Zometa® reduces risk of breast cancer recurrence in premenopausal women, study in The New England Journal of Medicine reports

Zometa® reduces risk of breast cancer recurrence in premenopausal women, study in The New England Journal of Medicine reports

Adding Zometa to post-surgery hormone therapy reduced risk of breast cancer return or death by 36% more than hormone therapy alone

First Phase III data to substantiate anticancer effect of Zometa
Zometa is the most widely prescribed drug for prevention of bone complications due to bone metastases, with more than 2.7 million patients treated worldwide

East Hanover, N.J., February 11, 2009 /PRNewswire/ – A newly published study in The New England Journal of Medicine shows that in premenopausal women with early breast cancer administering Zometa® (zoledronic acid) along with post-surgery hormone therapy provided a reduction in risk of recurrence or death that was 36% beyond that achieved with hormone therapy alone1.

The study, from the Austrian Breast & Colorectal Cancer Study Group (ABCSG), is the first large, randomized, Phase III clinical trial to show that Zometa offers significant protection against the return of early breast cancer in premenopausal women. Prior laboratory research suggested that Zometa might have direct anticancer effects, including helping to protect against the return and spread of cancer before it reaches an advanced stage2.

"The possible return of breast cancer is a major concern among women who've undergone surgery to remove their tumors. We anticipate that this publication in The New England Journal of Medicine will provide oncologists with evidence regarding an additional treatment regimen to further help reduce the risk of breast cancer recurrence, or even death, for premenopausal women with hormone-sensitive breast cancer," said lead investigator Michael Gnant, MD, of the Medical University of Vienna.

"It is encouraging to see a significant reduction in risk of recurrence in these patients from a therapy that was also well-tolerated," said David Epstein, President and CEO of Novartis Oncology. "The findings of this landmark trial substantiate the strong anticancer effect of Zometa beyond the well-established benefit of this treatment in preventing bone complications in advanced cancers."

The ABCSG Trial 12 (ABCSG-12) included more than 1,800 premenopausal women with early-stage breast cancer who, following curative surgery and goserelin treatment to suppress the ovaries, were treated with hormone therapy with or without Zometa for three years. The results demonstrated that the addition of Zometa to hormone therapy (tamoxifen or anastrozole) significantly prolonged both disease-free survival and recurrence-free survival.

Study details
ABCSG-12 is an open-label, multicenter, Phase III study that enrolled 1,803 premenopausal women with estrogen receptor-positive Stage I or II breast cancer, with fewer than 10 axillary lymph nodes involved. Patients were recruited for the study after curative surgery and initiation of goserelin treatment for ovarian suppression, and randomly assigned into one of four study groups: (1) anastrozole plus Zometa; (2) anastrozole alone; (3) tamoxifen plus Zometa; (4) tamoxifen alone. The treatment period was three years and the median follow-up period was 48 months1.

The primary endpoint for all four study arms was disease-free survival. Recurrence-free survival, overall survival and bone-mineral density were secondary endpoints. Disease-free survival was defined as the length of time after randomization during which patients had no local recurrence, contralateral breast cancer, distant metastasis, secondary carcinoma and/or death from any cause. Recurrence-free survival was defined as the length of time after randomization during which patients had no local recurrence, contralateral breast cancer, distant metastasis and/or secondary carcinoma. Exploratory endpoints included bone metastasis-free survival1.

At the median follow-up of 48 months, disease-free survival events were reduced by 36% (P=0.01) and the risk of recurrence-free survival events fell by 35% (P=0.02) with Zometa added to hormone therapy versus hormone therapy alone. Sixteen deaths had occurred among patients who received Zometa with hormone therapy versus 26 deaths in patients who received hormone therapy alone, which resulted in a non-significant reduction in the risk of death in patients who received Zometa compared with those who received hormone therapy alone (P=0.11). A similar trend was noted toward a reduction in bone metastases among patients who received Zometa compared with those who received hormone therapy alone (P=0.22). Longer follow-up and a larger number of events will be necessary to determine if any significant differences exist between the groups for overall survival and bone metastasis-free survival. Overall, treatment was generally well-tolerated and side effects were consistent with known drug safety profile1.

About Zometa
Zometa is indicated for patients with multiple myeloma and documented bone metastases from solid tumors in conjunction with standard antineoplastic therapy; prostate cancer should have progressed after treatment with at least one hormonal therapy.

Important safety information
Zometa is contraindicated in patients with hypersensitivity to zoledronic acid or other bisphosphonates, or any of the excipients in the formulation of Zometa. Hypersensitivity reactions, including rare cases of urticaria and angioedema and very rare cases of anaphylactic reaction/shock, have been reported.

Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of Zometa should not exceed 4 mg, and the duration of infusion should be no less than 15 minutes. Risk factors for the deterioration of renal function include impaired baseline renal function and multiple cycles of bisphosphonate treatment.

Zometa is not recommended in patients with bone metastases with severe renal impairment. In patients with mild to moderate renal impairment at baseline, lower doses of Zometa are recommended based on calculated creatinine clearance. Before each Zometa dose, serum creatinine should be measured and treatment should be withheld for renal deterioration until serum creatinine has returned to within 10% of the baseline value.

Zometa should not be used during pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.

Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids, which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma) and dental status (dental extraction, periodontal disease, local trauma, including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection, including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures, if possible. No data are available as to whether discontinuation of bisphosphonate therapy reduces the risk of ONJ in patients requiring dental procedures. A causal relationship between bisphosphonate use and ONJ has not been established. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

In postmarketing experience, severe and occasionally incapacitating bone, joint and/or muscle pain has been reported infrequently in patients taking bisphosphonates.

The most common adverse events (≥15%) in bone metastases clinical trials, regardless of causality, with Zometa 4 mg (n=1031) were as follows: bone pain (55%), nausea (46%), fatigue (39%), anemia (33%), pyrexia (32%), vomiting (32%), constipation (31%), dyspnea (27%), diarrhea (24%), weakness (24%), myalgia (23%), anorexia (22%), cough (22%), arthralgia (21%), lower-limb edema (21%), malignant neoplasm aggravated (20%), headache (19%), dizziness (excluding vertigo) (18%), insomnia (16%), decreased weight (16%), back pain (15%) and paresthesia (15%).

Caution is advised when bisphosphonates are administered with aminoglycosides, loop diuretics and potentially nephrotoxic drugs.

Zometa contains the same active ingredient as found in Reclast® (zoledronic acid). Patients being treated with Zometa should not be treated with Reclast.

Patients should be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily.

Please see full Prescribing Information.

Disclaimer
The foregoing release contains forward-looking statements that can be identified by terminology such as "anticipate," "will," "might," "encouraging," "may" or similar expressions, or by express or implied discussions regarding potential new indications or labeling for Zometa or regarding potential future revenues from Zometa. 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 Zometa to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Zometa will be approved for any additional indications or labeling in any market. Nor can there be any guarantee that Zometa will achieve any particular levels of revenue in the future. In particular, management’s expectations regarding Zometa 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.

About Novartis Pharmaceuticals Corporation
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, preventive vaccines, diagnostic tools, cost-saving generic pharmaceuticals and consumer health products. Novartis is the only company with leading positions in these areas. In 2008, the Group’s continuing operations achieved net sales of USD 41.5 billion and net income of USD 8.2 billion. Approximately USD 7.2 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 96,700 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.novartis.com.

For more information
Additional information regarding Zometa and Novartis Oncology can be found on the websites http://www.novartisoncologyvpo.com/zometa, www.us.zometa.com and www.us.novartisoncology.com.

References
1. Gnant, M. et al. Adjuvant Endocrine Therapy Plus Zoledronic Acid in Premenopausal Women With Early Breast Cancer: First Efficacy Results from ABCSG-12. N Engl J Med. 2009 Feb 12; 360.

2. Mundy, GR, et al. Metastases to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002;2:584-593.

Contact Information
Media Only:
Megan Humphrey
Novartis Oncology
P: +1 862 778 6724
Dana Kahn Cooper
P: +1 732 817 1800
C: +1 732 239 6664
Investors Only:
Jill Pozarek
Novartis Corporation
P: +1 212 830 2445