Study at ASCO shows Novartis drug Afinitor® first to shrink SEGA brain tumors in children and adults with tuberous sclerosis
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Novartis International AG / Study at ASCO shows Novartis drug Afinitor® first to shrink SEGA brain tumors in children and adults with tuberous sclerosis processed and transmitted by Hugin AS. The issuer is solely responsible for the content of this announcement.
* Phase II study shows meaningful reduction in brain tumor size in 75% of
patients with subependymal giant cell astrocytomas (SEGAs) from baseline to
six months[1]
* SEGAs are benign brain tumors associated with tuberous sclerosis (TS) that
primarily affect children and adolescents and can cause severe brain
swelling[2]
No patient developed new tumors or needed brain surgery, the only current
treatment option for patients with SEGAs that are growing( )[1]
* Novartis submitted file to FDA based on this study of 28 patients and is
enrolling the EXIST Phase III trials to further study everolimus in patients
with TS
Basel, June 5, 2010 - Novartis announced today that results from a Phase II
study show Afinitor(®) (everolimus) tablets is the first medication in a
clinical trial to decrease the size of subependymal giant cell astrocytomas
(SEGAs), benign brain tumors associated with tuberous sclerosis (TS)[1],[2]. In
this study of 28 patients presented today at the 46th American Society of
Clinical Oncology (ASCO) annual meeting in Chicago, 75% of patients experienced
a reduction of 30% or greater in the size of their brain tumors from baseline to
six months (p<0.001)[1].
Everolimus is approved under the trade name Afinitor(®) (everolimus) tablets for
the treatment of patients with advanced renal cell carcinoma whose disease has
progressed on or after treatment with vascular endothelial growth factor
(VEGF)-targeted therapy.
Tuberous sclerosis is a genetic disorder that causes tumors to form in many
vital organs. It is estimated to affect 25,000 to 40,000 people in the US and
one to two million worldwide[3]. These tumors can grow in any organ, but
typically occur in the brain, kidneys, heart, eyes, lungs and skin[3]. Common
symptoms include seizures, mental retardation, autism, behavior problems and
kidney and skin abnormalities[3].
SEGAs, occurring in 5-20% of patients with TS, primarily affect children and
adolescents and can cause severe swelling in the brain or hydrocephalus[1],[2].
Currently, the only treatment option for patients with growing SEGAs is brain
surgery( )[1]. Patients enrolled in the study had evidence of established SEGA
growth. The data show everolimus significantly decreased the size of SEGAs and
no patient required surgery or developed new SEGAs while receiving everolimus.
These data formed the basis for a regulatory submission to the US Food and Drug
Administration (FDA) for the treatment of patients with SEGA associated with TS.
Everolimus has orphan drug designation for TS in the US. Orphan drugs are those
developed to treat diseases affecting fewer than 200,000 people
nationally[4],[5].
"Our hope is to offer these patients the first approved medication to treat
SEGAs associated with tuberous sclerosis," said Herve Hoppenot, President of
Novartis Oncology. "As part of our worldwide everolimus development program,
Novartis has launched the EXIST Phase III trial program to continue to evaluate
the impact of everolimus in the fight against tuberous sclerosis."
Tuberous sclerosis is caused by defects in the TSC1 and TSC2 genes that
negatively control mTOR, a protein that acts as a central regulator of tumor
cell division, blood vessel growth, cell metabolism and cell orientation in
neurons[3],[6]. By inhibiting mTOR activity in this protein pathway, everolimus
may inhibit tumor growth and resulting symptoms caused by tumor growth in the
brain, including hydrocephalus[1],[7].
About the Phase II study
In this open-label study, 28 patients aged three years and above (median age=11,
range 3-34) with evidence of established SEGA growth received everolimus orally
at a dose of 3 mg/m(2)/day (once-daily or on an alternate day regimen), which
was subsequently adjusted subject to tolerability to attain a whole blood trough
concentration of 5-15 ng/mL. The median duration of treatment was 21.5 months.
The study met its primary 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 6). Results from the independent central
review assessment showed that 75% (21 of 28 patients) experienced a reduction in
SEGA volume of 30% or greater from baseline to six months (p<0.001)[1].
Study findings also showed that everolimus was associated with a clinically
relevant reduction in overall frequency of seizures (p=0.022). Of 16 patients
with seizures at the start of the study for whom video-EEGs were available, 9
experienced decreases in seizure frequency, 6 reported no change and 1
experienced an increase (median change -1.0, p=0.022). A reduction was also
evident in the proportion of patients experiencing seizures on a daily basis
from 7 of 26 patients at baseline to 2 of 25 patients at month 6 (based on
caregiver observation)[1].
In the study, everolimus had a safety profile consistent with previous studies
with this drug. The most common adverse events (?10%) included: stomatitis or
mouth sores (79%), upper respiratory tract infection (79%), sinusitis (39%),
middle ear infection (36%), fever (36%), convulsion (25%), acne-like skin
inflammation (25%), diarrhea (25%), cellulitis (21%), vomiting (21%), body tinea
or fungal infection (18%), cough (18%), headache (18%), personality change
(18%), rash (18%), contact dermatitis (14%), dizziness (14%), gastroenteritis
(14%), external ear infection (14%), allergic rhinitis or inflammation of nasal
passages (14%), skin infection (14%), acne (11%), constipation (11%), dry skin
(11%), gastric infection (11%), hypertriglyceridemia or high blood triglyceride
levels(11%), skin disorder (11%) and leukopenia or decreased white blood cell
count (11%). Grade three adverse events included convulsion (7%), stomatitis
(4%), sinusitis (4%), vomiting (4%), dizziness (4%), leukopenia (4%), pneumonia
(4%), aspiration or breathing in a foreign object (4%), viral bronchitis (4%),
cyclic neutropenia or cyclical decrease in white blood cell count (4%), sleep
apnea syndrome or suspension of breathing while asleep (4%) and tooth infection
(4%). A single grade 4 convulsion was reported.
About the EXIST trial program
Two Phase III trials called EXIST (EXamining everolimus In a Study of TS) have
been initiated and are currently enrolling patients to further explore the
potential of everolimus for the treatment of TS[8],[9].
The EXIST-1 study will examine everolimus treatment in patients with SEGAs,
including tumor shrinkage, as well as evaluate the effect of everolimus
treatment on seizures and skin abnormalities associated with TS[8]. The EXIST-2
study will evaluate everolimus in patients with angiomyolipoma associated with
either TS or sporadic lymphangioleiomyomatosis (LAM)[9]. Angiomyolipomas, benign
tumors of blood vessels, muscle and fat typically located in the kidney, are
common in patients with TS[3],[10]. The trials are currently enrolling patients
in 11 countries, including Australia, Belgium, Canada, France, Germany, Italy,
the Netherlands, Poland, Russia, the UK and the US[8],[9].
For more information about the EXIST studies and other everolimus clinical
trials across tumor types, healthcare professionals can visit
www.theWIDEprogram.com
About everolimus
In the European Union (EU), everolimus is approved under the trade name
Afinitor(®) (everolimus) tablets 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. In the US,
Afinitor is approved 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.
As an investigational compound, the safety and efficacy profile of everolimus
has not yet been established in TS. The dosage strength of everolimus when used
for studying the TS patient population is different from that when used for its
approved RCC indication. Everolimus is available for TS through carefully
controlled and monitored clinical trials. These trials are designed to better
understand the potential benefits and risks of the compound. Because of the
uncertainty of clinical trials, there is no guarantee that everolimus will
become commercially available for TS anywhere in the world.
Afinitor (everolimus) tablets important safety information
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.
Avoid concurrent treatment with strong CYP3A4 and PgP inhibitors and use caution
with moderate inhibitors. Avoid concurrent treatment with strong CYP3A4 or PgP
inducers.
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,
dyspnea and dysgeusia. Common adverse reactions (?1 to <10%) include headache,
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.
Disclaimer
The foregoing release contains forward-looking statements that can be identified
by terminology such as "can," "to further study," "encouraged," "hope," "to
continue to evaluate," "may," "to further explore," "potential," "will," 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 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 clinical trial results, including
unexpected new clinical data and unexpected additional analysis of existing
clinical data; unexpected regulatory actions or delays or government regulation
generally; 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 visit http://www.novartis.com
Novartis is on Twitter. Sign up to follow (at)Novartis at
http://twitter.com/novartis. For more information about the 2010 ASCO Annual
Meeting on Twitter, search for #ASCO10.
References
[1] Franz DN, et al. Everolimus for subependymal giant-cell astrocytomas
(SEGAs) in tuberous sclerosis (TS). Abstract # 2004. American Society of
Clinical Oncology 2010 Annual Meeting, Chicago.
[2] Tuberous Sclerosis Alliance. Available at
http://www.tsalliance.org/documents/Subependymal%20Giant%20Cell%20Tumor%20SGCT%2
0or%20Subependymal%20Giant%20Cell%20Astrocytoma%20SEGA.pdf. Accessed May 2010.
[3] National Institute of Neurological Disorders and Stroke. National
Institute of Health. Available at
http://www.ninds.nih.gov/disorders/tuberous_sclerosis/detail_tuberous_sclerosis.
htm. Accessed May 2010.
[4] US Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm. Accessed May
2010.
[5] Orphan Drug Act. Sec. 316.21 (c). US Food and Drug Administration.
Available at:
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/Howto
applyforOrphanProductDesignation/DefinitionofDiseasePrevalence/ucm135130.htm.
Accessed May 2010.
[6] Meikle L, et al. Response of a neuronal model of tuberous sclerosis to
mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt
signaling lead to improved survival and function. J Neurosci. 2008 May
21;28(21):5422-32.
[7] Meric-Bernstam F and Gonzalez-Angulo AM. Targeting the mTOR signaling
network for cancer therapy. J Clin Oncol. 2009 May 1;27(13):2278-87. Epub 2009
Mar 30.
[8] 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 May
2010.
[9] Efficacy and Safety of RAD001 in Patients Aged 18 and Over With
Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or
Sporadic Lymphangioleiomyomatosis (LAM) (EXIST-2). Available at:
http://clinicaltrials.gov/ct2/show/NCT00790400?term=exist-2&rank=1. Accessed May
2010.
[10] The LAM Foundation. Renal Angiomyolipomas. Available at:
http://www.thelamfoundation.org/medical-providers/hrct-screening.html. Accessed
May 2010.
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