Phase III data in The Lancet show significant benefit of Novartis drug AfinitorÂ® in patients with non-cancerous tumors associated with TSC
Novartis International AG /
Phase III data in The Lancet show significant benefit of Novartis drug AfinitorÂ®
in patients with non-cancerous tumors associated with TSC
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* More than 40% of TSC patients on everolimus had their kidney tumor volume
reduced by at least half with no tumor progression
* Separate data show 35% of TSC patients treated with everolimus had their
SEGA brain tumor volume reduced by one half or more
* Tuberous sclerosis complex (TSC), a genetic disorder, may cause non-
cancerous tumors to form in vital organs, including the kidney and brain
Basel, January 10, 2013 - Data published today in The Lancet showed that
patients on Afinitor(Â®) (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. 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.
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. Known as Votubia(Â®) 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
"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
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). 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
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. 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).
Everolimus works by inhibiting mTOR, a protein implicated in many tumor-causing
pathways. TSC is caused by defects in the TSC1 and/or TSC2 genes. When
these genes are defective, mTOR activity is increased and can cause uncontrolled
tumor cell growth and proliferation, blood vessel growth and altered cellular
"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
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.
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.
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
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.
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.
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.
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.
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.
Everolimus is approved in the European Union (EU) as Votubia(Â®) (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(Â®) (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
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(Â®) and Zortress(Â®) 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
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.
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.
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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
3. National Institute of Neurological Disorders and Stroke. Tuberous Sclerosis
Fact Sheet. Available at
sis.htm. Accessed January 2013.
4. VotubiaÂ® (everolimus) tablets Summary of Product Characteristics. Basel,
Switzerland: Novartis; January 2013.
5. Afinitor US Prescribing Information.
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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