New Data Show Higher Dosing of Gleevec Achieved Higher Response Rates in Patients with Newly Diagnosed Chronic Myeloid Leukemia (CML)


Early Findings Among Clinical Research Presented at American Society of Hematology (ASH) Meeting; At 12 months, 92% of evaluable CML patients taking 800 mg Gleevec achieved a CCR compared to 72% taking the standard 400 mg

East Hanover, NJ, December 8, 2003 -
New data demonstrated that at 12 months, newly diagnosed patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) taking 800 mg/day of Gleevec® (imatinib mesylate)* achieved higher complete cytogenetic responses (CCR) compared to those taking the standard 400 mg/day dose. Significantly more patients in the higher dose group also achieved a molecular response compared to those in the standard dose group. These early data were presented this week at the annual meeting of the American Society of Hematology (ASH) in San Diego, California.

Researchers found that 53% of evaluable patients with newly diagnosed CML who were taking 800 mg of Gleevec achieved a CCR at three months compared to 37% of patients who were taking the standard dose. At 12 months, 92% of evaluable patients taking 800 mg achieved a CCR compared to 72% of those taking the standard dose. A CCR is the elimination of cells containing the Ph chromosome, the genetic abnormality that characterizes most cases of CML. CCR is a major goal of therapy.

"Previously published data of other therapies suggest that the earlier patients achieve a CCR, the better their prognosis," said Jorge Cortes, Associate Professor of Medicine and Deputy Chair, Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center. "If confirmed, these early results may provide a new approach for initial treatment."
*Outside the U.S.: Glivec® (imatinib)
In addition to more rapid CCR, researchers found that more patients achieved a molecular response with 24% (15/62) patients achieving undetectable Bcr-Abl at the higher dose (800 mg/day) compared to 5% (2/43) patients taking the standard dose (400 mg/day). Molecular response is a relatively new and more sensitive tool capable of detecting extremely minute quantities of residual leukemia cells in the body following treatment. Molecular response may prove a possible new benchmark for evaluating drug therapy effectiveness and prognosis.

Study Details
In two consecutive trials in patients with previously untreated newly diagnosed Ph+ CML, researchers treated 167 patients with previously untreated CML in early chronic phase with Gleevec. One trial included 50 patients treated with the standard dose of Gleevec (400 mg/day). The other trial included 117 patients treated with a total daily dose of 800 mg. At 12 months, 105 patients were evaluable (43 at the 400 mg dose and 62 at the 800 mg dose).

The median follow-up for patients treated at the standard dose was 24 months while the median follow-up for patients treated at the 800 mg dose was 13 months. Although side effects were similar with the two dose schedules, myelosuppression was more common at the higher dose, with grade 3 anemia, neutropenia and thrombocytopenia occurring in 10%, 35%, and 25% of patients treated with 800 mg, respectively, versus 4%, 20% and 10% of patients treated with 400 mg, respectively. Generally, in most patients side effects such as neutropenia were transient and did not require permanent dose reduction below 600 mg. At 12 months, median actual dose for the group started at 800 mg was still 800 mg with 19% (15/79) patients requiring dose reduction to 400 or 300 mg of Gleevec.

About Gleevec
Gleevec is indicated for the treatment of newly diagnosed adult patients with Ph+ CML in chronic phase. Follow-up is limited. Gleevec is also indicated for the treatment of patients with Ph+ CML in blast crisis, in accelerated phase, or in chronic phase after failure of interferon-alpha therapy. Gleevec is also approved for the treatment of pediatric patients with Ph+ chronic phase CML whose disease has recurred after stem cell transplant or who are resistant to interferon-alpha therapy.

In February 2002, just nine months following the initial CML approval, Gleevec received FDA approval for the treatment of patients with Kit (CD 117) positive unresectable (inoperable) and/or metastatic malignant gastrointestinal stromal tumors (GISTs). The effectiveness of Gleevec in GIST is based on the objective response rate. In the pediatric
indication, the original CML indication and in the GIST indication in adults, there are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

Gleevec is approved as Glivec® (imatinib) in the EU, Switzerland and other countries.

Contraindications, Warnings and Adverse Events
The majority of CML patients who received Gleevec in clinical studies experienced adverse events, but they were usually mild or moderate. The most frequently reported adverse events (all grades) regardless of suspected relationship to treatment were superficial edema (53%-71%), nausea (43%-71%), diarrhea (30%-55%), muscle cramps (27%-55%), musculoskeletal pain (34%-46%), rash (32%-44%), and abdominal pain (23%-33%). In most cases, these events were managed without having to reduce the dose of Gleevec or interrupt treatment. Gleevec was discontinued because of adverse events in only 2% of patients in chronic phase, 3% in accelerated phase, and 5% in blast crisis.

Severe (NCI Grades ¾) neutropenia (2%-48%), thrombocytopenia (<1%-33%), hemorrhage (<1%-19%), fluid retention (including severe superficial edema) (<1%-12%), musculoskeletal pain (2%-9%), and hepatotoxicity (<1%-4%) were also reported among Gleevec recipients.

In the GIST trial that was the basis for GIST approval, drug was discontinued for adverse events in six patients (8%). In this clinical trial, the most common adverse events were edema, nausea, diarrhea, abdominal pain, muscle cramps, fatigue and rash. In this trial, seven patients (5%) were reported to have gastrointestinal bleeds and/or intratumoral bleeds. Gastrointestinal tumor sites may have been the source of GI bleeds.

Use of Gleevec is contraindicated in patients with hypersensitivity to imatinib or to any other component of Gleevec.

Women of childbearing potential should be advised to avoid becoming pregnant while taking Gleevec.

Gleevec should be taken with food and a large glass of water to minimize GI irritation.

Dose adjustments may be necessary due to hepatotoxicity, other nonhematologic adverse events, or hematologic adverse events.
Gleevec is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6,
and CYP2C9. Please see full Prescribing Information for potential drug interactions.
Patients should be weighed and monitored regularly for signs and symptoms of edema, which can be serious or life threatening.
Numbers indicate the range in percentages in 4 studies among patients with CML in blast crisis, accelerated phase, and chronic phase.

The foregoing release contains forward-looking statements that can be identified by terminology such as "new approach", "may provide," "greater," "faster," "more rapid," "suggest" or similar expressions, or by discussions regarding potential new indications for Gleevec, or regarding the long-term impact of a patient's use of Gleevec. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results with Gleevec to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Gleevec will be approved for any additional indications in any market. Neither can there be any guarantee regarding the long-term impact of a patient's use of Gleevec. In particular, management's ability to ensure satisfaction of the health authorities' further requirements is not guaranteed and management's expectations regarding commercialization of Gleevec could be affected by, among other things, additional analysis of Gleevec clinical data; new clinical data; unexpected clinical trial results; 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; and other risks and factors referred to in the Company'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.

About Novartis
Novartis Oncology is a business unit within Novartis AG (NYSE: NVS), a world leader in pharmaceuticals and consumer health. In 2002, the Group's businesses achieved sales of USD 20.9 billion and a net income of USD 4.7 billion. The Group invested approximately USD 2.8 billion in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ about 77,200 people and operate in over 140 countries around the world. For further information please consult
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