Novartis drug Afinitor® approved by FDA as first medication to treat patients with non-cancerous kidney tumors associated with TSC

4/26/2012, 11:50 PM (Source: GlobeNewswire)

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Novartis drug Afinitor® approved by FDA as first medication to treat patients
with non-cancerous kidney tumors associated with TSC
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* Kidney tumors affect up to 80% of patients with tuberous sclerosis complex
(TSC) and growing tumors may lead to unpredictable life-threatening
complications[1]
* Prior to the approval of Afinitor, surgical intervention was the only
treatment option for patients with these kidney tumors associated with
TSC[2],[3]
* Approval marks the second TSC-related indication for Afinitor in the US,
where it is also approved to treat subependymal giant cell astrocytoma
(SEGA) in TSC[3]

Basel, April 26, 2012 - Novartis announced today that the US Food and Drug
Administration (FDA) approved Afinitor(®) (everolimus) tablets* for the
treatment of adult patients with kidney tumors known as renal angiomyolipomas
and tuberous sclerosis complex (TSC), who do not require immediate surgery[2].
This marks the first approval of a medical treatment in this patient
population[2],[3].

The accelerated approval was based on the Phase III EXIST-2 (EXamining
everolimus In a Study of TSC) trial, which found that 42% of patients on
everolimus experienced an angiomyolipoma response versus 0% of patients in the
placebo arm (p<0.0001)[2],[4]. The time to angiomyolipoma progression was also
statistically significantly longer in patients on everolimus (p<0.0001). Among
the 97% of trial patients with skin lesions, one of the key concerns for the
majority of patients with TSC, a 26% response rate was seen with everolimus
versus 0% with placebo (p=0.0011)[2],[5].

"Renal angiomyolipomas are one of the greatest causes of morbidity and mortality
in adult TSC patients and can be one of the most challenging aspects of the
disease to treat," said John Bissler, MD, Clark D. West Endowed Chair of
Nephrology at Cincinnati Children's Hospital Medical Center. "Today marks an
important step for the TSC community, as Afinitor is now the only approved
medicine to reduce the kidney tumor burden in these patients."

Up to 80% of patients with TSC, a genetic disorder that may cause non-cancerous
tumors to form in vital organs, will develop renal angiomyolipomas. Typical
onset occurs between the ages of 15 and 30 and prevalence increases with age.
Over time, these tumors may grow large enough to cause severe internal bleeding,
require emergency surgical interventions, such as embolization and nephrectomy,
or lead to kidney failure[1]. The tumors can be difficult to manage as they
often form in both kidneys[5],[6]. In addition, skin lesions occur in more than
90% of patients with TSC[7]. They may develop in infancy, can become more
prevalent with age and cause disfigurement[1],[5].

"With this FDA approval, Afinitor becomes the first medical option to treat two
of the most debilitating manifestations of this challenging, lifelong disease -
kidney tumors called renal angiomyolipomas and brain tumors known as SEGAs,"
said Hervé Hoppenot, President, Novartis Oncology. "This approval further
strengthens our commitment to address unmet needs in TSC as we continue to
research everolimus and mTOR inhibition across other manifestations of the
disease."

Based on an effect on a clinical endpoint other than survival or irreversible
morbidity, this indication was approved under the FDA's accelerated approval
program, which provides patients access to a treatment for a serious or life-
threatening illness and that provides meaningful therapeutic benefit to patients
over existing treatments[2]. Novartis previously received approval for
everolimus for the treatment of adult and pediatric patients, aged three or
older, with subependymal giant cell astrocytoma (SEGA) associated with TSC who
require therapeutic intervention but are not candidates for curative surgical
resection in the US, and in more than 40 additional countries. Filings for renal
angiomyolipoma are under way in multiple countries outside of the US.

Afinitor works by inhibiting mTOR, a protein implicated in many tumor-causing
pathways[1],[8]. TSC is caused by defects in the TSC1 and/or TSC2 genes[1]. When
these genes are defective, mTOR activity is increased, which can cause
uncontrolled tumor cell growth and proliferation, blood vessel growth and
altered cellular metabolism[8],[9]. According to preclinical studies, by
inhibiting mTOR activity in this signaling pathway, everolimus reduces cell
proliferation and blood vessel growth[1],[2].

Affecting approximately one to two million people worldwide, TSC can affect many
different parts of the body, including the kidneys and brain, as well as the
heart, lungs and skin. Tuberous sclerosis complex is associated with a variety
of resulting disorders, including skin lesions, seizures, swelling in the brain
(hydrocephalus), kidney failure, developmental delays and behavioral issues[1].

About EXIST-2
EXIST-2 is the first double-blind, randomized, placebo-controlled,
international, multicenter Phase III study for the treatment of patients with
renal angiomyolipoma associated with TSC[2],[4]. 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 starting dose of 10 mg. By the cut-off of October 14, 2011,
the median treatment duration in the double-blind period was 48 weeks in the
everolimus arm and 45 weeks in the placebo arm[2].

In the study, 42% of patients on everolimus (33 of 79; 95% CI 30.8-53.4)
experienced an angiomyolipoma response versus 0% on placebo (0 of 39; 95% CI
0.0-9.0)(p<0.0001), defined as a 50% or greater reduction in the sum of
angiomyolipoma volume relative to baseline, the absence of new tumor growth at
least 1 cm in longest diameter, absence of kidney volume increase of 20% or
greater and no renal angiomyolipoma-related bleeding of Grade 2 or higher[2].

Everolimus demonstrated superiority to placebo for both supportive efficacy
outcomes measured: time to angiomyolipoma progression and skin lesion response
rate. There were three patients in the Afinitor 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 (p<0.0001; HR 0.08, 95% CI 0.02-0.37). Skin
lesion response rate was significantly higher in the everolimus arm. A partial
clinical response in skin lesions (corresponding to a 50% or greater
improvement) was observed by Physician Global Assessment in 26% of patients on
everolimus, compared with 0% of patients on placebo (p=0.0011). No complete
responses were observed[2].

The most common adverse event (AE) in the everolimus arm (with an incidence of
at least 30%) was stomatitis. The most common Grade 3-4 adverse reactions
(incidence >= 2%) were stomatitis, amenorrhea and convulsion. The most common
laboratory abnormalities (incidence >= 50%) were hypercholesterolemia,
hypertriglyceridemia and anemia. The most common Grade 3-4 laboratory
abnormality (incidence >= 3%) was hypophosphatemia. Adverse events observed in
this study were for the most part consistent with the known safety profile of
everolimus in the TSC setting[2].

About everolimus
Everolimus is now approved as Afinitor(®) (everolimus) tablets in the United
States (US) for the treatment of adult patients with renal angiomyolipomas and
tuberous sclerosis complex (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 European Union (EU) as Votubia(®)
(everolimus) tablets and in the US as Afinitorto treat adult and pediatric
patients, aged three years or older, with SEGA associated with TSC who require
therapeutic intervention but are not candidates or amenable for surgery. The
effectiveness of everolimus is based on an analysis of change in SEGA volume in
patients three years of age and older. Further clinical benefit has not been
demonstrated.

Everolimus is approved as Afinitor in more than 80 countries including the US
and throughout the EU in the adult oncology settings of advanced renal cell
carcinoma following progression on or after vascular endothelial growth factor
(VEGF)-targeted therapy in the EU and after failure of treatment with sunitinib
or sorafenib in the US. Afinitor is approved for the treatment of locally
advanced, metastatic or unresectable progressive neuroendocrine tumors of
pancreatic origin in adults in the US and EU.

Everolimus is also available from Novartis 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. 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," "continue to," "under way," or similar
expressions, or by express or implied discussions regarding potential new
indications or labeling for Afinitor or regarding potential future revenues from
Afinitor. 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 will be approved for any new
indications or labeling in any market, or at any particular time. Nor can there
be any guarantee that Afinitor will achieve any particular levels of revenue in
the future. In particular, management's expectations regarding Afinitor 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; competition in general; government, industry and general public
pricing pressures; unexpected manufacturing issues; the company's ability to
obtain or maintain patent or other proprietary intellectual property protection;
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'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 124,000 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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*Known as Votubia® (everolimus) tablets for certain patients with SEGA
associated with TSC in the EU and Switzerland.

References
[1] 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 April 2012.
[2] Novartis data on file.
http://www.pharma.us.novartis.com/product/pi/pdf/afinitor.pdf. Accessed April
2012.
[3] Ewalt D, et al. Long-term outcome of transcatheter embolization of renal
angiomyolipomas due to tuberous sclerosis complex J of Urology 2005 ;174:1764-
1766.
[4] US National Institutes of Health. Efficacy and Safety of RAD001 in Patients
Aged 18 and Over With Angiomyolimpoma Associated With Either Tuberous Sclerosis
Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM) (EXIST-2) Available at:
http://clinicaltrials.gov/ct2/show/NCT00790400?term=NCT00790400&rank=1. Accessed
April 2012.
[5] Roach S, et al. Diagnosis of Tuberous Sclerosis Complex. J Child Neurol.
2004 Sep;19(9):643-647
[6] Bissler J, et al. Perspectives in Renal Medicine Renal Angiomyolipomata
Kidney International 2004; 66;924-34.
[7] Crino P, et al. The Tuberous Sclerosis Complex. N. Engl J Med. 2006
Sep;355(13):1345-56.
[8] Motzer, et al. Phase 3 Trial of Everolimus for Metastatic Renal Cell
Carcinoma. Cancer 2010 Sep;116(18):4256-4265.
[9] Krueger D, et al. Everolimus for Subependymal Giant-Cell Astrocytomas in
Tuberous Sclerosis. Engl J Med. 2010 Nov; 363(19): 1801-11.

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