{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T15:05:08Z","timestamp":1783955108514,"version":"3.55.0"},"reference-count":34,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100031585","name":"Takeda Development Center Americas","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100031585","id-type":"DOI","asserted-by":"publisher"}]}],"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>There remains a need for new treatments for Lennox\u2013Gastaut syndrome (LGS), a developmental and epileptic encephalopathy with a heterogenous patient population that often requires polytherapy. The phase 3, randomized SKYWAY study (NCT04938427) investigated the efficacy and safety of the cholesterol 24\u2010hydroxylase inhibitor soticlestat (TAK\u2010935) in participants with LGS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This global, double\u2010blind, placebo\u2010controlled trial enrolled participants aged 2\u201355\u2009years with LGS (adjudicated by the Epilepsy Study Consortium). Participants were randomized 1:1 to stable background medication plus either soticlestat (\u2264300\u2009mg twice daily, weight\u2010adjusted) or placebo over 16\u2009weeks (4\u2010week titration plus 12\u2010week maintenance). The primary endpoint was percentage change from baseline in major motor drop (MMD) seizure frequency per 28\u2009days.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SKYWAY enrolled 270 participants (placebo,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009136; soticlestat,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009134); mean age was 12.9\u2009years; 95% were receiving \u22652 antiseizure medications. The difference in median change from baseline in MMD seizure frequency for soticlestat versus placebo was \u22121.17% (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.785) during the full treatment period and 2.43% (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.778) during maintenance. No meaningful difference was observed between soticlestat and placebo for most key secondary endpoints; numerical trends for small effects favoring soticlestat were seen in the proportions of participants showing improvement in the Clinical Global Impression of Improvement (CGI\u2010I) Non\u2010seizure Symptoms Disruptive Behaviors domain (odds ratio\u2009=\u20091.91, nominal\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.032) and CGI\u2010I Seizure Intensity and Duration (odds ratio\u2009=\u20091.67, nominal\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.029). Treatment\u2010related adverse events (TEAEs; mostly mild or moderate) were reported in 68.4% of placebo\u2010treated and 74.6% of soticlestat\u2010treated participants; the most frequent treatment\u2010related TEAE with soticlestat was somnolence. Serious treatment\u2010related TEAEs occurred in one placebo\u2010treated and three soticlestat\u2010treated participants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>Soticlestat did not demonstrate efficacy versus placebo in reducing MMD seizure frequency; the safety findings were consistent with those of previous studies. These data suggest that targeting cholesterol 24\u2010hydroxylase is not a suitable pharmacotherapeutic strategy for LGS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi.70216","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T12:27:12Z","timestamp":1774614432000},"page":"3420-3431","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A phase 3, randomized clinical trial of soticlestat as adjunctive therapy for Lennox\u2013Gastaut syndrome"],"prefix":"10.1002","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7272-7079","authenticated-orcid":false,"given":"Renzo","family":"Guerrini","sequence":"first","affiliation":[{"name":"Neuroscience and Human Genetics Department Meyer Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico  Florence Italy"},{"name":"University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3264-0902","authenticated-orcid":false,"given":"Eric D.","family":"Marsh","sequence":"additional","affiliation":[{"name":"Division of Neurology Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Departments of Neurology and Pediatrics University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9929-9185","authenticated-orcid":false,"given":"Wei\u2010Ping","family":"Liao","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsumi","family":"Imai","sequence":"additional","affiliation":[{"name":"National Epilepsy Center Shizuoka Institute of Epilepsy and Neurological Disorders  Shizuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruzica","family":"Kravljanac","sequence":"additional","affiliation":[{"name":"Faculty for Medicine University of Belgrade, Institute for Mother and Child Health Care of Serbia  Belgrade Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Altmann","sequence":"additional","affiliation":[{"name":"Szent Janos Korhaz es Eszak\u2010Budai Egyesitett Korhazak  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0887-8761","authenticated-orcid":false,"given":"Cecil D.","family":"Hahn","sequence":"additional","affiliation":[{"name":"Division of Neurology, Hospital for Sick Children and Department of Paediatrics University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3874-9749","authenticated-orcid":false,"given":"St\u00e9phane","family":"Auvin","sequence":"additional","affiliation":[{"name":"Assistance Publique \u2013 H\u00f4pitaux de Paris, Pediatric Neurology Department Reference Center for Rare Epilepsies, member of European Reference Network EpiCARE, H\u00f4pital Universitaire Robert\u2010Debr\u00e9  Paris France"},{"name":"Institut Hospitalo\u2010Universitaire Robert\u2010Debr\u00e9 du Cerveau de L'enfant  Paris France"},{"name":"Universit\u00e9 Paris\u2010Cit\u00e9, Inserm NeuroDiderot  Paris France"},{"name":"Institut Universitaire de France  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy","family":"Schiemann","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasir","family":"Khan","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pranab","family":"Mitra","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah I.","family":"Sheikh","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"von Rosenstiel","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8060-2148","authenticated-orcid":false,"given":"Mahnaz","family":"Asgharnejad","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3088-7645","authenticated-orcid":false,"given":"Dennis","family":"Dlugos","sequence":"additional","affiliation":[{"name":"Departments of Neurology and Pediatrics University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5053-560X","authenticated-orcid":false,"given":"Venkatesha","family":"Murthy","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528\u20101157.1997.tb00065.x"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17241"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13709"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023\u2010023\u201002626\u20104"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17932"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17866"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.18265"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073817714394"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13368"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10072\u2010017\u20103188\u2010y"},{"key":"e_1_2_12_12_1","unstructured":"BenitezA RothJ AndrewsJS ShahD ButcherE CrossJH et\u00a0al.Burden of illness of Lennox\u2013Gastaut syndrome: a systematic literature review. Presented at the American Epilepsy Society Annual Meeting; December 2\u20136 2022; Nashville TN USA."},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2019.01.045"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2017.00505"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1684\/epd.2011.0409"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.2147\/NDT.S115996"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010020\u201074036\u20106"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17367"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2022.105835"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2021.106646"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14854"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.15225"},{"key":"e_1_2_12_23_1","unstructured":"DlugosD ForgacsP AsgharnejadM ArkiloD.Major motor drop seizures for endpoint assessments in a phase 3 trial of soticlestat in individuals with Lennox\u2013Gastaut syndrome. Presented at the 75th Annual Meeting of the American Epilepsy Society; December 3\u20137 2021; Chicago IL USA."},{"issue":"7","key":"e_1_2_12_24_1","first-page":"28","article-title":"The clinical global impressions scale: applying a research tool in clinical practice","volume":"4","author":"Busner J","year":"2007","journal-title":"Psychiatry (Edgmont)"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s41687\u2010024\u201000829\u20102"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11136\u2010018\u20102057\u20103"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.13075"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1080\/14737175.2024.2439512"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD003277.pub4"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528\u20101157.1989.tb05321.x"},{"key":"e_1_2_12_31_1","unstructured":"Jazz Pharmaceuticals plc.Jazz Pharmaceuticals provides update on cannabidiol oral solution phase 3 trial in Japan in treatment\u2010resistant epilepsies.2024[cited July 2 2025]. Available from:https:\/\/investor.jazzpharma.com\/node\/21156\/pdf"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318232de76"},{"key":"e_1_2_12_33_1","unstructured":"US Food and Drug Administration.\u201cSilver Spring (MD): US Food and Drug Administration. EPIDIOLEX prescribing\u2009information.\u201d2018\u2009[cited April 2 2025]. Available from:https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2020\/210365s005s006s007lbl.pdf."},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(18)30136\u20103"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)32393-2"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/epi.70216","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/epi.70216","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/epi.70216","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T14:15:14Z","timestamp":1783952114000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/epi.70216"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,27]]},"references-count":34,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1002\/epi.70216"],"URL":"https:\/\/doi.org\/10.1002\/epi.70216","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,27]]},"assertion":[{"value":"2025-10-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}