Targeting Pharmacoresistant Epilepsy and Epileptogenesis with Eslicarbazepine Acetate

In a manuscript just published in “BRAIN”, a journal of neurology, Anna Doeser et al 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.

Eslicarbazepine acetate, a once-daily antiepileptic drug, is currently approved in the European Union (Zebinix), US and Canada (Aptiom), for the adjunctive treatment of partial-onset seizures in adults. 

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). 

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, 8 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.

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.

“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-daSilva, 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."