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European Commission Approves Licence Variation for Use of Zonegran® (zonisamide) in Children With Partial Epilepsy

     European Commission Approves Licence Variation for Use of Zonegran®
                (zonisamide) in Children With Partial Epilepsy

  PR Newswire

  HATFIELD, England, October 3, 2013

HATFIELD, England, October 3, 2013 /PRNewswire/ --

PRESS RELEASE FOR EU MEDIA ONLY NOT FOR U.S. MEDIA

The European Commission (EC) has approved the paediatric licence variation of
Zonegran ^® (zonisamide), a novel anti-epileptic drug (AED) with multiple
mechanisms of action and a chemical structure unrelated to any other AED. ^[1]
Zonisamide is now indicated as an adjunctive therapy in the treatment of
partial seizures, with or without secondary generalisation, in adolescents and
children aged six years and above in addition to its existing license in adult
patients. ^[ ^1]

Epilepsy is a common condition in children and adolescents, affecting around
10.5 million worldwide, with nearly one million living in Europe. ^[2]
However, only two thirds of these youngsters will achieve seizure control and
many will require additional AEDs to improve seizure control. ^[3] Epilepsy in
children often presents major challenges such as developmental and behavioural
problems resulting in educational underachievement and a lack of self-esteem.
These issues, which are frequently manifested in an attention deficit
disorder, withdrawal, anxiety or depression, have a negative impact on both
the child and their family. ^[ ^4]

"It is pleasingthat Zonegran has now been licensed to be prescribed for
children, as new options for young people with epilepsy are needed
desperately," said Professor Helen Cross, Great Ormond Street Hospital and
Young Epilepsy. "Epilepsyaffects all aspects of children and their family's
lives. New, effective and well tolerated treatments that can be used in
children to achieve a balance between stopping seizures and keeping side
effects to a minimum are welcomed by doctors, patients and parents."

The zonisamide paediatric licence variation was based on Study 312 (CATZ)
published in Epilepsia in July 2013. ^[ ^5] These data from a double-blind,
randomised, multicentre, placebo-controlled Phase III study, showed that
significantly more patients responded positively to treatment with zonisamide
(50%) versus treatment with placebo (31%), p=0.0044. ^[ ^5] The overall
incidence of treatment-emergent adverse events (TEAEs) was similar for
zonisamide versus placebo. ^[ ^5]

"We're delighted to announce Zonegran's EC paediatric license variation as the
drug has the potential to improve the lives of many young people living with
epilepsy," commented Gary Hendler, President and CEO, Eisai EMEA. "This
licence variation strengthens our epilepsy portfolio, enabling us to help more
people with epilepsy across a wide age range and achieve our vision of
becoming the number one epilepsy company by 2015."

The continued development of zonisamide underscores Eisai's human health care
mission, the company's commitment to innovative solutions in prevention, cure
and care for the health and wellbeing of people worldwide. Eisai is committed
to the therapeutic area of epilepsy and addressing the unmet medical needs of
patients with epilepsy and their families. Eisai is proud to currently market
more epilepsy products in EMEA than any other company.

Notes to Editors

About Zonegran (zonisamide)

Zonisamide is licensed in Europe as monotherapy in the treatment of partial
seizures, with or without secondary generalisation, in adults with newly
diagnosed epilepsy. Zonisamide is also indicated as adjunctive therapy in the
treatment of partial seizures, with or without secondary generalisation, in
adults, adolescents and children aged six years and above. ^[ ^1] It has a
broad spectrum of anti-epileptic modes of action and has no appreciable
effects on steady-state plasma concentrations of other AEDs, such as
phenytoin, carbamazepine and valproate. ^[ ^1] Zonegran is one of only four
AEDs with level A efficacy/effectiveness evidence as initial monotherapy for
adults with partial onset seizures. ^[ ^6]

Zonisamide is available in 25mg, 50mg, and 100mg capsule strengths. The
recommended daily dose for monotherapy use is 100mg once daily. In the third
and fourth weeks the dose may be increased to 200mg daily and then increased
to 300mg daily after the next two weeks. The recommended initial daily dose
for adjunctive use is 50mg in two divided doses. After one week the dose may
be increased to 100 mg daily and thereafter the dose may be increased at
weekly intervals, in increments of up to 100 mg. ^[ ^1]

For more information please visit: http://www.zonegran.eu

Phase III Study 312 (CATZ) ^[5]

Study 312 was a double-blind, randomised, placebo-controlled, multi-centre
study (n=207) to assess the efficacy and safety of adjunctive zonisamide in
paediatric partial onset seizures (6 - 17 years old). In the study, children
with partial epilepsy, receiving one or two antiepileptic drugs, were
randomised to receive either adjunctive zonisamide or placebo. Zonisamide was
initiated at 1 mg/kg/day, titrated to a target dose of 8 mg/kg/day over eight
weeks (one down-titration permitted) and maintained for 12 weeks. The primary
efficacy end point of the study was the proportion of responders (defined as a
≥50% seizure frequency reduction from baseline) during the 12-week maintenance
period.

The responder rates were found to be 50% for zonisamide vs. 31% for placebo (p
= 0.0044). The overall incidence of treatment emergent adverse events (TEAEs)
was similar for zonisamide (55.1%) vs. placebo (50.0%), with low rates of
serious TEAEs in both arms of the study (3.7% zonisamide vs. 2.0% placebo) and
TEAEs leading to withdrawal (0.9% vs. 3.0%).

Results of the Phase III study were published in July 2013 in Epilepsia.

Phase III Study 313 (CATZ Extension) ^[7],[8]

Study 313 was an open-label extension study to assess the efficacy and safety
of adjunctive zonisamide in paediatric partial onset seizures (6 - 18 years
old), following Phase III study 312 (CATZ). The safety study comprised a
double-blind transition period (patients previously treated with placebo were
up-titrated to a target zonisamide dose of 8 mg/kg/day; patients previously
treated with zonisamide continued at same dose) followed by flexible,
open-label dosing (duration 45‒57 weeks). The efficacy study began with a
double-blind transition period (duration 2‒11 weeks), during which patients
already receiving zonisamide continued at same dose, while those previously
receiving placebo switched to zonisamide, initiated at 1 mg/kg/day and
up-titrated to a target of 8 mg/kg/day (maximum 500 mg/day). This was followed
by an open-label period (duration 45‒57 weeks), during which zonisamide dosing
could be adjusted according to tolerability/response.

Most TEAEs were of mild or moderate intensity. Treatment-related TEAEs were
reported by 39/144 (27.1%) patients; most frequently, decreased weight (6.3%),
decreased appetite (4.2%) and headache (2.1%). Rates of serious
treatment-related TEAEs and TEAEs leading to discontinuation were low (2.1%
and 2.8%, respectively).

Efficacy results were similar for patients who initially received placebo
(40/72; 55.6%; 95% CI, 43.4%, 67.3%) and zonisamide (41/72; 56.9%; 95% CI,
44.7%, 68.6%) before entering the open label trial. Overall, 16/144 (11.1%)
patients achieved seizure freedom during open-label period (95% CI, 6.5%,
17.4%); results being identical for patients initially receiving placebo and
zonisamide (for both populations: 8/72; 11.1%; 95% CI, 4.9%, 20.7%). Seizure
frequency reduction was maintained throughout the study; the median percentage
decrease in seizure frequency being 65.9% during open-label period.

Results of the Phase III extension study were presented in September 2013 at
EPNS.

Pooled Data Study ^[9]

The pooled data study analysed data from 17 studies (including four
randomised, double-blind trials, n=398) to assess the safety of adjunctive
zonisamide in paediatric patients (≤16 years old) receiving ≥1 dose of study
drug. Analysis included 398 patients treated with zonisamide (

Most TEAEs were of mild or moderate intensity; the most frequently reported
treatment-related TEAEs (≥5%) being decreased appetite (13.7%), somnolence
(12.3%), fatigue (9.6%), irritability (7.5%) and lethargy (5.5%) in patients
aged 6-11 years, and decreased appetite (15.9%), fatigue (10.1%), somnolence
(8.7%), weight decreased (7.7%), dizziness (7.7%), headache (6.8%) and
insomnia (5.3%) in patients aged 12-16 years. Incidence of serious
zonisamide-related TEAEs was low (4.1% and 3.9% in patients aged 6-11 and
12-16 years, respectively). Incidence of TEAEs leading to discontinuation was
10.3%.

Results of the pooled data study were presented in September 2013 at EPNS.

About Epilepsy

Epilepsy is one of the most common neurological conditions in the world. ^[10]
There are an estimated six million people who live with epilepsy in Europe,
and an estimated 50 million people with the condition worldwide. Epilepsy is a
chronic disorder of the brain that affects people of all ages. It is
characterised by abnormal discharges of neuronal activity which causes
seizures. Seizures can vary in severity, from brief lapses of attention or
jerking of muscles, to severe and prolonged convulsions. Depending on the
seizure type, seizures may be limited to one part of the body, or may involve
the whole body. Seizures can also vary in frequency from less than one per
year, to several per day. Epilepsy has many possible causes but often the
cause is unknown.

About Eisai EMEA in Epilepsy

Eisai is committed to developing and delivering highly beneficial new
treatments to help improve the lives of people with epilepsy. The development
of AEDs is a major strategic area for Eisai in Europe, the Middle East,
Africa, Russia and Oceania (EMEA).

In the EMEA region, Eisai currently has four marketed treatments including:

  *Zonegran ^® (zonisamide) as monotherapy and adjunctive therapy in adults,
    adolescents and children above the age of 6 with partial onset seizures,
    with or without secondary generalisation. (Zonegran is under license from
    the originator Dainippon Sumitomo Pharma)
  *Zebinix ^® (eslicarbazepine acetate) as adjunctive therapy in adult
    patients with partial onset seizures, with or without secondary
    generalisation. (Zebinix is under license from BIAL)
  *Inovelon ^® (rufinamide) for the adjunctive treatment of seizures
    associated with Lennox-Gastaut Syndrome in patients >4 years. (Rufinamide
    was originally developed by Novartis)
  *Fycompa ^® (perampanel) for use as an adjunctive treatment for partial
    onset seizures, with or without secondarily generalised seizures, in
    patients with epilepsy aged 12 years and older

About Eisai

Eisai is one of the world's leading research and development (R&D) based
pharmaceutical companies and we define our corporate mission as "giving first
thought to patients and their families and to increasing the benefits health
care provides," which we call human health care ( hhc ).

Eisai concentrates its R&D activities in three key areas:

  *Neuroscience, including: Alzheimer's disease, epilepsy, pain and weight
    loss
  *Oncology including: anticancer therapies; tumour regression, tumour
    suppression, antibodies, etc.
  *Vascular/Immunological reaction including: thrombocytopenia, rheumatoid
    arthritis, psoriasis, inflammatory bowel disease

With operations in the U.S., Asia, Europe and its domestic home market of
Japan, Eisai employs more than 10,000 people worldwide. From its EMEA
Knowledge Centre in Hatfield, UK, Eisai has recently expanded its business
operations to include Europe, the Middle East, Africa, Russia and Oceania
(EMEA). Eisai EMEA has sales and marketing operations in over 20 markets,
including the United Kingdom, France, Germany, Italy, Spain, Switzerland,
Sweden, Ireland, Austria, Denmark, Finland, Norway, Portugal, Czech Republic,
Slovakia, the Netherlands, Belgium, Russia and the Middle East.

For further information please visit our web site http://www.eisai.co.uk

References

1. Eisai Ltd 2013. Zonegran Summary of Product Characteristics (last updated
February 2013)

2. Forsgren L. et al. The epidemiology of epilepsy in Europe - a systematic
review. European Journal of Neurology 2005: 12(4) 245-253)

3. Epilepsy Society. Medication for children.
http://www.epilepsysociety.org.uk/AboutEpilepsy/Treatment/Medicationforchildren
[Accessed 16 July 2012].

4. Sabbagh S, et al. Impact of epilepsy characteristics and behavioral
problems on school placement in children.  Epilepsy & Behavior 9 (2006)
573-578

5. Guerrini R. et al. A randomized, phase III trial of adjunctive zonisamide
in pediatric patients with partial epilepsy. Epilepsia 2013

6. Glauser T. et al. Updated ILAE evidence review of antiepileptic drug
efficacy and effectiveness as initial monotherapy for epileptic seizures and
syndromes.
http://www.ilae.org/Visitors/Documents/Guidelines-epilepsia-12074-2013.pdf
[Accessed April 2013]

7. Guerrini R. et al. Safety and potential impact on growth and developmental
skills of long-term adjunctive zonisamide therapy in paediatric patients with
partial epilepsy. EPNS 2013 abstract 1765

8. Rosati, A. et al. Efficacy of long-term adjunctive zonisamide therapy in
paediatric patients with partial epilepsy: results of an open-label extension
study of a Phase III, randomised, double-blind, placebo-controlled trial. EPNS
2013 abstract 1768

9. Giorgi, L. et al. Safety of adjunctive zonisamide in paediatric epilepsy
patients: results from a pooled analysis of 17 studies. EPNS 2013 abstract
1767

10. Pugliatti M et al. Estimating the cost of epilepsy in Europe: A review
with economic modeling. Epilepsia 2007: 48(12) 2224-2233.

Date of preparation: October 2013 Job code: Zonegran-UK2511

Contact: Media Enquiries: Eisai Europe Ltd: Cressida Robson / Charlotte
Andrews, +44(0)7908 314 155/+44(0)7947 231 513, Cressida_Robson@eisai.net,
Charlotte_Andrews@eisai.net; Tonic Life Communications: Frances Murphy/Nicola
Lilley, +44(0)207 798 9262 /+44 (0) 207 798 9905, frances.murphy@toniclc.com,
nicola.lilley@toniclc.com