Proceedings of the 15th Antiepileptic Drug and Device Trials Meeting: State of the Science

Boada, Christina; French, Jacqueline A.; Dumanis, Sonya B.

doi:10.1016/j.yebeh.2020.107189

Cited by 8 publications

(9 citation statements)

References 97 publications

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“…Today, the randomized, double-blind, placebo-controlled adjunctive therapy trial in patients with drug-resistant focal seizures continues to be the primary tool to obtain regulatory approval of novel ASMs. Because of the existence of ~30 ASMs on the market, this creates major hurdles to demonstrating the efficacy of any novel compound, discouraging pharmaceutical companies from investing in ASM development [22,23]. The ASM market is crowded, and the costs of drug development are steadily increasing.…”

Section: The Development Of Antiseizure Medicationsmentioning

confidence: 99%

The Pharmacology and Clinical Efficacy of Antiseizure Medications: From Bromide Salts to Cenobamate and Beyond

2021

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Epilepsy is one of the most common and disabling chronic neurological disorders. Antiseizure medications (ASMs), previously referred to as anticonvulsant or antiepileptic drugs, are the mainstay of symptomatic epilepsy treatment. Epilepsy is a multifaceted complex disease and so is its treatment. Currently, about 30 ASMs are available for epilepsy therapy. Furthermore, several ASMs are approved therapies in nonepileptic conditions, including neuropathic pain, migraine, bipolar disorder, and generalized anxiety disorder. Because of this wide spectrum of therapeutic activity, ASMs are among the most often prescribed centrally active agents. Most ASMs act by modulation of voltage-gated ion channels; by enhancement of gamma aminobutyric acid-mediated inhibition; through interactions with elements of the synaptic release machinery; by blockade of ionotropic glutamate receptors; or by combinations of these mechanisms. Because of differences in their mechanisms of action, most ASMs do not suppress all types of seizures, so appropriate treatment choices are important. The goal of epilepsy therapy is the complete elimination of seizures; however, this is not achievable in about one-third of patients. Both in vivo and in vitro models of seizures and epilepsy are used to discover ASMs that are more effective in patients with continued drug-resistant seizures. Furthermore, therapies that are specific to epilepsy etiology are being developed. Currently, ~ 30 new compounds with diverse antiseizure mechanisms are in the preclinical or clinical drug development pipeline. Moreover, therapies with potential antiepileptogenic or disease-modifying effects are in preclinical and clinical development. Overall, the world of epilepsy therapy development is changing and evolving in many exciting and important ways. However, while new epilepsy therapies are developed, knowledge of the pharmacokinetics, antiseizure efficacy and spectrum, and adverse effect profiles of currently used ASMs is an essential component of treating epilepsy successfully and maintaining a high quality of life for every patient, particularly those receiving polypharmacy for drug-resistant seizures.

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Section: The Development Of Antiseizure Medicationsmentioning

confidence: 99%

The Pharmacology and Clinical Efficacy of Antiseizure Medications: From Bromide Salts to Cenobamate and Beyond

2021

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“…The EILAT XV Conference also hosted presentations on antisense oligonucleotide therapy for Lafora disease, bumetanide derivatives, and omaveloxolone (RTA‐408), but presenters or sponsors did not wish to have a summary of these compounds included in the progress report. Additional investigational drugs for seizures/epilepsy are listed in the proceedings of the 15th Antiepileptic Drug and Device Trials Conference (AEDD), which took place in Miami, Florida on May 22‐24, 2019 5 . The AEDD is also a biennial event dedicated to drug and device development in epilepsy, with a format similar to the EILAT Conference but generally with greater emphasis on methodological issues.…”

Section: Introductionmentioning

confidence: 99%

“…The AEDD is also a biennial event dedicated to drug and device development in epilepsy, with a format similar to the EILAT Conference but generally with greater emphasis on methodological issues. The AEDD proceedings, however, do not provide detailed information on compounds presented at the meeting 5 …”

Section: Introductionmentioning

confidence: 99%

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

Bialer

Johannessen

Koepp³

et al. 2020

Epilepsia

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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...

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“…Following the discovery and preclinical characterization of a novel ASM and clinical phase I trial for evaluation of the drug’s tolerability and pharmacokinetics, randomized, double-blind, placebo-controlled adjunctive-therapy trials in patients with drug-resistant focal seizures continue to be the primary tool to obtain regulatory approval of novel ASMs ( Perucca, 2019 ; Boada et al, 2020 ). However, because the ASM market is crowded and costs of drug development are constantly increasing, the interest of industry has increased in developing novel molecules for orphan indications (i.e., rare genetic epilepsies) where unmet needs are particularly large ( Perucca, 2019 ).…”

Section: Preclinical Discovery and Development Of Antiseizure Medicationsmentioning

confidence: 99%

Single-Target Versus Multi-Target Drugs Versus Combinations of Drugs With Multiple Targets: Preclinical and Clinical Evidence for the Treatment or Prevention of Epilepsy

Löscher¹

2021

Front. Pharmacol.

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Rationally designed multi-target drugs (also termed multimodal drugs, network therapeutics, or designed multiple ligands) have emerged as an attractive drug discovery paradigm in the last 10–20 years, as potential therapeutic solutions for diseases of complex etiology and diseases with significant drug-resistance problems. Such agents that modulate multiple targets simultaneously are developed with the aim of enhancing efficacy or improving safety relative to drugs that address only a single target or to combinations of single-target drugs. Although this strategy has been proposed for epilepsy therapy >25 years ago, to my knowledge, only one antiseizure medication (ASM), padsevonil, has been intentionally developed as a single molecular entity that could target two different mechanisms. This novel drug exhibited promising effects in numerous preclinical models of difficult-to-treat seizures. However, in a recent randomized placebo-controlled phase IIb add-on trial in treatment-resistant focal epilepsy patients, padsevonil did not separate from placebo in its primary endpoints. At about the same time, a novel ASM, cenobamate, exhibited efficacy in several randomized controlled trials in such patients that far surpassed the efficacy of any other of the newer ASMs. Yet, cenobamate was discovered purely by phenotype-based screening and its presumed dual mechanism of action was only described recently. In this review, I will survey the efficacy of single-target vs. multi-target drugs vs. combinations of drugs with multiple targets in the treatment and prevention of epilepsy. Most clinically approved ASMs already act at multiple targets, but it will be important to identify and validate new target combinations that are more effective in drug-resistant epilepsy and eventually may prevent the development or progression of epilepsy.

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Proceedings of the 15th Antiepileptic Drug and Device Trials Meeting: State of the Science

Cited by 8 publications

References 97 publications

The Pharmacology and Clinical Efficacy of Antiseizure Medications: From Bromide Salts to Cenobamate and Beyond

The Pharmacology and Clinical Efficacy of Antiseizure Medications: From Bromide Salts to Cenobamate and Beyond

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

Single-Target Versus Multi-Target Drugs Versus Combinations of Drugs With Multiple Targets: Preclinical and Clinical Evidence for the Treatment or Prevention of Epilepsy

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