Press Release in re Sprycel approval

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ress Release Source: Bristol-Myers Squibb Company

FDA Approves SPRYCEL (dasatinib) With Two Indications

Wednesday June 28, 4:58 pm ET

PRINCETON, N.J., June 28 /PRNewswire-FirstCall/ -- Bristol-Myers

Squibb Company (NYSE: BMY - News) announced today that the U.S. Food

and Drug Administration (FDA) has granted accelerated approval of

SPRYCEL, an oral inhibitor of multiple tyrosine kinases, for the

treatment of adults in all phases of chronic myeloid leukemia (CML)

(chronic, accelerated, or myeloid or lymphoid blast phase) with

resistance or intolerance to prior therapy, including Gleevec®*

(imatinib mesylate). The effectiveness of SPRYCEL is based on

hematologic and cytogenetic response rates. There are no controlled

trials demonstrating a clinical benefit, such as improvement in

disease-related symptoms or increased survival. The FDA also granted

full approval of SPRYCEL for the treatment of adults with Philadelphia

chromosome-positive acute lymphoblastic leukemia (Ph+ALL) with

resistance or intolerance to prior therapy. Bristol-Myers Squibb

anticipates that SPRYCEL will be available within days nationwide.

SPRYCEL is the first approved oral tyrosine kinase inhibitor predicted

to bind to multiple conformations of the ABL kinase based on modeling

studies. At nanomolar concentrations, dasatinib inhibits BCR-ABL, SRC

family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFR-B. By targeting

these kinases, dasatinib inhibits the overproduction of leukemia cells

in the bone marrow of patients with CML and Ph+ALL and allows normal

red cell, white cell, and blood platelet production to resume.

" SPRYCEL provides a new treatment option for patients with CML or

Ph+ALL who are resistant or intolerant to prior therapy, " said

J. Druker, M.D., investigator, Medical Institute and

JELD-WEN chair of Leukemia Research, Oregon Health & Science

University Cancer Institute, Portland, OR.

Known mechanisms of imatinib resistance include mutations in the

protein sequence of the BCR-ABL tyrosine kinase, multi-drug resistance

gene overexpression, and the activation of alternate signaling

pathways involving the SRC family kinases. For many patients with CML,

the risk of developing resistance increases with the number of years

of prior treatment and severity of disease. Patients with advanced

Ph+ALL generally develop resistance more rapidly than CML patients,

including those in blast phase (an average of 2 months versus 10

months, respectively).

" SPRYCEL builds on our company's long legacy of providing innovative

oncology medicines to patients around the world, " said R. Dolan,

chief executive officer, Bristol-Myers Squibb. " Discovered and

developed in our own research facilities, SPRYCEL is a key part of our

robust pipeline of anti-cancer compounds that holds the promise of

further inroads in the struggle against this terrible disease. Our

commitment to finding innovative medicines for patients is an

important way that Bristol-Myers Squibb continues to live its mission. "

The FDA reviewed the efficacy (n=445) and safety (n=911) of SPRYCEL

based on the analysis of four Phase II multi-center studies in

patients with resistance or intolerance to imatinib in all phases of

CML (n=409) or Ph+ ALL (n=36). The studies were conducted on five

continents (33 countries).

IMPORTANT SAFETY INFORMATION

SPRYCEL is not recommended for use in pregnant women or those

contemplating pregnancy. Dasatinib may cause fetal harm. Sexually

active male/female patients taking SPRYCEL should use adequate

contraception.

Myelosuppression: Treatment with SPRYCEL is associated with severe CTC

Grade 3/4 thrombocytopenia, neutropenia, and anemia. Their occurrence

is more frequent in advanced CML or Ph+ALL than in chronic phase CML.

Myelosuppression was reported in patients with normal baseline

laboratory values as well as in patients with preexisting laboratory

abnormalities. Complete blood counts (CBC) should be performed weekly

for the first 2 months and then monthly thereafter, or as clinically

indicated. In clinical studies, myelosuppression was managed by dose

interruption, dose reduction, or discontinuation of study therapy.

Hematopoietic growth factor has been used in patients with persistent

myelosuppression.

Hemorrhage: Dasatinib caused platelet dysfunction in-vitro and

thrombocytopenia in humans. Severe CNS hemorrhage, including

fatalities occurred in 1% of patients. Severe GI hemorrhage occurred

in 7% of patients and generally required treatment interruptions and

transfusions. Other cases of severe hemorrhage occurred in 4% of

patients. Most bleeding events were associated with severe

thrombocytopenia. Caution is advised in patients required to take

medications that inhibit platelet function or anticoagulants.

Fluid Retention: Fluid retention was severe in 9% of patients,

including pleural and pericardial effusions reported in 5% and 1%,

respectively. Severe ascites and generalized edema were each reported

in 1%. Severe pulmonary edema was reported in 1% of patients. Patients

who develop symptoms suggestive of pleural effusion (dyspnea or dry

cough) should be evaluated by chest x-ray. Severe pleural effusion may

require oxygen therapy and thoracentesis. Fluid retention was

typically managed by supportive care measures that include diuretics

or short courses of steroids.

QT Prolongation: In-vitro data suggest that dasatinib has the

potential to prolong cardiac ventricular repolarization (QT interval).

Nine patients had QTc prolongation as an adverse event. Three patients

(<1%) experienced a QTcF >500 msec. SPRYCEL should be administered

with caution in 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, or cumulative

high-dose anthracycline therapy. Hypokalemia or hypomagnesemia should

be corrected prior to dasatinib administration.

Drug Interactions: Dasatinib is a CYP3A4 substrate. Drugs that may

increase dasatinib concentrations are: CYP3A4 inhibitors (e.g.,

ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir,

atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, and

telithromycin). Concomitant use of dasatinib and drugs that inhibit

CYP3A4 should be avoided. If systemic administration of a potent

CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and

dose reduction should be considered. Drugs that may decrease dasatinib

concentrations are: CYP3A4 inducers (e.g., dexamethasone, phenytoin,

carbamazepine, rifampicin, phenobarbital). Alternative agents with

less enzyme induction potential should be used or a dose increase of

SPRYCEL should be considered. St. 's Wort (Hypericum perforatum)

may decrease dasatinib plasma concentrations unpredictably. Patients

taking SPRYCEL should not take St. 's Wort.

Dasatinib is a time-dependent inhibitor of CYP3A4. Drugs that may have

their plasma concentration altered by dasatinib are: CYP3A4 substrates

with a narrow therapeutic index (e.g., alfentanil, astemizole,

terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine,

sirolimus, tacrolimus, or ergot alkaloids [ergotamine,

dihydroergotamine]) should be administered with caution.

Long-term suppression of gastric acid secretion by use of H2 blockers

or proton pump inhibitors (e.g., famotidine and omeprazole) is likely

to reduce dasatinib exposure. Therefore, concomitant use of H2

blockers or proton pump inhibitors with SPRYCEL is not recommended.

The use of antacids should be considered. 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.

Nursing Mothers: Women who are taking SPRYCEL should avoid breast-feeding.

Adverse Reactions: The safety data reflect exposure to SPRYCEL in 911

patients in clinical studies with leukemia from one Phase I and five

Phase II studies. The majority of SPRYCEL-treated patients experienced

adverse drug reactions at some time. Drug was discontinued for adverse

drug reactions in 6% of patients in chronic phase, 5% in accelerated

phase and 11% in myeloid blast phase CML and in 6% in lymphoid blast

phase CML or Ph+ALL.

The most frequently reported adverse events included fluid retention

events, such as pleural effusion, gastrointestinal events including

diarrhea, nausea, abdominal pain and vomiting and bleeding events. The

most frequently reported serious adverse events (SAEs) included

pyrexia (9%), pleural effusion (8%), febrile neutropenia (7%),

gastrointestinal bleeding (6%), pneumonia (6%), thrombocytopenia (5%),

dyspnea (4%), anemia (3%), diarrhea (2%), and cardiac failure (3%).

Grade 3/4 elevations of transaminases or bilirubin were reported in

all patients, with increased frequency in patients with myeloid or

lymphoid blast CML or Ph+ALL. Elevations in transaminases or bilirubin

were managed with dose reduction or interruption. Grade 3/4

hypocalcemia was reported in patients with all phases of CML, but with

an increased frequency in patients with myeloid or lymphoid blast CML

or Ph+ALL. Patients developing Grade 3/4 hypocalcemia during the

course of SPRYCEL therapy often had recovery with oral calcium

supplementation.

For full Prescribing Information, visit http://www.bms.com.

About Bristol-Myers Squibb

Bristol-Myers Squibb is dedicated to the discovery, development and

exhaustive exploration of innovative cancer fighting therapies that

extend and enhance the lives of patients living with cancer. More than

40 years ago, Bristol-Myers Squibb built a unified vision for the

future of cancer treatment. With expertise, dedication and resolve,

that vision led to the development of a diverse global portfolio of

anti-cancer therapies that are an important cornerstone of care today.

Hundreds of scientists at Bristol-Myers Squibb's Pharmaceutical

Research Institute are studying ways to improve current cancer

treatments and identify better, more effective medicines for the future.

Bristol-Myers Squibb is a global pharmaceutical and related health

care products company whose mission is to extend and enhance human life.

For information regarding access to SPRYCEL please call 1-877-477-7923

(Monday through Friday 9:00 am-7:00 pm ET).

This press release contains " forward-looking statements " as that term

is defined in the Private Securities Litigation Reform Act of 1995.

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 as to when SPRYCEL (dasatinib) will be available

or that it will be commercially successful. 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, 2005 and in our Quarterly Reports on Form 10-Q.

Bristol-Myers Squibb undertakes no obligation to publicly update any

forward-looking statement, whether as a result of new information,

future events or otherwise.

* Gleevec® is a registered trademark of Novartis AG

Source: Bristol-Myers Squibb Company