New Data For Zonegran® (Zonisamide) to be Presented at The European Paediatric Neurology Society Congress

HATFIELD, England, September 25, 2013 /PRNewswire/ --

New Zonegran^® (zonisamide) data in adolescents and children will be presented at the EPNS congress in Brussels.^[1],[2],[3]On 25 July, Eisai received CHMP positive opinion to extend the current indication for zonisamide in the European Union (EU) to include adjunctive treatment of partial seizures with or without secondary generalisation for adolescents and children aged 6 years and above. This indication is awaiting final European Commission ratification.

Epilepsy is a common condition in children and adolescents, affecting around 10.5 million worldwide, with nearly one million living in Europe.^[4],[5]Although epilepsy is common among children and adolescents, only two thirds will achieve seizure control and many will require additional AEDs to improve seizure control.^[6]

Two of the abstracts focus on long-term safety and efficacy data for zonisamide as an adjunctive therapy in paediatric patients (6 - 18 years old) with partial epilepsy.^[7] The first study demonstrated an acceptable long-term (>1 year) safety profile versus placebo with no consistent detrimental effects on growth and development skills.^[4] The second demonstrated that efficacy versus placebo in this patient group was maintained over a treatment period of >1 year.^[5] A third study presented is a pooled safety analysis of 17 studies and demonstrated that zonisamide has an acceptable safety profile when used as an adjunctive treatment in paediatric patients.^[6]

Zonisamide is an anti-epileptic drug (AED) with multiple mechanisms of action and a structure which is chemically unrelated to any other AED.^[8] Zonisamide is indicated in Europe as monotherapy in the treatment of partial seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy and as adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation, in adults.^[4]

The zonisamide CHMP positive opinion and EMA application file are based on Study 312 (CATZ) published in Epilepsia in July 2013.^[7] 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.^[7] The overall incidence of treatment-emergent adverse events (TEAEs) was similar for zonisamide versus placebo.^[7]

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.^[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.^[9]

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)^[7]

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)^[4],[5]

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 ^[6]

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.^[9] 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 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. 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

2. 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

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

4. Guerrini R. et al. Epilepsy in children. The Lancet. 2006 367 (9509): 499-524

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

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

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

8. Eisai Ltd 2013. Zonegran Summary of Product Characteristics [http://www.medicines.org.uk/emc/medicine/16240/SPC/Zonegran+25%2c+50%2c+100+mg+Hard+Capsules ] (last updated February 2013)

9. 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: September 2013

Job code: Zonegran-UK2510