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

The Eilat Conferences have provided a forum for discussion of novel treatments of epilepsy among basic and clinical scientists, clinicians, and representatives from regulatory agencies as well as from the pharmaceutical industry for 3 decades. Initially with a focus on pharmacological treatments, the Eilat Conferences now also include sessions dedicated to devices for treatment and monitoring. The Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI) was held in Madrid, Spain, on May 22-25, 2022 and was attended by 157 delegates from 26 countries. As in previous Eilat Conferences, the core of EILAT XVI consisted of a sequence of sessions where compounds under development were presented and discussed. This progress report summarizes preclinical and, when available, phase 1 clinical data on five different investigational compounds in preclinical or early clinical development, namely GAO-3-02, GRT-X, NBI-921352 (formerly XEN901), OV329, and XEN496 (a pediatric granular formulation of retigabine/ezogabine). Overall, the data presented in this report illustrate novel strategies for developing antiseizure medications, including an interest in novel molecular targets, and a trend to pursue potential new treatments for rare and previously neglected severe epilepsy syndromes.

Pharmacokinetics of XEN496, a Novel Pediatric Formulation of Ezogabine, Under Fed and Fasted Conditions: A Phase 1 Trial.

INTRODUCTION: XEN496 is a novel, granular, immediate-release formulation of ezogabine intended for pediatric use. The objective of this study was to assess the effect of food on the pharmacokinetics (PK) of XEN496 and its N-acetyl metabolite (NAMR) in healthy volunteers. METHODS: Twenty-four adult subjects were enrolled in this phase 1, single center, open-label, randomized, single-dose, two-way crossover study. Subjects received 400 mg XEN496 as an oral suspension in both fed and fasted states separated by a 6-day washout period. Serial blood samples were collected up to 48 h post-administration. PK parameters evaluated included maximum observed plasma concentration (Cmax), time of maximum observed plasma concentration (Tmax), and area under the concentration-time curve (AUC(0-t) and AUCinf). Safety was assessed by laboratory evaluations, physical exam, and adverse event monitoring. RESULTS: For XEN496, median Tmax was 3 and 2 h in the fed and fasted states, respectively. AUC parameters in the fed and fasted states were equivalent, whereas food decreased Cmax of XEN496 by 32% compared to the fasted state. The ratio of geometric means [90% CI] for Cmax was 72% [64-82%]. For NAMR, food delayed Tmax by 1 h, while Cmax and AUC parameters were equivalent in the fed and fasted states. The safety profile of XEN496 in this study appeared comparable to that previously reported for ezogabine tablets. CONCLUSION: The biopharmaceutical performance of XEN496 in this study was as expected for an immediate-release, granular dosage formulation, and generally comparable to that reported for ezogabine tablets. Future studies are needed to characterize the efficacy, safety, and PK of XEN496 in a pediatric population.

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.

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 novel mechanisms of action, transplantation of interneurons into epileptogenic brain regions, and the targeting of rare, previously neglected syndromes.