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

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 pleasing that 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. "Epilepsy affects 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 (<12 years, n=191; 12-16 years, n=207). All but seven patients received zonisamide as adjunctive therapy. Mean zonisamide dose was 253.1 mg/day and mean exposure duration was 318.7 days.  

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