{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:46:45Z","timestamp":1790862405023,"version":"4.1.0"},"reference-count":24,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1176426"],"award-info":[{"award-number":["APP1176426"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP2034258"],"award-info":[{"award-number":["APP2034258"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia Open"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>ES\u2010481 is a novel potent and selective antagonist of TARP\u2010y8\u2010dependent AMPA receptors. We aimed to assess the potential efficacy, safety and tolerability, and pharmacokinetics of different doses of ES\u2010481 as an add\u2010on anti\u2010seizure medication (ASM) in adults with drug\u2010resistant epilepsy (DRE).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This was a Phase 2A double\u2010blind, randomized, dose\u2010titration, cross\u2010over, placebo\u2010controlled trial followed by an open\u2010label extension (OLE) conducted across four Australian Comprehensive Epilepsy Centers. The primary outcomes were: (i) efficacy, measured via change in seizure frequency for each treatment week, (ii) safety and tolerability, and (iii) pharmacokinetics. Secondary endpoints were change in anxiety and depressive symptom scores.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      22 participants were randomized, 17 (77.3%) completed the double\u2010blind treatment phase, and 16 entered the OLE study. Overall, based on seizure diaries, participants had 68%\u201380% improvement in seizure frequency on ES\u2010481 treatment, compared with 38%\u201349% on placebo treatment (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.097). For the highest dose of ES\u2010481 treatment (75\u2009mg bid), subjects had 80% improvement (90% confidence interval [Cl] 43%\u201397%), while participants on placebo for the corresponding week had 49% improvement (90% Cl 1%\u201374%) (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.047). There was no significant difference in the reduction of seizure frequency at the lower ES\u2010481 treatment doses. There were no significant differences in change in frequency of EEG epileptiform\/seizure discharges &gt;3\u2009s in duration between the ES\u2010481 and placebo treatments. There was no significance difference in serious treatment\u2010emergent adverse events between the groups (placebo 14.3% vs. ES\u2010481 4.8%) or treatment\u2010emergent adverse events of special interest (e.g., dizziness, drowsiness; placebo 19.0% vs. ES\u2010481 52.4%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.052). Treatment was well tolerated in the OLE for up to 36\u2009weeks.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>ES\u2010481 in doses up to 75\u2009mg bid was safe and well tolerated for up to 36\u2009weeks in participants with DRE and demonstrated potential anti\u2010seizure efficacy compared with placebo at this dose.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Plain Language Summary<\/jats:title>\n                    <jats:p>This was a first\u2010in\u2010disease, proof\u2010of\u2010concept early\u2010phase trial of a novel anti\u2010seizure medication, ES\u2010481, in adults with a broad group of patients drug\u2010resistant epilepsy, who continue to have seizures despite treatment with currently available medications. ES\u2010481 was generally safe and well tolerated, and participants receiving the highest dose showed fewer seizures compared with placebo. These findings suggest ES\u2010481 may offer a promising new treatment approach for people with difficult\u2010to\u2010control epilepsy, supporting the need for larger future studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial Registration Information<\/jats:title>\n                    <jats:p>Registered at ClinicalTrials.gov ID: NCT04714996 (first submitted and met QC criteria Jan 14, 2021, first posted Jan 20, 2021) and Australian and New Zealand Clinical Trials Registry ID: ACTRN12621000033842 (registered January 15, 2021). First participant\/first visit (assessment) occurred on January 29, 2021.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi4.70294","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T11:39:27Z","timestamp":1781782767000},"page":"1329-1342","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A first in disease trial of the safety, tolerability, and anti\u2010seizure effects of\n                    <scp>ES<\/scp>\n                    \u2010481 in drug\u2010resistant epilepsy"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8958-3844","authenticated-orcid":false,"given":"Emma C.","family":"Foster","sequence":"first","affiliation":[{"name":"Department of Neuroscience, School of Translational Medicine Monash University  Melbourne Victoria Australia"},{"name":"Department of Neurology The Alfred Hospital  Melbourne Victoria 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Translational Medicine Monash University  Melbourne Victoria Australia"},{"name":"Department of Neurology The Alfred Hospital  Melbourne Victoria Australia"},{"name":"Department of Neurology The Royal Melbourne Hospital  Parkville Victoria Australia"},{"name":"Bladin\u2010Berkovic Comprehensive Epilepsy Program, Department of Neurology Austin Health  Heidelberg Victoria Australia"},{"name":"Department of Medicine (Austin Health) The University of Melbourne  Heidelberg Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1224-4101","authenticated-orcid":false,"given":"Saul","family":"Mullen","sequence":"additional","affiliation":[{"name":"Bladin\u2010Berkovic Comprehensive Epilepsy Program, Department of Neurology Austin Health  Heidelberg Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Robinson","sequence":"additional","affiliation":[{"name":"Bladin\u2010Berkovic Comprehensive Epilepsy Program, Department of Neurology Austin Health  Heidelberg Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Wharrie","sequence":"additional","affiliation":[{"name":"Bladin\u2010Berkovic Comprehensive Epilepsy Program, Department of Neurology Austin Health  Heidelberg Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany","family":"Walsh","sequence":"additional","affiliation":[{"name":"Bladin\u2010Berkovic Comprehensive Epilepsy Program, Department of Neurology Austin Health  Heidelberg Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1652-9369","authenticated-orcid":false,"given":"David","family":"Reutens","sequence":"additional","affiliation":[{"name":"The Royal Brisbane and Women's Hospital  Herston Queensland 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