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

    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)

PR Newswire

EAST HANOVER, N.J., Jan. 10, 2013

EAST HANOVER, N.J., Jan. 10, 2013 /PRNewswire/ -- 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 cannot be
curatively resected^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 Pharmaceuticals Corporation 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 greater than or equal to 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/m^2 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

Afinitor^® (everolimus) tablets is approved by the US Food and Drug
Administration (FDA) for the treatment of adult patients with renal
angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate
surgery. The effectiveness of Afinitor in the 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. Afinitor is also approved in the US
as Afinitor tablets and Afinitor Disperz™ for pediatric and adult patients
with TSC for the treatment of subependymal giant cell astrocytoma (SEGA) that
requires therapeutic intervention but cannot be curatively resected. The
effectiveness of Afinitor tablets and Afinitor Disperz 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.

Afinitor is also approved in the US for the treatment of postmenopausal women
with advanced hormone receptor-positive, HER2-negative breast cancer (advanced
HR+ breast cancer) in combination with exemestane after failure of treatment
with letrozole or anastrozole, adult patients with advanced renal cell
carcinoma after failure of treatment with sunitinib or sorafenib and for the
treatment of adults with progressive neuroendocrine tumors of pancreatic
origin in patients with unresectable, locally advanced or metastatic disease.
The FDA determined that the safety and effectiveness of Afinitor in the
treatment of patients with carcinoid tumors have not been established.

In the US, everolimus is available from Novartis in different dosage strengths
and for different uses in non-oncology patient populations under the trade
name Zortress^®. Everolimus is exclusively licensed to Abbott and sublicensed
to Boston Scientific for use in drug-eluting stents.

Not all indications are available in every country.

Important safety information about Afinitor (everolimus) tablets

Patients should not take Afinitor or Afinitor Disperz if they are allergic to
Afinitor or Afinitor Disperz or to any of its ingredients. Patients should
tell their healthcare provider before taking Afinitor or Afinitor Disperz if
they are allergic to sirolimus (Rapamune^®) or temsirolimus (Torisel^®).

Afinitor or Afinitor Disperz can cause serious side effects including lung or
breathing problems, infections, and kidney failure, which can even lead to
death. If patients experience these side effects, they may need to stop
taking Afinitor or Afinitor Disperz for a while or use a lower dose. Patients
should follow their healthcare provider's instructions.

In some patients, lung or breathing problems may be severe and can even lead
to death. Patients should tell their healthcare provider right away if they
have any of these symptoms: new or worsening cough, shortness of breath, chest
pain, difficulty breathing, or wheezing.

Afinitor or Afinitor Disperz may make patients 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. Patients may need to be treated as soon as possible.
Patients should tell their healthcare provider right away if they 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 stools or
dark urine, yellowing of the skin, or pain in the upper right side of the
stomach.

Afinitor or Afinitor Disperz may cause kidney failure. In some people this
may be severe and can even lead to death. Patients should have tests to check
their kidney function before and during their treatment with Afinitor or
Afinitor Disperz.

Common side effects include mouth ulcers. Afinitor or Afinitor Disperz can
cause mouth ulcers and sores. Other common side effects include infections,
feeling weak or tired, nausea and vomiting, skin problems, headache, weight
loss, loss of appetite, cough, diarrhea, fever, swelling of the hands, arms,
legs, feet, face or other parts of the body, joint pain, abnormal taste,
stomach-area (abdomen) pain, nose bleeds, seizure, increased blood cholesterol
and sugar levels, decreased blood phosphate levels, low red and white blood
cells, and the absence of menstrual periods (menstruation).

Please see full Prescribing Information for Afinitor and Afinitor Disperz
available at afinitor.com.

Rapamune^® (sirolimus) and Torisel^® (temsirolimus) are registered trademarks
of Wyeth Pharmaceuticals Inc.

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 Pharmaceuticals Corporation researches, develops, manufactures and
markets innovative prescription drugs used to treat a number of diseases and
conditions, including cardiovascular, dermatological, central nervous system,
bone disease, cancer, organ transplantation, psychiatry, infectious disease
and respiratory. 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 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's continuing operations 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
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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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