{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T19:51:14Z","timestamp":1792007474265,"version":"4.4.0"},"reference-count":34,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Novel epilepsy treatments for patients with tuberous sclerosis complex (TSC) and focal cortical dysplasia type II (FCDII) are urgently needed. In these patients, mutations in the mechanistic target of rapamycin (mTOR) pathway genes lead to mTOR hyperactivity and focal cortical malformations that frequently cause intractable epilepsy and neurological sequelae. Recent evidence suggests that administration of simufilam, a small molecule thought to modulate the function of filamin A, reduces seizure activity independent of mTOR in a mouse model of FCDII. Here, we tested the hypothesis that simufilam treatment reduces seizure activity in a TSC mouse model and characterized its pharmacokinetic (PK) profile in wild\u2010type mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Seizure activity was recorded via electroencephalography (EEG) in juvenile\u2009\n                      <jats:italic>Tsc1<\/jats:italic>\n                      \u2009conditional knockout (cKO) mice treated with simufilam or vehicle twice daily (BID). Simufilam plasma concentrations were measured at study termination using liquid chromatography\u2013tandem mass spectrometry. PK analysis was performed in CD1 mice following daily administration of simufilam for 1 or 7\u2009days at two different doses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Vehicle\u2010 and 5\u2009mg\/kg\u2010treated\u2009\n                      <jats:italic>Tsc1<\/jats:italic>\n                      \u2009cKO mice showed a significant increase in seizure frequency and total ictal duration between the first and the last 5\u2009days of EEG monitoring (Wilcoxon signed\u2010rank test,\u2009\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.05), whereas the 10\u2010 and 20\u2010mg\/kg\u2010treated groups did not. In addition, simufilam treatment shifted the distribution of total ictal durations, with fewer mice exhibiting total ictal durations above the median of the vehicle\u2010treated group (Fisher's exact test,\u2009\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.021). Increasing simufilam dose and plasma concentration were associated with fewer daily seizures recorded during the last 5\u2009days of EEG monitoring (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.017 and\u2009\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.012, respectively). Every 100\u2009ng\/mL increase in plasma concentration corresponded to a decrease of ~.2 seizures per day during the last 5\u2010day period.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>These findings suggest that simufilam treatment in a TSC mouse model prevented the worsening of seizure activity in a dose\u2010dependent manner and supports clinical investigation of simufilam as a potential therapeutic intervention for seizures in TSC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi.70227","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T08:03:50Z","timestamp":1776153830000},"page":"3753-3765","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The small molecule simufilam dose\u2010dependently attenuates the worsening of seizures in a mouse model of tuberous sclerosis complex"],"prefix":"10.1002","volume":"67","author":[{"given":"Branden","family":"Stansley","sequence":"first","affiliation":[{"name":"Filana Therapeutics, Inc.  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md. Monirul","family":"Islam","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Cellular &amp; Molecular Physiology Yale School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean J.","family":"Aguiar","sequence":"additional","affiliation":[{"name":"TSC Alliance\u00ae  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1891-3196","authenticated-orcid":false,"given":"Zo\u00eb","family":"Fuchs","sequence":"additional","affiliation":[{"name":"TSC Alliance\u00ae  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mackenzie","family":"Catron","sequence":"additional","affiliation":[{"name":"Translational EEG, PsychoGenics, Inc.  Paramus New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Morairty","sequence":"additional","affiliation":[{"name":"Translational EEG, PsychoGenics, Inc.  Paramus New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Division of Discovery Science The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radleigh","family":"Santos","sequence":"additional","affiliation":[{"name":"Nova Southeastern University  Fort Lauderdale Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingguo","family":"Hou","sequence":"additional","affiliation":[{"name":"Early Phase Unit Worldwide Clinical Trials  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelies","family":"de Kater","sequence":"additional","affiliation":[{"name":"W\/D Nonclinical Consulting Services  San Francisco Bay Area California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George B.","family":"Thornton","sequence":"additional","affiliation":[{"name":"Filana Therapeutics, Inc.  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelique","family":"Bordey","sequence":"additional","affiliation":[{"name":"Filana Therapeutics, Inc.  Austin Texas USA"},{"name":"Department of Neurosurgery and Cellular &amp; Molecular Physiology Yale School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra055323"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2010.02777.x"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2012.00581.x"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24368"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24126"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.191"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001594"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000118"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv045"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24444"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.01.030"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3824"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1177\/1550059417697841"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.31887\/DCNS.2008.10.1\/rjleventer"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2007.01421.x"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1703784"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-018-0870-y"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)78872-3"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2010.10.023"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(15)00069-1"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz411"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31419-2"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.13013"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.09.009"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aay0289"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10283"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12596"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-2487"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13923"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2009.02474.x"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21331"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2007.01270.x"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a022442"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.00899"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/epi.70227","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/epi.70227","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/epi.70227","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T14:15:42Z","timestamp":1783952142000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/epi.70227"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,14]]},"references-count":34,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1002\/epi.70227"],"URL":"https:\/\/doi.org\/10.1002\/epi.70227","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,14]]},"assertion":[{"value":"2025-09-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-13","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}