FDA Approves U.S. Product Labeling Update for Sprycel® (dasatinib) to Include Three-Year First-Line and Five-Year Second-Line

  FDA Approves U.S. Product Labeling Update for Sprycel® (dasatinib) to
  Include Three-Year First-Line and Five-Year Second-Line Efficacy and Safety
  Data in Chronic Myeloid Leukemia in Chronic Phase

 Data added to Sprycel U.S. labeling are among the longest follow-up data of
                        current CML treatment options

Business Wire

PRINCETON, N.J. -- June 20, 2013

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 three-year efficacy and safety data in patients with newly
diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia
(CML) in chronic phase (CP) and five-year data in CP Ph+ CML patients who are
resistant or intolerant to Gleevec^®1 (imatinib mesylate).

Sprycel is a kinase inhibitor indicated for the treatment of adults with newly
diagnosed CP Ph+ CML. The effectiveness of Sprycel is based on cytogenetic
response and major molecular response rates. The trial is ongoing and further
data will be required to determine long-term outcome. Sprycel is also
indicated for Ph+ CML in all phases (chronic, accelerated, or myeloid or
lymphoid blast) with resistance or intolerance to prior therapy including
imatinib and Ph+ acute lymphoblastic leukemia (ALL) with resistance or
intolerance to prior therapy.

“These longer-term data add to the growing body of research around the safety
and efficacy of Sprycel in first-line CP Ph+ CML patients and those who are
resistant or intolerant to imatinib,” 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.”

“Bristol-Myers Squibb remains committed to helping patients with newly
diagnosed and imatinib-resistant or intolerant CP Ph+ CML through treatment
with Sprycel, a convenient once-daily treatment option,” said Laura Bessen,
MD, vice president and head of U.S. Medical, Bristol-Myers Squibb. “The
longer-term safety and efficacy data that have been added to the Sprycel^®
(dasatinib) U.S. labeling underscore this longstanding commitment. Since the
initial FDA approval in 2006, more than 175,000 Sprycel prescriptions have
been written in the U.S.”

“We are fortunate to be living at a time when, for many patients, CML can
often be managed as a chronic disease, thanks to treatments like Sprycel,”
said Greg Stephens, executive director, National CML Society. “As patients
continue to benefit from these treatments, understanding their safety and
effectiveness over time becomes increasingly important and may help inform the
decisions of healthcare providers as to which therapy they choose.”

Sprycel Demonstrated Higher Response than Imatinib in Newly-diagnosed Patients

Information added to the Sprycel label in the first-line CP Ph+ CML setting is
based on three-year data from DASISION (Dasatinib versus Imatinib Study in
Treatment-Naïve CML Patients), an open-label, randomized, Phase 3
international trial. In the study, Sprycel demonstrated superior efficacy as
defined by higher molecular (major molecular response^2 or MMR) and confirmed
cytogenetic response rates (CCyR^3) by 12 months, compared to imatinib.

In DASISION, 77% [95% CI, 71% - 82%] of patients treated with Sprycel (n=259)
vs. 66% [95%, CI, 60% - 72%] of patients treated with imatinib (n=260)
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 36
months follow-up, median time to confirmed CCyR was 3.1 months in 214 Sprycel
responders and 5.8 months in 201 imatinib responders. In the long-term (by 3
years), confirmed CCyR rates continued to increase (83% Sprycel vs. 77%
imatinib).^4

Sprycel patients were more likely than imatinib patients to achieve MMR^2, 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 3), MMR at any time was higher for Sprycel than imatinib (69% [95% CI,
63% - 75%] vs. 56% [95% CI, 50% - 62%], respectively).^4 The study also showed
higher MMR rates at any time with Sprycel,  across all Hasford^5 risk groups
vs. imatinib (low risk: 81% vs. 64%; medium risk: 64% vs. 56%; and high risk:
61% vs. 42%). ^ In patients treated with Sprycel^® (dasatinib)  the vast
majority did not transform to accelerated or blast phase CML by three years
(3% with Sprycel and 5% with imatinib).

The most frequently reported serious adverse reactions in patients with newly
diagnosed CP Ph+ CML included pleural effusion (4%), hemorrhage (2%),
congestive heart failure (1%), pulmonary hypertension (1%), and pyrexia (1%).
^ The most frequently reported adverse reactions reported in ≥10% of patients
with newly diagnosed CP Ph+ CML included myelosuppression, fluid retention
events (pleural effusion and superficial localized edema), diarrhea, headache,
musculoskeletal pain, rash, and nausea. ^ The safety and efficacy evaluation
in this trial is ongoing.

About the DASISION Study (CA180-056)

DASISION is an open-label, randomized, Phase 3 international trial of Sprycel
100 mg taken once-daily vs. imatinib 400 mg taken once-daily, in the treatment
of newly-diagnosed CP Ph+ CML. ^ The study enrolled 519 patients; 259 patients
were randomized to receive Sprycel and 260 patients were randomized to receive
imatinib. ^ The primary study endpoint was confirmed CCyR^3 by 12 months. ^
Select secondary endpoints were MMR^2 at any time, time to MMR, and time to
confirmed CCyR. ^ With a minimum of three years follow-up, 71% of Sprycel
patients and 69% of imatinib patients were still on study.

Phase 3 Study Is First to Demonstrate Five-Year Data in Second-Line Setting

Information added to the Sprycel labeling for CP Ph+ CML patients with
resistance or intolerance to prior imatinib therapy includes data up to six
years after the last patient was enrolled in Study CA180-034, a Phase 3
open-label, dose-optimization trial. At five years, 64% of patients were known
to be alive with an additional 14% having unknown survival data (the remaining
22% of patients were known to have died prior to five years). While on
treatment, less than 5% of Sprycel patients transformed to accelerated or
blast phase CML by five years. The primary endpoint was major cytogenetic
response (MCyR) in imatinib-resistant patients; 63% of imatinib-resistant or
-intolerant patients taking Sprycel^® (dasatinib) 100 mg once-daily achieved
MCyR at two years [95% CI: 56% - 71%].

The most frequently reported serious adverse reactions included pleural
effusion (11%), gastrointestinal bleeding (4%), febrile neutropenia (4%),
dyspnea (3%), pneumonia (3%), pyrexia (3%), diarrhea (3%), infection (2%),
congestive heart failure/cardiac dysfunction (2%), pericardial effusion (1%),
and CNS hemorrhage (1%). ^ The most frequently reported adverse reactions
(reported in ≥20% of patients) included myelosuppression, fluid retention
events (pleural effusion and superficial localized edema), headache, diarrhea,
fatigue, dyspnea, and musculoskeletal pain. ^ The efficacy evaluation,
including transformation rates, is ongoing.

About Dose Optimization Study (CA 180-034)

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 1.9%; 95% CI [-6.8 – 10.6%]). ^ In this population, the
median time from onset of CML to randomization in patients on the 100 mg
once-daily arm was 55 months and 46% of these patients had more than three
years of prior imatinib treatment. The study supports the recommended starting
dose, 100 mg once-daily, for CP Ph+ CML patients resistant or intolerant to
imatinib. The safety data through year five were consistent with the
previously reported safety profile of Sprycel 100 mg once-daily in patients
resistant or intolerant to imatinib.

About Sprycel Patient Support

Bristol-Myers Squibb is committed to patient support, which includes co-pay
assistance for eligible Sprycel patients. Through the Sprycel One Card
Program, commercially insured Sprycel patients may be able to pay no more than
$25 per month, with a maximum annual benefit of $25,000. Eligibility
requirements and terms and conditions apply.

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
28,900 people are living with the disease in the United States. It is
estimated that 5,920 new cases will be diagnosed in 2013. 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 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 for the treatment of adults with CP Ph+ CML who
are resistant or intolerant to prior therapy including imatinib in 2006 by the
FDA. 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 kinase
inhibitor with survival data in its label for CP Ph+ CML patients who are
resistant or intolerant to imatinib. Sprycel is now approved and marketed
worldwide for these indications in more than 60 countries including the
European Union (EU), Japan and Canada.

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. The effectiveness of Sprycel is based on cytogenetic response
and major molecular response rates. ^ The trial is ongoing and further data
will be required to determine long-term outcome. 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 chronic myeloid leukemia
    (Ph+ CML) in chronic phase. The effectiveness of SPRYCEL is based on
    cytogenetic and major molecular response rates. The trial is ongoing and
    further data will be required to determine long-term outcome
  *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® (dasatinib) can cause severe (NCI CTC Grade 3/4)
thrombocytopenia, neutropenia, and anemia. Myelosuppression was reported in
patients with normal baseline laboratory values as well as in patients with
pre-existing laboratory abnormalities

  *Perform complete blood counts (CBCs) weekly for the first 2 months and
    then monthly thereafter, or as clinically indicated
  *Myelosuppression was generally reversible and usually managed by dose
    interruption, dose reduction, or discontinuation
  *Hematopoietic growth factor has been used in patients with resistant
    myelosuppression

Bleeding Related Events:

SPRYCEL caused platelet dysfunction in vitro and thrombocytopenia in humans.
In all clinical trials, severe central nervous system (CNS) hemorrhage,
including fatalities, occurred in 1% of patients receiving SPRYCEL. Severe
gastrointestinal hemorrhage, including fatalities, occurred in 4% of patients
and generally required treatment interruptions and transfusions. Other cases
of severe hemorrhage occurred in 2% of patients

  *Most bleeding events were associated with severe thrombocytopenia.
    Exercise caution in patients required to take medications that inhibit
    platelet function or anticoagulants

Fluid Retention:

SPRYCEL is associated with fluid retention. In clinical trials, fluid
retention was severe in up to 10% of patients. Severe ascites, pulmonary
edema, and generalized edema were each reported in ≤1% of patients

  *Patients who develop symptoms suggestive of pleural effusion, such as
    dyspnea or dry cough, should be evaluated by chest X-ray
  *Severe pleural effusion may require thoracentesis and oxygen therapy
  *Fluid retention was typically managed by supportive care measures that
    included diuretics or short courses of steroids

QT Prolongation:

In vitro data suggest that SPRYCEL has the potential to prolong cardiac
ventricular repolarization (QT interval)

  *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 ms to 13.4 ms
  *In clinical trials of patients treated with SPRYCEL (N=2440), 16 patients
    (1%) had QTc prolongation as an adverse reaction. Twenty-two patients (1%)
    experienced a QTcF >500 ms
  *Administer SPRYCEL with caution to patients who have or may develop
    prolongation of QTc, including patients with hypokalemia, hypomagnesemia,
    or congenital long QT syndrome and patients taking anti-arrhythmic drugs,
    other medicinal products that lead to QT prolongation, and cumulative
    high-dose anthracycline therapy

       *Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration

Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial
Infarction:

Cardiac adverse reactions were reported in 7% of 258 patients taking SPRYCEL,
including 1.6% of patients with cardiomyopathy, heart failure congestive,
diastolic dysfunction, fatal myocardial infarction, and left ventricular
dysfunction.

  *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 one 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.

Use in Pregnancy:

SPRYCEL may cause fetal harm when administered to a pregnant woman. There are
no adequate and well-controlled studies of SPRYCEL in pregnant women.

  *Women of childbearing potential should be advised of the potential hazard
    to the fetus and to avoid becoming pregnant when taking SPRYCEL.

Nursing Mothers:

It is unknown whether SPRYCEL is excreted in human milk.

  *Because of the potential for serious adverse reactions in nursing infants,
    a decision should be made whether to discontinue nursing or to discontinue
    SPRYCEL.

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 H[2] antagonists or proton pump inhibitors is likely to reduce
         SPRYCEL exposure. Therefore, concomitant use of H[2] 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 reflect exposure to SPRYCEL in 258 patients with newly
diagnosed chronic phase CML in a clinical trial (minimum of 36 months follow
up; median duration of therapy was 37 months), and in 2182 patients with
imatinib-resistant or -intolerant CML or Ph+ ALL in clinical trials (1520
patients had a minimum of 2 years follow-up and 662 patients with chronic
phase CML had a minimum of 60 months follow up).

The majority of SPRYCEL-treated patients experienced adverse reactions at some
time. Patients aged 65 years and older are more likely to experience toxicity.
In the newly diagnosed chronic phase CML trial, the cumulative discontinuation
rate was 9% with a minimum of 36 months follow up. In patients resistant or
intolerant to prior imatinib therapy, the discontinuation rate for SPRYCEL at
2 years for adverse reactions was: 15% of patients in chronic phase CML (all
doses), 16% of patients in accelerated phase CML, 15% of patients in myeloid
blast phase CML, 8% in lymphoid blast phase CML, and 8% in Ph+ ALL. In
patients resistant or intolerant to prior imatinib therapy with chronic phase
CML (minimum 60 months follow up), the rate of discontinuation for adverse
reactions was 18% in patients treated with 100 mg once daily.

  *In newly diagnosed chronic phase CML patients:

       *The most frequently reported serious adverse reactions included
         pleural effusion (4%), hemorrhage (2%), congestive heart failure
         (1%), pulmonary hypertension (1%), and pyrexia (1%)
       *The most frequently reported adverse reactions (reported in ≥10% of
         patients) included myelosuppression, fluid retention events (pleural
         effusion and superficial localized edema), diarrhea, headache,
         musculoskeletal pain, rash, and nausea
       *Grade 3/4 laboratory abnormalities included neutropenia (24%),
         thrombocytopenia (19%), anemia (12%), hypophosphatemia (7%),
         hypocalcemia (3%), elevated bilirubin (1%), and elevated creatinine
         (1%)

  *In patients resistant or intolerant to prior imatinib therapy:

       *The most frequently reported serious adverse reactions included
         pleural effusion (11%), gastrointestinal bleeding (4%), febrile
         neutropenia (4%), dyspnea (3%), pneumonia (3%), pyrexia (3%),
         diarrhea (3%), infection (2%), congestive heart failure/cardiac
         dysfunction (2%), pericardial effusion (1%), and CNS hemorrhage (1%)
       *The most frequently reported adverse reactions (reported in ≥20% of
         patients) included myelosuppression, fluid retention events (pleural
         effusion and superficial localized edema), headache, diarrhea,
         fatigue, dyspnea, 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 or 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 transaminase or bilirubin and Grade 3/4
    hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients
    with all phases of CML

       *Elevations in transaminase 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

The full Prescribing Information is available at www.bms.com.

SPRYCEL is a registered trademark of Bristol-Myers Squibb Company.

SPRYCEL, REYATAZ and COUMADIN are registered trademarks of Bristol-Myers
Squibb. All other brands listed are the trademarks of their respective owners.

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^® (dasatinib) in the United
States, Japan, and major European countries. Sprycel was discovered and
developed by Bristol-Myers Squibb.

For more information about Bristol-Myers Squibb, visit www.bms.com or follow
us on Twitter at http://twitter.com/bmsnews.

For information about Otsuka Pharmaceutical Co., Ltd., visit
www.otsuka-global.com.

^1 Gleevec is a registered trademark of Novartis AG

^2 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.

^3 Complete cytogenetic response (CCyR) is defined as the absence of
Philadelphia chromosome-positive metaphases on cytogenetic assessment of bone
marrow cells.

^4 Formal statistical comparison of cCCyR and MMR rates was only performed at
the time of the primary endpoint (cCCyR within 12 months)

^5 Hasford is a prognostic scoring system.

Contact:

Bristol-Myers Squibb
Media:
Melanie Brunner, 609-252-6338
melanie.brunner@bms.com
or
Investors:
Ranya Dajani, 609-252-5330
ranya.dajani@bms.com
or
Ryan Asay, 609-252-5020
ryan.asay@bms.com
or
Otsuka
US:
Otsuka America Pharmaceutical Inc.
Rose Weldon, 609-524-6879
rose.weldon@otsuka-us.com
or
Japan:
Otsuka Pharmaceutical Co., Ltd.
Jeffrey Gilbert
gilbert.jeffrey@otsuka.co.jp
 
Press spacebar to pause and continue. Press esc to stop.