Healthcare Industry News:  Cytogen 

Biopharmaceuticals Oncology

 News Release - December 11, 2006

Pivotal Submission Data Shows Tasigna(R) Achieved Impressive Response Rates In Chronic Myeloid Leukemia Patients No Longer Helped by Gleevec(R)

New data support US and EU submissions of next-generation targeted therapy offering hope to patients with resistance or intolerance to Gleevec

Tasigna shown to have impressive efficacy and manageable safety profile, with patients intolerant to Gleevec rarely experiencing same side-effects on Tasigna

About one of two patients treated with Tasigna had significantly reduced or no presence of cells with the defective chromosome that causes this blood cancer


EAST HANOVER, N.J., Dec. 11 (HSMN NewsFeed) -- New clinical data presented today demonstrated that Tasigna® (nilotinib) eliminated or significantly reduced the presence of blood cells containing a defective chromosome in approximately half of adult patients with a form of life-threatening leukemia who developed resistance and/or intolerance to treatment with Gleevec® (imatinib mesylate) tablets*.

The reductions achieved in these patients resistant to Gleevec, one of the first oncology drugs developed based on an understanding of how some cancer cells work, may be the highest ever reported with a targeted therapy at a minimum of six months follow-up.

The Phase II data, which forms the basis for US and EU regulatory submissions completed earlier in 2006, showed that the use of Tasigna in patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) reduced or eliminated the presence of this defective chromosome in 51% of Gleevec-resistant patients in chronic phase of this disease and led to normalized white blood cell counts in 74% of these patients.

The study also showed a similar magnitude of elimination or reduction of these defective cells in 55% of intolerant patients. Data from this trial were presented today at the American Society of Hematology annual meeting.

Novartis has filed applications with both the US Food and Drug Administration (FDA) and European Medicines Agency (EMEA) for Tasigna as a therapy for adult patients with chronic or accelerated phase Ph+ CML with intolerance and/or resistance to Gleevec.

Tasigna was developed by Novartis as a next-generation targeted therapy based on the success of Gleevec. Although data from the landmark IRIS trial -- the largest-ever conducted in CML patients -- demonstrated that nearly 90% of chronic-phase Ph+ CML patients taking Gleevec were alive at five years, a small subset of patients develop resistance or cannot tolerate this therapy.

Both Tasigna and Gleevec are designed to inhibit production of cells containing the Philadelphia chromosome by inhibiting the Bcr-Abl protein. Bcr- Abl is recognized as the key cause and driver of the proliferation of white blood cells that characterizes Ph+ CML.

While Tasigna and Gleevec target the same pathways, the strategy behind the Tasigna research program was to design a preferentially Bcr-Abl targeted therapy that would be more potent against Gleevec mutations but avoid the potential side effects of less targeted agents.

"These exciting data demonstrate that Tasigna has the potential to offer a compelling new treatment option for patients with Ph+ CML. Designing Tasigna to be an even more targeted Bcr-Abl inhibitor than Gleevec appears to be providing impressive efficacy results with a manageable safety profile," said David Epstein, CEO and President of Novartis Oncology. "We look forward to further exploring the potential benefits of Tasigna through our broad Phase III clinical trial program in earlier CML settings."

Study details

The open-label Phase II study was designed to evaluate the safety and efficacy, as defined by hematologic (normalization of white blood cell counts) and Cytogenetic (reduction or elimination of the Ph+ chromosome) response rates of Tasigna administered to Gleevec-resistant or intolerant patients with Ph+ CML in chronic phase and accelerated phase. The 316 chronic-phase patients in the Phase II study were heavily pre-treated for Ph+ CML, with a significant majority (72%) having received at least 600 mg of Gleevec as well as having been treated earlier with interferon (65%) and hydroxyurea (83%).

Among 279 assessable patients (i.e., those patients with at least six months of follow up) with chronic-phase disease, major Cytogenetic response was observed in 145 (52%) of which 96 (34%) were complete. Complete hematologic response was reported in 137 (74%) of 185 assessable patients. In patients with at least 10 months follow up, the median time to Cytogenetic response was 2.8 months (range 1 to 11), and the median time to complete hematologic response was 1.0 (range 1 to 8) months.

Among 64 patients with accelerated-phase disease, major Cytogenetic response was observed after at least eight months follow-up in 23 (36%), of which 14 (22%) were complete. Confirmed hematologic response occurred in 38 (59%), of which 15 (23%) were complete. The median time to Cytogenetic response was 2.0 months (range 1 to 8), and the median time to complete hematologic response was 1.0 (range 1 to 3) months.

The Phase II study showed an acceptable tolerability profile with a low incidence of events related to fluid retention such as edema, a side effect common with other tyrosine kinase inhibitors. The most frequent Grade 3 or 4 adverse events were primarily hematological in nature and include neutropenia and thrombocytepenia. Elevations were seen in bilirubin, liver function tests, lipase enzymes and blood sugar, which were mostly transient and resolved over time. These cases were easily managed and rarely led to discontinuation. Pancreatitis was reported in less than 1% of cases.

The study also showed virtually no non-hematologic cross-intolerance between Gleevec and Tasigna. (Cross-intolerance occurs when patients cannot tolerate two different drugs because of the same side effects.) Causes of non- hematologic intolerance to Gleevec, which occurred in 95 patients, included Grade 3 or 4 rash/skin toxicity, fluid retention, gastrointestinal intolerance, liver toxicity, and myalgia/arthralgia. When treated with Tasigna, none of these patients experienced severe rash/skin toxicity, fluid retention or myalgia/arthralgia. One patient each experienced severe gastrointestinal intolerance and liver toxicity.

About Tasigna

Discovered in the biomedical research facilities of Novartis, Tasigna (nilotinib, formerly AMN107) entered Phase I clinical studies in 2004 just 21 months after it was first synthesized in August 2002.

As an investigational compound, the safety and efficacy profile of Tasigna has not yet been established. Access to Tasigna is available only through carefully controlled and monitored clinical trials. These trials are designed to better understand the compound's potential benefits and risks and data has been filed with regulatory authorities.

About Gleevec Tablets

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-including neutropenia (3%-48%), anemia (<1%-42%), thrombocytopenia (<1%-33%), and hepatotoxicity (3%-6%)-and severe adverse experiences (NCI Grades 3/4), including severe fluid retention (eg, pleural effusion, pulmonary edema, and ascites) and superficial edema (1.8%-11%), hemorrhage (1%-19%), and musculoskeletal pain (2%-9%) were reported among Gleevec patients. Severe fluid retention appears to be dose related, was more common in the advanced phase studies (where the dosage was 600 mg/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, papilledema, and gastrointestinal (GI) perforation.

Severe congestive heart failure and left ventricular dysfunction have occasionally been reported. Most of the patients with reported cardiac events have had other co-morbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.

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 5% of patients

Patients with severe hepatic impairment should be treated at a starting dose of 300 mg/day and should be closely monitored.

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

For daily dosing of 800 mg and above, dosing should be accomplished using the 400 mg tablet 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 adult patients who received Gleevec in clinical studies experienced adverse events at some time. Most adverse events were mild to moderate in severity. The most frequently reported adverse events (all Grades) were superficial edema (58%-74%), nausea (47%-73%), muscle cramps (28%-62%), vomiting (21%-58%), diarrhea (39%-57%), musculoskeletal pain (38%-49%), and rash related terms (36%-47%).**+

Supportive care may help management of some mild to moderate adverse events so that the prescribed dose can be maintained whenever possible. However, in some cases either a reduction of dose or interruption of treatment with Gleevec may be necessary.

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

Disclaimer

The foregoing release contains forward-looking statements that can be identified by terminology such as "offering hope," "may be," "strategy," "would be," "potential," "appears to be," "look forward to further exploring," "potential benefits," "designed to," or similar expressions, or by express or implied discussions regarding potential new regulatory approvals for Tasigna or potential future sales of Gleevec or Tasigna, or regarding the long-term impact of a patient's use of Gleevec or Tasigna. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results with Gleevec 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 Tasigna will be approved for any indications in any market. Nor can there be any guarantee regarding potential future sales of Gleevec or Tasigna. Neither can there be any guarantee regarding the long-term impact of a patient's use of Gleevec or Tasigna. In particular, management's expectations regarding Gleevec and Tasigna could be affected by, among other things, unexpected regulatory actions or delays or government regulation generally; unexpected clinical trial results, including additional analysis of clinical data, or new clinical data; competition in general; government, industry, and general public pricing pressures; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; 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.

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 (NYSE: NVS ) -- a world leader in pharmaceuticals and consumer health. In 2005, the Group's businesses achieved sales of USD 32.2 billion and pro forma net income of USD 6.1 billion. The Group invested approximately USD 4.8 billion in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 99,000 people and operate in over 140 countries around the world. For further information please consult http://www.novartis.com.

* Known as Glivec® (imatinib) outside the US, Canada and Israel

** Numbers indicate the range of percentages in 4 studies among adult patients with Ph+ CML in blast crisis, accelerated phase, and chronic phase.

+ For more detailed study information please see full Prescribing Information

(1) Gleevec® (imatinib mesylate) tablets prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2006.


Source: Novartis Pharmaceuticals

Issuer of this News Release is solely responsible for its content.
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