Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). I. Drugs in preclinical and early clinical development

Abstract

Since 1992, the Eilat Conferences have provided a forum for all stakeholders in the epilepsy community to appraise the latest data on new antiepileptic drugs and emergency seizure treatments, including, in recent years, updates on progress with the development of novel monitoring and therapeutic devices. Because of the COVID-19 pandemic, the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference on July 27-30, 2020 for the sessions on drugs and on August 3, 2020 for the sessions on devices, and was attended during the 5 days by >500 participants from 63 countries. This progress report summarizes key preclinical and initial (phase 1) clinical data on eight investigational treatments that are currently in early development, including 2-deoxy-D-glucose, GAO-3-02, JNJ-40411813, NBI-921352, NTX-001, sec-butylpropylacetamide, XEN1101, and XEN496. This report provides an overview of current scenarios in the area of treatment discovery and development. The information presented illustrates a variety of innovative strategies, including exploration of compounds with | 2341 BIALER Et AL. 1 | INTRODUCTION Despite the introduction of >20 second-generation antiepileptic drugs (AEDs) during the past 3 decades, including 10 new AEDs between 2008 and 2020, >30% of people with epilepsy do not attain seizure control with currently available medications, and for some epilepsy syndromes seizure outcome is even worse. 1 Hence, there is still an urgent need for newer, more effective treatments for epilepsy. Efforts to develop treatments with improved tolerability and safety are also warranted. Since 1992, the Eilat Conferences have provided a forum for stakeholders involved in clinical care, basic and clinical research, and regulatory agencies to meet on a biennial basis and discuss the latest advances in the discovery and development of new epilepsy treatments. Since 2016, sessions dedicated to discussion of novel therapeutic devices as well as devices for seizure monitoring were added to the Conferences' program. Because of the disruption caused by the COVID-19 pandemic, the 2020 Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held virtually on July 27-30, 2020 for the sessions on drugs, and on August 3, 2020 for the sessions on devices. A total of 534 participants from 63 countries attended the conference, with about 75% of attendees being health care professionals/academic researchers and 25% being professionals working in the pharmaceutical industry. The virtual format did not prevent lively interactions among participants, and presenters were able to address in real time the many questions raised by the audience. Nevertheless, the face-to-face discussions, the social interaction, and the networking opportunities made possible by the physical presence of participants were surely missed. Accordingly, the Organizing Committee is confident that the next conference scheduled for 2022 will revert to the traditional format and unique boutique a...

Soluble tumor necrosis factor-alpha-induced hyperexcitability contributes to retinal ganglion cell apoptosis by enhancing Nav1.6 in experimental glaucoma

“…Indeed, specific inhibition of Nav1.6 has showed to effectively relieve neuronal hyperexcitability and neuropathic pain [ 87 , 88 ]. NBI 921352 (known as XEN 901), a novel small molecule Nav1.6 inhibitor, has been approved by FDA to initiate the phase 2 clinical trial in epilepsy patients [ 89 ].…”

Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). II. Drugs in more advanced clinical development

“…The core of the conference was the presentation of data on compounds that are under development for the treatment of seizures and epilepsy. The identification and selection of these compounds are explained in an accompanying article, which presents summaries of data on eight compounds in preclinical or early (phase 1) clinical development 1 . The current article provides summary updates on compounds in more advanced clinical development, for which at least preliminary efficacy and safety data from relevant epilepsy patient groups are available.…”

Synthesis and Enantioselective Pharmacokinetic/Pharmacodynamic Analysis of New CNS-Active Sulfamoylphenyl Carbamate Derivatives

“…Two of the 21 AEDs contain a carbamate moiety (felbamate and cenobamate) in their chemical structure and two contain a sulfonamide (zonisamide) or a sulfamate (topiramate) moiety [ 2 ]. In addition, some new AEDs in development such as NBI-921352 (formerly XEN901), a selective inhibitor of Nav1.6 sodium channels, CVL-865, a selective positive allosteric modulator of GABAA, and bumetanide derivatives contain a sulfonamide in their chemical structure [ 3 , 4 , 5 , 6 ]. AND-287 is a chiral CNS-active sulfonamide derivative currently in development that its (R)-enantiomer demonstrated a more potent anticonvulsant activity than its (S)-enantiomer [ 1 , 7 ].…”

“…AND-287 has the following three structural elements: (a) an aryl portion that modulates potency, stability, and efficacy; (b) a benzyl substituent to increase the neuroprotective effect and bioavailability, and (c) a sulfamide moiety necessary to produce antiseizure and neuroprotective activity [ 7 ]. The anticonvulsant retigabine, currently being developed in a new oral formulation (XEN496), also contains a carbamate moiety in its molecular structure [ 3 , 4 ]. All the above shows that sulfonamide and carbamate moieties are of relevance in the development and design of new AEDs [ 8 ].…”