Bristol -Myers Squibb Company and Otsuka Pharmaceutical Co. Ltd

Three-Year Follow-Up Data for SPRYCEL®? (dasatinib) 100 mg Once-Daily Demonstrates Faster and Deeper Responses Compared With Imatinib 400 mg in Patients With Newly Diagnosed Philadelphia+ Chronic Myeloid Leukaemia in Chronic Phase

Paris (ots/PRNewswire) - Results Presented at 17th Congress of the European Hematology Association

Bristol-Myers Squibb Company and Otsuka Pharmaceutical Europe Ltd., today announced results from the 3-year follow-up of the DASISION trial, which show that first-line treatment with SPRYCEL(R) 100 mg results infaster and deeper response rates compared with Glivec(R) (imatinib) 400 mg [as defined by time to achieve Complete Cytogenic Response (CCYR) or Major Molecular Response (MMR)].

Additionally, an exploratory landmark analysis of the study suggests that patients with a deeper molecular response at three months (defined as having a less than or equal to 10% BCR-ABL) show a trend towards improved outcomes [such as Progression Free Survival (PFS), Overall Survival (OS) and a lower risk of disease transformation to Accelerated Phase or Blast Phase (AP/BP)] than the patients who did not achieve this level of response at three months. In this analysis, a deeper molecular response at three months was achieved in 84% of dasatinib treated patients and 64% of imatinib treated patients.[1]

"These findings are meaningful for newly diagnosed patients with Chronic Myeloid Leukaemia (CML)," said Dr Andreas Hochhaus, Professor of Internal Medicine and Head of the Department of Hematology and Medical Oncology at the Jena University Hospital, Germany. "We are now seeing that, in general, in CML an early and deep level of response to treatment appears to be associated with a lower rate of disease progression, and may be a promising indicator of better long-term outcomes for patients. However, longer follow up is needed."

Faster and Deeper Response by 3 Months

Research suggests that achieving a deep response earlier may predict better long-term outcomes for patients.[2,3] In this 3 year follow up of the DASISION study, the median time to response (Complete Cytogenic Response, or CCYR) for dasatinib was 3.2 months vs 6.0 months for imatinib. The median time to major molecular response (MMR) was 15 vs 36 months, respectively.[4]By 3 years, MMR was achieved in 68% of dasatinib treated and in 55% of imatinib treated patients (p<0.0001)[1]

Additional exploratory analyses of the three year follow-up of DASISION show:

        - At 3 months, 84% of evaluable patients receiving dasatinib achieved less
          than or equal to 10% BCR-ABL levels vs 64% of imatinib treated patients (p=0.0001)[1]
        - A higher probability of 3-year PFS and OS was seen in patients achieving less
          than or equal to 10% BCR-ABL compared to patients who had >10% BCR-ABL levels at 3
          months[1]
        - A lower level of transformation to AP/BP was seen in patients achieving less
          than or equal to 10% BCR-ABL (dasatinib 3%: 6 of 198 patients; imatinib 2.6%: 4 of 154
          patients) compared with patients who had >10% BCR-ABL levels at 3 months (dasatinib
          13%: 5 of 37 patients; imatinib 13%: 11 of 85 patients) during this three year
          follow-up.[1] 

Continued Tolerability at 3 Years

The overall three-year dataalso showed that the safety profile for dasatinib continues to be generally well-tolerated. Specifically, the data show:

        - Minimal changes in the tolerability profile at three years and with a
          similar pattern of adverse events as previously observed[1]
        - Rates of grade 3/4 non-hematologic AEs at 3 years in both arms remained low
          (0-3%)[1]
        - By the third year of treatment, 11% of patients discontinued dasatinib and 6%
          discontinued imatinib due to intolerance[5] 

Efficacy and safety Results in the European Subpopulation

Results of an exploratory analysis of the European subpopulation (defined as patients treated in the European Union) of DASISION were also presented at the 17th Congress of the European Hematology Association. This analysis demonstrated that the efficacy and safety profile of dasatinib in the European population (170 out of 519 included in DASISION) appeared comparable to that seen in the total study population. The exploratory data for the EU subgroup show:

        - Rates of MMR (65% for dasatinib and 56% for imatinib by 3 years)[5]
        - Level of transformation; no patients treated with dasatinib vs 3 patients on
          imatinib had transformation of CP-CML to AP/BP at or by 3 years [5]
        - Tolerability generally consistent with previously reported at 3 years for
          entire population[5] 

For full information on SPRYCEL (dasatinib) please refer to SmPC at http://www.ema.europa.eu.

About the DASISION Trial

The DASISION trial is a pivotal Phase 3, randomised open-label study looking at the efficacy and safety of dasatinib versus imatinibin newly diagnosed, treatment-naïve CP-CML patients. Patients were randomised to receive treatment with dasatinib 100 mg once-daily (n=259) or imatinib 400 mg once-daily (n=260).[6] Dasatinib was superior to imatinib for the primary endpoint of the study, confirmed complete cytogenetic response (cCCyR) by 12 months (77% vs 66%; p=0.007).[6] Given the established relationship between achieving CCyR by 12 months and improved survival rates, longer follow-up may demonstrate that dasatinib improves long-term outcomes.[6] Three-year data is now available. Patients will be followed for a planned 5 years.

About SPRYCEL(R)

Discovered and developed by Bristol-Myers Squibb, dasatinib was initially approved by the FDA and the European Commission in 2006 as a treatment for adults for all phases of Ph+ CML (chronic, accelerated, or myeloid or lymphoid blast phase) with resistance or intolerance to prior therapy including imatinib and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) intolerant or resistant to prior therapy. In the U.S., dasatinib received accelerated FDA approval for this indication. Since then, dasatinib has been approved for this indication in more than 60 countries worldwide.

In 2010, dasatinib 100 mg once daily was approved by the FDA and European Commission for the treatment of adult patients with newly diagnosed Ph+ CML in chronic phase. In the U.S., dasatinib received accelerated FDA approval for this indication. The effectiveness of dasatinib is based on cytogenetic response and major molecular response rates. Now, more than 50 countries have approved dasatinib for this indication.

About Chronic Myeloid Leukemia

CML is a slow-growing type of leukaemia in which the body produces an uncontrolled number of abnormal white blood cells.[7] CML accounts for 15% of all leukaemias.[8] The incidence is estimated at 1-2 cases per 100,000.[9]

CML occurs when pieces of two different chromosomes (9 and 22) break off and attach to each other. The new chromosome is called the Philadelphia 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.

Response to treatment can be measured either by Complete Cytogenetic Response (CCYR) or Major Molecular Response (MMR). CCYR is the absence of Philadelphia+ chromosomes in a Cytogenetic Testing made from a bone marrow aspiration. MMR is a 3-log reduction of BCR-ABL compared to a standardized baseline sample usually measured in peripheral blood.

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.

About Otsuka Pharmaceutical Co., Ltd.

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 Pharmaceutical Co., Ltd. is a wholly owned subsidiary of Otsuka Holdings Co., Ltd., the holding company for the Otsuka Group. The Otsuka Group has business operations in 23 countries and regions around the world.

Visit Otsuka Pharmaceutical Co., Ltd. at http://www.otsuka.co.jp/en.

References: 1. Hochhaus A, et al. Molecular response kinetics and BCR-ABL reductions in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) receiving dasatinib vs imatinib: DASISION 3-year follow-up. To be presented at: 17th Congress of the European Hematology Association (EHA); June 14-17, 2012; Amsterdam, The Netherlands.

2 Hanfstein B, et al. Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia accepted article preview 26 March 2012; doi: 10.1038/leu.2012.85.

3. Marin D, et al. Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol. 2012;30:232-8.

4. Jabbour E, et al. An exploratory analysis from 3-year DASISION follow-up examining the impact on patient outcomes of early complete cytogenetic response at 3 months and major molecular response at 12 months. To be presented at: 17th Congress of the European Hematology Association (EHA); June 14-17, 2012; Amsterdam, The Netherlands

5. Mayer J, et al. Efficacy and safety of dasatinib vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): European subpopulation analysis of the phase 3 DASISION trial. To be presented at: 17th Congress of the European Hematology Association (EHA); June 14-17, 2012; Amsterdam, The Netherlands.

6. Kantarjian H et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010; 362:2260-2270.

7. Macmillan Cancer Support. Leukaemia Overview.

Available at: http://www.macmillan.org.uk/Cancerinformation/Cance rtypes/Leukaemia/Leukaemiaoverview.aspx . Last accessed April 2012.

8. National Comprehensive Cancer Network (NCCN). Chronic Myelogenous Leukemia - Clinical Practice Guidelines in Oncology - v.1.2007.

9. Baccarani, M. and Dreyling, M. Annals of Oncology. 2010;21:165-167.

UK job codes: 729UK12NP019/ OPUK/0612/SPC/2017, date of preparation June 2012

Media Contacts Bristol-Myers Squibb Astrid Harmel, +33-1-58-83-61-49, astrid.harmel@bms.com Otsuka Pharmaceutical Europe Ltd. Ali Ross, +44-7768-337128, aross@otsuka-europe.com



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