Pooled Data from 17 Clinical Studies Support Safety of Adjunctive Zonegran® (Zonisamide) in Children Aged Six and Above

HATFIELD, England, November 10, 2014 /PRNewswire/ --

PRESS RELEASE FOR EU MEDIA ONLY: NOT FOR SWISS/U.S. JOURNALISTS  

The safety profile of adjunctive Zonegran^® (zonisamide) in paediatric patients with partial epilepsy is confirmed by pooled data published in the European Journal of Paediatric Neurology (EJPN).^[1] These newly published safety data from 17 studies support zonisamide's proven clinical efficacy in children aged six years and above.^[2],[3] Zonisamide is 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.^[4]

"Selection of the most appropriate treatment approach for children with epilepsy is a challenge as epileptic seizures can often impact a child's neurological development, as well as physical well-being. This makes well-tolerated treatment options that can be used in this age group, such as zonisamide, valuable for doctors and patients alike," commented Professor Helen Cross, Great Ormond Street Hospital and Young Epilepsy, UK.

It is estimated that there are 900,000 children and adolescents who live with active epilepsy in Europe.^[5] Although epilepsy is common among this age group, only two thirds will achieve seizure control and many will require additional AEDs to improve seizure control.^[6] Epilepsy in children often presents major challenges such as developmental and behavioural problems which can result 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.^[7]

The pooled analysis includes 507 people aged ≤16 years involved in four randomised, double-blind studies and 13 uncontrolled, open-label trials.^[1] A total of 398 children received zonisamide and 109 received placebo. Most treatment emergent adverse events (TEAEs) were of mild or moderate intensity, the majority of which are already described in the safety profile for zonisamide. The most frequent treatment-related TEAEs were decreased appetite (15.6%), somnolence (12.1%), fatigue (9.3%), dizziness (6.0%), decreased weight (5.8%), irritability (5.8%) and headache (5.3%). The incidence of TEAEs that led to discontinuation was low 10.3%.^[1]

Zonisamide has multiple mechanisms of action and a chemical structure unrelated to any other AED.^[2] The use of adjunctive zonisamide in the treatment of partial seizures (with or without secondary generalisation) in children aged six years and above was approved by the European Commission in October 2013.

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 well-being 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.^[4] 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.^[4] Worldwide there has been an estimated 1,274,963 patient-years of exposure to zonisamide (from 31.03.1989 to 31.03.2013).^[8]

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.^[4]

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

About Phase III Study 312 (CATZ)^[2]

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 anti-epileptic 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%).

About Phase III Study 313 (CATZ Extension)^[3]

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]      

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.^[9],[10]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 various 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. Cross H, et al. Safety and tolerability of zonisamide in paediatric patients with epilepsy. EJPN 2014. DOI: 10.1016/j.ejpn.2014.07.005 

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

3. 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. 2014:55(4):568-578   

4. Zonegran, Summary of Product Characteristics (updated October 2013): http://www.medicines.org.uk/emc/medicine/16240/  (accessed September 2014) 

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://www.epilepsysociety.org.uk/AboutEpilepsy/Treatment/Medicationforchildren (accessed September 2014) 

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

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

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

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: November 2014
Job code: Zonegran-UK2541