Novartis Pharmaceuticals Corporation Release: More Than 90% Of Patients Taking Gleevec(R) For A Form Of Chronic Myeloid Leukemia (CML) Alive After 4-1/2 Years In Landmark Study

EAST HANOVER, N.J., Dec. 12 /PRNewswire/ -- More than 90% of patients with a form of chronic myeloid leukemia (CML) who are taking Gleevec(R) (imatinib mesylate)* tablets in a landmark clinical trial continue to survive and are free from progressing to advanced disease after four and a half years of treatment. These results were presented today at the 47th Annual Meeting of the American Society of Hematology.

Results from the IRIS study (International Randomized Interferon versus STI571), the largest clinical trial to date for newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase, showed that 90.3% of patients who were initially randomized to take Gleevec were still alive after 54 months.

Moreover, the yearly risk of progressing to advanced disease fell to less than 1% in the fourth year, the lowest rate seen in this Phase III study so far. The results also showed that 100% of patients who achieved a major molecular response to treatment at 12 months -- meaning that their disease was at extremely low levels -- were free of progression to accelerated phase or blast crisis at 54 months.

"After collecting nearly five years of data in this trial and also considering 178,000 patient years of clinical use, we see that the longer CML patients continue to take Gleevec the lower their yearly risk of progressing to accelerated phase or blast crisis," said David Epstein, President of Novartis Oncology. "These results are remarkable because they have been reported in patients taking the recommended starting dose of 400 mg per day. In addition, data from several international studies presented at ASH show that investigational daily doses of Gleevec as high as 800 mg can produce even higher rates of molecular response."

New data from a retrospective comparative analysis based partially on Gleevec data from IRIS, which was also presented at ASH, showed for the first time that Gleevec significantly extended overall survival in newly diagnosed Ph+ CML patients in chronic phase compared with the historical treatment of interferon plus cytarabine (IFN+Ara-C).

Investigators at the Clinical Research Centre of the University Hospital in Poitiers, France, undertook this retrospective historical analysis because a large number of patients in the IRIS study who received IFN+Ara-C were switched to Gleevec early in the study, making it difficult to perform an adequate long-term prospective comparative analysis. At 36 months, the overall survival rate for patients receiving Gleevec as a first-line treatment was 92% compared to 84% for patients receiving first-line IFN+Ara-c. This overall survival benefit was highly statistically significant (p=0.0001).

IRIS study details

The International Randomized Interferon versus STI571 (IRIS) study is an open-label Phase III clinical trial enrolling 1,106 newly diagnosed patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase in 177 centers across 16 countries. There are two arms to the study: one group of patients receiving Gleevec 400 mg per day and another receiving interferon (IFN) 5 MIU M2 per day with Ara-C 20 mg/M2/day for 10 days each month.

At 54 months after randomization, overall estimated survival for patients receiving Gleevec was 90.3% (87%-93%). Estimated responses to first-line drug treatment with Gleevec at 54 months were 98%, 92% and 86% for complete hematologic responses, major cytogenetic responses and complete cytogenetic responses respectively.

Gleevec continued to be generally well tolerated as first-line drug therapy for Ph+ CML at the 54-month follow-up.

About Gleevec

Gleevec (imatinib mesylate) tablets are indicated for the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. Follow-up is limited. Gleevec tablets are 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 (IFN-a) therapy.

Important Safety Information(1)

Severe (NCI Grades 3/4) lab abnormalities (400mg/day; 600mg/day)-including neutropenia (3%-48%), anemia (<1%-42%), thrombocytopenia (<1%-33%), and hepatotoxicity (3%-6%)-and severe adverse experiences (NCI Grades 3/4), including hemorrhage (1%-19%), fluid retention (eg, pleural effusion, pulmonary edema, and ascites), superficial edema (1.8%-11%), and musculoskeletal pain (2%-9%), were reported among Gleevec patients. In CML studies, severe fluid retention appears to be dose related, was more common in the advanced phase studies (where the dosage was 600mg/day), and is more common in the elderly. Patients should be weighed and monitored regularly for signs and symptoms of edema, which can be serious or life-threatening. There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, increased intracranial pressure, and papilledema.

There have been rare reports, including fatalities, of gastrointestinal perforation.

Gleevec safety and efficacy have been demonstrated only in children with Ph+ chronic phase CML with recurrence after stem cell transplantation or resistance to interferon-alpha therapy. There are no data in children under 3 years of age.

Bullous dermatologic reactions (eg, erythema multiforme and Stevens- Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing cases note a resolution or improvement of bullous reaction following dose reduction with or without supportive care.

Dose adjustments may be necessary due to hepatotoxicity, other nonhematologic adverse events, or hematologic adverse events. Therapy with Gleevec was discontinued for adverse events in 3% to 8% of patients.

Gleevec is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Examples of commonly used drugs that may significantly interact with Gleevec include acetaminophen, warfarin, erythromycin, and phenytoin. Dosage of Gleevec tablets should increase by at least 50% and clinical response should be carefully monitored in patients receiving Gleevec tablets with a potent CYP3A4 inducer such as rifampin or phenytoin. (Please see full prescribing information for other potential drug interactions).

For daily dosing of 800mg and above, dosing should be accomplished using the 400mg tablets to reduce exposure to iron.

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

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

Because of the potential for serious adverse reactions in nursing infants, women should be advised to avoid breast-feeding while taking Gleevec tablets.

Common Side Effects(1)

The majority of the approximately 1700 adult patients who received Gleevec in clinical studies experienced adverse events at some time, but most were mild to moderate in severity. The most frequently reported adverse events were superficial edema (58%-76%), nausea (47%-73%), diarrhea (39%-60%), fatigue (30%-48%), abdominal pain (30%-37%), muscle cramps (28%-62%), rash with related terms (26%-47%), vomiting (21%-58%), and musculoskeletal pain (11%- 49%).*

Supportive care may help the management of most mild to moderate adverse events so that the prescribed dose can be maintained whenever possible.

Gleevec tablets should be taken with food and a large glass of water to minimize gastrointestinal (GI) irritation. Gleevec tablets should not be taken with grapefruit juice.

The foregoing release contains forward-looking statements that can be identified by terminology such as "can produce," "over time," "continue to survive," "overall survival," or similar expressions, or by express or implied discussions regarding potential new indications for Gleevec or potential future sales of 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. Nor can there be any guarantee regarding potential future sales of Gleevec. Neither can there be any guarantee regarding the long-term impact of a patient's use of Gleevec. In particular, 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; government, industry, and general public pricing pressures; 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 this information as of this date and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.

For More Information

Information about Gleevec is available at http://www.gleevec.com. Reporters interested in more information regarding Gleevec or Novartis Oncology can visit the Novartis Oncology Virtual Press Office at http://www.novartisoncologyVPO.com. The site features background information on Novartis Oncology products.

About Novartis

Novartis Pharmaceuticals Corporation researches, develops, manufactures and markets leading innovative prescription drugs used to treat a number of diseases and conditions, including central nervous system disorders, organ transplantation, cardiovascular diseases, dermatological diseases, respiratory disorders, cancer and arthritis. The company's mission is to improve people's lives by pioneering novel healthcare solutions.

Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG -- a world leader in pharmaceuticals and consumer health. In 2004, the Group's businesses achieved sales of USD 28.2 billion and pro forma net income of USD 5.6 billion. The Group invested approximately USD 4.1 billion in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 91,700 people and operate in over 140 countries around the world. For further information please consult http://www.novartis.com.

For further information please consult http://www.novartis.com. Media only: Investors only: Kim Fox Jill Pozarek Novartis Oncology Novartis Corporation P: 1-862-778-7692 P: 1-212-830-2445 F: 1-773-781-2074 Dana Kahn Cooper P: 1-732-817-1800 F: 1-732-817-1834 Veronique Boissonnas Ruder Finn P: 1-212-593-6396 F: 1-212-583-2702 * Known as Glivec(R) (imatinib) outside the U.S. * Numbers indicate the range of percentages in 4 studies among adult patients with Ph+ CML. For more detailed study information, please see the full prescribing information for Gleevec. (1) Gleevec(R) (imatinib mesylate) tablets prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2005.

Novartis Pharmaceuticals Corporation

CONTACT: Media: Kim Fox, Novartis Oncology, +1-862-778-7692, F:+1-773-781-2074, or Dana Kahn Cooper, +1-732-817-1800, F: +1-732-817-1834;or Veronique Boissonnas, Ruder Finn, +1-212-593-6396, F: +1-212-583-2702;Investors: Jill Pozarek, Novartis Corporation, +1-212-830-2445

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