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Femara Granted FDA Priority Review for New Indication as Adjuvant Treatment for Postmenopausal Women with Early Breast Cancer

EAST HANOVER, N.J., August 29, 2005 -- Novartis announced today that the US Food and Drug Administration has granted priority review to Femara (letrozole tablets) in the adjuvant (post-surgery) treatment of postmenopausal women with hormone receptor-positive early breast cancer.

The FDA grants priority review to products that could potentially offer a significant improvement compared to marketed products in the treatment, diagnosis or prevention of a disease. Novartis asked for consideration for priority review based on enhanced efficacy in high risk subgroups for which existing therapies have not demonstrated benefit. Specifically, Femara showed significantly improved efficacy compared with tamoxifen in women with node-positive disease and those who received chemotherapy treatment. Femara also demonstrated a significantly reduced risk of distant metastases compared with tamoxifen.

If approved for this new indication, Femara will become the only breast cancer treatment approved in the US to significantly reduce the risk of recurrence for both the adjuvant setting and in extended adjuvant treatment following standard tamoxifen therapy. The supplemental new drug application for use of Femara in the adjuvant setting was submitted in June 2005. Novartis has submitted marketing applications for this indication globally.

"This priority review acknowledges the potential for Femara to represent a significant advance in treating postmenopausal women with early breast cancer immediately following surgery," said Diane Young, MD, vice president, global head, Clinical Development, Novartis Oncology.

The FDA submission is based on data from the Breast International Group (BIG) 1-98 study, a Phase III, randomized, double-blind study that compared the safety and efficacy of adjuvant Femara vs. tamoxifen in more than 8,000 postmenopausal women with hormone receptor-positive early breast cancer.

The overall results of BIG 1-98 demonstrated that at a median follow-up of 26 months, Femara prolonged disease-free survival by reducing risk of recurrence by an additional 21% (p=0.002) over the reduction offered by tamoxifen. Women who were treated with Femara experienced a 27% reduction in the risk that their cancer would spread to other parts of the body (distant metastases) compared with tamoxifen (p=0.001), a clinically relevant finding since women who develop distant metastases may be at greater risk of dying from their disease. Femara also provided a 14% reduction in the risk of death, although this did not reach statistical significance (p=0.155).

In two separate pre-planned subset analyses, Femara also reduced the risk of cancer returning by 29% among patients whose initial cancer had already spread to the lymph nodes at the time of diagnosis (node-positive breast cancer) and by 30% in those who had received chemotherapy, two groups that are at increased risk of recurrence. Additionally, in node-positive patients and in patients who received adjuvant chemotherapy, the risk of distant metastases was reduced by more than 30% with Femara compared to tamoxifen.

About BIG 1-98

BIG 1-98 is the only clinical trial designed to incorporate both a head-to-head comparison of Femara with tamoxifen during the first five years following breast cancer surgery and a sequencing of both agents to determine the most effective approach to minimizing the risk of recurrence. Patients were randomized to the following arms: tamoxifen for five years, Femara for five years, tamoxifen for two years followed by Femara for three years, and Femara for two years followed by tamoxifen for three years. BIG 1-98 was conducted by the International Breast Cancer Study Group (IBCSG) with many independent centers and was supported by Novartis.

The adverse events in the BIG 1-98 study were consistent with published data on both Femara and tamoxifen. In the BIG 1-98 study, the two treatments were generally well tolerated and the safety profile in the two treatment arms overall was similar. Arthralgia/arthritis, bone fractures and osteoporosis were significantly more common with Femara treatment than with tamoxifen. Hot flashes/flushes, night sweats, vaginal bleeding, thromboembolic events and endometrial proliferative disorders were significantly more frequent in the tamoxifen arm.

Overall, more deaths were reported on tamoxifen (n=192) than on Femara (n=166). More patients on tamoxifen (n=154) than on Femara (n=111) died after a recurrence from cancer- and non-cancer-related causes. In patients whose breast cancer did not recur, more deaths due to cardiac causes were reported in the Femara arm than in the tamoxifen arm. In the trial, the number of all cardiovascular events was overall lower in the Femara arm than in the tamoxifen arm (9.7% vs. 10.5%). Irrespective of causality, the following adverse events occurred in both the Femara and tamoxifen groups: thromboembolic events, angina pectoris, myocardial infarction and cardiac failure. In the tamoxifen arm, there was a modest median decrease from baseline of 10-15% over 5 years in total serum cholesterol, compared with no change (0-7% median decrease) in the Femara arm.

The frequency of bone fractures and osteoporosis on both treatments was low, but the numbers were higher in the Femara arm (fractures: 5.7%; osteoporosis 2.0%) compared to tamoxifen (fractures 4.0%; osteoporosis: 1.1%). Endometrial proliferative disorders were reported more often for tamoxifen (1.8%) than for Femara (0.3%).

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Posted: August 2005