Study in NEJM shows Novartis drug AfinitorÂ® reduces size of SEGAs, benign brain tumors associated with tuberous sclerosis
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Study in NEJM shows Novartis drug AfinitorÂ® reduces size of SEGAs, benign brain
tumors associated with tuberous sclerosis
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* Subependymal giant cell astrocytoma (SEGA) is a benign brain tumor found in
children and adults with tuberous sclerosis (TS) that can cause severe brain
* These data previously reported at ASCO show nearly one-third of the 28
patients studied had a reduction of 50% or greater in the size of their
* Additional study findings showed treatment with everolimus resulted in a
clinically relevant reduction in overall frequency of seizures, which are
associated with TS
* Afinitor approved in US for patients with SEGA associated with TS who
require therapeutic intervention but are not candidates for curative
Basel, November 3, 2010 - The New England Journal of Medicine (NEJM) today
published a study that found patients taking AfinitorÂ® (everolimus) tablets
experienced a decrease in the size of their subependymal giant cell astrocytoma
(SEGA), a benign brain tumor associated with tuberous sclerosis (TS),.
This study, which was previously presented at the 46th American Society of
Clinical Oncology annual meeting, is the first prospective clinical trial of a
drug to show treatment benefit in these patients.
Tuberous sclerosis is a genetic disorder affecting approximately 25,000 to
40,000 people in the US. Tuberous sclerosis may cause benign tumors to form in
vital organs, including the brain, where they can cause seizure and
developmental delay, as well as the kidney, heart, eyes, lungs and skin.
SEGAs, benign brain tumors, occur in up to 20% of patients with TS and primarily
affect children and adolescents,,. SEGAs may pose a significant medical
risk, including the potential for swelling in the brain, or hydrocephalus.
According to data published in NEJM from this Phase I/II study of 28 patients
conducted by Cincinnati Children's Hospital Medical Center, treatment with
everolimus was associated with a significant reduction in primary SEGA volume at
six months relative to baseline on independent central review (p<0.001).
Seventy-five percent of patients (21 of 28) experienced a reduction of 30% or
greater in the size of their largest SEGA and 32% (9 of 28) experienced a
reduction of 50% or greater at six months relative to baseline.
The published study findings also showed that everolimus therapy was associated
with a clinically relevant reduction from baseline to six months in overall
frequency of seizures per 24 hour video electroencephalograms (EEG) (n=16;
median change -1 seizure, p=0.022). Additionally, no patients required surgery
or developed a new SEGA while receiving everolimus.
Everolimus was recently approved in the US under the FDA's accelerated approval
program as Afinitor for patients with SEGA associated with TS who require
therapeutic intervention but are not candidates for curative surgical resection.
The effectiveness of Afinitor is based on an analysis of change in SEGA
volume. A Phase III study is underway that compares everolimus to placebo to
explore the clinical benefits of Afinitor for the treatment of patients with
SEGA associated with TS.
The most common adverse reactions observed (incidence â‰¥30%) in this trial were
mouth sores, upper respiratory tract infections, sinusitis, middle ear
infections and fever.
"This is the first clinical trial to show that a drug has the potential to
provide patients with growing SEGAs, many of whom are children, another
treatment option besides brain surgery," said David Franz, MD, Director,
Tuberous Sclerosis Clinic at Cincinnati Children's Hospital Medical Center and
principal investigator of the study. "In addition to decreasing the size of the
brain tumors, everolimus was associated with a significant reduction in the
frequency of seizures, which occur in 90% of affected individuals."
About the study published in NEJM
In this Phase I/II study, 28 patients aged three years and above (median age=11,
range 3-34) with evidence of SEGA growth initially received everolimus orally at
a dose of 3 mg/m2 once-daily or on an alternate day regimen. Doses were
subsequently adjusted subject to tolerability to attain a trough concentration
of 5-15 ng/mL.
The study met its primary efficacy endpoint of change in primary SEGA lesion
volume from baseline to six months (or at the last available assessment if a
patient discontinued treatment prior to month six [one patient discontinued the
trial before six months]). Everolimus was associated with a statistically
significant reduction in primary SEGA volume at six months relative to baseline
on independent central review (p<0.001). As of December 9, 2009, the median
duration of treatment was 21.5 months.
Study findings also showed that everolimus was associated with a clinically
relevant reduction from baseline to six months in overall frequency of seizures
per 24 hour EEG (n=16; median change -1.0 seizure, p=0.022). Of 16 patients with
seizures at the start of the study for whom EEGs were available, nine
experienced decreases in seizure frequency, six reported no change and one
experienced an increase at six months.
The reliability of the frequency of adverse reactions and laboratory
abnormalities reported in this trial is limited because of the small number of
patients. The most common adverse reactions reported (incidence â‰¥30%) in this
trial were mouth sores, upper respiratory tract infections, sinusitis, middle
ear infections and fever.
All data reported in this study published in NEJM are based on the cut-off date
of December 9, 2009.
About the EXIST-1 Phase III trial
EXIST-1, a Phase III randomized, placebo-controlled trial aimed at evaluating
the results of the Phase I/II study, is examining everolimus treatment in
patients with SEGAs associated with TS. Endpoints include SEGA response rate,
seizure rate, skin lesion response rate and safety. The trial has completed
accrual and patients continue to be followed.
The trial involves patients in 10 countries, including Australia, Belgium,
Canada, Germany, Italy, the Netherlands, Poland, Russia, the UK and the US.
About Afinitor (everolimus)
AfinitorÂ® (everolimus) tablets is approved in the US to treat patients with SEGA
associated with tuberous sclerosis who require therapeutic intervention but are
not candidates for curative surgical resection. The effectiveness of Afinitor is
based on an analysis of change in SEGA volume. Improvement in disease-related
symptoms or increase in survival has not been shown.
Novartis has submitted marketing applications for everolimus to the European
Medicines Agency (EMA) and the Swiss Agency for Therapeutic Products
(Swissmedic), and additional regulatory submissions are underway worldwide. If
approved in the European Union (EU) for this indication, everolimus will be made
available under the trade name VotubiaÂ®.
There is no guarantee that everolimus will become commercially available for
SEGA anywhere else in the world. As an investigational compound, the safety and
efficacy profile of everolimus has not yet been established outside the US in
patients with SEGA associated with TS.
Afinitor is approved in the European Union (EU) for the treatment of patients
with advanced renal cell carcinoma (RCC) whose disease has progressed on or
after treatment with vascular endothelial growth factor (VEGF)-targeted therapy
and also in the US for the treatment of patients with advanced RCC after failure
of treatment with sunitinib or sorafenib.
In the EU, everolimus is available in different dosage strengths under the trade
name CerticanÂ® for the prevention of organ rejection in heart and kidney
transplant recipients. In the US, everolimus is available in different dosage
strengths under the trade name ZortressÂ® for the prophylaxis of organ rejection
in adult patients at low-moderate immunologic risk receiving a kidney
Not all indications are available in every country.
Important Safety Information about Afinitor (everolimus) tablets
Afinitor is contraindicated in patients with hypersensitivity to everolimus, to
other rapamycin derivatives or to any of the excipients.
Cases of non-infectious pneumonitis have been described; some of these have been
severe and occasionally fatal. Management of pneumonitis may require dose
adjustment and/or interruption, or discontinuation of treatment and/or addition
of corticosteroid therapy.
Afinitor is immunosuppressive. Localized and systemic bacterial, fungal, viral
or protozoal infections (e.g., pneumonia, aspergillosis, candidiasis, hepatitis
B reactivation) have been described; some of these have been severe and
occasionally fatal. Pre-existing infections should be treated prior to starting
treatment. Patients and physicians should be vigilant for symptoms and signs of
infection; in case of emergent infections, appropriate treatment should be
promptly instituted and interruption or discontinuation of Afinitor should be
considered. Patients with systemic invasive fungal infections should not receive
Mouth ulcers, stomatitis and oral mucositis have been seen in patients treated
with Afinitor. Monitoring of renal function, blood glucose and complete blood
counts is recommended prior to initiation and periodically during treatment.
Afinitor is not recommended in patients with severe hepatic impairment. Use of
live vaccines should be avoided. Afinitor is not recommended during pregnancy or
for women of childbearing potential not using contraception. Afinitor may cause
fetal harm in pregnant women. Women taking Afinitor should not breast feed.
Avoid concurrent treatment with strong CYP3A4 and PgP inhibitors and use caution
with moderate inhibitors. Avoid concurrent treatment with strong CYP3A4 or PgP
In advanced RCC, the most common adverse reactions (â‰¥10%) include stomatitis,
rash, fatigue, asthenia, diarrhea, anorexia, nausea, mucosal inflammation,
vomiting, cough, infections, peripheral edema, dry skin, epistaxis, pneumonitis,
pruritus, and dyspnea. Common adverse reactions (â‰¥1 to <10%) include headache,
dysgeusia, dry mouth, pyrexia, weight loss, hand-foot syndrome, abdominal pain,
erythema, insomnia, dyspepsia, dysphagia, hypertension, increased daytime
urination, dehydration, chest pain, hemoptysis and exacerbation of diabetes
mellitus. Uncommon adverse reactions (<1%) include ageusia, congestive cardiac
failure, new-onset diabetes mellitus, impaired wound healing, grade 1 hemorrhage
and hepatitis B reactivation.
In the SEGA study, the most common adverse reactions (â‰¥10%, all grades)
irrespective of relationship to the drug reported among the 28 patients with
evidence of established SEGA growth included: stomatitis or mouth sores, upper
respiratory tract infection, sinusitis, middle ear infection, fever, convulsion,
acne-like skin inflammation, diarrhea, cellulitis or acute infection of the deep
tissues of skin or muscle, vomiting, cough, body tinea or fungal infection,
headache, personality change, rash, skin infection, dry skin, gastroenteritis or
inflammation of the gastrointestinal tract, contact dermatitis, dizziness,
external ear infection, allergic rhinitis or inflammation of nasal passages,
gastric infection, nasal congestion, excoriation or skin abrasion, acne,
constipation, abdominal pain and pharyngitis or inflammation of the pharynx.
Grade three adverse reactions irrespective of relationship to the study drug
included convulsion, infections (single cases of sinusitis, pneumonia, tooth
infection and viral bronchitis) and single cases of stomatitis, aspiration,
cyclic neutropenia, sleep apnea syndrome, vomiting, dizziness, white blood cell
count decreased and neutrophil count decreased. A grade four convulsion was
The foregoing release contains forward-looking statements that can be identified
by terminology such as "may," "potential," "will," "aimed at," 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. Â 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 submitted or
approved for any additional indications or labeling in any market. 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; 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.
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1. Adriaensen ME, et al. Prevalence of subependymal giant cell tumors in
patients with tuberous sclerosis and a review of the literature. Eur J Neurol
2009; 16: 691-6.
2. Krueger D, et al. Everolimus for Subependymal Giant-Cell Astrocytomas in
Tuberous Sclerosis. N Engl J Med 2010; 363:1801-1811.
3. Novartis data on
4. National Institute of Neurological Disorders and Stroke. Tuberous Sclerosis
Fact Sheet. Available
s.htm. Accessed October 2010.
5. Medkour A, et al. Neonatal Subependymal Giant Cell Astrocytoma. Pediatr
6. Nabbout R, et al. Early diagnosis of subependymal giant cell astrocytoma in
children with tuberous sclerosis. J Neurol Neurosurg Psychiatry 1999;66:370-375.
7. US National Institutes of Health. Efficacy and Safety of RAD001 in Patients
of All Ages With Subependymal Giant Cell Astrocytoma Associated With Tuberous
Sclerosis Complex (TSC) (EXIST-1). Available
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