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Complete results presented at ASH.

Novartis Tasigna(R) Trial Shows Superior Results to Gleevec(R) in Patients With Early-Stage

http://www.forbes.com/feeds/prnewswire/2009/12/08/prnewswire200912080915PR_NEWS_USPR_____NY22511.html

EAST HANOVER, N.J., Dec. 8 /PRNewswire/ -- In a large Phase III clinical trial, Tasigna® (nilotinib) 200 mg capsules demonstrated greater efficacy over Gleevec® (imatinib mesylate) tablets* in the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase(1).

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In the first head-to-head comparison of these two oral therapies as initial treatment for this life-threatening blood cancer, Tasigna results showed statistically significant improvement over Gleevec in every measure of efficacy, including major molecular response (MMR), complete cytogenetic response (CCyR) and prevention of progression to accelerated or blastic phase(1). The new data were presented as a late breaker abstract at the 51st annual meeting of the American Society of Hematology (ASH), held in December, in New Orleans, USA.

At 12 months, significantly fewer patients progressed to accelerated or blastic phase 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(1). In the study, Tasigna was well tolerated. 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 >500 milliseconds(1). No sudden deaths occurred with either treatment(2).

"The outstanding rates of response observed with Tasigna, combined with the very low rate of disease progression, strongly indicate that patients who begin their treatment with Tasigna may have long-term improvement of progression-free survival," said Giuseppe Saglio, University of Turin, San Luigi Hospital, Orbassano-Torino, Italy, a member of the study management committee. "The efficacy results and tolerability of Tasigna should support its use in newly diagnosed Ph+ CML patients."
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 < 0.0001)(1). In addition, 80% of patients achieved CCyR with Tasigna versus 65% with Gleevec 400 mg once daily (p < 0.0001)(1). Responses were achieved faster in the Tasigna group than in the Gleevec group(1).

MMR was defined in the study as 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). This can be interpreted to mean that for every 1,000 cells containing Bcr-Abl that were present in the blood at the start of therapy, only one cell was present at the 12-month follow-up. CCyR indicates that no CML cells containing the diagnostic Ph chromosome can be seen in a sample of bone marrow taken from the patient.

"Novartis is pioneering research targeting the molecular origin of Ph+ CML, which has led to treatments of unprecedented effectiveness and safety," said David Epstein, President and CEO of Novartis Oncology and Novartis Molecular Diagnostics. "Considering the already low rates of progression to advanced disease and the excellent long-term survival of patients on Gleevec, the efficacy and safety profile of Tasigna at 12 months is fantastic news and brings promise for further improving the outcomes of patients with Ph+ CML."

Tasigna is a potent and selective inhibitor of the Bcr-Abl protein that causes production of cancer cells in Ph+ CML(2,3). Upon initial reports of resistance in the Gleevec registration trials, Novartis scientists created a new molecule, Tasigna, just a year after the launch of Gleevec. The first clinical trials began just 21 months after discovery. The drug received its first regulatory approval in the second-line indication in 2007.

Novartis plans to file worldwide applications for approval of Tasigna as a treatment for adult patients with newly diagnosed Ph+ CML. Tasigna is currently approved in more than 80 countries including the European Union, United States and other countries for the treatment of adult patients with Ph+ CML in chronic phase or accelerated phase who are resistant or intolerant to prior treatment including Gleevec.

Study details

The clinical trial, Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+ CML Patients (ENESTnd), is a Phase III randomized, open-label, multicenter trial comparing the efficacy and safety of Tasigna versus Gleevec in adult patients with newly diagnosed Ph+ CML in chronic phase(1). It is the largest global randomized comparison of two oral therapies ever conducted in newly diagnosed Ph+ CML patients. Designed to detect a difference in MMR between Tasigna and Gleevec after 12 months of treatment, it is also the first registration study in which molecular traces of a key biomarker specific to Ph+ CML have been used as a primary endpoint for regulatory review. The trial's secondary endpoints included CCyR, as well as progression to accelerated or blastic phase, and overall survival.

ENESTnd is being conducted at 220 global sites 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; a secondary endpoint was CCyR by 12 months(1). Planned follow-up is for five years(2). Patients on the Gleevec treatment arm who had suboptimal response or treatment failure will be able to escalate dose and/or switch to Tasigna via a protocol extension.

Samples for molecular response were evaluated by a single reference laboratory. The blood test used to determine molecular response can detect a single cell containing traces of Bcr-Abl in up to one million normal blood cells(4). In addition to being simpler and less invasive for patients, the test has a much greater sensitivity than standard cytogenetic tests, which require a sample of bone marrow to be drawn for visual detection of cells containing the Ph chromosome(5).

All patients had a minimum of 12 months of treatment or discontinued early; the median follow-up was 14 months. Overall, 84%, 82% and 79% of patients remained in the study on Tasigna 300 mg twice daily, Tasigna 400 mg twice daily and Gleevec 400 mg once daily, respectively.

Rates of MMR at 12 months were statistically higher for patients in the Tasigna 300 mg twice daily group compared with Gleevec 400 mg once daily (44% vs. 22%, p < 0.0001) and also for Tasigna 400 mg twice daily compared with Gleevec 400 mg once daily (43% vs. 22%, p < 0.0001). Among patients who achieved MMR, median time to MMR was faster for Tasigna 300 mg twice daily (5.7 months) and Tasigna 400 mg twice daily (5.8 months) compared with Gleevec 400 mg once daily (8.3 months). Molecular response was assessed by polymerase chain reaction (PCR) at baseline, monthly for three months, and every three months thereafter.

Rates of CCyR by 12 months were significantly higher for Tasigna at 300 mg twice daily compared with Gleevec 400 mg once daily (80% vs. 65%, p < 0.0001) and for Tasigna 400 mg twice daily compared with Gleevec 400 mg once daily (78% vs. 65%, p = 0.0005). Overall, progression to advanced disease was lower for Tasigna 300 mg twice daily (2 patients) and Tasigna 400 mg twice daily (1 patient) compared with Gleevec 400 mg once daily (11 patients).

Both Tasigna and Gleevec were well tolerated overall. Rates of discontinuation due to adverse events or laboratory abnormalities were 7% for Tasigna 300 mg twice daily, 11% for Tasigna 400 mg twice daily, and 9% for Gleevec 400 mg once daily.

About Ph+ CML ...snip