{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T10:35:47Z","timestamp":1787654147661,"version":"build-2736575974"},"reference-count":38,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100018529","name":"Alkermes","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018529","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Sleep Research"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Idiopathic hypersomnia (IH) and narcolepsy type 2 (NT2) are central disorders of hypersomnolence characterised by excessive daytime sleepiness and substantial functional burden. Narcolepsy type 1 (NT1), defined by orexin deficiency, serves as an established biologic standard for evaluating therapies targeting the orexin system. Alixorexton (ALKS 2680) is a highly potent, oral, selective orexin 2 receptor (OX2R) agonist in clinical development for IH, NT2 and NT1. In this phase 1b, randomised, double\u2010blind, placebo\u2010controlled, four\u2010way crossover study (ISRCTN98204977), adults aged 18\u201365\u2009years with IH (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20098), NT2 (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20099) or NT1 (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200910) received single oral doses of alixorexton (IH\/NT2: 5, 12, 25\u2009mg; NT1: 1, 3, 8\u2009mg) and placebo across four treatment periods. The primary endpoint was safety and tolerability. Wakefulness was assessed by mean sleep latency on the Maintenance of Wakefulness Test (MWT) over 8\u2009h post\u2010dose and subjective alertness by the Karolinska Sleepiness Scale (KSS). Alixorexton was generally well tolerated; all treatment\u2010emergent adverse events (TEAEs) were mild or moderate, with no serious TEAEs and no discontinuations due to TEAEs. In IH and NT2, alixorexton demonstrated statistically significant, clinically meaningful, dose\u2010dependent increases in MWT sleep latency versus placebo and improved self\u2010reported alertness. NT1 showed a similarly robust, dose\u2010dependent response at lower doses, consistent with orexin\u2010deficient biology. These findings support OX2R agonism as a therapeutic approach for central disorders of hypersomnolence, including conditions with uncertain orexin dysfunction and informed ongoing phase 2 evaluation in IH and narcolepsy.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial Registration:<\/jats:bold>\n                    A study in healthy subjects to see the effects of the test medicine ALKS 2680 in single\u2010 and multi\u2010dose regimen; prospectively registered at ISRCTN on October 17, 2022 (identifier: ISRCTN98204977; URL:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.isrctn.com\/ISRCTN98204977\">https:\/\/www.isrctn.com\/ISRCTN98204977<\/jats:ext-link>\n                    ).\n                  <\/jats:p>","DOI":"10.1111\/jsr.70429","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:08Z","timestamp":1785888008000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting Orexin 2 Receptors in Idiopathic Hypersomnia and Narcolepsy: A Randomised Phase 1b Proof\u2010Of\u2010Concept Study of Alixorexton"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6682-5812","authenticated-orcid":false,"given":"Ronald R.","family":"Grunstein","sequence":"first","affiliation":[{"name":"Woolcock Institute of Medical Research, Macquarie University  Sydney New South Wales Australia"},{"name":"Department of Respiratory and Sleep Medicine Royal Prince Alfred Hospital  Sydney New South Wales Australia"},{"name":"University of Sydney  Sydney New South Wales Australia"},{"name":"Macquarie Medical School, Faculty of Medicine, Health and Human Sciences Macquarie University  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2196-8649","authenticated-orcid":false,"given":"Brendon J.","family":"Yee","sequence":"additional","affiliation":[{"name":"Woolcock Institute of Medical Research, Macquarie University  Sydney New South Wales Australia"},{"name":"Department of Respiratory and Sleep Medicine Royal Prince Alfred Hospital  Sydney New South Wales Australia"},{"name":"University of Sydney  Sydney New South Wales Australia"},{"name":"Macquarie Medical School, Faculty of Medicine, Health and Human Sciences Macquarie University  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5512-827X","authenticated-orcid":false,"given":"Julia L.","family":"Chapman","sequence":"additional","affiliation":[{"name":"Woolcock Institute of Medical Research, Macquarie University  Sydney New South Wales Australia"},{"name":"Macquarie Medical School, Faculty of Medicine, Health and Human Sciences Macquarie University  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8380-6003","authenticated-orcid":false,"given":"Jian Eu","family":"Tai","sequence":"additional","affiliation":[{"name":"Woolcock Institute of Medical Research, Macquarie University  Sydney New South Wales Australia"},{"name":"University of Sydney  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7024-5543","authenticated-orcid":false,"given":"Sheila","family":"Sivam","sequence":"additional","affiliation":[{"name":"Woolcock Institute of Medical Research, Macquarie University  Sydney New South Wales Australia"},{"name":"Department of Respiratory and Sleep Medicine Royal Prince Alfred Hospital  Sydney New South Wales Australia"},{"name":"University of Sydney  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Hopkinson","sequence":"additional","affiliation":[{"name":"Alkermes, Inc.  Waltham Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel G.","family":"Smith","sequence":"additional","affiliation":[{"name":"Alkermes, Inc.  Waltham Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Lovett","sequence":"additional","affiliation":[{"name":"Alkermes, Inc.  Waltham Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shifang","family":"Liu","sequence":"additional","affiliation":[{"name":"Alkermes, Inc.  Waltham Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4103-4827","authenticated-orcid":false,"given":"Sergey","family":"Yagoda","sequence":"additional","affiliation":[{"name":"Alkermes, Inc.  Waltham Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhaskar","family":"Rege","sequence":"additional","affiliation":[{"name":"Alkermes, Inc.  Waltham Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3109\/00207459008994241"},{"key":"e_1_2_11_3_1","volume-title":"International Classification of Sleep Disorders, Third Edition, Text Revision","author":"American Academy of Sleep Medicine","year":"2023"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.books.9780890425787"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/jsr.14087"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sleep.2016.07.010"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.115.225466"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsae150"},{"key":"e_1_2_11_9_1","unstructured":"Centessa Pharmaceuticals Press Release.2025.Centessa Pharmaceuticals Reports Financial Results for the Third Quarter of 2025 and Provides Update on Potential Best\u2010in\u2010Clas Orexin Receptor 2 (OX2R) Agonist Program.https:\/\/investors.centessa.com\/news\u2010releases\/news\u2010release\u2010details\/centessa\u2010pharmaceuticals\u2010reports\u2010financial\u2010results\u2010third\u20100."},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sleep.2025.107567"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsaa009"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smrv.2022.101709"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2301940"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2405847"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0013\u20104694(97)00010\u20102"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/jsr.13878"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.5664\/jcsm.5594"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0169\u2010328x(01)00039\u20100"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2013.00235"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sleep.2021.01.018"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/14.6.540"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.5664\/jcsm.9620"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.124.035168"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.5665\/sleep.2232"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2013.00057"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sleep.2025.107565"},{"key":"e_1_2_11_27_1","unstructured":"Mignot E. R.Bogan R.Del Rio Villegas et\u00a0al.2024.O79 Efficacy and Safety of TAK\u2010861 an Oral Orexin Receptor 2 Agonist in Individuals With Narcolepsy Type 2: Results From Phase 2 Studies. Paper Presented at the Journal of Sleep Research."},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsad049"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/jsr.13902"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/jsr.13665"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.5664\/jcsm.9682"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/nau.25602"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.2147\/nss.S396641"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/jsr.13383"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/32.8.993"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25423"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1212\/CON.0000000000000883"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smrv.2024.101993"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0271901"}],"container-title":["Journal of Sleep Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jsr.70429","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jsr.70429","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jsr.70429","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:11Z","timestamp":1785888011000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jsr.70429"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,4]]},"references-count":38,"alternative-id":["10.1111\/jsr.70429"],"URL":"https:\/\/doi.org\/10.1111\/jsr.70429","archive":["Portico"],"relation":{},"ISSN":["0962-1105","1365-2869"],"issn-type":[{"value":"0962-1105","type":"print"},{"value":"1365-2869","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,4]]},"assertion":[{"value":"2026-02-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70429"}}