Video: Tasigna Demonstrates Rapid Response as Initial Therapy in Life-Threatening Form of Leukemia

EAST HANOVER, N.J., December 08, 2008 /PRNewswire/ --New results from two separate trials demonstrate that Tasigna(R) (nilotinib) 200 mg capsules helps achieve rapid responses when used as initial therapy in newly diagnosed patients with a life threatening form of leukemia. The study results were presented today at the 50th Annual Meeting of the American Society of Hematology.

To view the Multimedia News Release, go to: http://www.prnewswire.com/mnr/novartis/36314/

In both Phase II studies, 96% of patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in early chronic phase achieved a complete cytogenetic response (CCyR) after six months of Tasigna treatment(1,2). CCyR is defined as undetectable Philadelphia chromosome cells in a patient's bone marrow.

Although CCyR remains the primary goal of therapy, achieving major molecular response (MMR) may be a more sensitive predictor of long-term progression-free survival. In the two studies, 74%(2) and 45%(1) of patients treated with Tasigna exhibited MMR after six months. Tasigna was well tolerated in both studies.

"Newly diagnosed patients taking Tasigna experienced remarkable responses with minimal toxicity," said Jorge Cortes, MD, Professor of Medicine and Deputy Chair of Leukemia at the MD Anderson Cancer Center in Houston. "These results indicate there is potential for patients to reach important clinical milestones faster."

Gleevec(R) (imatinib mesylate) tablets* is the standard treatment for Ph+ CML and rapidly transformed the treatment of CML when it was introduced in 2001. An ongoing Phase III trial called ENESTnd (Evaluating Nilotinib Efficacy in Clinical Trials of Newly Diagnosed Ph+ CML Patients) is evaluating Tasigna vs. Gleevec in newly diagnosed patients and is now fully accrued. Data from ENESTnd will be reported once available.

"Building on the wealth of scientific and clinical knowledge we have gained with Gleevec, Novartis strives to continually uncover novel approaches to help Ph+ CML patients achieve the best long-term outcomes," said David Epstein, President and CEO, Novartis Oncology.

Tasigna is a tyrosine kinase inhibitor approved for the treatment of adult Ph+ CML patients in the chronic or accelerated phases who are resistant or intolerant to prior treatment including Gleevec. Tasigna was specifically designed to inhibit Bcr-Abl, the key cause and driver of Ph+ CML and its mutations. The Philadelphia chromosome is found in nearly all patients with CML.

The first study, conducted by the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA), is an ongoing, open-label, single-stage, multicenter Phase II clinical trial, designed to evaluate the therapeutic efficacy and safety of Tasigna 800 mg/day as a first-line treatment. Seventy-three patients with newly diagnosed Ph+ CML in early chronic phase are enrolled in the trial. After six months of treatment, 96% of patients had achieved CCyR(2).

In addition, 74% of patients achieved MMR, defined as Bcr-Abl/Abl ratio < 0.1%. The percentage of patients achieving this level of response rapidly increased after one month of treatment. Adverse reactions were manageable with dose adaptations. The incidence of any Grade 2 and 3 non-hematologic adverse events decreased considerably between months one to three and months four to six(2).

The second study, conducted by researchers at MD Anderson Cancer Center, is an ongoing Phase II clinical trial investigating the efficacy and safety of Tasigna as initial therapy for patients with CML-CP (chronic phase). The current analysis, which includes data from 48 patients, shows that nearly all evaluable patients (96%) achieved CCyR. By six and 12 months, 45% and 52% of patients achieved MMR, respectively. Adverse reactions were manageable with temporary treatment interruptions or dose reductions(1). Notably, there was no marked incidence of severe fluid retention or effusions, side effects commonly observed with other drugs of this class.

Tasigna (nilotinib) capsules is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib. Tasigna has been approved in more than 50 countries. The effectiveness of Tasigna is based on hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival. Please see Important Safety Information, including below.

    WARNING: QT PROLONGATION AND SUDDEN DEATHS

    TASIGNA prolongs the QT interval. Sudden deaths have been reported in
    patients receiving nilotinib. TASIGNA should not be used in patients with
    hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or
    hypomagnesemia must be corrected prior to TASIGNA administration and
    should be periodically monitored. Drugs known to prolong the QT interval
    and strong CYP3A4 inhibitors should be avoided. Patients should avoid food
    2 hours before and 1 hour after taking dose. Use caution in patients with
    hepatic impairment. ECGs should be obtained to monitor the QTc at
    baseline, seven days after initiation, and periodically thereafter, as
    well as following any dose adjustments.

Treatment with Tasigna is associated with Grade 3/4 neutropenia, thrombocytopenia, and anemia. Complete blood counts should be performed every 2 weeks for the first 2 months, then monthly thereafter as clinically indicated. Myelosuppression with Tasigna was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction.

Tasigna prolongs the QT interval. Correct hypokalemia or hypomagnesemia prior to administration and monitor periodically. Avoid drugs known to prolong the QT interval and strong CYP3A4 inhibitors. Use caution in patients with hepatic impairment. Obtain ECGs at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.

There were sudden deaths reported in the safety population and the expanded access program. Ventricular repolarization abnormalities may have contributed to their occurrence.

Caution is recommended in patients with history of pancreatitis. Check serum lipase periodically.

The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Check hepatic function tests periodically.

Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hyponatremia and hypocalcemia. Correct electrolyte abnormalities prior to initiating Tasigna and monitor periodically during therapy.

Metabolism of Tasigna is mainly hepatic. Tasigna has not been investigated in patients with hepatic impairment. Caution is recommended in these patients and QT interval should be monitored closely.

The concomitant use of QT prolonging drugs and strong inhibitors or inducers of CYP3A4 should be avoided as they may affect serum concentration of Tasigna.

The concomitant use of strong CYP3A4 inhibitors should be avoided (including, but not limited to, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval, and a dose reduction to 1/2 the daily dose is recommended (400 mg once daily). If the strong inhibitor is discontinued, a washout period should be allowed before Tasigna is adjusted upward to the indicated dose. Close monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors. Grapefruit products and other foods that are known to inhibit CYP3A4 should also be avoided.

The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital). Patients should also refrain from taking St John's Wort. If patients must be co-administered a strong CYP3A4 inducer, the dose of Tasigna may need to be increased, depending on patient tolerability. If the strong inducer is discontinued, the Tasigna dose should be reduced to the indicated dose. Tasigna is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and UGT1A1. Since warfarin is metabolized by CYP2C9 and CYP3A4, it should be avoided if possible. Tasigna inhibits human P-glycoprotein. If Tasigna is administered with drugs that are substrates of Pgp, increased concentrations of the substrate are likely and caution should be exercised. Tasigna may also induce CYP2B6, CYP2C8, and CYP2C9. Therefore, Tasigna may alter serum concentration of other drugs.

Food increases blood levels of Tasigna. Patients should avoid food 2 hours before and 1 hour after taking dose.

Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency, or of glucose-galactose malabsorption.

Fetal harm can occur when Tasigna is administered to a pregnant woman. Women should be advised not to become pregnant when taking Tasigna.

In chronic phase patients, the most commonly reported adverse reactions (>10%) were rash (33%), pruritus (29%), nausea (31%), fatigue (28%), headache (31%), constipation (21%), diarrhea (22%), and vomiting (21%). The most common ( > 10%) Grade 3/4 adverse reactions were thrombocytopenia (28%), neutropenia (28%), elevated lipase (15%), and hyperglycemia (11%). In accelerated phase patients, the most commonly reported adverse reactions ( > 10%) were rash (28%), pruritus (20%), and constipation (18%). The most common ( > 10%) Grade 3/4 adverse reactions were thrombocytopenia (37%), neutropenia (37%), anemia (23%), and elevated lipase (17%). Other serious adverse reactions included pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, and pyrexia (Grade 3/4: 2%).

Tasigna may need to be temporarily withheld and/or dose reduced for QT prolongation, hematological toxicities that are not related to underlying leukemia, clinically significant moderate or severe nonhematologic toxicities, laboratory abnormalities, or concomitant use of strong CYP3A4 inhibitors. With concomitant use of strong CYP3A4 inducers, the dose of Tasigna may need to be increased, depending on patient tolerability.

Tasigna should not be used during pregnancy. Sexually active female patients should use effective contraception during treatment. Women should not breast feed while taking Tasigna. There are no data to support the use of Tasigna in pediatric patients. Use with caution in patients with hepatic impairment.

Gleevec(R) (imatinib mesylate) tablets are indicated for the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic phase. Follow-up is limited to 5 years. Gleevec is also indicated for patients with Ph+ CML in blast crisis (BC), accelerated phase (AP), or in the chronic phase (CP) after failure of interferon-alpha therapy.

Fetal harm can occur when administered to a pregnant woman; therefore, women of childbearing potential should be advised to not become pregnant while taking Gleevec tablets and to avoid breast-feeding while taking Gleevec tablets because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking Gleevec should use adequate contraception. If the patient does become pregnant while taking Gleevec, the patient should be advised of the potential hazard to the fetus.

Severe (NCI Grades 3/4) lab abnormalities -- including neutropenia (3.6%-48%), anemia (1%-42%), thrombocytopenia ( > 1%-33%), and hepatotoxicity (approx 5%) -- and severe adverse experiences (NCI Grades 3/4), including severe fluid retention (e.g., pleural effusion, pulmonary edema, and ascites) and superficial edema (1.3%-11%), hemorrhage (1.8%-19%), and musculoskeletal pain (2%-9%) were reported among patients receiving Gleevec*. 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.

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.

Dose adjustments may be necessary due to hepatotoxicity, other nonhematologic adverse reactions, or hematologic adverse reactions. Therapy with Gleevec was discontinued for drug-related adverse reactions in 2.4% to 5% of patients. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months).

A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment. Patients with moderate renal impairment (CrCL = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose and increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min). For patients with moderate renal impairment doses greater than 400 mg are not recommended. Gleevec should be used with caution in patients with severe renal impairment.

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, acute respiratory failure, and GI perforation.

Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon re-challenge. Several post marketing reports describe patients able to tolerate the reintroduction of Gleevec at a lower dose with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction.

Consider potential toxicities-specifically liver, kidney, and cardiac toxicity, and immunosuppression from long-term use.

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 ketoconazole, 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.

The majority of adult Ph+ CML patients who received Gleevec in clinical studies experienced adverse reactions at some time, but most were mild to moderate in severity. The most frequently reported adverse reactions (all Grades) were superficial edema (60%-74%), nausea (50%-73%), muscle cramps (28%-62%), vomiting (23%-58%), diarrhea (43%-57%), musculoskeletal pain (38%-49%), and rash and related terms (36%-47%)*+.

Supportive care may help management of some mild-to-moderate adverse reactions so that the prescribed dose can be maintained whenever possible. However, in some cases, either a dose reduction 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 and other foods known to inhibit CYP3A4.

Patients should be informed to take Gleevec exactly as prescribed, not to change their dose or stop taking Gleevec unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose.

*Numbers indicate the range of percentages in 4 studies among adult patients, with newly diagnosed Ph+ CML, patients in blast crisis, accelerated phase, and in the chronic phase after failure of interferon-alpha therapy.

+ For more detailed study information please see full Prescribing Information.

The foregoing release contains forward-looking statements that can be identified by terminology such as "suggesting," "may," "commitment," or similar expressions, or by express or implied discussions regarding potential new indications or labeling for Tasigna, the long-term impact of a patient's use of Tasigna or regarding potential future revenues from Tasigna. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with 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 additional indications or labeling in any market. Nor can there be any guarantee regarding the long-term impact of a patient's use of Tasigna. Neither can there be any guarantee that Tasigna will achieve any particular levels of revenue in the future. In particular, management's expectations regarding Tasigna could be affected by, among other things, unexpected regulatory actions or delays or government regulation generally; unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; 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; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, 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.

Novartis Pharmaceuticals Corporation researches, develops, manufactures and markets leading innovative prescription drugs used to treat a number of diseases and conditions, including those in the cardiovascular, metabolic, cancer, organ transplantation, central nervous system, dermatological, GI and respiratory areas. 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, which provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic pharmaceuticals, preventive vaccines, diagnostic tools and consumer health products. Novartis is the only company with leading positions in these areas. In 2007, the Group's continuing operations (excluding divestments in 2007) achieved net sales of USD 38.1 billion and net income of USD 6.5 billion. Approximately USD 6.4 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 97,000 full-time associates and operate in over 140 countries around the world.

    (1) Cortes J, et al. Efficacy of Nilotinib (AMN107) in Patients (Pts)
     with Newly Diagnosed, Previously Untreated Philadelphia Chromosome
    (Ph)-Positive Chronic Myelogenous Leukemia in Early Chronic Phase
    (CML-CP). Abstract # 446. American Society of Hematology 2008 Annual
    Meeting, San Francisco, CA.

    (2) Rosti G, et al. High and Early Rates of Cytogenetic and Molecular
    Response with Nilotinib 800 Mg Daily as First Line Treatment of
    Ph-Positive Chronic Myeloid Leukemia in Chronic Phase: Results of a Phase
    2 Trial of the GIMEMA CML Working Party. Abstract # 181. American Society
    of Hematology 2008 Annual Meeting, San Francisco, CA.

    (3) Gleevec(R) (imatinib mesylate) tablets prescribing information. East
    Hanover, NJ: Novartis Pharmaceuticals Corporation; Nov 2007.

    *Known as Glivec(R) (imatinib) outside the US, Canada and Israel.
    Media only:
    Kim Fox
    Novartis Oncology
    P: +1 862 778 7692
    Dana Kahn Cooper
    P: +1 732 817 1800
    C: +1 732 239 6664

    Investors only:
    Richard Jarvis
    Novartis Corporation
    P: +1 212 830 2433

Posted: December 2008

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