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Higher initial dose of Glivec achieved better early responses than standard dose for patients with chronic myeloid leukemia


Efficacy and safety profile in large randomized Phase III study consistent with landmark IRIS trial, which established Glivec as standard of care

Study did not meet primary endpoint at 1 year, yet shows faster time to molecular responses with 800 vs. 400 mg dose

Findings reinforce that monitoring blood levels of Glivec may help optimize treatment benefit for individual patients

Novartis committed to improving first-line treatment through additional study follow-up and completing enrollment to Tasigna vs. Glivec trial

Basel, June 2008 - New data from a large, international clinical trial find that patients with newly diagnosed chronic myeloid leukemia who received Glivec® (imatinib)

  • at 800 mg/day as their initial treatment achieved clinical milestones significantly faster than those receiving the standard 400 mg/day dose.
    The Tyrosine Kinase Inhibitor Optimization and Selectivity Study (TOPS) is the first Phase III, randomized, controlled clinical trial designed to evaluate the potential benefits of an 800 mg starting dose across all risk categories of newly diagnosed, previously untreated patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML).
    Numerically, more patients achieved a major molecular response (MMR) with the 800 mg dose than the 400 mg dose (46.4% vs. 40.1%); however, the difference between the two arms -- the primary endpoint of the study -- was not statistically significant. This trend of improved MMR rate at 12 months in the 800 mg vs. 400 mg arms was most pronounced in the subset of patients with the highest risk for disease progression (41.1% vs. 26.2%). Further, patients in the 800 mg arm achieved MMR significantly faster than those who started treatment with Glivec at 400 mg[1]. Achievement of a MMR is an important goal of therapy for CML.
    “TOPS reaffirms Glivec as the standard of care for newly diagnosed CML patients,” said Jorge Cortes, MD, Professor of Medicine and Deputy Chair of Leukemia at the University of Texas MD Anderson Cancer Center in Houston. “We see a strong trend for rapid response with the 800 mg dose. As with trials like IRIS, further follow up will be needed to assess what this rapid early response will mean in terms of long-term benefit.”
    TOPS also showed that patients with lower blood levels of Glivec at one month had a lower molecular response at a year, an observation made in previous studies[2]. Cumulatively, these data suggest that maintaining adequate blood levels may help attain better clinical responses[2].
    These findings, from the first analysis of the TOPS data set, will be presented on Saturday, June 14, at the 2008 Congress of the European Hematology Association (EHA) in Copenhagen.
    “Our robust clinical program with Glivec continues to provide meaningful insights into the treatment of Ph+ CML and other types of cancer,” said Diane Young, MD, Head of Global Medical Affairs at Novartis Oncology. “Novartis continues to invest in trials like ENESTnd, which is comparing Tasigna to Glivec in the first-line setting, to build on this knowledge and further enhance treatment outcomes for patients.”
    ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials of newly diagnosed Ph+ CML patients) is designed to study the efficacy and safety of Tasigna® (nilotinib) vs. Glivec in newly diagnosed patients in the chronic phase. ENESTnd is currently underway and will enroll approximately 771 patients at 220 centers worldwide. Tasigna is currently approved for the treatment of Ph+ CML in the chronic or accelerated phase in patients resistant to, or intolerant of, Glivec.
    Chronic myeloid leukemia (CML) is a cancer of the blood and bone marrow in which the body produces cancerous white blood cells. Almost all patients with CML have an abnormality known as the Philadelphia chromosome, which produces a protein called Bcr-Abl that causes malignant white blood cells to proliferate. Glivec, the first therapy to inhibit the activity of Bcr-Abl, revolutionized the treatment of Ph+ CML and is now the standard of care for this disease.
    Study details
    TOPS is a Phase III, international, open label, randomized, multi-center clinical trial that included 103 study sites from 19 countries. The 476 patients with newly diagnosed, previously untreated Ph+ CML in chronic phase were randomized to receive Glivec at either 800 mg/day or the standard 400 mg/day dose in a 2:1 ratio. Patients were stratified by Sokal score for evaluation. Sokal score is a clinical measure that is used to identify those at highest risk for disease progression[1].
    A secondary endpoint of the study was the rate of complete cytogenetic response (the elimination of Ph+ cells) at 12 months. Patients in the 800 mg arm achieved complete cytogenetic response (CCyR) faster than patients in the 400 mg arm. The response rates for the 800 mg and 400 mg arms were 56.7% vs. 44.6% by six months (p=0.0146) and 69.9% vs. 65.6% by 12 months (p=0.3470), respectively. More than 95% of patients on either dose achieved some cytogenetic response by six months.
    The safety profile in the TOPS trial was similar to that previously reported for both doses of Glivec. At twelve months, discontinuation rates due to adverse events were 5.6% and 1.3% in the 800 mg arm and 400 mg arm, respectively. The 800 mg/day dose was associated with a higher frequency of adverse events, including grade 3/4 hematologic laboratory abnormalities. There was no difference between the two doses in the rate of grade 3/4 biochemical laboratory abnormalities.
    The foregoing release contains forward-looking statements that can be identified by terminology such as “may”, “committed”, “designed to”, “potential”, “will”, “suggest”, “continues to”, or similar expressions, or by express or implied discussions regarding potential new indications or labelling for Glivec or Tasigna or regarding potential future revenues from Glivec or Tasigna, or regarding the long-term impact of a patient’s use of Glivec or Tasigna. Such forward-looking statements reflect the current views of the Company regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with Glivec or Tasigna to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Glivec or Tasigna will be submitted or approved for any additional indications or labelling in any market. Nor can there be any guarantee that Glivec or Tasigna will achieve any particular levels of revenue in the future. Neither can there be any guarantee regarding the long-term impact of a patient’s use of Glivec or Tasigna. In particular, management’s expectations regarding Glivec and Tasigna could be affected by, among other things, unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company’s ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry and general public pricing pressures, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.


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