FDA Approves SPRYCEL(TM) (dasatinib) With Two Indications

PRINCETON, N.J., June 28 /PRNewswire-FirstCall/ -- Bristol-Myers Squibb Company 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(R)* (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 Brian J. Druker, M.D., investigator, Howard Hughes 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 Peter 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. 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 (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(R) is a registered trademark of Novartis AG