Phase III data in The Lancet show significant benefit of Novartis drug Afinitor® in patients with non-cancerous tumors associated with TSC

• More than 40% of TSC patients on everolimus had their kidney tumor volume reduced by at least half with no tumor progression[1]

• Separate data show 35% of TSC patients treated with everolimus had their SEGA brain tumor volume reduced by one half or more[2]

• Tuberous sclerosis complex (TSC), a genetic disorder, may cause non-cancerous tumors to form in vital organs, including the kidney and brain[3]

Basel, 11-1-2013 — /europawire.eu/ — Data published today in The Lancet showed that patients on Afinitor^® (everolimus) tablets with non-cancerous kidney tumors known as renal angiomyolipomas associated with tuberous sclerosis complex (TSC) experienced a significant reduction in tumor size and the absence of tumor progression[1]. Additionally, a recent issue of The Lancet featured results from a separate everolimus trial demonstrating a reduction in the size of non-cancerous brain tumors known as subependymal giant cell astrocytomas (SEGAs) associated with TSC[2].

Affecting one to two million people worldwide, TSC is a genetic disorder that may cause non-cancerous tumors to form in vital organs, including the kidney and brain[3]. Known as Votubia^® in the European Union (EU) and Switzerland for the treatment of certain patients with TSC, everolimus is the first and only medication for adult patients with these kidney tumors associated with TSC who do not require immediate surgery, and separately for pediatric and adult patients with SEGAs who require therapeutic intervention but are not amenable to surgery[4],[5].

“The positive findings of these two trials published in The Lancet represent a significant advance for people living with TSC,” said Dr. John Bissler, lead EXIST-2 study author and Clark D. West Endowed Chair of Nephrology at Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio. “Rare diseases such as TSC are often overlooked, making publication of these studies important to help further awareness among the medical community, as well as reinforcing the importance of monitoring individuals for this serious and difficult-to-treat condition.”

The Phase III EXIST-2 trial published in The Lancet reported that 42% of patients taking everolimus experienced an angiomyolipoma response versus 0% of patients in the placebo arm (p<0.0001). Everolimus also demonstrated superiority to placebo for both secondary endpoints assessed. Time to angiomyolipoma progression was statistically significantly longer in patients on everolimus versus placebo (p<0.0001). In patients with skin lesions, a key concern for those with TSC, a 26% response rate was seen with everolimus versus 0% with placebo (p=0.0002)[1]. Results from a separate Phase III trial of TSC patients called EXIST-1, also published in a recent issue of The Lancet, showed that 35% of patients with SEGAs associated with TSC treated with everolimus experienced a 50% or greater reduction in SEGA volume versus 0% of patients on placebo (p<0.0001)[2].

Renal angiomyolipomas, or potentially life-threatening kidney tumors, occur in up to 80% of patients with TSC, with typical onset occurring between the ages of 15 and 30 and prevalence increasing with age[3]. SEGAs occur in up to 20% of children and adults with TSC and may pose a significant medical risk, including the potential for swelling in the brain (hydrocephalus)[2].

Everolimus works by inhibiting mTOR, a protein implicated in many tumor-causing pathways[6]. TSC is caused by defects in the TSC1 and/or TSC2 genes[3]. When these genes are defective, mTOR activity is increased and can cause uncontrolled tumor cell growth and proliferation, blood vessel growth and altered cellular metabolism[6],[7].

“Novartis has a long-standing commitment to meeting the needs of patients affected by rare diseases, such as TSC, with a focus on understanding the fundamental mechanisms of the underlying condition,” said Alessandro Riva, Global Head, Oncology Development & Medical Affairs, Novartis Oncology. “We strive to improve the lives of these patients with the goal of bringing the right treatment to the right patient across a broad range of diseases, based on patient need, not population size.”

Novartis is committed to supporting individuals affected by TSC through therapeutic innovation, patient assistance, disease education and support of advocacy organizations.

About EXIST-2
EXIST-2 (EXamining everolimus In a Study of TSC) is the first double-blind, randomized, placebo-controlled, international, multicenter Phase III study to evaluate the treatment of patients with renal angiomyolipomas associated with TSC. Trial patients (median age=31, range 18-61) were randomized 2:1 to receive either everolimus (n=79) or placebo (n=39) at a daily dose of 10 mg. The median exposure duration of blinded study treatment was 38 weeks in the everolimus arm and 34 weeks in the placebo arm[1].

In the study, 42% of patients on everolimus (33 of 79; 95% confidence interval [CI] 31-53) experienced an angiomyolipoma response versus 0% on placebo (0 of 39; 95% CI 0-9; p<0.0001), defined as a reduction in angiomyolipoma volume (sum of volumes of all target angiomyolipomas identified at baseline) of 50% or more relative to baseline and absence of angiomyolipoma progression[1].

Everolimus demonstrated superiority to placebo for both secondary efficacy outcomes measured: time to angiomyolipoma progression and skin lesion response rate. There were three patients in the everolimus arm and eight patients in the placebo arm with documented angiomyolipoma progression by central radiologic review. The time to angiomyolipoma progression was statistically significantly longer in patients on everolimus (hazard ratio [HR] 0.08, 95% CI 0.02-0.37; p<0.0001). Skin lesion response rate was significantly higher in the everolimus arm, with a 26% response rate seen with everolimus versus 0% with placebo (p=0.0002)[1].

Adverse events were mostly consistent with the known everolimus safety profile. Stomatitis, nasopharyngitis, acne-like skin lesions, headache, cough and hypercholesterolaemia were the most common adverse events with everolimus therapy (each reported in >=20% of patients) and were primarily Grade 1-2. Infections (most frequently urinary tract and upper respiratory tract infections) occurred in 65% (51 of 79) of patients on everolimus and 72% (28 of 39) on placebo; there were no Grade 4 infections. Adverse events leading to discontinuation occurred in 4% (3 patients) of everolimus patients and 10% (4 patients) of placebo patients[1].

About EXIST-1
EXIST-1 is the first randomized, placebo-controlled, double-blind, international, multicenter Phase III study examining the efficacy and safety of everolimus for the treatment of patients with SEGA and TSC irrespective of age. A total of 117 patients (median age=9.5 years, range 0.8-26.6) were randomized to receive either everolimus (n=78) or placebo (n=39) at a daily starting dose of 4.5 mg/m² and adjusted to a trough of 5-15 ng/ml. The median duration of study treatment was 41.9 weeks (range 24.0-78.9) for individuals in the everolimus group and 36.1 weeks (13.9-79.7) for those in the placebo group[2].

In the study, 35% of patients on everolimus (27 of 78) experienced a SEGA response versus 0% on placebo (0 of 39; p<0.0001), defined as a reduction in the total volume of all target SEGAs of 50% or more relative to baseline, in the absence of worsening of non-target SEGAs, new lesions of 1 cm or greater in diameter and new or worsening hydrocephalus[2].

Key secondary endpoints as reported in The Lancet included absolute change from baseline to 24 weeks in seizure frequency, time to SEGA progression and skin lesion response rate of SEGA in patients with at least one skin lesion at baseline. In this trial, the impact on seizure frequency was not demonstrated. Analysis of change in seizure frequency was inconclusive because most patients had no seizures at baseline or at follow-up. Seizure frequency was evaluated as a secondary endpoint only and patients were selected for the trial on the basis of their need for intervention for progression of the SEGAs, rather than presence of seizures. Given the results of the first secondary endpoint, the statistical plan did not provide for a formal analysis of subsequent secondary endpoints. Of those patients receiving everolimus, 0% of patients (0 of 78) experienced disease progression, while 15% of patients (6 of 39) on placebo progressed. A skin lesion response was observed in 42% of patients (30 of 72) receiving everolimus, compared with 11% of patients (4 of 38) receiving placebo (p=0.0004). No complete responses were observed[2].

The adverse event profile was consistent with the known safety profile of everolimus. Most adverse events were Grade 1 or 2. The most common events were mouth ulceration, stomatitis, convulsion and pyrexia. The most common Grade 3 adverse events were stomatitis, pyrexia and convulsion; Grade 4 events were rare. Infections, mostly of the upper respiratory tract, were reported by 56 (72%) patients in the everolimus group and 26 (67%) in the placebo group. Other than one (1%) case of Grade 1 herpes zoster in the everolimus group, no opportunistic infections were reported; one (1%) infection (gastroenteritis in the everolimus group) was classified as Grade 4[2].

About everolimus
Everolimus is approved in the European Union (EU) as Votubia^® (everolimus) tablets for the treatment of adult patients with renal angiomyolipoma associated with tuberous sclerosis complex (TSC) who are at risk of complications (based on factors such as tumor size or presence of aneurysm, or presence of multiple or bilateral tumors) but who do not require immediate surgery. The evidence is based on analysis of change in sum of angiomyolipoma volume. Everolimus is also approved in the United States (US) as Afinitor^® (everolimus) tablets for the treatment of adult patients with renal angiomyolipomas and TSC, who do not require immediate surgery. The effectiveness of Afinitor in treatment of renal angiomyolipoma is based on an analysis of durable objective responses in patients treated for a median of 8.3 months. Further follow-up of patients is required to determine long-term outcomes.

Everolimus is also approved in the EU as Votubia for the treatment of patients aged 3 years and older with subependymal giant cell astrocytoma (SEGA) associated with TSC, who require therapeutic intervention but are not amenable to surgery. The evidence is based on analysis of change in SEGA volume. Further clinical benefit, such as improvement in disease-related symptoms, has not been demonstrated. In the US, everolimus is approved as Afinitor and Afinitor Disperz(TM) in pediatric and adult patients with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The effectiveness is based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume. Improvement in disease-related symptoms and overall survival in patients with SEGA and TSC have not been demonstrated.

Everolimus is also available from Novartis as Afinitor for use in oncology settings and for use in other non-oncology patient populations under the brand names Certican^®and Zortress^® and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

Indications vary by country and not all indications are available in every country.

Important Safety Information about Afinitor/Votubia
Afinitor/Votubia can cause serious side effects including lung or breathing problems, infections and renal failure which can lead to death. Mouth ulcers and mouth sores are common side effects. Afinitor/Votubia can affect blood cell counts, kidney and liver function, and blood sugar and cholesterol levels. Afinitor/Votubia may cause fetal harm in pregnant women. Highly effective contraception is recommended for women of child-bearing potential while receiving Afinitor and for up to eight weeks after ending treatment. Women taking Afinitor/Votubia should not breast feed.

The most common adverse drug reactions (incidence >=15%) are mouth ulcers, diarrhea, feeling weak or tired, skin problems (such as rash or acne), infections, nausea, swelling of extremities or other parts of the body, loss of appetite, headache, inflammation of lung tissue, abnormal taste, nose bleeds, inflammation of the lining of the digestive system, weight decreased and vomiting. The most common Grade 3-4 adverse drug reactions (incidence >=2%) are mouth ulcers, feeling tired, low white blood cells (a type of blood cell that fights infection), diarrhea, infections, inflammation of lung tissue, diabetes and amenorrhea. Cases of hepatitis B reactivation and blood clot in the lung and leg have been reported.

Disclaimer
The foregoing release contains forward-looking statements that can be identified by terminology such as “commitment,” “strive,” “goal,” “committed,” “potential,” or similar expressions, or by express or implied discussions regarding potential new indications or labeling for everolimus or regarding potential future revenues from everolimus. 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 everolimus to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that everolimus will be submitted or approved for any new indications or labeling in any market, or at any particular time. Nor can there be any guarantee that everolimus will achieve any particular levels of revenue in the future. In particular, management’s expectations regarding everolimus 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; unexpected manufacturing issues; 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
Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2011, the Group achieved net sales of USD 58.6 billion, while approximately USD 9.6 billion (USD 9.2 billion excluding impairment and amortization charges) was invested in R&D throughout the Group. Novartis Group companies employ approximately 127,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.novartis.com.

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References

1. Bissler J, et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: a multicentre, randomised, double-blind, placebo-controlled trial. The Lancet 2012: 380.
2. Franz D, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. The Lancet 2012:1-8.
3. National Institute of Neurological Disorders and Stroke. Tuberous Sclerosis Fact Sheet. Available at http://www.ninds.nih.gov/disorders/tuberous_sclerosis/detail_tuberous_sclerosis.htm. Accessed January 2013.
4. Votubia® (everolimus) tablets Summary of Product Characteristics. Basel, Switzerland: Novartis; January 2013.
5. Afinitor US Prescribing Information. http://www.pharma.us.novartis.com/product/pi/pdf/afinitor.pdf. Accessed January 2013.
6. Motzer, et al. Phase 3 Trial of Everolimus for Metastatic Renal Cell Carcinoma. Cancer. 2010 Sep;116(18):4256-4265.
7. Krueger D, et al. Everolimus for Subependymal Giant-Cell Astrocytomas in Tuberous Sclerosis. N Engl J Med. 2010 Nov;363(19):1801-11.

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