CST New Data Show Zometa Enhances Impact of Chemotherapy on Reducing Breast Tumor Size

 • Adding Zometa to chemotherapy prior to surgery led to an additional 33% reduction in tumor size, resulting in fewer mastectomies

 • New data are first to demonstrate direct effect of Zometa to help shrink primary tumors; further evidence of Zometa as a potential anticancer therapy

EAST HANOVER, N.J., December 11, 2008 — New data released today demonstrate that the addition of Zometa® (zoledronic acid) injection to standard chemotherapy before breast cancer surgery reduces the size of breast tumors more effectively than chemotherapy alone in women with early-stage disease.

These neo-adjuvant subset results from the retrospective exploratory analysis of the international AZURE (Adjuvant Zoledronic acid to redUce REcurrence) trial are the first to show the direct effect of Zometa in combination with chemotherapy to help shrink cancerous breast tumors, potentially resulting in less radical surgery for some women. The data were presented at the 31st Annual CTRC-AACR San Antonio Breast Cancer Symposium.

“These results support a potential anti-tumor benefit of combining Zometa with chemotherapy in the neoadjuvant treatment of breast cancer,” said Matthew Winter, MBChB MSc, Clinical Research Fellow, University of Sheffield, UK, a lead investigator of this subset analysis. “Adding Zometa to chemotherapy prior to surgery increased tumor shrinkage in this analysis. When breast cancer treatment is given prior to surgery, the goal is to reduce the size of the tumor and in doing so potentially improve breast conservation rates and longer-term outcomes.”

In the analysis, pre- and postmenopausal women who received Zometa in addition to chemotherapy before surgery (neo-adjuvant use) experienced a significant 33% reduction in the size of their primary tumor (14.1 mm reduction in tumor size) compared with patients who received chemotherapy alone (P=0.002)(1). The proportion of patients requiring mastectomy was higher (77.9%) in the chemotherapy-alone group than in the Zometa group (65.3%).

“Clinical evidence continues to demonstrate that Zometa may play a role in protecting patients from the return and spread of early-stage breast cancer,” said David Epstein, President and CEO, Novartis Oncology. “We are encouraged by these latest results, which show Zometa may help some women avoid mastectomies, and we remain committed to further exploring the benefit of Zometa as an anticancer treatment.”

Zometa is the world’s leading treatment to reduce or delay bone complications in patients with advanced cancer that has spread to the bones across a broad range of solid tumors, including breast cancer.

The potential anticancer properties of Zometa were previously observed in premenopausal women with early-stage breast cancer from the Austrian Breast & Colorectal Cancer Study Group-12 (ABCSG-12) study, which was presented at the American Society of Clinical Oncology annual meeting (ASCO) earlier this year. Final results from the AZURE trial are expected in the next two to three years.

Novartis is further exploring the anticancer effect of Zometa in a broad clinical program in breast, lung and prostate cancers with the results expected over the next two to three years. Laboratory research has suggested that Zometa may help protect patients with early-stage breast cancer from the return or spread of the cancer to other parts of the body (distant metastatic sites) through several different pathways, including inhibiting angiogenesis (formation of blood vessels that grow and feed cancer cells), stimulating cancer-fighting Tcells, inducing tumor cell apoptosis (programmed cell death) and increasing the activity of anticancer agents that target tumor cell metastases(2).

Study details
AZURE is a randomized, open-label, multicenter, parallel group trial with a five-year treatment phase and a subsequent five-year follow-up phase designed to determine whether Zometa, added to standard therapy (chemotherapy and/or hormonal therapy) before (neoadjuvant) or after (adjuvant) surgery, is superior to each therapy alone in improving diseasefree survival in pre- and post-menopausal women with early-stage breast cancer. The trial includes 3,360 patients from 174 centers in seven countries and is coordinated by the Cancer Research Centre, Weston Park Hospital, Sheffield, England with support from Novartis(1).

The neo-adjuvant subset in the current analysis included 205 participants who received either chemotherapy alone or in combination with Zometa once every three to four weeks for six months prior to breast cancer surgery. Following adjustment for other prognostic factors, the adjusted mean tumor size after treatment was 28.2 millimeters in the Zometa group and 42.4 millimeters in the chemotherapy group, a significant reduction of 33%(1). The pathologic complete response rate (no evidence of residual cancer in the breast or lymph nodes) increased to 10.9% in the Zometa group from 5.8% in the chemotherapy group (P=0.033). The proportion of women needing a mastectomy was reduced by 16% in patients taking Zometa (65.3% in the Zometa group versus 77.9% in the chemotherapy-alone group)(1).

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 3/5 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 “potential,” “potentially,” “may,” “encouraged,” “committed,” 4/5 “exploring,” “expected,” “suggested,” “risk,” “should,” “suggest,” or similar expressions, or by express or implied discussions regarding potential new indications or labelling 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 submitted or 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 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 Corporation

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.

Posted: December 2008

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