Eisai Receives Approval in Russia for its Antiepileptic Treatment Zonegran® (Zonisamide) for Use in Children and Adolescents

HATFIELD, England, November 17, 2014 /PRNewswire/ --

Zonegran^® (zonisamide) receives approval in Russia for the treatment of partial epilepsy in children and adolescents. Zonisamide, a novel anti-epileptic drug (AED) with multiple mechanisms of action and a chemical structure unrelated to any other AED, is indicated in Russia and 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, adolescents and children aged six years and above.^[1]

Epilepsy is one of the most common neurological diseases in the world.^[2] Around three out of every 1,000 people in Russia live with epilepsy, 82% of whom have partial (focal) epilepsy.^[3] Epilepsy diagnosed in childhood has long-term implications for health and well-being and timely diagnosis and appropriate treatment are essential.^[4] Although epilepsy is common among children, only two thirds of those with the condition will achieve seizure control and many will require additional AEDs to improve seizure control.^[5]

"It is good news that we have a new treatment option available for children and adolescents with partial epilepsy in Russia. Epilepsy can affect every aspect of a child's and their family's life; well-tolerated and effective treatments are therefore very welcome," commented Andrey Petrukhin, Professor of the Child Neurology Department at the Russian State Medical University, Russia.  

This paediatric approval in Russia is based on Study 312 (CATZ) published in Epilepsia in July 2013.^[6] The double-blind, randomised, multicentre, placebo-controlled Phase III study showed that significantly more patients responded positively to treatment with zonisamide (50%) compared to treatment with placebo (31%), p=0.0044.^[6] The overall incidence of treatment-emergent adverse events (TEAEs) was similar in patients receiving zonisamide compared to placebo.^[6] These data are supported by results from the long-term Phase III study (Study 313), which demonstrate that zonisamise is well tolerated and efficacious when used as an adjunctive treatment in children aged between 6-17 years for at least one year.^[7]

"The availability of Zonegran in Russia for use in children and adolescents is in line with our on-going commitment to the therapeutic area of epilepsy and our drive to increase the benefits provided through our medicines," commented Olga Konopleva, Managing Director, Eisai Russia.

The continued development of zonisamide underscores Eisai's human health care (hhc) mission, the company's commitment to innovative solutions in disease prevention, cure and care for the health and wellbeing of people worldwide. Eisai is committed to the therapeutic area of epilepsy and to address the unmet medical needs of people with epilepsy and their families. Eisai is proud to market currently 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 in Europe as adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation, in adults, adolescents and children aged six years and above.^[8] 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] Worldwide there has been an estimated 1,274,963 patient-years of exposure to zonisamide (from 31.03.1989 to 31.03.2013).^[9]

Zonisamide is available in 25mg, 50mg, and 100mg capsule strengths. The recommended initial daily dose for adjunctive use in children aged 6 and above is 1mg/kg. The recommended daily dose is 6-8mg/kg/day for patients weighing 22-55kg and 300-500mg/day for patients over 55kg.^[8]

Phase III Study 312 (CATZ)^[6]

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%).

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

Study 313 was an open-label extension study to assess the long-term efficacy and safety of adjunctive zonisamide in paediatric partial onset seizures (n=144, 6-18 years old), following Phase III study 312 (CATZ). Patients started with a double-blind transition period (2-11 weeks), during which patients on zonisamide continued at the same dose and those on placebo switched to zonisamide 1mg/kg/day, up-titrated to 8mg/kg/day to a maximum of 500mg/day. During the subsequent open label period (45-57 weeks), zonisamide dosing was adjusted according to tolerability and response. Tolerability, efficacy, growth and development assessments were made throughout the study.

The results of the study showed a low incidence of serious treatment-emergent adverse events (TEAEs) (2.1%) and TEAEs leading to discontinuation from the study (2.8%). During the open-label period, 56.3% of patients were classified as responders to treatment and 11.1% achieved seizure freedom. Tanner staging (a scale of physical development in children, adolescents and adults) and skeletal development were as expected for the age range of children in the study. Changes were minimal for the Child Behaviour Checklist (a widely used method of identifying problem behavior in children) and for school performance scores.  Most of the children studied were 'much improved'/'very much improved' based on physician (73.8%) and parent/guardian (75.4%) global impressions of change. The results of the Controlled Oral Word Association Test (COWAT), an evaluation that measures the verbal fluency of an individual, and letter fluency scores, showed no evidence of impairment with zonisamide treatment.^[1]      

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.

About Epilepsy  

Epilepsy is one of the most common neurological conditions in the world, affecting approximately eight in 1,000 people in Europe, and an estimated 50 million people worldwide.^[10],[11] Epilepsy is a chronic disorder of the brain that affects people of all ages. It is characterised by abnormal discharges of neuronal activity causing 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 the development and delivery of 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:

• 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
• Inovelon^® (rufinamide) for the adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome in patients >4 years. (Rufinamide was originally developed by Novartis)
• Zonegran^® (zonisamide) 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 generalisation, in adults, adolescents and children aged six years and above. (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)

About Eisai Co., Ltd. 

Eisai Co., Ltd. is a leading global research and development-based pharmaceutical company headquartered in Japan. 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 our human health care (hhc) philosophy. With over 10,000 employees working across our global network of R&D facilities, manufacturing sites and marketing subsidiaries, we strive to realise our hhc philosophy by delivering innovative products in multiple therapeutic areas with high unmet medical needs, including Oncology and Neurology. 

As a global pharmaceutical company, our mission extends to patients around the world through our investment and participation in partnership-based initiatives to improve access to medicines in developing and emerging countries.

For more information about Eisai Co., Ltd., please visit http://www.eisai.com.  

References 

1. http://www.grls.rosminzdrav.ru/ImgInstr.aspx?folder=ScanVavilova&Filepath=\Ne_trebuet_vnesenia\Net_ND_IZM\451051\IP_IZM&idReg=132455&isOld=0&fileType=jpg&pfolder=2

2. ILAE/IBE/WHO, Epilepsy in the WHO European Region: Fostering Epilepsy Care in Europe 2010. Available at: http://www.ilae.org/Visitors/Documents/ILAEAnnual-Report2010Final_000.pdf (accessed September 2014)

3. Guekht A. et al. The epidemiology of epilepsy in the Russian Federation. Epilepsy Res 2010; 92(2-3):209-18

4. Meeraus WH. et al. Childhood epilepsy recorded in primary care in the UK. Arch Dis Child 2013;98:195-202

5. Epilepsy Society. Medication for children. http://www.epilepsysociety.org.uk/AboutEpilepsy/Treatment/Medicationforchildren (accessed September 2014)

6. Guerrini R. et al. A randomized, phase III trial of adjunctive zonisamide in pediatric patients with partial epilepsy. Epilepsia 2013; 54(8):1473-80

7. Guerrini R. et al. Adjunctive zonisamide therapy in the long-term treatment of children with partial epilepsy: Results of an open-label extension of a phase III, randomised, double-blind, placebo-controlled trial. Epilepsia. doi: 10.1111/epi.12548  

8. Zonegran, Summary of Product Characteristics (updated October 2013): http://www.medicines.org.uk/emc/medicine/16240

9. Data on file: ZON2013-0003. Eisai Europe Ltd.

10. Epilepsy in the WHO European Region: Fostering Epilepsy Care in Europe. http://www.ibe-epilepsy.org/downloads/EURO%20Report%20160510.pdf (accessed September 2014)

11. 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: November 2014

Job code: Zonegran-UK2542