SPRYCEL (dasatinib) Demonstrates Superior Confirmed Complete Cytogenetic Response Rates Compared to Gleevec®* in Study of Adult Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase

Study Meets Primary Endpoint Demonstrating that 77 Percent of SPRYCEL patients vs. 66 Percent of Gleevec Patients Achieved Confirmed Complete Cytogenetic Response Rates by 12 Months

Early Cytogenetic Response Important in Management of Patients Living with Chronic Myeloid Leukemia

Results Published in New England Journal of Medicine and Presented at 46th Annual Meeting of the American Society of Clinical Oncology

Companies in Process of Submitting DASISION Data to Health Authorities Worldwide

PRINCETON, N.J. & TOKYO--(BUSINESS WIRE)--Jun 5, 2010 - Bristol-Myers Squibb Company (NYSE:BMY) and Otsuka Pharmaceutical Co., Ltd. today announced Phase III study results in which SPRYCEL (dasatinib) 100 mg once daily demonstrated a superior rate of confirmed complete cytogenetic response(CCyR)  compared to Gleevec® (imatinib mesylate). This study, known as DASISION, compared the investigational use of SPRYCEL versus Gleevec as a first-line treatment for patients with chronic phase chronic myeloid leukemia (CML-CP).

The data were published today in the New England Journal of Medicine and presented at the 46th Annual Meeting of the American Society of Clinical Oncology.

In this study, SPRYCEL 100 mg once daily demonstrated rates of overall adverse events and discontinuations comparable to Gleevec. Hematologic adverse events were commonly seen with both agents.

“Current treatment guidelines state that achieving a complete cytogenetic response rate by 12 months is important because data suggest that there is an increased risk of disease progression in CML patients who do not attain this treatment goal,” said Hagop Kantarjian, MD, Chairman and Professor, Leukemia Department, The University of Texas MD Anderson Cancer Center, and lead author of the New England Journal of Medicine paper.

Study Results

In the DASISION study, 77% of SPRYCEL patients vs. 66% of Gleevec patients achieved confirmed CCyR (two consecutive assessments of CCyR) by 12 months (p=0.007). Additionally, 83% of SPRYCEL patients vs. 72% of Gleevec patients achieved CCyR by one year (p=0.001). The time to CCyR was shorter for SPRYCEL patients than Gleevec patients (hazard ratio = 1.5, p<0.0001), with more than half of SPRYCEL patients (54%) achieving CCyR within three months. SPRYCEL patients were also twice as likely as Gleevec patients to achieve a major molecular response¡ (MMR), a more sensitive index of treatment response,1,2 during the course of the study (hazard ratio = 2.0, p<0.0001).

Commonly reported adverse events (of all grades) with SPRYCEL and Gleevec included superficial edema (9% and 36%), nausea (8% and 20%), rash (11% and 17%) and muscle inflammation (4% and 17%). Overall rates of fluid retention observed in the study were 19% with SPRYCEL and 42% with Gleevec. Pleural effusions were seen only in the SPRYCEL arm (10%).

Bristol-Myers Squibb and Otsuka are in the process of submitting the DASISION data to worldwide health authorities this year for the approval of SPRYCEL as a first-line treatment for newly diagnosed adult patients with CML-CP.

About the DASISION Study

DASISION (Dasatinib versus Imatinib Study in Treatment-Naïve CML Patients) is an open-label, randomized, Phase 3 international trial of SPRYCEL 100 mg taken once daily with no food restrictions vs. Gleevec 400 mg taken once daily, in the treatment of newly diagnosed chronic phase CML. The study enrolled 519 patients; 259 patients were randomized to receive SPRYCEL and 260 patients were randomized to receive Gleevec. The primary study endpoint was confirmed CCyR by 12 months. Other key endpoints were CCyR by 12 months, MMR at any time, time to confirmed CCyR and MMR, progression-free survival and overall survival. The estimated rates of overall survival at 12 months are 97% for those subjects receiving SPRYCEL and 99% for those receiving Gleevec. The cardiac adverse reactions of congestive heart failure/cardiac dysfunction and fatal myocardial infarction were reported in 1.6% of patients taking SPRYCEL compared to 1.6% of patients taking Gleevec.

About SPRYCEL

SPRYCEL, an oral BCR-ABL inhibitor, is currently approved by the U.S. Food and Drug Administration for the treatment of adults for all phases of CML (chronic, accelerated, or myeloid or lymphoid blast phase) with resistance or intolerance to prior therapy including Gleevec. SPRYCEL is also approved for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy.

The active ingredient of SPRYCEL is dasatinib. At nanomolar concentrations, dasatinib reduces the activity of one or more proteins responsible for the uncontrolled growth of the leukemia cells of patients with CML or Ph+ ALL.

About Chronic Myeloid Leukemia

CML is a slow-growing type of leukemia in which the body produces an uncontrolled number of abnormal white blood cells. According to the most recent statistics, about 22,475 people are living with the disease in the United States.3 It is estimated that 5,050 new cases were diagnosed in 2009.4 CML occurs when pieces of two different chromosomes break off and attach to each other. The new chromosome is called the Philadelphia-positive chromosome, which contains an abnormal gene called BCR-ABL that signals cells to make too many white blood cells. There is no known cause for the genetic change that causes CML.

IMPORTANT SAFETY INFORMATION ABOUT SPRYCEL

Myelosuppression:

Treatment with SPRYCEL® (dasatinib) is associated with severe NCI CTC Grade 3/4 thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent in advanced phase 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 pre-existing laboratory abnormalities. Complete blood counts (CBCs) 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 resistant myelosuppression.

Bleeding Related Events:

SPRYCEL® (dasatinib) caused platelet dysfunction in vitro and thrombocytopenia in humans. Severe central nervous system (CNS) hemorrhage, including fatalities, occurred in 1% of patients. Severe gastrointestinal (GI) hemorrhage 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. Caution is advised in patients required to take medications that inhibit platelet function or anticoagulants.

Fluid Retention:

Fluid retention was severe in 10% of patients, including pleural and pericardial effusions reported in 7% and 1%, respectively. Severe ascites and generalized edema were each reported in <1% of patients. Severe pulmonary edema was 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. Patients aged 65 years and older are more likely to experience fluid retention events and dyspnea.

QT Prolongation:

In vitro data suggest that SPRYCEL has the potential to prolong cardiac ventricular repolarization (QT interval). In 865 patients with leukemia from five single-arm studies, the mean changes in QTcF from baseline were 4–6 msec; the upper 95% confidence intervals (CIs) for all mean changes from baseline were <7 msec. Of the 2182 patients treated with SPRYCEL in clinical studies, 14 (<1%) patients had QTc prolongation as an adverse reaction. Twenty-one patients (1%) experienced a QTcF >500 msec. SPRYCEL should be administered 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. Hypokalemia or hypomagnesemia should be corrected prior to SPRYCEL administration.

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. If SPRYCEL is used during pregnancy, or if the patient becomes pregnant while taking SPRYCEL, the patient should be apprised of the potential hazard to the fetus.

Drug Interactions:

SPRYCEL® (dasatinib) is a CYP3A4 substrate. Drugs that may increase SPRYCEL plasma concentrations are: Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 should be avoided. If systemic administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and a SPRYCEL dose reduction 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: Strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital), which should be avoided. Alternative agents with less enzyme induction potential should be considered. If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered. St John's Wort may decrease SPRYCEL plasma concentrations unpredictably and should be avoided.

SPRYCEL is a time-dependent inhibitor of CYP3A4. Drugs that may have their plasma concentration altered by SPRYCEL are: CYP3A4 substrates such as simvastatin. Therefore, 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 in patients receiving SPRYCEL.

Long-term suppression of gastric acid secretion by use of H2 antagonists or proton pump inhibitors (e.g., famotidine and omeprazole) is likely to reduce SPRYCEL exposure. Therefore, concomitant use of H2 antagonists 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:

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 the drug.

Adverse Reactions:

The safety data reflect exposure to SPRYCEL® (dasatinib) in 2182 patients with CML or Ph+ ALL in clinical studies with a minimum of 2 years follow-up (starting dosage 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily). The median duration of therapy was 15 months.

The majority of SPRYCEL-treated patients experienced adverse reactions at some time. Drug was discontinued for adverse reactions in 15% of patients in chronic phase, 16% in accelerated phase, 15% in myeloid blast phase, 8% in lymphoid blast phase CML, and 8% in Ph+ ALL.

The most frequently reported adverse reactions (reported in ‰¥20% of patients) included myelosuppression, fluid retention events, diarrhea, headache, dyspnea, skin rash, fatigue, nausea and hemorrhage.

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%).

Grade 3/4 laboratory abnormalities in chronic phase CML patients who received SPRYCEL 100 mg once daily included neutropenia (36%), thrombocytopenia (23%), anemia (13%), hypophosphatemia (10%) and hypokalemia (2%).

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, but were reported with an increased frequency in patients with myeloid or lymphoid blast phase 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.

Full Prescribing Information is available at www.SPRYCEL.com.

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 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.

Founded in 1964, Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: 'Otsuka-people creating new products for better health worldwide.' Otsuka researches, develops, manufactures and markets innovative and original products, with a focus on pharmaceutical products for the treatment of diseases and consumer products for the maintenance of everyday health. Otsuka is committed to being a corporation that creates global value, adhering to the high ethical standards required of a company involved in human health and life, maintaining a dynamic corporate culture, and working in harmony with local communities and the natural environment.

Otsuka Pharmaceutical Co., Ltd. is a wholly owned subsidiary of Otsuka Holdings Co., Ltd., the holding company for the Otsuka Group. The Otsuka Group comprises 145 companies and employs approximately 39,000 people in 23 countries and regions worldwide. Otsuka and its consolidated subsidiaries earned ¥1,084.2 billion (approx. US $11.7 billion*) in annual revenues in fiscal 2009. Visit Otsuka Pharmaceutical Co., Ltd. at www.otsuka-global.com.

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 relating to the development and commercialization of certain compounds. 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 the clinical trials mentioned in this release will support a regulatory filing. Forward-looking statements in the 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, 2009, its Quarterly Reports on Form 10-Q, and 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.

* Gleevec® is a registered trademark of Novartis AG.

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

¡ 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.

References

1 Branford S. Hematology. 2007:376-83.

2 Hughes T, et al. Blood. 2006;108:28-37.

3 The Leukemia & Lymphoma Society Web site. ”Chronic Myelogenous Leukemia”. Available at: http://www.leukemia-lymphoma.org/all_page?item_id=8501. Accessed on May 17, 2010.

4 American Cancer Society Web site. What Are the Key Statistics About Chronic Myeloid Leukemia (CML)? Available at: http://www.cancer.org/docroot/CRI/content/CRI_2_4_1x_What_Are_the_Key_Statistics_About_Chronic_Myeloid_Leukemia_CML.asp?sitearea. Accessed on May 17, 2010.

Contact: Bristol-Myers Squibb
Media:
Bristol-Myers Squibb
Sarah Koenig, 609-252-4145
sarah.koenig@bms.com
or
Investors:
Bristol-Myers Squibb
John Elicker, 609-252-4611
john.elicker@bms.com
or
Otsuka
US:
Otsuka America Pharmaceutical Inc.
David Caruba, 609-524-6798
david.caruba@otsuka-us.com
or
Japan:
Otsuka Pharmaceutical Co., Ltd.
Masamitsu Kitada
kitadams@otsuka.jp

 

Posted: June 2010

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