In a manuscript just published in "BRAIN", a journal of neurology, Anna Doeser et al (1) provide evidence on how eslicarbazepine, the main active metabolite of eslicarbazepine acetate, overcomes a cellular resistance mechanism to conventional antiepileptic drugs. Furthermore, eslicarbazepine acetate showed an antiepileptogenic effect in an animal model of chronic epilepsy, likely associated with the eslicarbazepine-induced inhibition of Cav3.2 T-type Ca2+ channels, which have been shown to be key mediators of epileptogenesis (1).
Eslicarbazepine acetate, a once-daily antiepileptic drug, is currently approved in the European Union (Zebinix®), United States and Canada (Aptiom®), for the adjunctive treatment of partial-onset seizures in adults (2,3).
Chronically epileptic tissue was obtained from epileptic patients that underwent brain surgery in an attempt to control their seizures and from rats with previously induced chronic epilepsy. Electrophysiological studies performed in hippocampal cells derived from those tissues showed that eslicarbazepine maintained its activity on sodium channels, with significant additional effects to carbamazepine (a classic antiepileptic drug) (1).
The antiepileptogenic effects were tested in a standard animal model of chronic epilepsy. Eslicarbazepine acetate was transiently administered (p.o., once-daily for 6 weeks) starting nine days after induction of epilepsy in mice through the injection of pilocarpine. Control mice were administered placebo instead of eslicarbazepine acetate, during the same 6-week period. Importantly, eight weeks after the end of treatment, mice that had received eslicarbazepine acetate showed significantly less spontaneous seizures and a pronounced reduction in neuropathology. Thus, eslicarbazepine acetate proved to be the first drug approved for use in humans that results in pronounced antiepileptogenic effects (1).
These findings are of critical importance because two major limitations of currently available treatments for epilepsy are that i) around one third of patients are uncontrolled despite being treated with anticonvulsant drugs and ii) currently available treatments so far act mainly by inhibiting seizure activity, but do not target the underlying disease process (4,5). "This publication offers an explanation as to why some of the patients with resistance to carbamazepine responded to eslicarbazepine acetate in the previous phase III trials. Also of note, the authors have presented evidence that suggests eslicarbazepine acetate may have anti-epileptogenic effects, which needs of course to be confirmed in properly conducted studies in humans" commented Holger Lerche, University of Tübingen, Department of Neurology and Epileptology, Hertie-Institute of Clinical Brain Research, Germany.
"We are really excited with this groundbreaking results, obtained through a very close partnership with the Experimental Epileptology and Cognition Research group from the Life and Brain Center, University of Bonn Medical Center, led by Professor Heinz Beck", said Professor Patrício Soares-da- Silva, Head of the R&D Department at BIAL and co-author of this publication. "Bial will further evaluate, in conjunction with the scientific community and clinical epilepsy experts, the possibility and best options to further study the potential antiepileptogenic effects of eslicarbazepine acetate in humans".
About epilepsy, partial-onset seizures and their treatment
Epilepsy is a chronic neurological disease characterized by abnormal discharges of neuronal activity causing seizures. Clinically, these manifest as convulsions or jerking of muscles. Depending on the seizure type, seizures may be limited to one part of the body, or may be generalized to involve the whole body. Patients may also experience abnormal sensations, altered behaviour or altered consciousness. Epilepsy is a disorder with many possible causes. Often the cause of epilepsy is unknown. However, anything that disturbs the normal pattern of neuron activity - from illness to brain damage to abnormal brain development, can lead to seizures.
Epilepsy is characterised by abnormal firing of impulses from nerve cells in the brain. In partial-onset seizures, these bursts of electrical activity are initially focused in specific areas of the brain, but may become more generalised; the symptoms vary according to the affected areas. Nerve impulses are triggered via voltage-gated sodium channels in the nerve cell membrane.
Treatment of partial-onset seizures, the most common type of epilepsy, presents a constant challenge - up to 40% of patients with partial-onset seizures do not achieve sustained seizure control with current anti-epileptic drugs (4). Furthermore, central nervous system related adverse events, such as lightheadedness (dizziness), somnolence (sleepiness), and cognitive slowing (attention and memory deficits), are highly prevalent with existing anti-epileptic agents. Hence, there is a need for new anti-epileptic agents that offer effective reduction in seizure frequency combined with a favourable safety profile.
About eslicarbazepine acetate (Zebinix® / Exalief®/Aptiom®)
Eslicarbazepine acetate is a once-daily anticonvulsant, extensively and rapidly converted to eslicarbazepine after oral administration (6). Eslicarbazepine reduces voltage-gated sodium channels availability through enhancement of slow inactivation and blocks T-type voltage-gated calcium channels (1,7,8).
Eslicarbazepine acetate is currently marketed in Europe by BIAL-Portela & Ca, S.A and by BIAL ́s licensee, Eisai Europe Limited, a European subsidiary of Eisai Co., Ltd. under the trade name Zebinix®.
The EU approved file is based on efficacy and safety data from an initial proof-of concept phase II study (9) and four subsequent phase III randomized, placebo controlled studies in more than 1700 patients with refractory partial-onset seizures (10-15). These patients had a history of at least four partial-onset seizures per month despite treatment with up to three concomitant anti-epileptic drugs (10-15).
Over the 12-week maintenance period, eslicarbazepine acetate 800mg and 1200mg once-daily significantly reduced seizure frequency, and was significantly more effective than placebo (10-15). Long-term safety and maintenance of therapeutic effect was demonstrated in one-year open-label extensions of these studies (16,17).
In the Phase III clinical trials adverse events mainly occurred during the first 6 weeks of treatment and the majority of patients experienced adverse events of mild to moderate intensity (10-15). After 6 weeks of treatment, there were no observed differences in the incidence of side effects between patients treated with eslicarbazepine acetate and the placebo group. Treatment-emergent adverse events affecting more than10% of patients in the pivotal studies were dizziness and somnolence (2, 10-15).
Quality of life and depressive symptoms
The effect of eslicarbazepine acetate on quality of life was assessed using the Quality of Life in Epilepsy Inventory-31 (QOLIE-31) scale. There was a statistically and clinically significant improvement from baseline during long-term open-label therapy, including a mean relative improvement in overall quality of life and improvements in individual elements of the QOLIE-31 scale including seizure worry, emotional wellbeing, energy/fatigue, medication effects and social function (16,17). Improvement in depressive symptoms was also measured using the Montgomery- Asberg Depression Rating Scale (MADRS). During long-term, open-label therapy, eslicarbazepine acetate demonstrated a statistically significant improvement from baseline in the overall MADRS score and individual domains of the MADRS scale including pessimistic thoughts, concentration difficulties, apparent sadness and inner tension (16,17).