Progress report on new antiepileptic drugs: A summary of the Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII)

Abstract

SUMMARYThe Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII) took place in Madrid, Spain, on June 26-29, 2016, and was attended by >200 delegates from 31 countries. The present Progress Report provides an update on experimental and clinical results for drugs presented at the Conference. Compounds for which summary data are presented include an AED approved in 2016 (brivaracetam), 12 drugs in phase I-III clinical development (adenosine, allopregnanolone, bumetanide, cannabidiol, cannabidivarin, 2-deoxy-D-glucose, everolimus, fenfluramine, huperzine A, minocycline, SAGE-217, and valnoctamide) and 6 compounds or classes of compounds for which only preclinical data are available (bumetanide derivatives, sec-butylpropylacetamide, FV-082, 1OP-2198, NAX 810-2, and SAGE-689). Overall, the results presented at the Conference show that considerable efforts are ongoing into discovery and development of AEDs with potentially improved therapeutic profiles compared with existing agents. Many of the drugs discussed in this report show innovative mechanisms of action and many have shown promising results in patients with pharmacoresistant epilepsies, including previously neglected rare and severe epilepsy syndromes. KEY WORDS: Antiepileptic drugs, Drug development, Epilepsy, Epilepsy targets.The first Eilat Conference on New Antiepileptic Drugs (AEDs) (EILAT I) took place in Eilat, Israel on May 31-June 2, 1992, and thereafter became a biannual event bringing together basic scientists and clinicians interested in the development of new pharmacologic treatments for epilepsy. Over the years, the Conference established itself as a landmark event, providing an interactive forum for scientists working in academia, industry, regulatory bodies, and other institutions to meet and discuss methodologic issues related to drug development, as well as the most recent findings from studies of antiepileptic compounds undergoing preclinical and clinical investigation.The Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII) took place in Madrid, Spain, on June 26-29, 2016, and was attended by >200 delegates from 31 countries. The present Progress Report builds on the content of the most recent reports, CRITICAL REVIEW AND INVITED COMMENTARY information derived from literature searches, consultation with colleagues, and websites (including clinicaltrials.gov) to identify compounds currently being developed as potential AEDs, and to select presenters. For products currently in commercial development, presenters were typically selected in consultation with the company responsible for development. The presenters of acetone analogs, cerliponase alfa (BMN190) oxinytams, pitolisant (tiprolisant), and PRX0023, which were also included in the Conference's program, declined to provide a summary or did not respond to an invitation to do so.

Brexanolone as adjunctive therapy in super‐refractory status epilepticus

“…Unlike benzodiazepines, the site of allopregnanolone binding to the GABAaR for PAM activity is on the α subunit. Unlike benzodiazepines, which bind at the interface between α and β subunits, the binding site for allopregnanolone allows for modulation of both synaptic GABA A Rs and extrasynaptic GABA A Rs, the latter not being internalized during SE 15, 16…”

“…Allopregnanolone is a potent, endogenously produced neuroactive steroid that acts as a positive allosteric modulator (PAM) on a broad range of γ‐aminobutyric acid type A receptor (GABA A R) isoforms12, 13, 14, 15, 16 expressed throughout the brain, including those that mediate either phasic or tonic inhibition 17, 18, 19. Extrasynaptic receptors containing the δ‐subunit that mediate tonic inhibition are particularly sensitive to modulation by neurosteroids 18.…”

“…Allopregnanolone has demonstrated significant protection against seizures in several animal models 15, 16, 21. Continuous allopregnanolone IV administration in two murine seizure models predict that anticonvulsant effects should occur at plasma concentrations within the range of 37 to 142ng/ml 22, 23, 24.…”

Serotonergic modulation as a pharmacological modality in the treatment of Dravet syndrome

“…Using our procedure, we have clearly demonstrated that fenfluramine significantly decreased epileptiform activity in the scn1 mutant zebrafish (Sourbron et al , 2016). As fenfluramine has shown effectiveness in patients with Dravet syndrome in an ongoing 27-year observational study in Belgium (Ceulemans et al , 2012; and reviewed in Bialer et al , 2017), we assert that our approach is scientifically sound, and represents a validated testing platform for the discovery of therapeutics in the field of Dravet research. Significantly, using the same model it was shown that fenfluramine is also active after short incubations at 10-fold higher concentrations (Dinday and Baraban, 2015).…”

“…In that paper we further concluded that the findings open up new possibilities in the search for effective drugs to treat patients with Dravet syndrome. For this reason, but also because clinically tested fenfluramine is known to exert its action through a serotonergic mechanism (Bialer et al , 2017), we believe that the conclusion drawn by Griffin et al (2017) that 5-HT signalling represents a ‘novel’ therapeutic intervention for the treatment of patients with Dravet syndrome is invalid.…”