Novartis drug Votubia® receives EU approval to treat refractory partial-onset seizures in patients with TSC
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Novartis International AG /
Novartis drug Votubia® receives EU approval to treat refractory partial-onset
seizures in patients with TSC
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* Votubia is the first adjunctive treatment approved in the EU specifically
for partial-onset seizures in children and adults with tuberous sclerosis
complex (TSC)
* Approval addresses unmet need as up to 60% of patients with TSC suffering
from seizures become unresponsive to available anti-epileptic therapies[1]
* Decision marks the third TSC-related indication for Votubia in the EU, where
it is also approved to treat SEGA and renal angiomyolipomas[2]
Basel, January 31, 2017 - Novartis today announced that the European Commission
has approved Votubia(®) (everolimus) dispersible tablets* as an adjunctive
treatment for patients aged two years and older whose refractory partial-onset
seizures, with or without secondary generalization, are associated with tuberous
sclerosis complex (TSC). Votubia is now the first approved pharmacologic therapy
in all 28 member states of the European Union (EU), plus Iceland and Norway,
specifically for the treatment of refractory partial-onset seizures associated
with TSC[2].
"With this latest approval of Votubia in the EU, patients with TSC suffering
from refractory partial-onset seizures - one of the most debilitating
manifestations of TSC - now have a new therapeutic option to address a critical
unmet need," said Bruno Strigini, CEO, Novartis Oncology. "This is a welcome
advance and an important milestone in our ongoing commitment to improving care
for this patient community."
The EU approval of Votubia was based on efficacy and safety data from a pivotal
Phase III study (EXIST-3: EXamining everolimus In a Study of TSC), which found
that when used as an adjunctive therapy, Votubia significantly reduced the
frequency of refractory partial-onset seizures associated with TSC compared to
placebo. Efficacy and safety of two trough exposure concentrations of Votubia,
3-7 ng/mL (low exposure) and 9-15 ng/mL (high exposure) were assessed. Patients
in all treatment arms concomitantly received one to three anti-epileptic drugs
(AEDs) during the eighteen weeks of study core phase. The youngest patient
enrolled was two years of age. Seizure response rate (>=50% reduction) was
significantly greater with Votubia low exposure (LE) (28.2%, 95% confidence
interval [CI] 20.3 - 37.3; p=0.008) and high exposure (HE) (40.0%, 95% CI 31.5 -
49.0; p<0.001) vs placebo (15.1%, 95% CI 9.2 - 22.8). The median percentage
reduction from baseline in seizure frequency was also significantly greater
among patients randomized to Votubia LE (29.3%, 95% CI 18.8 - 41.9; p=0.003) and
HE (39.6%, 95% CI 35.0 - 48.7; p<0.001) vs placebo (14.9%, 95% CI 0.1 - 21.7).
The most common all-grade adverse events (AEs) of any cause reported during the
core phase at frequencies >=15% in Votubia LE/HE arms included stomatitis,
diarrhea, nasopharyngitis, upper respiratory tract infection, and pyrexia[3].
Tuberous sclerosis complex is a rare genetic disorder affecting up to one
million people worldwide[4]. Approximately 85% of individuals with TSC are
affected by epilepsy, and uncontrolled seizures associated with TSC can be
debilitating for patients[1]. Votubia is the only approved non-surgical option
indicated for treating non-cancerous brain and kidney tumors in certain patients
with TSC. EXIST-3 is the first Phase III study to demonstrate the significant
benefit of adjunctive Votubia in the treatment of refractory partial-onset
seizures in patients with TSC[2],[5]. These data may be used to support
regulatory filings in other countries.
Votubia works by inhibiting the mammalian target of rapamycin (mTOR), a protein
that regulates multiple cellular functions. TSC is caused by mutations in the
TSC1 or TSC2 genes, resulting in hyperactive signaling of the mTOR pathway which
can lead to increased cellular growth and proliferation, neuronal hyper-
excitability, abnormalities in cortical architecture and network function and
impaired synaptic plasticity[6],[7]. Pre-clinical research suggests that
hyperactive mTOR activity may influence several mechanisms of epileptogenesis,
the gradual process by which the brain develops epilepsy in TSC[8].
About EXIST-3 (EXamining everolimus In a Study of TSC)
EXIST-3 is a Phase III, three-arm, randomized, double-blind, placebo-controlled
study of the efficacy and safety of high and low exposure ranges of Votubia as
adjunctive therapy in patients with TSC who have refractory partial-onset
seizures, defined as seizures persisting despite the use of two or more
sequential regimens of single or combined anti-epileptic drugs (AEDs). The study
enrolled male and female participants (ages 2.2 - 56.3 years) with clinically
defined TSC, who were on stable doses of one to three AEDs for at least four
weeks prior to a two-month, pre-randomization, evaluation period[2],[3].
The primary objective was to assess the effectiveness of adjunctive Votubia as
compared to placebo in reducing refractory partial-onset seizures in patients
with TSC. Secondary objectives included the percentage of patients free from
seizure during the maintenance period, change in seizure frequency, and safety.
The most frequent (>=10%) all grade adverse events (AEs), of any cause, reported
with Votubia LE/HE vs placebo included stomatitis (54.7%/63.8% vs 9.2%),
diarrhea (17.1%/21.5% vs 5.0%), nasopharyngitis (13.7%/16.2% vs 16.0%), upper
respiratory tract infection (12.8%/15.4% vs 12.6%), pyrexia (fever) (19.7%/13.8%
vs 5.0%), vomiting (12.0%/10.0% vs 9.2%), cough (11.1%/10.0% vs 3.4%), and rash
(6.0%/10.0% vs 2.5%). Grade 3 or 4 AEs occurred in 13 (10.9%) patients in the
placebo group, 21 (17.9%) patients in the LE group, and 31 (23.8%) patients in
the HE group[3].
About tuberous sclerosis complex
Tuberous sclerosis complex (TSC) may cause non-cancerous tumors to form in vital
organs including the brain, kidney, heart, lungs, and skin, as well as resulting
disorders such as epilepsy, autism, cognitive impairment, behavioral problems,
and psychiatric disorders. Many people with TSC show evidence of the disease in
the first year of life. However, because manifestations vary from person to
person and can take years to develop, many children are not diagnosed until
later in life, often with the onset of seizures, skin lesions or other
significant symptoms, such as developmental delays. Because TSC is a lifelong
condition, the latest professional diagnostic guidelines issued in 2012 advise
that individuals be monitored by a doctor experienced with the disorder to
ensure tumor growth or new symptoms are identified early[6],[9].
About Votubia (everolimus)
In the European Union (EU), everolimus is approved as Votubia tablets for the
treatment of adult patients with renal angiomyolipoma associated with 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 in sum of angiomyolipoma
volume. Votubia tablets and dispersible tablets are also indicated in the EU for
the treatment of patients 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. Votubia dispersible tablets are also indicated in the EU as an
adjunctive treatment for patients aged 2 years and older whose refractory
partial-onset seizures, with or without secondary generalization, are associated
with TSC.
In the United States (US), everolimus is approved as Afinitor(®) tablets for the
treatment of adult patients with renal angiomyolipoma and TSC, not requiring
immediate surgery. Afinitor tablets and Afinitor Disperz(TM) (dispersible
tablets) are also indicated in the US in pediatric and adult patients with TSC
for the treatment of SEGA that requires therapeutic intervention but cannot be
curatively resected.
Additionally, Afinitor tablets are approved in >110 countries, including the US
and EU, for the treatment of advanced renal cell carcinoma following progression
on or after vascular endothelial growth factor (VEGF)-targeted therapy (in the
US, specifically following sunitinib and sorafenib); locally advanced,
metastatic or unresectable progressive neuroendocrine tumors (NET) of pancreatic
origin; and for advanced HR+/HER2- breast cancer in combination with exemestane,
after prior endocrine therapy. It is also approved in >40 countries, including
the US and EU, for the treatment of adult patients with progressive, well-
differentiated (Grade 1 or 2), nonfunctional NET of gastrointestinal (GI) or
lung origin that are unresectable, locally advanced or metastatic.
Everolimus is available from Novartis under the brand names Afinitor,
Certican(®) and Zortress(®) for use in oncology and transplant patient
populations 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. The safety and efficacy profile of everolimus has not yet been
established outside the approved indications. Because of the uncertainty of
clinical trials, there is no guarantee that everolimus will become commercially
available for additional indications anywhere else in the world.
Important safety information
Votubia/Afinitor can cause serious side effects including lung or breathing
problems, infections (including sepsis), and kidney failure, which can lead to
death. Patients taking concomitant angiotensin-converting enzyme (ACE)
inhibitors may be at an increased risk for angioedema. Mouth ulcers and mouth
sores are common side effects. Votubia/Afinitor can affect blood cell counts,
kidney and liver function, and blood sugar, cholesterol, and triglyceride
levels. Votubia/Afinitor may cause fetal harm in pregnant women. Highly
effective contraception is recommended for women of child-bearing potential
while receiving Votubia/Afinitor and for up to eight weeks after ending
treatment. Women taking Votubia/Afinitor should not breast feed. Fertility in
women and men may be affected by treatment with Votubia/Afinitor.
The most common adverse drug reactions (incidence >=10 percent) are infections
(including sore throat and runny nose, upper respiratory tract infection,
pneumonia, sinusitis, and urinary tract infection), mouth ulcers, skin rash,
feeling tired, diarrhea, fever, vomiting, nausea, cough, decreased appetite, low
level of red blood cells, headache, abnormal taste, absence of menstrual
periods, acne, inflammation of lung tissue, irregular menstrual periods,
swelling of extremities or other parts of the body, high level of blood sugar,
feeling weak, itching, weight loss, high levels of cholesterol, and nose bleeds.
The most common Grade 3-4 adverse drug reactions (incidence >=2 percent) are
mouth ulcers, infections (including pneumonia), low level of red blood cells,
high level of blood sugar, feeling tired, absence of menstrual periods,
diarrhea, low white blood cells, inflammation of lung tissue, feeling weak,
fever, and spontaneous bleeding or bruising. Cases of hepatitis B reactivation,
blood clots in the lung or legs, and pneumocystis jirovecii pneumonia (PJP) have
been reported. Abnormalities were observed in hematology and clinical chemistry
laboratory tests.
Disclaimer
The foregoing release contains forward-looking statements that can be identified
by words such as "advance," "milestone," "ongoing," "commitment," "may,"
"suggests," "yet," "will," or similar terms, or by express or implied
discussions regarding potential new indications or labeling for Votubia, or
regarding potential future revenues from Votubia. You should not place undue
reliance on these statements. Such forward-looking statements are based on the
current beliefs and expectations of management regarding future events, and are
subject to significant known and unknown risks and uncertainties. Should one or
more of these risks or uncertainties materialize, or should underlying
assumptions prove incorrect, actual results may vary materially from those set
forth in the forward-looking statements. There can be no guarantee that Votubia
will be submitted or approved for any additional indications or labeling in any
market, or at any particular time. Nor can there be any guarantee that Votubia
will be commercially successful in the future. In particular, management's
expectations regarding Votubia could be affected by, among other things, the
uncertainties inherent in research and development, including clinical trial
results and additional analysis of existing clinical data; regulatory actions or
delays or government regulation generally; the company's ability to obtain or
maintain proprietary intellectual property protection; general economic and
industry conditions; global trends toward health care cost containment,
including ongoing pricing pressures; safety, quality or manufacturing issues,
and other risks and factors referred to in Novartis AG's current Form 20-F on
file with the US Securities and Exchange Commission. 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,
cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has
leading positions globally in each of these areas. In 2016, the Group achieved
net sales of USD 48.5 billion, while R&D throughout the Group amounted to
approximately USD 9.0 billion (USD 8.4 billion excluding impairment and
amortization charges). Novartis Group companies employ approximately 118,000
full-time-equivalent associates. Novartis products are sold in approximately
155 countries around the world. For more information, please visit
http://www.novartis.com.
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*Known as Afinitor (everolimus) for certain patients with SEGA or renal
angiomyolipoma associated with TSC in the US and other countries.
References
[1] Chu-Shore C.J., et al. The natural history of epilepsy in tuberous
sclerosis complex. Epilepsia. 2010: 51(7): 1236-1241.
[2] Votubia Summary of Product Characteristics. January 2017.
[3] French. J.A., et al. Adjunctive everolimus therapy for treatment-
resistant focal-onset seizures associated with tuberous sclerosis (EXIST-
3): a phase 3, randomised, double-blind, placebo-controlled study.
Lancet. Available at http://dx.doi.org/10.1016/S0140-6736(16)31419-2.
Accessed January 2017.
[4] Budde, K. and Gaedeke, J. Tuberous sclerosis complex-associated
angiomyolipomas: focus on mTOR inhibition. American Journal of Kidney
Diseases. 2012:276-283.
[5] Afinitor (everolimus) Prescribing information. East Hanover, New Jersey,
USA: Novartis Pharmaceuticals Corporation; February 2016.
[6] National Institute of Neurological Disorders and Stroke fact sheet. 2010.
[7] Wong, M. Mammalian target of rapamycin (mTOR) pathways in neurological
diseases. Biomed Journal. 2013; 36(2): 1-17.
[8] Ostendorf, A. and Wong, M. mTOR inhibition in epilepsy: rationale and
clinical perspectives. CNS Drugs. 2015:91-99.
[9] Northrup, H. et al. Tuberous sclerosis complex diagnostic criteria
update: recommendations of the 2012 international tuberous sclerosis
complex consensus conference. Pediatric Neurology. 2013; 49: 243-254
# # #
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Datum: 31.01.2017 - 07:15 Uhr
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