FDA Approves U.S. Product Labeling Update for Sprycel® (dasatinib) to Include Three-Year First-Line and Five-Year Second-Line Efficacy and Safety Data in Chronic Myeloid Leukemia in Chronic Phase

Data added to Sprycel U.S. labeling are among the longest follow-up data of current CML treatment options

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) and Otsuka America Pharmaceutical, Inc. today announced that the U.S. Food and Drug Administration (FDA) has approved an update to the Sprycel (dasatinib) product labeling. The labeling now includes three-year efficacy and safety data in patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) and five-year data in CP Ph+ CML patients who are resistant or intolerant to Gleevec^®1 (imatinib mesylate).

Sprycel is a kinase inhibitor indicated for the treatment of adults with newly diagnosed CP Ph+ CML. The effectiveness of Sprycel is based on cytogenetic response and major molecular response rates. The trial is ongoing and further data will be required to determine long-term outcome. Sprycel is also indicated for Ph+ CML in all phases (chronic, accelerated, or myeloid or lymphoid blast) with resistance or intolerance to prior therapy including imatinib and Ph+ acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior therapy.

“These longer-term data add to the growing body of research around the safety and efficacy of Sprycel in first-line CP Ph+ CML patients and those who are resistant or intolerant to imatinib,” said Neil Shah, MD, PhD, Associate Professor, Division of Hematology/Oncology, University of California, San Francisco. “CML requires ongoing treatment and assessment of treatment milestones in order to manage the disease properly. Given the chronic nature of CML, these long-term data are particularly important for patient care.”

“Bristol-Myers Squibb remains committed to helping patients with newly diagnosed and imatinib-resistant or intolerant CP Ph+ CML through treatment with Sprycel, a convenient once-daily treatment option,” said Laura Bessen, MD, vice president and head of U.S. Medical, Bristol-Myers Squibb. “The longer-term safety and efficacy data that have been added to the Sprycel^® (dasatinib) U.S. labeling underscore this longstanding commitment. Since the initial FDA approval in 2006, more than 175,000 Sprycel prescriptions have been written in the U.S.”

“We are fortunate to be living at a time when, for many patients, CML can often be managed as a chronic disease, thanks to treatments like Sprycel,” said Greg Stephens, executive director, National CML Society. “As patients continue to benefit from these treatments, understanding their safety and effectiveness over time becomes increasingly important and may help inform the decisions of healthcare providers as to which therapy they choose.”

Sprycel Demonstrated Higher Response than Imatinib in Newly-diagnosed Patients

Information added to the Sprycel label in the first-line CP Ph+ CML setting is based on three-year data from DASISION (Dasatinib versus Imatinib Study in Treatment-Naïve CML Patients), an open-label, randomized, Phase 3 international trial. In the study, Sprycel demonstrated superior efficacy as defined by higher molecular (major molecular response² or MMR) and confirmed cytogenetic response rates (CCyR³) by 12 months, compared to imatinib.

In DASISION, 77% [95% CI, 71% - 82%] of patients treated with Sprycel (n=259) vs. 66% [95%, CI, 60% - 72%] of patients treated with imatinib (n=260) achieved the primary endpoint of confirmed CCyR (defined as two consecutive assessments of CCyR at least 28 days apart) by 12 months (p=0.007). After 36 months follow-up, median time to confirmed CCyR was 3.1 months in 214 Sprycel responders and 5.8 months in 201 imatinib responders. In the long-term (by 3 years), confirmed CCyR rates continued to increase (83% Sprycel vs. 77% imatinib).⁴

Sprycel patients were more likely than imatinib patients to achieve MMR², a measure of deeper treatment response, by year one (52% [95% CI, 46% - 58%] vs. 34% [95% CI, 28% - 40%], respectively; p<0.0001). In the long term (by year 3), MMR at any time was higher for Sprycel than imatinib (69% [95% CI, 63% - 75%] vs. 56% [95% CI, 50% - 62%], respectively).⁴ The study also showed higher MMR rates at any time with Sprycel, across all Hasford⁵ risk groups vs. imatinib (low risk: 81% vs. 64%; medium risk: 64% vs. 56%; and high risk: 61% vs. 42%). In patients treated with Sprycel^® (dasatinib) the vast majority did not transform to accelerated or blast phase CML by three years (3% with Sprycel and 5% with imatinib).

The most frequently reported serious adverse reactions in patients with newly diagnosed CP Ph+ CML included pleural effusion (4%), hemorrhage (2%), congestive heart failure (1%), pulmonary hypertension (1%), and pyrexia (1%). The most frequently reported adverse reactions reported in ≥10% of patients with newly diagnosed CP Ph+ CML included myelosuppression, fluid retention events (pleural effusion and superficial localized edema), diarrhea, headache, musculoskeletal pain, rash, and nausea. The safety and efficacy evaluation in this trial is ongoing.

About the DASISION Study (CA180-056)

DASISION is an open-label, randomized, Phase 3 international trial of Sprycel 100 mg taken once-daily vs. imatinib 400 mg taken once-daily, in the treatment of newly-diagnosed CP Ph+ CML. The study enrolled 519 patients; 259 patients were randomized to receive Sprycel and 260 patients were randomized to receive imatinib. The primary study endpoint was confirmed CCyR³ by 12 months. Select secondary endpoints were MMR² at any time, time to MMR, and time to confirmed CCyR. With a minimum of three years follow-up, 71% of Sprycel patients and 69% of imatinib patients were still on study.

Phase 3 Study Is First to Demonstrate Five-Year Data in Second-Line Setting

Information added to the Sprycel labeling for CP Ph+ CML patients with resistance or intolerance to prior imatinib therapy includes data up to six years after the last patient was enrolled in Study CA180-034, a Phase 3 open-label, dose-optimization trial. At five years, 64% of patients were known to be alive with an additional 14% having unknown survival data (the remaining 22% of patients were known to have died prior to five years). While on treatment, less than 5% of Sprycel patients transformed to accelerated or blast phase CML by five years. The primary endpoint was major cytogenetic response (MCyR) in imatinib-resistant patients; 63% of imatinib-resistant or -intolerant patients taking Sprycel^® (dasatinib) 100 mg once-daily achieved MCyR at two years [95% CI: 56% - 71%].

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%). The most frequently reported adverse reactions (reported in ≥20% of patients) included myelosuppression, fluid retention events (pleural effusion and superficial localized edema), headache, diarrhea, fatigue, dyspnea, and musculoskeletal pain. The efficacy evaluation, including transformation rates, is ongoing.

About Dose Optimization Study (CA 180-034)

The dose optimization study (CA180-034) is an open-label, randomized study designed to assess the efficacy and safety of Sprycel in CP Ph+ CML patients with resistance (n=497) or intolerance (n=173) to imatinib. The trial enrolled 670 CML patients who were randomized to one of four treatment arms: 100 mg once-daily (n=167), 50 mg twice-daily (n=168), 140 mg once-daily (n=167), and 70 mg twice-daily (n=168). Efficacy was achieved across all Sprycel treatment groups with the once-daily schedule demonstrating comparable efficacy (non-inferiority) to the twice-daily schedule on the primary efficacy endpoint (difference in MCyR 1.9%; 95% CI [-6.8 – 10.6%]). In this population, the median time from onset of CML to randomization in patients on the 100 mg once-daily arm was 55 months and 46% of these patients had more than three years of prior imatinib treatment. The study supports the recommended starting dose, 100 mg once-daily, for CP Ph+ CML patients resistant or intolerant to imatinib. The safety data through year five were consistent with the previously reported safety profile of Sprycel 100 mg once-daily in patients resistant or intolerant to imatinib.

About Sprycel Patient Support

Bristol-Myers Squibb is committed to patient support, which includes co-pay assistance for eligible Sprycel patients. Through the Sprycel One Card Program, commercially insured Sprycel patients may be able to pay no more than $25 per month, with a maximum annual benefit of $25,000. Eligibility requirements and terms and conditions apply.

About Chronic Myeloid Leukemia

CML is a type of leukemia in which the body produces an uncontrolled number of abnormal white blood cells. According to the most recent statistics, about 28,900 people are living with the disease in the United States. It is estimated that 5,920 new cases will be diagnosed in 2013. CML occurs when pieces of two different chromosomes (chromosomes 9, 22) break off and attach to each other. The newly formed chromosome is called the Philadelphia chromosome, which contains an abnormal gene called BCR-ABL gene. This gene produces the BCR-ABL protein that signals cells to make too many white blood cells. There is no known cause for the genetic change that results in CML.

About Sprycel^® (dasatinib)

Sprycel was first approved for the treatment of adults with CP Ph+ CML who are resistant or intolerant to prior therapy including imatinib in 2006 by the FDA. At that time, Sprycel was also approved for adults with Ph+ ALL who are resistant or intolerant to prior therapy. It is the first and only kinase inhibitor with survival data in its label for CP Ph+ CML patients who are resistant or intolerant to imatinib. Sprycel is now approved and marketed worldwide for these indications in more than 60 countries including the European Union (EU), Japan and Canada.

Sprycel is also an FDA-approved treatment for adults with newly diagnosed CP Ph+ CML (since October 2010). Sprycel received accelerated FDA approval for this indication. The effectiveness of Sprycel is based on cytogenetic response and major molecular response rates. The trial is ongoing and further data will be required to determine long-term outcome. Additional country approvals for this indication total more than 50.

SPRYCEL® (dasatinib) INDICATIONS & IMPORTANT SAFETY INFORMATION

INDICATIONS

SPRYCEL® (dasatinib) is indicated for the treatment of adults with:

• Newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of SPRYCEL is based on cytogenetic and major molecular response rates. The trial is ongoing and further data will be required to determine long-term outcome
• Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib
• Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy

IMPORTANT SAFETY INFORMATION

Myelosuppression:

Treatment with SPRYCEL® (dasatinib) can cause severe (NCI CTC Grade 3/4) thrombocytopenia, neutropenia, and anemia. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities

• Perform complete blood counts (CBCs) weekly for the first 2 months and then monthly thereafter, or as clinically indicated
• Myelosuppression was generally reversible and usually managed by dose interruption, dose reduction, or discontinuation
• Hematopoietic growth factor has been used in patients with resistant myelosuppression

Bleeding Related Events:

SPRYCEL caused platelet dysfunction in vitro and thrombocytopenia in humans. In all clinical trials, severe central nervous system (CNS) hemorrhage, including fatalities, occurred in 1% of patients receiving SPRYCEL. Severe gastrointestinal hemorrhage, including fatalities, 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. Exercise caution in patients required to take medications that inhibit platelet function or anticoagulants

Fluid Retention:

SPRYCEL is associated with fluid retention. In clinical trials, fluid retention was severe in up to 10% of patients. Severe ascites, pulmonary edema, and generalized edema were each 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

QT Prolongation:

In vitro data suggest that SPRYCEL has the potential to prolong cardiac ventricular repolarization (QT interval)

• In 865 patients with leukemia treated with SPRYCEL in five phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms
• In clinical trials of patients treated with SPRYCEL (N=2440), 16 patients (1%) had QTc prolongation as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms
• Administer SPRYCEL 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
  • Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration

Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction:

Cardiac adverse reactions were reported in 7% of 258 patients taking SPRYCEL, including 1.6% of patients with cardiomyopathy, heart failure congestive, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction.

• Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.

Pulmonary Arterial Hypertension (PAH):

SPRYCEL may increase the risk of developing PAH, which may occur any time after initiation, including after more than one year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of SPRYCEL.

• Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment. If PAH is confirmed, SPRYCEL should be permanently discontinued.

Use in 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 when taking 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 SPRYCEL.

Drug Interactions:

SPRYCEL is a CYP3A4 substrate and a weak time-dependent inhibitor of CYP3A4.

• Drugs that may increase SPRYCEL plasma concentrations are:
  • CYP3A4 inhibitors: Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 should be avoided. If administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and a SPRYCEL dose reduction should be considered
  • Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease 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:
  • CYP3A4 inducers: If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered
  • Strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) should be avoided. Alternative agents with less enzyme induction potential should be considered. If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity
    • St John’s Wort may decrease SPRYCEL plasma concentrations unpredictably and should be avoided
  • Antacids may decrease SPRYCEL drug levels. 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
  • H₂ antagonists/proton pump inhibitors (eg, famotidine and omeprazole): Long-term suppression of gastric acid secretion by use of H₂ antagonists or proton pump inhibitors is likely to reduce SPRYCEL exposure. Therefore, concomitant use of H₂ antagonists or proton pump inhibitors with SPRYCEL is not recommended
• Drugs that may have their plasma concentration altered by SPRYCEL are:
  • CYP3A4 substrates (eg, simvastatin) with a narrow therapeutic index should be administered with caution in patients receiving SPRYCEL

Adverse Reactions:

The safety data reflect exposure to SPRYCEL in 258 patients with newly diagnosed chronic phase CML in a clinical trial (minimum of 36 months follow up; median duration of therapy was 37 months), and in 2182 patients with imatinib-resistant or -intolerant CML or Ph+ ALL in clinical trials (1520 patients had a minimum of 2 years follow-up and 662 patients with chronic phase CML had a minimum of 60 months follow up).

The majority of SPRYCEL-treated patients experienced adverse reactions at some time. Patients aged 65 years and older are more likely to experience toxicity. In the newly diagnosed chronic phase CML trial, the cumulative discontinuation rate was 9% with a minimum of 36 months follow up. In patients resistant or intolerant to prior imatinib therapy, the discontinuation rate for SPRYCEL at 2 years for adverse reactions was: 15% of patients in chronic phase CML (all doses), 16% of patients in accelerated phase CML, 15% of patients in myeloid blast phase CML, 8% in lymphoid blast phase CML, and 8% in Ph+ ALL. In patients resistant or intolerant to prior imatinib therapy with chronic phase CML (minimum 60 months follow up), the rate of discontinuation for adverse reactions was 18% in patients treated with 100 mg once daily.

• In newly diagnosed chronic phase CML patients:
  • The most frequently reported serious adverse reactions included pleural effusion (4%), hemorrhage (2%), congestive heart failure (1%), pulmonary hypertension (1%), and pyrexia (1%)
  • The most frequently reported adverse reactions (reported in ≥10% of patients) included myelosuppression, fluid retention events (pleural effusion and superficial localized edema), diarrhea, headache, musculoskeletal pain, rash, and nausea
  • Grade 3/4 laboratory abnormalities included neutropenia (24%), thrombocytopenia (19%), anemia (12%), hypophosphatemia (7%), hypocalcemia (3%), elevated bilirubin (1%), and elevated creatinine (1%)
• In patients resistant or intolerant to prior imatinib therapy:
  • 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%)
  • The most frequently reported adverse reactions (reported in ≥20% of patients) included myelosuppression, fluid retention events (pleural effusion and superficial localized edema), headache, diarrhea, fatigue, dyspnea, and musculoskeletal pain
  • Grade 3/4 hematologic laboratory abnormalities in chronic phase CML patients resistant or intolerant to prior imatinib therapy who received SPRYCEL 100 mg once daily with a minimum follow up of 60 months included neutropenia (36%), thrombocytopenia (24%) and anemia (13%). Other grade 3/4 laboratory abnormalities included: hypophosphatemia (10%) and hypokalemia (2%)
    • Among chronic phase CML patients with resistance or intolerance to prior imatinib therapy, cumulative Grade 3 or 4 cytopenias were similar at 2 and 5 years including: neutropenia (36% vs 36%), thrombocytopenia (23% vs 24%), and anemia (13% vs 13%)
• 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
  • 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

The full Prescribing Information is available at www.bms.com.

SPRYCEL is a registered trademark of Bristol-Myers Squibb Company.

SPRYCEL, REYATAZ and COUMADIN are registered trademarks of Bristol-Myers Squibb. All other brands listed are the trademarks of their respective owners.

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.

For more information about Bristol-Myers Squibb, visit www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

For information about Otsuka Pharmaceutical Co., Ltd., visit www.otsuka-global.com.

¹ Gleevec is a registered trademark of Novartis AG

² 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. These are cumulative rates representing minimum follow-up for the timeframe specified.

³ Complete cytogenetic response (CCyR) is defined as the absence of Philadelphia chromosome-positive metaphases on cytogenetic assessment of bone marrow cells.

⁴ Formal statistical comparison of cCCyR and MMR rates was only performed at the time of the primary endpoint (cCCyR within 12 months)

⁵ Hasford is a prognostic scoring system.