https://doi.org/10.1177/0269881118773745 Journal of Psychopharmacology 1–10 © The Author(s) 2018 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0269881118773745 journals.sagepub.com/home/jop Introduction Insomnia disorder is a common clinical problem with an esti- mated incidence of 10–20% in the general population, and a higher incidence in women, the elderly, and those with comorbid medical and psychiatric conditions (Ohayon, 2002). Extensive research has shown that the orexin system plays a critical role in sleep and wakefulness (Mieda and Sakurai, 2013; Ohno and Sakurai, 2008; Scammell and Winrow, 2011). Orexin activity is mediated by two receptors, the orexin 1 receptor (OX1R) and the orexin 2 receptor (OX2R). Because the distribu- tion of orexin neurons is more discrete than the relatively global distribution of the gamma-aminobutyric acid (GABA)-ergic sys- tem in the brain, it was hypothesized that the orexin-targeted therapeutics would reduce or eliminate undesirable hypnotic adverse effects of GABA A receptor modulators, as “off-target” A randomized Phase 2 study to evaluate the orexin-2 receptor antagonist seltorexant in individuals with insomnia without psychiatric comorbidity Peter De Boer 1 , Wayne C Drevets 2 , Hany Rofael 3 , Peter van der Ark 1 , Justine M Kent 4 , Iva Kezic 1 , Silvia Parapatics 5 , Georg Dorffner 5,6 , Joop van Gerven 7 , Heike Beneš 8 , Christian Keicher 9 , Holger Jahn 10 , David J Seiden 11 and Remy Luthringer 12 Abstract Background: Seltorexant is a potent and selective antagonist of the orexin-2 receptor that is being developed for the treatment of insomnia and major depressive disorder. Aims: The primary objective was to investigate the effect of seltorexant on sleep efficiency after single and multiple dose administration in subjects with insomnia disorder without psychiatric comorbidity. Secondary objectives included evaluation of total sleep time, latency to persistent sleep, and wake after sleep onset. Subjects received 40 mg of seltorexant for five days during Period 1 and placebo during Period 2 or vice versa in this randomized, two-way crossover study. Objective sleep parameters were evaluated by polysomnography over 8 h on Day 1/2 (single dose) and on Day 5/6 (multiple doses). Subjective sleep parameters were assessed by questionnaires. Results: Twenty-seven subjects completed the study. The mean changes in sleep efficiency (% (SD)) of seltorexant from placebo at Day 1/2 were 5.8 (9.2), and 7.9 (9.8) at Day 5/6 (p < 0.001 at both time points); in total sleep time (min (SD)) 27.7 (44.3) and 37.9 (47.1), respectively; in latency to persistent sleep (min (SD)) -18.8 (21.3) and -29.9 (27.7), respectively; and in wake after sleep onset (min (SD)) -11.1 (36.4) and -11.3 (46.5). The most common adverse events were headache and somnolence. Conclusions: Sleep efficiency was increased with seltorexant treatment compared with placebo. Treatment with seltorexant resulted in a prolonged total sleep time, shorter latency to persistent sleep and wake after sleep onset. There were no unexpected safety findings. Keywords Insomnia, orexin antagonists, sleep efficiency, seltorexant, JNJ-42847922 1 Department of Neuroscience, Janssen Research & Development, LLC, Beerse, Belgium 2 Department of Neuroscience, Janssen Research & Development, LLC, Titusville, NJ, USA 3 Department of Neuroscience, Janssen Research & Development, LLC, Pennington, NJ, USA 4 Department of Clinical Research, Psychiatry, Sunovion Pharmaceuticals, Skillman, NJ, USA 5 The Siesta Group, Schlafanalyse GmbH, Vienna, Austria 6 The Medical University of Vienna, Center for Medical Statistics, Informatics and Intelligent Systems, Vienna, Austria 7 Center for Human Drug Research, Leiden University Medical Center, The Netherlands 8 Department of Early Development, Neuroscience, Somni Bene GmbH, Schwerin and Rostock University Medical Center, Schwerin, Germany 9 Clinical Pharmacology, Charité Research Organization GmbH, Berlin, Germany 10 Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 11 Baptist Sleep Center, Hollywood, FL, USA 12 Minerva Neurosciences, Waltham, MA, USA Corresponding author: Peter De Boer, Janssen Research & Development, LLC, Turnhoutseweg 30, B-2340 Beerse, Belgium. Email: pdeboer1@its.jnj.com 773745JOP 0 0 10.1177/0269881118773745Journal of PsychopharmacologyDe Boer et al. research-article 2018 Original Paper