-
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
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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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