PRINCETON, N.J. & TOKYO--(BUSINESS WIRE)-- Bristol-Myers Squibb Company (NYSE: BMY) and Otsuka Pharmaceutical Co., Ltd. today announced that the U.S. Food and Drug Administration (FDA) has accepted for filing and review the supplemental New Drug Application (sNDA) for SPRYCEL® (dasatinib) for the treatment of adult patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase. The companies also announced today that the application has been granted a priority review designation by the FDA. Based on FDA’s six month goal for completing priority reviews, the projected FDA action date is October 28, 2010. The filing is based on the results of the DASISION trial.
SPRYCEL, an oral BCR-ABL inhibitor, is currently approved by the FDA 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 (imatinib mesylate). SPRYCEL is also approved for the treatment of adults with Philadelphia chromosome 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. It is estimated that 5,050 new cases were diagnosed in 2009. CML occurs when pieces of two different chromosomes break off and attach to each other. The new chromosome is called the Philadelphia chromosome and 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
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 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.
In vitro data suggest that SPRYCEL® (dasatinib) 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.
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.
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® (dasatinib) 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.
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.
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® (dasatinib) in the United States, Japan and major European countries. SPRYCEL was discovered and developed by Bristol-Myers Squibb.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com/, or follow us on Twitter at http://twitter.com/bmsnews.
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 regulatory filings mentioned in this release will be approved or that any approval will occur within the time period mentioned in this release. 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
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.
Sarah Koenig, 609-252-4145
John Elicker, 609-252-4611
Otsuka America Pharmaceutical Inc.
David Caruba, 609-524-6798
Otsuka Pharmaceutical Co., Ltd.
KEYWORDS: United States North America New Jersey
INDUSTRY KEYWORDS: Health Biotechnology Clinical Trials Pharmaceutical FDA