STUDY SHOWS SPRYCEL(R) (DASATINIB) 100 MG ONCE A DAY PROVIDES RESPONSES SIMILAR TO THOSE IN PATIENTS TAKING APPROVED 70 MG TWICE A DAY DOSE, WITH REDUCED INCIDENCE OF SIDE EFFECTS

ORLANDO, Fla., Dec. 11 /PRNewswire-FirstCall/ -- Today, Bristol-Myers Squibb Company (NYSE: BMY) announced results from a randomized Phase III study showing that patients receiving SPRYCEL 100 mg once a day achieved similar cytogenetic responses at six months with considerably fewer hematologic and non-hematologic adverse events than patients receiving three other dosing schedules of SPRYCEL. The study evaluated four dosing schedules -- including the U.S. Food and Drug Administration approved dose of 70 mg twice a day -- and was conducted in patients with chronic-phase chronic myelogenous leukemia (CML) resistant or intolerant to Gleevec. Results were presented at the 48th Annual Meeting and Exposition of the American Society of Hematology (ASH).

"These data show that many patients who were resistant or intolerant to Gleevec responded to a once a day dose of SPRYCEL with an improved safety and tolerability profile compared to a twice a day schedule," said Andreas Hochhaus, MD, Professor of Internal Medicine, University of Heidelberg, Mannheim, Germany.

The Phase III, open-label, randomized, multi-center international trial was conducted in 139 clinical trial sites. Patients were randomized to receive 50 mg twice a day (bid), 70 mg bid, 100 mg once a day (qd), or 140 mg qd. The primary objective of the study was to compare major cytogenetic response at six months among qd and bid regimens. Major cytogenetic response was defined as complete (no sign of Philadelphia chromosome-positive [Ph+] cells in the bone marrow) plus partial (less than 35 percent Ph+ cells in the bone marrow) cytogenetic responses.

The data presented show that comparable major cytogenetic responses were observed in all four treatment arms (50 mg bid = 54 percent; 70 mg bid = 56 percent; 100 mg qd = 59 percent; 140 mg qd = 57 percent). When compared to patients in the other three treatment arms; however, patients who received 100 mg once a day experienced:

Considerably lower incidence of grade 3 or 4 hematologic toxicities: thrombocytopenia, (p = 0.001); anemia, (p = 0.032); neutropenia, (p = 0.035); leukopenia, (p = 0.079).

Considerably lower incidence of pleural effusions (p =0.028).

All other non-hematologic events were comparable across all four treatment arms.

About SPRYCEL

On June 28, 2006, the U.S. Food and Drug Administration (FDA) granted accelerated approval of SPRYCEL, an oral inhibitor of multiple tyrosine kinases, for the treatment of adults in all phases of CML (chronic, accelerated, or myeloid or lymphoid blast phase) with resistance or intolerance to prior therapy, including Gleevec. 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. 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.

Resistance to Gleevec is often due to mutations of BCR-ABL, BCR-ABL over-expression, or activation of new pathways. SPRYCEL is the first approved oral multiple tyrosine kinase that, at nanomolar concentrations, inhibits BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRB kinases. By targeting these kinases, SPRYCEL 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.

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 (eg, 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 (eg, 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. John's Wort (Hypericum perforatum) may decrease dasatinib plasma concentrations unpredictably. Patients taking SPRYCEL should not take St. John'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 (eg, 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 (eg, 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 with leukemia from one Phase I and five Phase II clinical 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.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global pharmaceutical and related health care products company whose mission is to extend and enhance human life.

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  * Gleevec(R) is a registered trademark of Novartis AG

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