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Biopharmaceuticals Oncology

 News Release - October 11, 2010

Phase III Novartis Data Show Potential Benefit of Afinitor(R) Plus Sandostatin(R) LAR Depot in Patients with Advanced Carcinoid Tumors

Everolimus plus octreotide LAR extended time without tumor growth from 11.3 to 16.4 months versus octreotide LAR alone in advanced carcinoid patients(1)

The study did not reach its primary endpoint of progression-free survival(1)

Analyses to adjust for imbalances in the treatment arms show everolimus plus octreotide LAR significantly reduced risk of disease progression(1)

Worldwide regulatory filings for everolimus planned this year based on study as well as results from a separate Phase III study in patients with pancreatic NET


EAST HANOVER, N.J., Oct. 11 -- (Healthcare Sales & Marketing Network) -- A Novartis Pharmaceuticals Corporation ("Novartis") Phase III study of Afinitor® (everolimus) tablets in combination with Sandostatin® LAR Depot (octreotide acetate for injectable suspension) extended median progression-free survival (PFS), or time without tumor growth, in patients with advanced carcinoid tumors compared to taking octreotide LAR alone. The study, RADIANT-2 (RAD001 In Advanced Neuroendocrine Tumors), was presented at the 35th European Society for Medical Oncology (ESMO) Congress and is part of the largest clinical trial program in patients with advanced neuroendocrine tumors (NET)(1).

Everolimus is not approved in this patient population. Octreotide LAR is indicated for long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors and long-term treatment of the profuse watery diarrhea associated with VIP-secreting tumors in patients in whom initial treatment with immediate-release octreotide acetate injection has been shown to be effective and tolerated(2). In patients with carcinoid syndrome and VIPomas, the effect of octreotide acetate and octreotide LAR on tumor size, rate of growth and development of metastases has not been determined.

The study did not meet its primary endpoint of PFS based on central radiologic review of the data (p=0.026 versus p=0.024 predefined). Findings demonstrated that everolimus plus octreotide LAR provided a clinically meaningful extension in the median time without tumor growth from 11.3 to 16.4 months when compared with placebo plus octreotide LAR (hazard ratio=0.77 [95% confidence interval, 0.59 to 1.00]; p=0.026)(1).

Further analyses of the study data were conducted using a well-established statistical model to adjust for imbalances in baseline characteristics between the two treatment arms and inconsistencies between the review of radiology scans for disease progression. The results show that everolimus plus octreotide LAR provided a statistically significant reduction in the risk of disease progression by 40% (hazard ratio=0.60 [95% confidence interval, 0.44 to 0.84]; p=0.0014) versus octreotide LAR alone(1).

Patients examined in the study had advanced carcinoid tumors that originated in the gastrointestinal (GI) tract, lungs and other locations in the body(1). Carcinoid tumors, the most common form of NET, are a rare cancer that can cause symptoms such as flushing and diarrhea(3,4). Most patients with carcinoid tumors are not diagnosed until their disease has advanced, meaning the cancer has spread to other parts of the body and has become more difficult to treat(5). Patients with advanced carcinoid tumors usually have a five year survival rate of less than 35%(6).

"A key goal of treating patients with advanced NET is to extend time without tumor growth," said Professor Marianne Pavel, MD, Leader, Section for Neuroendocrine Tumors and Clinical Trial Unit in Neuroendocrine Tumors, Charite University Medicine, Berlin, and primary investigator of the RADIANT-2 trial. "This Phase III study is important because it shows that everolimus plus octreotide LAR may provide a viable new treatment approach for patients with advanced NET, where there is a high unmet need."

Results from the Phase III RADIANT-3 trial, which were also presented at the ESMO Congress, show that everolimus more than doubled median time without tumor growth from 4.6 to 11.0 months when compared with placebo in patients with advanced pancreatic NET (hazard ratio=0.35 [95% confidence interval, 0.27 to 0.45]; p<0.0001)(7). Findings from this study were also presented earlier this year at the 12th World Congress on Gastrointestinal Cancer in Barcelona.

"Results from the RADIANT trials, the largest and broadest in patients with advanced NET, will form the basis for regulatory filings later this year and demonstrate the ongoing commitment Novartis has to the NET community," said Herve Hoppenot, President, Novartis Oncology.

About RADIANT-2

RADIANT-2 is a Phase III randomized, double-blind, placebo-controlled, multicenter study. The trial examined the efficacy and safety of everolimus plus octreotide LAR versus placebo plus octreotide LAR in 429 patients with advanced carcinoid tumors. Patients who met the study's entry criteria were randomized 1:1 to receive either oral everolimus (10 mg daily) plus octreotide LAR (30 mg intramuscularly every 28 days) or placebo daily plus octreotide LAR. Patients had radiological documentation of disease progression within 12 months prior to randomization(1).

The primary endpoint of RADIANT-2 is PFS. Secondary endpoints from the trial include safety, overall response rate and overall survival(1).

In the initial review of the data an imbalance in baseline characteristics was observed between the two treatment arms, including prior treatment with chemotherapy, primary tumors located in the lung and a poorer World Health Organization (WHO) performance status (an assessment of each patient's functional/physical performance). Further, inconsistencies were found between analyses of radiology scans, which resulted in censoring of patients from the trial. These imbalances and the censoring of data seem to favor the control arm and may have impacted the outcome of the study. A well established statistical model, inverse probability of censoring weighted analysis, was used to adjust for the imbalances and censoring(1).

In the study, the most frequent all grade drug-related adverse events with everolimus plus octreotide LAR were stomatitis, rash, fatigue and diarrhea; most were grade one or two. Grade three and four adverse events (greater than or equal to 5%) with everolimus plus octreotide LAR were stomatitis (6.5%), fatigue (6.5%), diarrhea (6%), infections/infestations (5.1%) and hyperglycemia (5.1%)(1).

About RADIANT-3

RADIANT-3 is a Phase III prospective, double-blind, randomized, parallel group, placebo-controlled, multicenter study. The trial examined the efficacy and safety of everolimus plus best supportive care (BSC) versus placebo plus BSC in 410 patients with advanced pancreatic NET, also known as islet cell tumors. Patients who met the study entry criteria were randomized 1:1 to receive either daily everolimus (10 mg) or daily placebo orally(7).

The primary endpoint of RADIANT-3 is PFS. Secondary endpoints include safety, objective response rate and overall survival(7).

In the study, the most frequent all grade drug-related adverse events with everolimus were stomatitis (64%), rash (53%), diarrhea (34%), fatigue (31%) and infections (23%); most were grade one or two. Stomatitis (6.9%), anemia (6%) and hyperglycemia (5%) were the most common grade three or four events. Median exposure to everolimus was 2.3-fold longer than exposure to placebo (38 versus 16 weeks)(7).

About neuroendocrine tumors (NET)

Neuroendocrine tumors arise from cells that can produce and secrete a variety of hormones that regulate bodily functions(8). There are many types of NET that can occur throughout the body; however, most are found in the GI tract, pancreas and lungs(6,9).

Because NET are relatively rare, there is no routine screening and patients often experience delays of five to seven years before receiving an accurate diagnosis. As a result of this, patients with NET often have advanced disease when diagnosed. The most recent available data show that in 2004, NET were diagnosed in approximately five cases per 100,000 per year. Although considered a rare cancer, the incidence of NET is increasing dramatically, having more than quadrupled in the past 30 years(5,6).

About Afinitor (everolimus)

Approved in more than 55 countries globally, Afinitor® (everolimus) tablets is approved in the US for the treatment of patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. In the European Union (EU), Afinitor is approved for the treatment of patients with RCC whose disease has progressed on or after treatment with vascular endothelial growth factor (VEGF)-targeted therapy.

In the US, everolimus is available in different dosage strengths under the trade name Zortress® for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant. In the EU, everolimus is available in different dosage strengths under the trade name Certican® for the prevention of organ rejection in heart and kidney transplant recipients.

With once-daily dosing Afinitor works by targeting mTOR in cancer cells, a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism.

As an investigational compound the safety and efficacy profile of everolimus has not yet been established in NET. Access to everolimus for NET has been carefully controlled and monitored in clinical trials designed to better understand the potential benefits and risks of the compound. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for NET anywhere in the world.

Afinitor (everolimus) tablets important safety information

Do not take Afinitor if you are allergic to Afinitor or to any of its ingredients. Tell your healthcare provider before taking this medicine if you are allergic to sirolimus (Rapamune®) or temsirolimus (Torisel®).

Afinitor can cause you to have serious side effects including lung or breathing problems or infections. In some people the lung or breathing problems may be severe, and can even lead to death. Tell your healthcare provider right away if you have any of these symptoms: new or worsening cough, shortness of breath, difficulty breathing, or wheezing. You may need to stop Afinitor for awhile or use a lower dose.

Afinitor may make you more likely to develop an infection, such as pneumonia, or a bacterial, fungal or viral infection. Viral infections may include reactivation of hepatitis B in people who have had hepatitis B in the past. In some people these infections may be severe, and can even lead to death. You may need to be treated as soon as possible. Tell your healthcare provider right away if you have a temperature of 100.5 degrees F or above, chills, or do not feel well. Symptoms of hepatitis B or infection may include the following: fever, skin rash, joint pain and inflammation, tiredness, loss of appetite, nausea, pale stool or dark urine, yellowing of the skin, pain in your upper right side.

Afinitor can cause mouth ulcers and sores. Tell your healthcare provider if you have pain, discomfort, or open sores in your mouth. Your healthcare provider may tell you to use a special mouthwash or mouth gel that does not contain alcohol or peroxide.

You will have regular blood tests before you start and during your treatment with Afinitor. These tests will monitor how your kidneys and liver are working, your blood sugar and cholesterol levels as well as the number of blood cells in your body.

Afinitor may affect the way other medicines work, and other medicines can affect how Afinitor works. Using Afinitor with other medicines can cause serious side effects. Tell your healthcare provider about all of the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements such as: St. John's Wort and medicine for fungal infections, bacterial infections, tuberculosis, seizures, HIV-AIDS, heart conditions or high blood pressure, and medicines that suppress your immune system. Do not drink grapefruit juice, or eat grapefruit, starfruit or Seville oranges during your treatment with Afinitor.

Do not take Afinitor tablets which are broken or crushed.

Tell your healthcare provider about all your medical conditions including if you have or have had liver problems, diabetes or high blood sugar, high cholesterol levels, infections, hepatitis B, or other medical conditions.

Tell your healthcare provider if you are scheduled to receive any vaccinations. You should not receive a live vaccine or be around people who have recently received a live vaccine.

It is not known if Afinitor will harm your unborn baby. You should use effective birth control while using Afinitor and for 8 weeks after stopping treatment.

Common side effects of Afinitor include mouth ulcers; feeling weak or tired; cough, shortness of breath; diarrhea; rash, dry skin, and itching; nausea and vomiting; fever; loss of appetite; swelling of arms, hands, feet, ankles, face or other parts of the body; abnormal taste; inflammation of lining of the digestive system; headache; nose bleeds; pain in arms and legs. Tell your healthcare provider if you have any side effect that bothers you or does not go away.

About Sandostatin LAR Depot

Sandostatin® LAR Depot (octreotide acetate for injectable suspension) is indicated for long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors and long-term treatment of the profuse watery diarrhea associated with VIP-secreting tumors in patients in whom initial treatment with immediate-release Sandostatin® (octreotide acetate) Injection has been shown to be effective and tolerated. In patients with carcinoid syndrome and VIPomas, the effect of Sandostatin Injection and Sandostatin LAR Depot on tumor size, rate of growth, and development of metastases has not been determined.

Sandostatin LAR Depot important safety information

Warnings and precautions: Treatment with Sandostatin LAR Depot may affect gallbladder function, sugar metabolism, thyroid and heart function, and nutritional absorption, which may require monitoring by your doctor.

Before taking Sandostatin LAR Depot: Tell your doctor if you have a history of heart disease or are taking other medications, including: cyclosporine, insulin, oral hypoglycemic agents, beta-blockers, and bromocriptine.

Common side effects: Most patients experience side effects at some time. Some common side effects you may experience include: back pain, fatigue, headache, abdominal pain, nausea, and dizziness.

Other information: Patients with carcinoid tumors and VIPomas should adhere closely to their scheduled return visits for reinjection in order to minimize exacerbation of symptoms.

Disclaimer

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

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, the Novartis Group offers a diversified portfolio to best meet these needs: innovative medicines, preventive vaccines, diagnostic tools, cost-saving generic pharmaceuticals and consumer health products. The Novartis Group is the only company with leading positions in each of these areas. In 2009, the Group's continuing operations achieved net sales of USD 44.3 billion, while approximately USD 7.5 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 102,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.us.novartis.com.

Novartis is on Twitter. Sign up to follow @Novartis at http://twitter.com/novartis.

References

1. Pavel et al. A randomized, double-blind, placebo-controlled, multicenter phase III trial of everolimus + octreotide LAR vs placebo + octreotide LAR in patients with advanced neuroendocrine tumors (NET) (RADIANT-2). 35th European Society for Medical Oncology Congress. October 9, 2010.

2. Sandostatin® LAR Depot (octreotide acetate for injectable suspension) US prescribing information. Basel, Switzerland: Novartis International AG; 2010.

3. Memorial Sloan-Kettering Cancer Center. Gastrointestinal Carcinoid Tumors. Available at: http://www.mskcc.org/mskcc/html/92542.cfm. Accessed October 2010.

4. Caring for Carcinoid Foundation. What is Carcinoid Cancer? Available at: http://caringforcarcinoid.org/patient-caregiver-resources/neuroendocrine-tumor-information/carcinoid-cancer. Accessed October 2010.

5. Modlin, et al. Priorities for Improving the Management of Gasteroenteropancreatic Neuroendocrine Tumors. J Natl Cancer Inst 2008;100:1282-1289.

6. Yao, et al. One Hundred Years After "Carcinoid:" Epidemiology of and Prognostic Factors for Neuroendocrine Tumors in 35,825 Cases in the United States. Journal of Clinical Oncology. June 20 2009; vol. 26, number 18.

7. Yao et al. A randomized, double-blind, placebo-controlled, multicenter phase III trial of everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET) (RADIANT-3). 35th European Society for Medical Oncology Congress. October 9, 2010.

8. National Library of Medicine and the National Institutes of Health. Neuroendocrine Tumor. Available at: http://www.cancer.gov/dictionary/?CdrID=44904. Accessed October 2010.

9. American Cancer Society Detailed Guides. What are the key statistics about gastrointestinal carcinoid tumors? Available at: http://www.cancer.org/Cancer/GastrointestinalCarcinoidTumor/DetailedGuide/gastrointestinal-carcinoid-tumors-key-statistics. Accessed October 2010.


Source: Novartis Pharmaceuticals

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