Novartis drug Afinitor® approved by FDA as first medication for children and adults with a benign brain tumor associated with tuberous sclerosis
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Novartis International AG /
Novartis drug Afinitor® approved by FDA as first medication for children and
adults with a benign brain tumor associated with tuberous sclerosis
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* Subependymal giant cell astrocytoma (SEGA) is a benign brain tumor
associated with tuberous sclerosis (TS)[1]
* Prior to the approval of Afinitor, brain surgery was the only treatment
option for patients with growing SEGAs[1]
* Worldwide regulatory submissions underway, including applications filed in
the EU and Switzerland
Basel, October 30, 2010 - Novartis announced, that the US Food and Drug
Administration (FDA) has approved Afinitor(®) (everolimus) tablets for patients
with subependymal giant cell astrocytoma (SEGA), a benign brain tumor associated
with tuberous sclerosis (TS), who require therapeutic intervention but are not
candidates for curative surgical resection[2].
This accelerated approval of Afinitor is based on an open-label, single-arm, 28-
patient study conducted by Cincinnati Children's Hospital Medical Center[2]. The
effectiveness of Afinitor is based on an analysis of change in SEGA volume. A
Phase III study is underway that compares Afinitor to placebo to explore the
clinical benefits of Afinitor for the treatment of patients with SEGA associated
with TS[3].
Prior to this FDA approval, the only treatment option for growing SEGAs, which
primarily affect children and adolescents, was brain surgery[1],[4],[5].
Tuberous sclerosis is a genetic disorder affecting approximately 25,000 to
40,000 people in the US that may cause benign tumors to form in vital organs[6].
SEGAs, benign brain tumors, occur in up to 20% of patients with TS[1].
"Today's FDA decision is an important milestone for the children and adults
living with SEGA associated with tuberous sclerosis," said Hervé Hoppenot,
President of Novartis Oncology. "We are committed to furthering research for
patients with tuberous sclerosis and will continue to work towards addressing
their unmet medical needs."
In this study, nearly one-third of patients (32%) experienced a reduction of
50% or greater in the size of their largest SEGA at six months relative to
baseline. None of the patients developed a new SEGA while receiving Afinitor[2].
"SEGAs can be challenging for individuals with tuberous sclerosis and for the
whole family, which is why we are encouraged to see ongoing research and new
treatment options like Afinitor for these individuals," said Vicky Whittemore,
Vice President and Chief Scientific Officer of the patient advocacy group the
Tuberous Sclerosis Alliance.
For the treatment of patients with SEGA associated with TS, Afinitor received
FDA priority review status, which is granted to drugs that offer major advances
in treatment. This indication was approved under the FDA's accelerated approval
program, which provides patients access to a treatment where previously there
was an unmet medical need even though clinical benefit has yet to be
confirmed[7]. Novartis is continuing to study the efficacy and clinical benefit
of Afinitor for patients with SEGA associated with TS in a Phase III trial[3].
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 Votubia(®).
About the study
In an open-label, single-arm 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. As of March 8, 2010, the median duration
of treatment was 24.4 months (range 4.7-37.3 months)[2].
In the study, 32% of patients experienced a reduction of 50% or greater in the
size of their largest SEGA at six months relative to baseline. None of the
patients developed a new SEGA while receiving Afinitor[2].
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 ?30%) in the
open-label, single-arm trial were mouth sores, upper respiratory tract
infections, sinusitis, middle ear infections and fever[2].
All data from the study reported in this press release are based on the cut-off
date of March 8, 2010.
About the EXIST-1 Phase III trial
EXIST-1, a Phase III randomized, placebo-controlled trial aimed at evaluating
the results of the open-label, single-arm trial, is examining everolimus
treatment in patients with SEGAs associated with TS. Endpoints include SEGA
response, seizure rate and skin lesion response rate. The trial has completed
accrual and patients continue to be followed[3].
The trial involves patients in 10 countries, including Australia, Belgium,
Canada, Germany, Italy, the Netherlands, Poland, Russia, the UK and the US[3].
About Afinitor (everolimus)
Afinitor(®) (everolimus) tablets is now 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.
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 Certican(®) 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 Zortress(®) for the prophylaxis of organ
rejection in adult patients at low-moderate immunologic risk receiving a kidney
transplant.
Not all indications are available in every country. 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. Because of
the uncertainty of clinical trials, there is no guarantee that everolimus will
become commercially available for SEGAs anywhere else in the world.
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
Afinitor.
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.
Patients should avoid concurrent treatment with strong CYP3A4 and PgP inhibitors
and use caution with moderate inhibitors. Avoid concurrent treatment with strong
CYP3A4 or PgP inducers.
In advanced RCC, the most common adverse reactions (?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 (?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 (?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
reported.
Disclaimer
The foregoing release contains forward-looking statements that can be identified
by terminology such as "to explore," "committed," "will," "can," "encouraged,"
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 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.
About Novartis
Novartis provides healthcare solutions that address the evolving needs of
patients and societies. Focused solely on healthcare, Novartis offers a
diversified portfolio to best meet these needs: innovative medicines, cost-
saving generic pharmaceuticals, preventive vaccines, diagnostic tools and
consumer health products. Novartis is the only company with leading positions in
these areas. In 2009, the Group's continuing operations achieved net sales of
USD 44.3 billion, while approximately USD 7.5 billion was invested in R&D
activities throughout the Group. Headquartered in Basel, Switzerland, Novartis
Group companies employ approximately 100,000 full-time-equivalent associates and
operate in more than 140 countries around the world. For more information,
please visithttp://www.novartis.com.
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References
[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] Novartis data on
file.http://www.pharma.us.novartis.com/product/pi/pdf/afinitor.pdf. Accessed
October 2010.
[3] 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
at:http://clinicaltrials.gov/ct2/show/NCT00789828?term=exist-1&rank=1. Accessed
October 2010.
[4] Medkour A, et al. Neonatal Subependymal Giant Cell Astrocytoma. Pediatr
Neurosurg 2002;36:271-274.
[5] Nabbout R, et al. Early diagnosis of subependymal giant cell astrocytoma in
children with tuberous sclerosis. J Neurol Neurosurg Psychiatry 1999;66:370-375.
[6] National Institute of Neurological Disorders and Stroke. Tuberous Sclerosis
Fact Sheet. Available
athttp://www.ninds.nih.gov/disorders/tuberous_sclerosis/detail_tuberous_sclerosi
s.htm. Accessed October 2010.
[7] US Food and Drug Administration. Fast Track, Accelerated Approval and
Priority Review. Available
athttp://www.fda.gov/forconsumers/byaudience/forpatientadvocates/speedingaccesst
oimportantnewtherapies/ucm128291.htm
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Datum: 30.10.2010 - 04:11 Uhr
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