{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T15:02:23Z","timestamp":1786978943085,"version":"build-2736575974"},"reference-count":53,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,16]],"date-time":"2026-08-16T00:00:00Z","timestamp":1786838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Curr. Issues Mol. Biol.","CIMB"],"abstract":"<jats:p>Background: Despite more than 30 licenced antiseizure medications (ASMs), approximately one third of people with epilepsy remain drug-resistant, and developmental and epileptic encephalopathies represent one of the greatest unmet needs in epilepsy therapeutics. The past decade has produced a substantial reorientation of ASM discovery, driven by epilepsy genetics, new disease models, advances in drug screening, and innovative therapeutic modalities. Objective: The objective of this study was to review the contemporary clinical-stage pipeline of ASMs with novel or differentiated mechanisms of action, organized by molecular target, while placing recent regulatory successes and instructive failures within the broader transition toward mechanism-based, precision, and potentially disease-modifying therapies. Findings: A 2024 pipeline analysis identified more than 200 epilepsy therapies in preclinical or clinical development; at the cutoff of the present literature search (30 June 2026), over 40 compounds had reached phase II or III, with the majority directed at DEEs. Functional-state-selective sodium channel modulation has emerged as a leading conceptual advance supported by converging mechanistic and early clinical evidence, exemplified by relutrigine (PRAX-562), a preferential persistent-current inhibitor for which a regulatory decision is pending in SCN2A\/SCN8A-DEEs, and vormatrigine (PRAX-628), whose large open-label effect was not reproduced in a controlled (blinded) trial. Several of the efficacy figures summarized here derive from congress presentations, interim analyses, or open-label extensions and await full peer-reviewed publication. Parallel advances include the selective Kv7 opener azetukalner; the dual-mechanism benchmark cenobamate; cholesterol-24-hydroxylase inhibition (soticlestat); selective serotonergic agonism (bexicaserin); glutamatergic precision agents (radiprodil); subtype-selective GABAA modulators (darigabat, ganaxolone); and gene-directed therapies (zorevunersen, elsunersen). Pre-symptomatic intervention in tuberous sclerosis complex provides an early, single-trial clinical proof of principle for delaying and reducing the incidence of epilepsy in a genetically defined population; this should not yet be equated with established disease prevention. Conclusions: The pipeline reflects an ongoing shift from broad symptomatic agents toward mechanism-led, genotype-matched, and potentially disease-modifying treatments. This shift is tempered by a persistent translational gap between early signals and randomized-trial confirmation, and by the preliminary status of much of the supporting evidence.<\/jats:p>","DOI":"10.3390\/cimb48080830","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T13:42:17Z","timestamp":1786974137000},"page":"830","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Antiseizure Medications in Development: Novel Mechanisms, Precision Therapy, and the Move Towards Disease Modification"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8752-5760","authenticated-orcid":false,"given":"William Alves","family":"Martins","sequence":"first","affiliation":[{"name":"Porto Alegre Epilepsy Surgery Program, Neurology and Neurosurgery Services, Hospital S\u00e3o Lucas, Porto Alegre 90610-000, Brazil"},{"name":"The Brain Institute, Porto Alegre 90610-000, Brazil"},{"name":"School of Medicine, Universidade Luterana do Brasil (ULBRA), Canoas 92425-900, Brazil"},{"name":"School of Medicine, Pontif\u00edcia Universidade Cat\u00f3lica do Rio Grande do Sul (PUCRS), Porto Alegre 90160-092, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/S1474-4422(23)00151-5","article-title":"Drug resistance in epilepsy","volume":"22","author":"Perucca","year":"2023","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"18024","DOI":"10.1038\/nrdp.2018.24","article-title":"Epilepsy","volume":"4","author":"Devinsky","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1124\/pr.120.019539","article-title":"Drug resistance in epilepsy: Clinical impact, potential mechanisms, and new innovative treatment options","volume":"72","author":"Potschka","year":"2020","journal-title":"Pharmacol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/s41573-024-00981-w","article-title":"New epilepsy therapies in development","volume":"23","author":"Klein","year":"2024","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1007\/s10309-024-00724-2","article-title":"Novel antiseizure medications in the development pipeline: Promising candidates and recent failures","volume":"38","year":"2025","journal-title":"Clin. Epileptol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e989","DOI":"10.1212\/WNL.0000000000200792","article-title":"Long-term efficacy and safety from an open-label extension of adjunctive cenobamate in patients with uncontrolled focal seizures","volume":"99","author":"Klein","year":"2022","journal-title":"Neurology"},{"key":"ref_7","unstructured":"(2026, January 18\u201322). Results from the Phase 3 X-TOLE2 Study Evaluating Azetukalner, a Kv7 Channel Opener, in Adults with Focal Onset Seizures. ClinicalTrials.gov Identifier NCT05614063. Proceedings of the American Academy of Neurology (AAN) Annual Meeting, Chicago, IL, USA. Late-breaking Science session, presentation 7."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1007\/s40263-023-01025-4","article-title":"New GABA-targeting therapies for the treatment of seizures and epilepsy: II. Treatments in clinical development","volume":"37","author":"Perucca","year":"2023","journal-title":"CNS Drugs"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1177\/1535759720973978","article-title":"The role of the persistent sodium current in epilepsy","volume":"21","author":"Wengert","year":"2021","journal-title":"Epilepsy Curr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1111\/j.0013-9580.2004.58403.x","article-title":"Inhibitory effect of lamotrigine on A-type potassium current in hippocampal neuron-derived H19-7 cells","volume":"45","author":"Huang","year":"2004","journal-title":"Epilepsia"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Mateias, A.L., Armasescu, F., Amuzescu, B., Corlan, A.D., and Radu, B.M. (2024). Inhibitory effects of cenobamate on multiple human cardiac ion channels and possible arrhythmogenic consequences. Biomolecules, 14.","DOI":"10.3390\/biom14121582"},{"key":"ref_12","first-page":"1063","article-title":"Investigations into the mechanism of action of the new anticonvulsant retigabine: Interaction with GABAergic and glutamatergic neurotransmission and with voltage gated ion channels","volume":"50","author":"Rundfeldt","year":"2000","journal-title":"Arzneimittelforschung"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1111\/epi.12950","article-title":"The anticonvulsant retigabine is a subtype selective modulator of GABA(A) receptors","volume":"56","author":"Treven","year":"2015","journal-title":"Epilepsia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1111\/j.1476-5381.2012.02133.x","article-title":"One man\u2019s side effect is another man\u2019s therapeutic opportunity: Targeting Kv7 channels in smooth muscle disorders","volume":"168","author":"Jepps","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2858","DOI":"10.1111\/epi.18075","article-title":"Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). II. Drugs in more advanced clinical development","volume":"65","author":"Bialer","year":"2024","journal-title":"Epilepsia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2831","DOI":"10.1111\/epi.18056","article-title":"Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). I. Drugs in preclinical and early clinical development","volume":"65","author":"Bialer","year":"2024","journal-title":"Epilepsia"},{"key":"ref_17","unstructured":"EMBOLD Study Group (2025, January 5\u20139). Relutrigine in SCN2A- and SCN8A-developmental and epileptic encephalopathies: Registrational (cohort 2) results and an interim analysis stopped early for efficacy. Proceedings of the American Epilepsy Society (AES) Annual Meeting, Atlanta, GA, USA."},{"key":"ref_18","unstructured":"U.S. National Library of Medicine (2026, June 30). A Double-Blind, Randomized Study of PRAX-628 (Vormatrigine) in Adults with Focal Onset Seizures (POWER1). ClinicalTrials.gov Identifier: NCT06999902, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06999902."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.seizure.2026.04.011","article-title":"Cenobamate: A comprehensive review","volume":"138","author":"Vossler","year":"2026","journal-title":"Seizure"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1016\/S0140-6736(19)32500-0","article-title":"Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A randomised, double-blind, placebo-controlled trial","volume":"394","author":"Lagae","year":"2019","journal-title":"Lancet"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1111\/epi.17149","article-title":"The novel persistent sodium current inhibitor PRAX-562 has potent anticonvulsant activity with improved protective index relative to standard of care sodium channel blockers","volume":"63","author":"Kahlig","year":"2022","journal-title":"Epilepsia"},{"key":"ref_22","unstructured":"EMBOLD Study Group (2024, January 6\u201310). Relutrigine reduces motor seizures in SCN2A- and SCN8A-developmental and epileptic encephalopathies: Cohort 1 results from the phase 2 EMBOLD study. Proceedings of the American Epilepsy Society (AES) Annual Meeting, Los Angeles, CA, USA."},{"key":"ref_23","unstructured":"EMBOLD Study Group (2025, January 5\u20139). Relutrigine demonstrates sustained seizure reduction with continued exposure on top of standard of care: Results from the EMBOLD open-label extension. Proceedings of the American Epilepsy Society (AES) Annual Meeting, Atlanta, GA, USA."},{"key":"ref_24","unstructured":"U.S. National Library of Medicine (2026, June 30). A Study to Evaluate the Efficacy, Safety, and Tolerability of PRAX-562 (Relutrigine) in Paediatric Participants with SCN2A-DEE and SCN8A-DEE (EMBOLD). ClinicalTrials.gov Identifier: NCT05818553, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05818553."},{"key":"ref_25","unstructured":"U.S. Food and Drug Administration (2026, June 30). Relutrigine New Drug Application Accepted with Priority Review (PDUFA Target Action Date 27 September 2026). Regulatory Status Record, Available online: https:\/\/www.fda.gov."},{"key":"ref_26","unstructured":"RADIANT Study Investigators (2025, January 5\u20139). Vormatrigine Rapidly Reduces Seizures in Adults with Treatment-Resistant Epilepsy: Full Results from the RADIANT Study. ClinicalTrials.gov Identifier NCT06908356. Proceedings of the American Epilepsy Society (AES) Annual Meeting, Atlanta, GA, USA. Available online: https:\/\/clinicaltrials.gov\/study\/NCT06908356."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e72468","DOI":"10.7554\/eLife.72468","article-title":"NBI-921352, a first-in-class, NaV1.6 selective, sodium channel inhibitor that prevents seizures in Scn8a gain-of-function mice, and wild-type mice and rats","volume":"11","author":"Johnson","year":"2022","journal-title":"eLife"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e2311","DOI":"10.1212\/WNL.0000000000009530","article-title":"Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures","volume":"94","author":"Chung","year":"2020","journal-title":"Neurology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/S1474-4422(19)30399-0","article-title":"Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: A multicentre, double-blind, randomised, placebo-controlled, dose-response trial","volume":"19","author":"Krauss","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1111\/epi.16832","article-title":"The ups and downs of alkyl-carbamates in epilepsy therapy: How does cenobamate differ?","volume":"62","author":"Sills","year":"2021","journal-title":"Epilepsia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.seizure.2026.04.013","article-title":"Efficacy and safety of novel antiseizure medications as adjunctive treatment of focal epilepsy: An updated network meta-analysis","volume":"138","author":"Le","year":"2026","journal-title":"Seizure"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1001\/jamaneurol.2023.3542","article-title":"Efficacy and safety of XEN1101, a novel potassium channel opener, in adults with focal epilepsy: A phase 2b randomized clinical trial","volume":"80","author":"French","year":"2023","journal-title":"JAMA Neurol."},{"key":"ref_33","unstructured":"(2026, January 18\u201322). Long-Term Efficacy and Safety of Azetukalner: 48-Month Interim Analysis of the X-TOLE Open-Label Extension. Proceedings of the American Academy of Neurology (AAN) Annual Meeting, Chicago, IL, USA."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1111\/cns.13927","article-title":"Pronounced antiseizure activity of the subtype-selective GABA(A) positive allosteric modulator darigabat in a mouse model of drug-resistant focal epilepsy","volume":"28","author":"Gurrell","year":"2022","journal-title":"CNS Neurosci. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1124\/jpet.123.001816","article-title":"Neurosteroids as novel anticonvulsants for refractory status epilepticus and medical countermeasures for nerve agents: A 15-year journey to bring ganaxolone from bench to clinic","volume":"388","author":"Reddy","year":"2024","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_36","unstructured":"U.S. National Library of Medicine (2026, June 30). An Open-Label Study of Radiprodil in Children with GRIN-Related Neurodevelopmental Disorder (Honeycomb). ClinicalTrials.gov Identifier: NCT05818943, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05818943."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1111\/epi.18689","article-title":"Bexicaserin for the treatment of seizures in developmental and epileptic encephalopathies: A phase 1b\/2a trial (PACIFIC)","volume":"67","author":"Dlugos","year":"2026","journal-title":"Epilepsia"},{"key":"ref_38","unstructured":"PACIFIC Study Investigators (2025, January 5\u20139). Long-term (12-month) open-label extension results of bexicaserin (LP352) in developmental and epileptic encephalopathies (PACIFIC). Proceedings of the American Epilepsy Society (AES) Annual Meeting, Atlanta, GA, USA."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1111\/epi.18287","article-title":"A review of the putative antiseizure and antiepileptogenic mechanisms of action for soticlestat","volume":"66","author":"Kondo","year":"2025","journal-title":"Epilepsia"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2671","DOI":"10.1111\/epi.17367","article-title":"A phase 2 randomized, double-blind, placebo-controlled study of soticlestat as adjunctive therapy in pediatric patients with Dravet syndrome or Lennox\u2013Gastaut syndrome (ELEKTRA)","volume":"63","author":"Hahn","year":"2022","journal-title":"Epilepsia"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"eaaz6100","DOI":"10.1126\/scitranslmed.aaz6100","article-title":"Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome","volume":"12","author":"Han","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1056\/NEJMoa2506295","article-title":"Zorevunersen in children and adolescents with Dravet syndrome","volume":"394","author":"Laux","year":"2026","journal-title":"N. Engl. J. Med."},{"key":"ref_43","unstructured":"U.S. National Library of Medicine (2026, June 30). EMPEROR: A Multicenter, Randomized, Double-Blind, Sham-Controlled, Parallel-Group, Phase 3 Study Evaluating the Efficacy, Safety, and Tolerability of Zorevunersen (STK-001) in Patients with Dravet Syndrome. ClinicalTrials.gov Identifier: NCT06872125, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06872125."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/epi.13965","article-title":"Commonalities in epileptogenic processes from different acute brain insults: Do they translate?","volume":"59","author":"Klein","year":"2018","journal-title":"Epilepsia"},{"key":"ref_45","first-page":"127","article-title":"Prevention of epileptogenesis\u2014Are we there yet?","volume":"37","author":"Koepp","year":"2024","journal-title":"Curr. Opin. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1002\/ana.25956","article-title":"Prevention of epilepsy in infants with tuberous sclerosis complex in the EPISTOP trial","volume":"89","author":"Kotulska","year":"2021","journal-title":"Ann. Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.jacbts.2019.02.005","article-title":"Phase II trials in drug development and adaptive trial design","volume":"4","year":"2019","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1002\/epi4.12656","article-title":"Efficacy and safety of adjunctive padsevonil in adults with drug-resistant focal epilepsy: Results from two double-blind, randomized, placebo-controlled trials","volume":"7","author":"Rademacher","year":"2022","journal-title":"Epilepsia Open"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"L\u00f6scher, W. (2021). Single-target versus multi-target drugs versus combinations of drugs with multiple targets: Preclinical and clinical evidence for the treatment or prevention of epilepsy. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.730257"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.eplepsyres.2016.02.002","article-title":"Response to placebo in clinical epilepsy trials\u2014Old ideas and new insights","volume":"122","author":"Goldenholz","year":"2016","journal-title":"Epilepsy Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1002\/ana.24470","article-title":"Confusing placebo effect with natural history in epilepsy: A big data approach","volume":"78","author":"Goldenholz","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1111\/j.1528-1167.2010.02915.x","article-title":"Factors determining response to antiepileptic drugs in randomized controlled trials: A systematic review and meta-analysis","volume":"52","author":"Rheims","year":"2011","journal-title":"Epilepsia"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"109653","DOI":"10.1016\/j.yebeh.2024.109653","article-title":"Efficacy and safety of six new antiseizure medications for adjunctive treatment of focal epilepsy and epileptic syndrome: A systematic review and network meta-analysis","volume":"152","author":"Tong","year":"2024","journal-title":"Epilepsy Behav."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/8\/830\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:15:31Z","timestamp":1786976131000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/8\/830"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,16]]},"references-count":53,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["cimb48080830"],"URL":"https:\/\/doi.org\/10.3390\/cimb48080830","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,16]]}}}