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

Bialer, Meir; Johannessen, Svein I.; Koepp, Matthias J.; Levy, René H.; Perucca, Emilio; Perucca, Piero; Tomson, Torbjörn; White, H. Steve

doi:10.1111/epi.16726

Cited by 47 publications

(42 citation statements)

References 40 publications

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“…Despite the lack of personalized treatment options in LoF SCN2A cases (other than avoiding sodium channel blockers), GoF variants in SCN2A might respond to sodium channel blockers [ 83 , 84 ]. Other examples include ketogenic diet in SLC2A1 -deficiency [ 83 ], retigabine in LoF KCNQ2- and KCNQ3- related disorders [ 85 ], carbamazepine in PRRT2 -deficiency [ 83 ], quinidine in KCNT1 -encephalopathies, and ganaxolone in CDKL5- and PCDH19- related disorders [ 83 , 86 ].…”

Section: Utility Of Early Genetic Testing For Precision Therapy Approachesmentioning

confidence: 99%

Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy

Bayat

Rubboli

et al. 2021

Genes

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The high pace of gene discovery has resulted in thrilling advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, or genomes are now increasingly available and have led to a significant higher diagnostic yield in early-onset epilepsies and enabled precision medicine approaches. These have been instrumental in providing insights into the pathophysiology of both early-onset benign and self-limited syndromes and devastating developmental and epileptic encephalopathies (DEEs). Genetic heterogeneity is seen in many epilepsy syndromes such as West syndrome and epilepsy of infancy with migrating focal seizures (EIMFS), indicating that two or more genetic loci produce the same or similar phenotypes. At the same time, some genes such as SCN2A can be associated with a wide range of epilepsy syndromes ranging from self-limited familial neonatal epilepsy at the mild end to Ohtahara syndrome, EIFMS, West syndrome, Lennox–Gastaut syndrome, or unclassifiable DEEs at the severe end of the spectrum. The aim of this study was to review the clinical and genetic heterogeneity associated with epilepsy syndromes starting in the first year of life including: Self-limited familial neonatal, neonatal-infantile or infantile epilepsies, genetic epilepsy with febrile seizures plus spectrum, myoclonic epilepsy in infancy, Ohtahara syndrome, early myoclonic encephalopathy, West syndrome, Dravet syndrome, EIMFS, and unclassifiable DEEs. We also elaborate on the advantages and pitfalls of genetic testing in such conditions. Finally, we describe how a genetic diagnosis can potentially enable precision therapy in monogenic epilepsies and emphasize that early genetic testing is a cornerstone for such therapeutic strategies.

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Section: Utility Of Early Genetic Testing For Precision Therapy Approachesmentioning

confidence: 99%

Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy

Bayat

Rubboli

et al. 2021

Genes

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“…The subsequent sections provide summaries of key data on eight treatments in preclinical or early (phase 1) clinical development, including 2‐deoxy‐D‐glucose, GAO‐3‐02, JNJ‐40411813, NBI‐921352, NTX‐001, sec ‐butylpropylacetamide (SPD), XEN1101, and XEN496 (also known as retigabine or ezogabine, but now being developed in a multiparticulate “sprinkle” oral formulation specifically for the treatment of KCNQ2 encephalopathy). Data on compounds in more advanced clinical development in epilepsy are presented in an accompanying article 2 …”

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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“…Ganaxolone was the most efficient drug in clinical trials as add-on therapy against partial seizures with or without secondary generalization in adult patients, 56 as well as for the treatment of refractory status epilepticus. 57 Although it was tested in children with infantile spasms, its beneficial effects were modest and did not reach clinical significance. However, ganaxolone is a remarkably safe drug: the most prominent adverse submit your manuscript | www.dovepress.com…”

Section: Gaba a Receptor Agonists In The Clinical Stage Of Developmentmentioning

confidence: 99%

Experimental GABA A Receptor Agonists and Allosteric Modulators for the Treatment of Focal Epilepsy

Janković

Dješević²

2021

JEP

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GABA A receptors are ubiquitous in the central nervous system and there is a huge diversity of receptor subtypes in almost all regions of the brain. However, the expression of GABA A receptor subtypes is altered in both the gray and white matter of patients with focal epilepsy. Although there is a number of anticonvulsants with marketing authorization for the treatment of focal epilepsy which act through GABA A receptors, potentiating the inhibitory effects of GABA, it is necessary to develop more potent and more specific GABAergic anticonvulsants that are effective in drug-resistant patients with focal epilepsy. There are three orthosteric and at least seven allosteric agonist binding sites at the GABA A receptor. In experimental and clinical studies, full agonists of GABA A receptors showed a tendency to cause desensitization of the receptors, tolerance, and physical dependence; therefore, partial orthosteric agonists and positive allosteric modulators of GABA A receptors were further developed. Preclinical studies demonstrated the anticonvulsant efficacy of positive allosteric modulators with selective action on GABA A receptors with α 2 /α 3 subunits, but only a handful of them were further tested in clinical trials. The best results were obtained for clobazam (already marketed), ganaxolone (in phase III trials), CVL-865 (in phase II trials), and padsevonil (in phase III trials). Several compounds with more selective action on GABA A receptors, perhaps only in certain brain regions, have the potential to become effective drugs against specific subtypes of focal-onset epilepsy. However, their development needs time, and in the near future we can expect only one or two new GABA A agonists to obtain marketing authorization for focal epilepsy, an advance that would be of use for just a fraction of patients with drug-resistant epilepsy.

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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

Cited by 47 publications

References 40 publications

Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy

Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy

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

Experimental GABA A Receptor Agonists and Allosteric Modulators for the Treatment of Focal Epilepsy

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