Eisai Europe Ltd, a subsidiary of Eisai Co., Ltd (Headquarters: Tokyo; President and CEO: Haruo Naito), today announced the results from a new Phase III study (E2090-E044-310 Monotherapy Study) which showed that the anti-seizure treatment Zonegran® (zonisamide / ZNS) is effective and well tolerated in newly diagnosed epilepsy patients when used as monotherapy.
Zonisamide is a second generation anti-epileptic drug with multiple mechanisms of action, with a chemical structure unrelated to other anti-seizure drugs, and with pharmacokinetic properties allowing once-daily dosing regimen. It was approved in Europe in 2005 as an adjunctive therapy in the treatment of partial seizures (with or without generalization) in adults with epilepsy.
The double-blind, randomised, multicentre study set out to compare the efficacy and safety of once-daily zonisamide with twice-daily controlled release carbamazepine (CBZ, Tegretol® retard) as monotherapy in 582 adults with newly diagnosed partial epilepsy. The study's primary endpoint was the proportion of seizure-free patients at 6 months (per protocol population). Secondary endpoints included the proportion of patients remaining seizure free for 12-months.
Results showed that in the per protocol population the proportion of patients who were seizure-free at 6-months was 79.4% for zonisamide and 83.7% for carbamazepine, with a 95% confidence limit for the difference between the two drugs (-0.122, 0.030). The target dose for zonisamide was 300mg/day and for carbamazepine was 600mg/day, and subjects who were seizure free at 6-months the entered maintenance period. The percentage of patients who were seizure free at 6-months was high and showed similar results across both treatments. The statistical comparison between zonisamide and carbamazepine met the criterion of non-inferiority as recommended by the guideline of the International League Against Epilepsy.
Results from secondary analyses including the results for 12 month seizure freedom were consistent with the results seen for 6-month seizure freedom of the per protocol population. The study is particularly meaningful since carbamazepine is considered as the gold standard in terms of efficacy .
In terms of safety and tolerability, both study medications were well tolerated with similar rates of treatment-emergent adverse events (TEAEs) in each group and low rates of discontinuations due to adverse events (AEs) or serious adverse events (SAEs). No significant new AEs were identified that were not already expected as part of the known pharmacological profile of both drugs .
The most frequently reported TEAEs were: headache (ZNS: 10.3%; CBZ: 12.3%), decreased appetite (ZNS: 7.8%; CBZ: 1.7%), somnolence (ZNS: 6.0%; CBZ: 7.7%), dizziness (ZNS: 3.9%; CBZ: 7.7%), weight decreased (ZNS: 6.8%; CBZ: 0%), fatigue (ZNS: 4.6%; CBZ: 4.0%), rash (ZNS: 2.1%; CBZ: 4.3%), and pyrexia (ZNS: 3.9%; CBZ: 4.0%). With the exception of decreased appetite and weight decrease, the most frequently reported TEAEs for zonisamide were at least comparable in frequency to carbamazepine.
Commenting on this new study, Michel Baulac, at the Hopital de la Pitie-Salpetriere, Paris, France said; "It was important to show that zonisamide, a successful drug as add-on treatment, is also a very effective therapy in newly diagnosed adults with epilepsy. The study employed flexible dosing, in order to optimise safety and efficacy, a design that reproduces very well in clinical practice". He continues; "Less than 50% of our patients have their seizures controlled by their first antiepileptic drug, and only a further 10-12 % will achieve seizure-freedom from alternative drugs given as monotherapies. It is therefore important to develop new options, and zonisamide would be a promising addition in the monotherapy armamentarium. Zonisamide also has the benefit of once-daily dosing that may help reduce the pill-burden a person with epilepsy experiences."
Based on the results of study 310, Eisai plans to seek EU approval for a first-line monotherapy indication for zonisamide in newly diagnosed adults with epilepsy.
About Zonegran (zonisamide)
Zonisamide is licensed as adjunctive therapy in the treatment of partial seizures (with or without generalization) in adults with epilepsy. It has a unique spectrum of anti-epileptic modes of actions and has no appreciable effects on steady-state plasma concentrations of other anti-epileptic drugs, such as phenytoin, carbamazepine, and valproate .
Zonisamide is available in 25mg, 50mg, and 100mg capsule strengths. The recommended initial daily dose is 50 mg 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.
In the monotherapy trial the dosing was once-daily both during titration and at the target dose. The starting dose was once-daily in the evening. Common adverse effects include somnolence, anorexia, dizziness, headache, nausea, and agitation/irritability .
Zonisamide is currently being investigated in paediatrics to assess the efficacy for children with partial onset seizures treated with one or two other anti-epileptic drugs.