Superior Phase III trial results with Tasigna* bring new hope to patients
with early-stage chronic myeloid leukemia

(Pr)Tasigna* surpassed gold standard in all designated measures of efficacy, including prevention of disease progression at 12 months(1)

DORVAL, QC, Dec. 10 /CNW/ - In a large Phase III clinical trial, Tasigna* (nilotinib capsules) demonstrated greater efficacy over Gleevec* (imatinib) in the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The new clinical data were just presented as a late breaking abstract at the 51st annual meeting of the American Society of Hematology (ASH), in New Orleans , Louisiana.

CML is one of the four most common types of leukemia. It is caused by an abnormal chromosome, called the Philadelphia (Ph) chromosome which produces an abnormal cancer protein called Bcr-Abl, which is responsible for blocking the normal signal that tells the body to stop producing white blood cells. As a result, CML patients have a significantly elevated cancerous white blood cell count. A form of blood cancer, CML is estimated to affect approximately 3,000 Canadians.(2)

Without treatment, CML typically progresses over three to five years from the initial (chronic) phase through a transition period (accelerated phase) to a rapidly fatal form (blast crisis).(3)

At 12 months, the randomized, open-label, clinical trial (which included Canadian sites) named Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+ CML Patients (ENESTnd), found that significantly fewer patients progressed to the accelerated or blastic phases on Tasigna* 300 mg twice daily than on Gleevec* 400 mg once daily (2 patients vs. 11 patients)(1), demonstrating a statistically significant improvement in disease control. Gleevec* tablets are the established treatment standard.

In the first head-to-head comparison of two oral therapies as initial treatment for this blood cancer, Tasigna* results showed statistically significant improvement over Gleevec* in every measure of efficacy, including major molecular response (MMR) (reduction in the level of the abnormal Bcr-Abl protein, to less than or equal to 0.1% of the pre-treatment level based on an internationally agreed standard)(1), complete cytogenetic response (CCyR - where no CML cells containing the Ph chromosome can be seen in a sample of bone marrow), and prevention of progression to the accelerated or blast crisis phases.(1)

With Tasigna* 300 mg twice daily, the rate of MMR at 12 months was twice that of patients receiving Gleevec* 400 mg once daily (44% vs. 22%, p (less than) 0.0001).(1) In addition, 80% of patients achieved CCyR with Tasigna* vs. 65% with Gleevec* 400 mg once daily (p (less than) 0.0001).(1) All types of responses were achieved faster in the Tasigna* group than in the Gleevec* group.(1)

"The strong response rates observed with Tasigna, combined with the very low rate of disease progression, indicate that patients who begin their treatment with Tasigna may have long-term improvement of progression-free survival," said Dr. Jeffrey Lipton , a haematological oncologist with Princess Margaret Hospital in Toronto , Ontario. "With Gleevec, the majority of chronic phase patients run into problems with disease progression early and the tolerability of Tasigna should support its use in newly diagnosed Ph+ CML patients," said Dr. Lipton .

Study details

ENESTnd was conducted at 220 global sites (including Canada ), with 846 patients enrolled. Patients were randomized to receive Tasigna* 400 mg twice daily (n = 281), Tasigna* 300 mg twice daily (n = 282) or Gleevec* 400 mg once daily (n = 283). The primary endpoint was MMR at 12 months. The trial's secondary endpoints included CCyR, as well as progression to accelerated or blastic phase, and overall survival. Planned follow-up is for five years.(4) Patients on the Gleevec* treatment arm who had suboptimal response or treatment failure were able to escalate dose and/or switch to Tasigna* via a protocol extension.

The estimated rate of progression to accelerated phase or blast crisis at 12 months was (less than)1% in both the Tasigna* groups (P=0.0095 for 300 mg bid, P=0.0037 for 400 mg bid) compared with 4% in the Gleevec* group.

Tasigna* was well tolerated in the study. Fewer patients discontinued due to adverse events from the Tasigna* 300 mg twice daily arm of the study compared to the Gleevec* 400 mg once daily arm. No patients in the study had prolongation of QT interval (greater than)500 milliseconds.(1) No sudden deaths occurred with either treatment.(1)

About Ph+ CML

CML is a slowly progressing cancer of the blood and bone marrow. It is characterized by an overproduction of white blood cells which do not mature, ultimately cannot carry out their intended function and crowd out the healthy cells. CML is distinguished from the other types of leukemia by a genetic abnormality in the white blood cells called the Philadelphia chromosome which promotes the growth of leukemia cells and seems to be present in nearly 90% of CML cases.

About Tasigna*

Tasigna* is a potent and highly selective inhibitor of the Bcr-Abl (a protein called oncoprotein) which causes CML. Currently, Tasigna* is approved for the treatment of accelerated-phase (AP) Ph+ CML in adult patients who are resistant or intolerant of at least one prior treatment that included Gleevec*. Novartis has submitted the chronic-phase (CP) indication for Tasigna* to Health Canada and the file is currently under review. Additionally, in light of this positive data, Novartis will be submitting for an indication in newly diagnosed CML CP.

Tasigna* important safety information(5)

Because taking Tasigna* with food may increase the amount of drug in the blood, Tasigna* should not be taken with food and patients should wait at least two hours after a meal before taking Tasigna*. In addition, no food should be consumed for at least one hour after the dose is taken.

Tasigna* may prolong the QT interval. Uncommon cases of sudden deaths have been reported in patients receiving Tasigna*. Ventricular repolarization abnormalities may have been contributory factors. Tasigna* should be used with caution in patients with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.

Tasigna* should not be used in patients with hypokalemia (low potassium levels), hypomagnesemia (low magnesium levels), 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. Tasigna* should be used with caution and careful clinical monitoring (including close monitoring of the QTc interval) in patients with hepatic impairment.

About Gleevec*

Gleevec* is approved in more than 90 countries. In Canada , a conditional marketing authorization has been issued for Gleevec* for adult and pediatric patients with newly diagnosed, Philadelphia-chromosome-positive, chronic myeloid leukemia in chronic phase and in adult patients with unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST). These authorizations are conditional upon confirmation of clinical benefit. Patients should be advised of the conditional nature of the authorization for Gleevec*.

In Canada , non-conditional approval has been issued for Gleevec* for the treatment of adult patients with Philadelphia chromosome-positive CML in blast crisis, accelerated phase or chronic phase (after failure of interferon-alpha therapy), for use as a single agent for induction phase therapy in adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) and adult patients with relapsed or refractory Ph+ ALL as monotherapy. Gleevec* has also been issued a non-conditional approval for the treatment of adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements, the treatment of adult patients with aggressive sub-types of systemic mastocytosis (ASM and SM-AHNMD) without the D816V c-Kit mutation. If c-Kit mutational status in patients with ASM or SM-AHNMD is not known or unavailable, treatment with Gleevec* may be considered if there is no satisfactory response to other therapies. Gleevec* is also approved for the treatment of adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) with FIP1L1-PDGFRa rearrangement, and the treatment of adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP).

The effectiveness of Gleevec* is based on overall hematological and cytogenetic response rates and progression-free survival in CML, on hematological and cytogenetic response rates in Ph+ ALL and MDS/MPD, on hematological response rates in ASM or SM-AHNMD, on hematological and cytogenetic response rates in HES/CEL, on objective response rates in DFSP and in unresectable and/or metastatic GIST.

Not all indications are available in every country.

Gleevec* important safety information(6)

The majority of patients treated with Gleevec* in clinical trials experienced adverse events at some time. Most events were of mild to moderate grade and treatment discontinuation was not necessary in the majority of cases. The safety profile of Gleevec* was similar in all approved indications. The most common side effects included nausea, superficial edema, fluid retention, muscle cramps, skin rash, vomiting, diarrhea, abdominal pain, myalgia, hemorrhage, fatigue, headache, joint pain, as well as neutropenia, thrombocytopenia and anemia. Patients known 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.

Rare/serious adverse reactions include: sepsis, pneumonia, depression, convulsions, cardiac failure, thrombosis/embolism, ileus, pancreatitis, hepatic failure, exfoliative dermatitis, angioedema, Stevens-Johnson syndrome, renal failure, fluid retention, edema (including brain, eye, pericardium, abdomen and lung), hemorrhage (including brain, eye, kidney and gastrointestinal tract), diverticulitis, gastrointestinal perforation, tumour hemorrhage/ necrosis, hip osteonecrosis/avascular necrosis, rhabdomyolysis.

Gleevec* is contraindicated in patients with known hypersensitivity to imatinib or any of its excipients. Women of childbearing potential should be advised to avoid becoming pregnant while taking Gleevec*.

Disclaimer

The foregoing press release contains forward-looking statements that can be identified by forward-looking terminology, such as "to file", "may", "should", "potential", "promise", "plans", "will", or similar expressions, or by express or implied discussions regarding potential new indications or labelling for Tasigna* or regarding potential future revenues from Tasigna* or Gleevec*. 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* or Gleevec* 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 that Tasigna* or Gleevec* will achieve any particular levels of revenue in the future. In particular, management's expectations regarding Tasigna* and Gleevec* 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; 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.

About Novartis Pharmaceuticals Canada

Novartis Pharmaceuticals Canada Inc., a leader in the healthcare field, is committed to the discovery, development and marketing of innovative products to improve the well-being of all Canadians. Novartis Pharmaceuticals Canada Inc. conducts hundreds of clinical trials across the country seeking new treatments for cardiovascular disease, oncology, diabetes, cancer, ophthalmology and organ transplantation. In 2008, the Company invested close to $96 million in research and development. Novartis Pharmaceuticals Canada Inc. employs more than 750 people in Canada and its headquarters are located in Dorval, Québec. In addition to Novartis Pharmaceuticals Canada Inc., the Novartis Group in Canada consists of Novartis Animal Health Canada Inc., Novartis Consumer Health Canada Inc., CIBA Vision Canada Inc. and Sandoz Canada Inc. For further information about Novartis Canada , please consult www.novartis.ca.

References

    
    1.  Saglio G, Kim DW, Issaragrisil S, Philipp le Coutre, et al. Nilotinib
        Demonstrates Superior Efficacy Compared with Imatinib in Patients
        with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase:
        Results from the International Randomized Phase III ENESTnd Trial.
        Abstract No.LBA-1. American Society of Hematology 2009 Annual
        Meeting.
    2.  CML Society of Canada: Understanding CML -
        http://www.cmlsociety.org/?q=node/14. Accessed November
        25, 2009.
    3.  Hematologica 2008; 93(s1): 47 Abstract 0118
    4.  Novartis data on file.
    5.  Tasigna* Product Monograph. Accessed December 1, 2009.
    6.  Gleevec* Product Monograph. Accessed December 1, 2009.
    

For further information: Stephanie Yack, Cohn & Wolfe, [phone], ext. 4043, [email protected]; Lise Huneault, Novartis Pharmaceuticals Canada Inc., [phone], ext. 1203, [email protected]