported for
      16.7% of patients. Serious adverse reactions reported in ≥5% of
      patients included pleural effusion (5%)
    • Grade 3/4 laboratory abnormalities included neutropenia (29%),
      thrombocytopenia (22%), anemia (13%), hypophosphatemia (7%),
      hypocalcemia (4%), elevated bilirubin (1%), and elevated
      creatinine (1%)
  • In adult patients resistant or intolerant to prior imatinib therapy:
    • Drug-related SARs 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%)
    • 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
  • In pediatric subjects with Ph+ CML in chronic phase
    • Drug-related SARs were reported for 14.4% of pediatric patients
    • In the pediatric studies, the rates of laboratory abnormalities
      were consistent with the known profile for laboratory parameters
      in adults
  • Most common adverse reactions (≥15%) in patients included
    myelosuppression, fluid retention events, diarrhea, headache, skin
    rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain

Please see 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, 2017 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.

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