A Phase II Dose-Ranging Study Evaluating the Efficacy and Safety of the Orexin Receptor Antagonist Filorexant (MK-6096) in Patients with Primary Insomnia

Kathryn M Connor, Erin Mahoney, Saheeda Jackson, Jill Hutzelmann, Xin Zhao, Nan Jia, Ellen Snyder, Duane Snavely, David Michelson, Thomas Roth, W Joseph Herring, Kathryn M Connor, Erin Mahoney, Saheeda Jackson, Jill Hutzelmann, Xin Zhao, Nan Jia, Ellen Snyder, Duane Snavely, David Michelson, Thomas Roth, W Joseph Herring

Abstract

Background: Filorexant (MK-6096) is an orexin receptor antagonist; here, we evaluate the efficacy of filorexant in the treatment of insomnia in adults.

Methods: A double-blind, placebo-controlled, randomized, two 4-week-period, adaptive crossover polysomnography study was conducted at 51 sites worldwide. Patients (18 to <65 years) with insomnia received 1 of 4 doses of oral filorexant (2.5, 5, 10, 20mg) once daily at bedtime during one period and matching placebo in the other period in 1 of 8 possible treatment sequences. Polysomnography was performed on night 1 and end of week 4 of each period. The primary endpoint was sleep efficiency at night 1 and end of week 4. Secondary endpoints included wakefulness after persistent sleep onset and latency to onset of persistent sleep.

Results: A total of 324 patients received study treatment, 315 received ≥1 dose of placebo, and 318 ≥1 dose of filorexant (2.5mg, n=79; 5mg, n=78; 10mg, n=80; 20mg, n=81). All filorexant doses (2.5/5/10/20mg) were significantly superior to placebo in improving sleep among patients with insomnia as measured by sleep efficiency and wakefulness after persistent sleep onset on night 1 and end of week 4. The 2 higher filorexant doses (10/20mg) were also significantly more effective than placebo in improving sleep onset as measured by latency to onset of persistent sleep at night 1 and end of week 4. Filorexant was generally well tolerated.

Conclusions: Orexin receptor antagonism by filorexant significantly improved sleep efficiency in nonelderly patients with insomnia. Dose-related improvements in sleep onset and maintenance outcomes were also observed with filorexant.

Trial registration: ClinicalTrials.gov NCT01021852.

Keywords: dose-ranging study; filorexant; insomnia; orexin receptor antagonist; sleep efficiency.

© The Author 2016. Published by Oxford University Press on behalf of CINP.

Figures

Figure 1.
Figure 1.
Patient disposition. AE, adverse event; FIL, filorexant; PL, placebo.
Figure 2.
Figure 2.
Difference in least-squares means between filorexant and placebo at night 1 and week 4 for (A) sleep efficiency (SE), (B) wakefulness after sleep onset (WASO), and (C) latency to persistent sleep (LPS). Footnote (A): night 1, P<.001 for all doses; week 4, P≤.001 for filorexant 2.5, 10, and 20mg and P=.004 for filorexant 5mg. Footnote (B): night 1, P<.001 for all doses; week 4, P=.006 for filorexant 2.5mg, P=.020 for filorexant 5mg, P<.001 for filorexant 10 and 20mg. Footnote (C): night 1, P=.022 for filorexant 2.5mg, P<.001 for filorexant 5, 10, and 20mg; week 4, P=.055 for filorexant 2.5mg, P=.060 for filorexant 5mg, P<.001 for filorexant 10mg, P=.015 for filorexant 20mg. LPS, latency to persistent sleep; LSM, least-squares mean; SE, sleep efficiency; WASO, wakefulness after sleep onset.

References

    1. Rechtschaffen A, Kales A. eds. A manual of standardized terminology, techniques, and scoring system for sleep states of human subjects (1968). Bethesda, MD: National Institutes of Health.
    1. Belsomra (suvorexant) Package Insert (2014). Available at: .
    1. Bettica P, Squassante L, Zamuner S, Nucci G, Danker-Hopfe H, Ratti E. (2012) The orexin antagonist SB-649868 promotes and maintains sleep in men with primary insomnia. Sleep 35:1097–1104.
    1. Bonnet MH, Arand DL. (2010) Hyperarousal and insomnia: state of the science. Sleep Med Rev 14:9–15.
    1. Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S, Mueller C, Nayler O, van Gerven J, de Haas SL, Hess P, Qiu CB, Buchmann S, Scherz M, Weller T, Fischli W, Clozel M, Jenck F. (2007) Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 13:150–155.
    1. Coleman PJ, Schreier JD, Cox CD, Breslin MJ, Whitman DB, Bogusky MJ, McGaughey GB, Bednar RA, Lemaire W, Doran SM, Fox SV, Garson SL, Gotter AL, Harrell CM, Reiss DR, Cabalu TD, Cui D, Prueksaritanont T, Stevens J, Tannenbaum PL, Ball RG, Stellabott J, Young SD, Hartman GD, Winrow CJ, Renger JJ. (2012) Discovery of [(2R,5R)-5-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl][5-methyl-2-(pyrimidin-2-yl)phenyl]methanone (MK-6096): a dual orexin receptor antagonist with potent sleep-promoting properties. ChemMedChem 7:415–24, 337.
    1. Cruz HG, Hay JL, Hoever P, Alessi F, Te Beek ET, van Gerven JM, Dingemanse J. (2014) Pharmacokinetic and pharmacodynamic interactions between almorexant, a dual orexin receptor antagonist, and desipramine. Eur Neuropsychopharmacol 24:1257–1268.
    1. Gotter AL, Webber AL, Coleman PJ, Renger JJ, Winrow CJ. (2012) International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin receptor function, nomenclature and pharmacology. Pharmacol Rev 64:389–420.
    1. Herring WJ, Snyder E, Budd K, Hutzelmann J, Snavely D, Liu K, Lines C, Roth T, Michelson D. (2012) Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology 79:2265–2274.
    1. Herring WJ, Connor KM, Ivgy-May N, Snyder E, Liu K, Snavely DB, Krystal AD, Walsh JK, Benca RM, Rosenberg R, Sangal RB, Budd K, Hutzelmann J, Leibensperger H, Froman S, Lines C, Roth T, Michelson D. (2016) Suvorexant in patients with insomnia: results from two 3-month randomized controlled clinical trials. Biol Psychiatry 79:136–148.
    1. Hoever P, Dorffner G, Benes H, Penzel T, Danker-Hopfe H, Barbanoj MJ, Pillar G, Saletu B, Polo O, Kunz D, Zeitlhofer J, Berg S, Partinen M, Bassetti CL, Hogl B, Ebrahim IO, Holsboer-Trachsler E, Bengtsson H, Peker Y, Hemmeter UM, Chiossi E, Hajak G, Dingemanse J. (2012) Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial. Clin Pharmacol Ther 91:975–985.
    1. Iber C, Ancoli-Israel S, Chesson A, Quan SF, for the American Academy of Sleep Medicine (2007) The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. Westchester: American Academy of Sleep Medicine.
    1. Ishak WW, Bagot K, Thomas S, Magakian N, Bedwani D, Larson D, Brownstein A, Zaky C. (2012) Quality of life in patients suffering from insomnia. Innov Clin Neurosci 9:13–26.
    1. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin XY, Qiu XH, de Jong PJ, Nishino S, Mignot E. (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98:365–376.
    1. Mai E, Buysse DJ. (2008) Insomnia: prevalence, impact, pathogenesis, differential diagnosis, and evaluation. Sleep Med Clin 3:167–174.
    1. Michelson D, Snyder E, Paradis E, Chengan-Liu M, Snavely DB, Hutzelmann J, Walsh JK, Krystal AD, Benca RM, Cohn M, Lines C, Roth T, Herring WJ. (2014) Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol 13:461–471.
    1. Morin CM, Benca R. (2012) Chronic insomnia. Lancet 379:1129–1141.
    1. Sakurai T, Mieda M, Tsujino N. (2010) The orexin system: roles in sleep/wake regulation. Ann N Y Acad Sci 1200:149–161.
    1. Sarsour K, Kalsekar A, Swindle R, Foley K, Walsh JK. (2011) The association between insomnia severity and healthcare and productivity costs in a health plan sample. Sleep 34:443–450.
    1. Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. (2008) Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med 4:487–504.
    1. Sun H, Brown KM, Calder N, Li X, Yee KL, Perlstein I, Wilbraham D, Rosen L, Chodakewitz J, Wagner JA, Murphy MG. (2011. a) MK-6096, a dual orexin receptor antagonist, enhances sleep onset and maintenance as measured by PSG in healthy male subjects. Sleep Biol Rhythms 9:334.
    1. Sun H, Kennedy WD, Lewis N, Laethem T, Tee K, Li X, Hoon J, van Bortel L, Rosen L, Chodakewitz J, Wagner JA, Murphy MG. (2011. b) The single dose pharmacokinetic (PK) and pharmacodynamic (PD) profiles of suvorexant (MK-4305), a dual orexin receptor antagonist, in healthy male subjects. Sleep Biol Rhythms 9:332, Abstract PO-1-235.
    1. Tyrer P, Murphy S, Riley P. (1990) The benzodiazepine withdrawal symptom questionnaire. J Affect Disord 19:53–61.
    1. Winrow CJ, Gotter AL, Cox CD, Doran SM, Tannenbaum PL, Breslin MJ, Garson SL, Fox SV, Harrell CM, Stevens J, Reiss DR, Cui D, Coleman PJ, Renger JJ. (2011) Promotion of sleep by suvorexant - a novel dual orexin receptor antagonist. J Neurogenet 25:52–61.
    1. Winrow CJ, Gotter AL, Cox CD, Tannenbaum PL, Garson SL, Doran SM, Breslin MJ, Schreier JD, Fox SV, Harrell CM, Stevens J, Reiss DR, Cui D, Coleman PJ, Renger JJ. (2012) Pharmacological characterization of MK-6096 - a dual orexin receptor antagonist for insomnia. Neuropharmacology 62:978–987.
    1. Winrow CJ, Renger JJ. (2014) Discovery and development of orexin receptor antagonists as therapeutics for insomnia. Br J Pharmacol 171:283–293.

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