546
Views
4
CrossRef citations to date
0
Altmetric
Review

Investigational therapies for the treatment of narcolepsy

, , &
Pages 953-963 | Received 03 Apr 2017, Accepted 14 Jul 2017, Published online: 20 Jul 2017

References

  • Mignot EJ. A practical guide to the therapy of narcolepsy and hypersomnia syndromes. Neurotherapeutics. 2012;9:739–752.
  • Thorpy MJ, Dauvilliers Y. Clinical and practical considerations in the pharmacologic management of narcolepsy. Sleep Med. 2015;16:9–18.
  • Frauscher B, Ehrmann L, Mitterling T, et al. Delayed diagnosis, range of severity, and multiple sleep comorbidities: a clinical and polysomnographic analysis of 100 patients of the innsbruck narcolepsy cohort. J Clin Sleep Med. 2013;9:805–812.
  • American Academy of Sleep Medicine, International classification of sleep disorders. 3rd. ( ICSD-3). Rochester: MN, 2014.
  • Ohayon MM, Priest RG, Zulley J, et al. Prevalence of narcolepsy symptomatology and diagnosis in the European general population. Neurology. 2002;58:1826–1833.
  • Thorpy M. Current concepts in the etiology, diagnosis and treatment of narcolepsy. Sleep Med. 2001;2:5–17.
  • Mignot E. Genetics of narcolepsy and other sleep disorders. Am J Hum Genet. 1997;60:1289–1302.
  • Thorpy MJ, Krieger AC. Delayed diagnosis of narcolepsy: characterization and impact. Sleep Med. 2014;15:502–507.
  • Dauvilliers Y, Montplaisir J, Molinari N, et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology. 2001;57:2029–2033.
  • Arii J, Kanbayashi T, Tanabe Y, et al. CSF hypocretin-1 (orexin-A) levels in childhood narcolepsy and neurologic disorders. Neurology. 2004;63:2440–2442.
  • Wozniak DR, Quinnell TG. Unmet needs of patients with narcolepsy: perspectives on emerging treatment options. Nat Sci Sleep. 2015;7:51–61.
  • Thannickal TC, Nienhuis R, Siegel JM. Localized loss of hypocretin (orexin) cells in narcolepsy without cataplexy. Sleep. 2009;32:993–998.
  • McCarley RW. Neurobiology of REM and NREM sleep. Sleep Med. 2007;8:302–330.
  • De Lecea L. A decade of hypocretins: past, present, and future of the neurobiology of arousal. Acta Physiol (Oxf). 2010;198:203–208.
  • Cao M. Advances in narcolepsy. Med Clin North Am. 2010;94:541–555.
  • Mignot E, Hayduk R, Grumet FC, et al. HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients. Sleep. 1997;20:1012–1020.
  • Aran A, Lin L, Nevsimalova S, et al. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep. 2009;32:979–983.
  • Partinen M, Kornum BR, Plazzi G, et al. Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neurol. 2014;13:600–613.
  • Szakács A, Darin N, Hallböök T. Increased childhood incidence of narcolepsy in western Sweden after H1N1 influenza vaccination. Neurology. 2013;80:1315–1321.
  • Nishino S, Okuro M. Emerging treatments for narcolepsy and its related disorders. Expert Opin Emerg Drugs. 2010;15:139–158.
  • European Medicines Agency. Wakix (pitolisant): summary of product characteristics. 2016. Available from: www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002616/WC500204746.pdf [ Last Accessed 31 March 2017]
  • Haas HL, Sergeeva OA, Selbach OF. Histamine in the nervous system. Physiol Rev. 2008;88:1183–1241.
  • Bayer L, Eggermann E, Serafin M, et al. Orexins (hypocretins) directly excite tuberomammillary neurons. Eur J Neurosci. 2001;14:1571–1575.
  • Nishino S, Sakurai E, Nevsimalova S, et al. Decreased CSF histamine in narcolepsy with and without low CSF hypocretin-1 in comparison to healthy controls. Sleep. 2009;32:175–180.
  • Medhurst AD, Atkins AR, Beresford IJ, et al. GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer’s disease brain and improves cognitive performance in preclinical models. J Pharmacol Exp Ther. 2007;321:1032–1045.
  • Medhurst SJ, Collins SD, Billinton A, et al. Novel histamine H3 receptor antagonists GSK189254 and GSK334429 are efficacious in surgically-induced and virally-induced rat models of neuropathic pain. Pain. 2008;138:61–69.
  • Guo RX, Anaclet C, Roberts JC, et al. Differential effects of acute and repeat dosing with the H3 antagonist GSK189254 on the sleep-wake cycle and narcoleptic episodes in Ox-/- mice. Brit J of Pharmac. 2009;157:104–117.
  • An open label, dose escalation study with a double blind randomised placebo controlled withdrawal to examine the effects of the histamine h3 antagonist GSK189254 In patients with narcolepsy. NCT00366080. 2017 Available from: https://clinicaltrials.gov/ [Last accessed 31 March 2017]
  • Semple G, Santora VJ, Smith JM, et al. Identification of biaryl sulfone derivatives as antagonists of the histamine H3 receptor: discovery of (R)-1-(2-(4ʹ- (3-methoxypropylsulfonyl)biphenyl-4-yl)ethyl)-2-methylpyrrolidine (APD916). Bioorg Med Chem Lett. 2012;22:71–75.
  • Arena pharmaceuticals announces phase 1 results for apd916 for narcolepsy with cataplexy. 2010. Available from: http://invest.arenapharm.com/releasedetail.cfm?ReleaseID=520672 [Last accessed 31 March 2017]
  • Brioni JD, Esbenshade TA, Garrison TR, et al. Discovery of histamine H3 antagonists for the treatment of cognitive disorders and Alzheimer’s disease. J Pharm Exp Ther. 2011;336:38–46.
  • Phase II randomized, double-blind, double-dummy, placebo and comparator-controlled, parallel group, multi-center study to investigate the safety and efficacy of a single dose of JNJ-17216498 administered to subjects with narcolepsy. NCT00424931. 2014. Available from: https://clinicaltrials.gov/ [ Last accessed 31 March 2017]
  • Barbier AJ, Berridge C, Dugovic C, et al. Acute wake-promoting actions of JNJ-5207852, a novel, diamine-based H3 antagonist. Br J Pharmacol. 2004;143:649–661, Erratum in Br J Pharmacol 2005;144:145
  • Barbier AJ, Aluisio L, Lord B, et al. Pharmacological characterization of JNJ-28583867, a histamine H3 receptor antagonist and serotonin reuptake inhibitor. Eur J Pharmacol. 2007;576:43–54.
  • A phase IIa, randomized, double blind, placebo controlled, three-treatment, two-period crossover study of the efficacy and safety of two doses of PF-03654746 in adults with attention deficit hyperactivity disorder. NCT00531752. 2016. Available from: https://clinicaltrials.gov/[ Last accessed 31 March 2017]
  • A phase 1, double-blind, placebo-controlled, sponsor-open, randomized, multiple dose study to evaluate the safety, tolerability, and pharmacokinetics of PF-03654746 in mild to moderate Alzheimer’s disease patients on stable donepezil therapy. NCT01028911. 2014. Available from: https://clinicaltrials.gov/[ Last accessed 31 March 2017]
  • A randomized phase 2, double blind, placebo-controlled, multi-center crossover study of PF-03654746 as a Daily Treatment for Excessive Daytime Sleepiness (EDS) associated with narcolepsy. NCT01006122. 2014. Available from: https://clinicaltrials.gov/[ Last accessed 31 March 2017].
  • Whitwam JG, Amrein R. Pharmacology of flumazenil. Acta Anaesthesiol Scand Suppl. 1995;108:3–14.
  • Rye DB, Bliwise DL, Parker K, et al. Modulation of vigilance in the primary hypersomnias by endogenous enhancement of GABAA receptors. Sci Transl Med. 2012;4: 161ra151
  • Dauvilliers Y, Evangelista E, Lopez R, et al. Absence of γ-aminobutyric acid-a receptor potentiation in central hypersomnolence disorders. Ann Neurol. 2016;80:259–268.
  • Trotti LM, Saini P, Koola C, et al. Flumazenil for the treatment of Refractory Hypersomnolence: clinical experience with 153 patients. J Clin Sleep Med. 2016;12:1389–1394.
  • Kelty E, Martyn V, O’Neil G, et al. Use of subcutaneous flumazenil preparations for the treatment of idiopathic hypersomnia: a case report. J Psychopharmacol. 2014;28:703–706.
  • A ten subjects, double-blind, placebo-controlled trial of single day dosing of sublingual flumazenil in individuals with primary hypersomnia or excessively long total sleep time and excess endogenous potentiation of GABAA Receptors. NCT01183312. 2013. Available from: https://clinicaltrials.gov/[ Last accessed 31 March 2017]
  • Fraschini F, Scaglione F, Demartini G. Clarithromycin clinical pharmacokinetics. Clin Pharmacokinet. 1993;25:189–204.
  • Trotti LM, Saini P, Freeman AA, et al. Improvement in daytime sleepiness with clarithromycin in patients with GABA-related hypersomnia: clinical experience. J Psychopharmacol. 2014;28:697–702.
  • Trotti LM, Saini P, Bliwise DL, et al. Clarithromycin in GABA-related hypersomnolence: a randomized, crossover trial. Ann Neurol. 2015;78:454–465.
  • Mason CR, Cooper RM. A permanent change in convulsive threshold in normal and brain-damaged rats with repeated small doses of pentylenetetrazol. Epilepsia. 1972;13:663–674.
  • Colas D, Chuluun B, Warrier D, et al. Short-term treatment with the GABAA receptor antagonist pentylenetetrazole produces a sustained pro-cognitive benefit in a mouse model of Down’s syndrome. Br J Pharmacol. 2013;169:963–973.
  • A phase IB, double-blind, randomized, placebo-controlled, parallel group study of the safety, tolerability, preliminary efficacy and pharmacodynamics of BTD-001 in young adults and adolescents with Down syndrome. ACTRN12612000652875. 2015 Available at: www.anzctr.org.au [ Last accessed 31 March 2017]
  • A randomized, placebo-controlled, double-blind, fixed-dose, multiple cohort, multiple crossover, dose-finding study of oral BTD-001 in adults with idiopathic hypersomnia (IH) or Narcolepsy type 2. NCT02512588. 2017. Available from: https://clinicaltrials.gov/ [ Last accessed 31 March 2017]
  • Sanchez-Ponce R, Wang LQ, Lu W, et al. Metabolic and pharmacokinetic differentiation of STX209 and racemic baclofen in humans. Metabolites. 2012;2:596–613.
  • Huang YS, Guilleminault C. Narcolepsy: action of two γ-aminobutyric acid type B agonists, baclofen and sodium oxybate. Pediatr Neurol. 2009;41:9–16.
  • Black SW, Morairty SR, Chen TM, et al. GABAB agonism promotes sleep and reduces cataplexy in murine narcolepsy. J Neurosci. 2014;34:6485–6494.
  • Fisone G, Borgkvist A, Usiello A. Caffeine as a psychomotor stimulant: mechanism of action. Cell Mol Life Sci. 2004;61:857–872.
  • Mandel HG. Update on caffeine consumption, disposition and action. Food Chem Toxicol. 2002;40:1231–1234.
  • Kaplan GB, Greenblatt DJ, Ehrenberg BL, et al. Dose-dependent pharmacokinetics and psychomotor effects of caffeine in humans. J Clin Pharmacol. 1997;37:693–703.
  • Roehrs T, Roth T. Caffeine: sleep and daytime sleepiness. Sleep Med Rev. 2008;12:153–162.
  • Landolt HP, Werth E, Borbély AA, et al. Caffeine intake (200 mg) in the morning affects human sleep and EEG power spectra at night. Brain Res. 1995;675:67–74.
  • Okuro M, Fujiki N, Kotorii N, et al. Effects of paraxanthine and caffeine on sleep, locomotor activity, and body temperature in orexin/ataxin-3 transgenic narcoleptic mice. Sleep. 2010;33:930–942.
  • The effect of caffeine on the narcoleptic patients randomized controlled clinical trial. NCT02832336. 2016. Available from: https://clinicaltrials.gov/[ Last accessed 31 March 2017]
  • Li J, Hu Z, De Lecea L. The hypocretins/orexins: integrators of multiple physiological functions. Br J Pharmacol. 2014;171:332–350.
  • Willie JT, Chemelli RM, Sinton CM, et al. Distinct narcolepsy syndromes in orexin receptor-2 and orexin null mice: molecular genetic dissection of non-REM and REM sleep regulatory processes. Neuron. 2003;38:715–730.
  • Kastin AJ, Akerstrom V. Orexin A but not orexin B rapidly enters brain from blood by simple diffusion. Jpet. 1999;289:219–223.
  • Mieda M, Willie JT, Hara J, et al. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc Natl Acad Sci U S A. 2004;101:4649–4654.
  • Nishino S. Clinical and neurobiological aspects of narcolepsy. Sleep Med. 2007;8:373–399.
  • Dhusa SV, Hanson LR, Frey WH. Intranasal drug targeting of hypocretin-1 (orexin-A) to the central nervous system. J Pharm Sci. 2009;98:2501–2515.
  • Deadwyler SA, Porrino L, Siegel JM, et al. Systemic and nasal delivery of orexin-A (hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci. 2007;27:14239–14247.
  • Baier PC, Hallschmid M, Seeck-Hirschner M, et al. Effects of intranasal hypocretin-1 (orexin A) on sleep in narcolepsy with cataplexy. Sleep Med. 2011;12:941–946.
  • Weinhold SL, Seeck-Hirschner M, Nowak A, et al. The effects of intranasal orexin-A (hypocretin-1) on sleep, wakefulness and attention in narcolepsy with cataplexy. Behav Brain Res. 2014;262:8–13.
  • Niewoehner J, Bohrmann B, Collin L, et al. Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron. 2014;81:49–60.
  • Liu M, Blanco-Centurion C, Konadhode R, et al. Orexin gene transfer into zona incerta neurons suppresses muscle paralysis in narcoleptic mice. J Neurosci. 2011;31:6028–6040.
  • Blanco-Centurion C, Liu M, Konadhode R, et al. Effects of orexin gene transfer in the dorsolateral pons in orexin knockout mice. Sleep. 2013;36:31–40.
  • Arias-Carrión O, Murillo-Rodríguez E. Effects of hypocretin/orexin cell transplantation on narcoleptic-like sleep behavior in rats. PLoS One. 2014;9:e95342.
  • Rothman RB, Baumann MH, Dersch CM, et al. Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse. 2001;39:32–41.
  • Hasan S, Pradevard S, Ahnaou A, et al. How to keep the brain awake? The complex molecular pharmacogenetics of wake promotion. Neuropsychopharmacology. 2009;34:1625–1640.
  • Amsterdam JD, Brunswick DJ, Hundert M. A single-site, double-blind, placebo-controlled, dose-ranging study of YKP10A – a putative, new antidepressant. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:1333–1338.
  • A six-week, double-blind, placebo-controlled, randomized-withdrawal, multicenter study of the safety and efficacy of JZP-110 ([R]-2-amino-3-phenylpropylcarbamate hydrochloride) in the Treatment of Excessive Sleepiness in Subjects with Obstructive Sleep Apnea (OSA). NCT02348619. 2016. Available from: https://clinicaltrials.gov/[ Last accessed 31 March 2017]
  • A twelve-week, double-blind, placebo-controlled, randomized, parallel-group, multicenter study of the safety and efficacy of JZP-110 ([R]-2-amino-3-phenylpropylcarbamate hydrochloride) in the Treatment of Excessive Sleepiness in Subjects with Obstructive Sleep Apnea (OSA). NCT02348606. 2016. Available from: https://clinicaltrials.gov/[ Last accessed 31 March 2017]
  • Bogan R, Feldman N, Emsellem HA, et al. Effect of oral JZP-110 (ADX-N05) treatment on wakefulness and sleepiness in adults with narcolepsy. Sleep Med. 2015;16:1102–1108.
  • Ruoff C, Swick TJ, Doekel R, et al. Effect of Oral JZP-110 (ADX-N05) on wakefulness and sleepiness in adults with narcolepsy: a phase 2b study. Sleep. 2016;39:7.
  • A twelve-week, double-blind, placebo-controlled, randomized, parallel-group, multicenter study of the safety and efficacy of JZP-110 ([R]-2-amino-3-phenylpropylcarbamate Hydrochloride) in the Treatment of Excessive Sleepiness in Subjects with Narcolepsy. NCT02348593. 2016. Available from: https://clinicaltrials.gov/ [ Last accessed 31 March 2017]
  • Sullivan SS, Guilleminault C. Emerging drugs for common conditions of sleepiness: obstructive sleep apnea and narcolepsy. Expert Opin Emerg Drugs. 2015;20:571–582.
  • Jazz pharmaceuticals and concert pharmaceuticals provide JZP-386 Program Update. 2015. Available from:http://investor.jazzpharma.com/phoenix.zhtml?c=210227&p=irol-newsArticle&ID=2045672 [ Last accessed 31 March 2017]
  • Rasetti R, Mattay VS, Stankevich B, et al. Modulatory effects of modafinil on neural circuits regulating emotion and cognition. Neuropsychopharm. 2010;35:2101–2109.
  • Giaume C, Theis M. Pharmacological and genetic approaches to study connexin-mediated channels in glial cells of the central nervous system. Brain Res Rev. 2010;63:160–176.
  • Liu X, Petit JM, Ezan P, et al. The psychostimulant modafinil enhances gap junctional communication in cortical astrocytes. Neuropharmacology. 2013;75:533–538.
  • Picoli C, Nouvel V, Aubry F, et al. Human connexin channel specificity of classical and new gap junction inhibitors. J Biomol Screen. 2012;17:1339–1347.
  • Duchêne A, Perier M, Zhao Y, et al. Impact of astroglial connexins on modafinil pharmacological properties. Sleep. 2016;39:1283–1292.
  • Safety and Efficacy of THN102 on Sleepiness in Narcoleptic Patients. NCT02821715. 2017. Available from: https://clinicaltrials.gov/[ Last accessed 31 March 2017]
  • Horita A. An update on the CNS actions of TRH and its analogs. Life Sci. 1998;62:1443–1448.
  • Kelly JA, Boyle NT, Cole N, et al. First-in-class thyrotropin releasing ormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective neurodegenerative models. Neuropharmacology. 2015;89:193–203.
  • Khomane KS, Meena CL, Jain R, et al. Novel thyrotropin-releasing hormone analogs: a patent review. Expert Opin Ther Pat. 2011;21:1673–1691.
  • Hara J, Gerashchenko D, Wisor JP, et al. Thyrotropin-releasing hormone increases behavioral arousal through modulation of hypocretin/orexin neurons. J Neurosci. 2009;29:3705–3714.
  • Nishino S, Arrigoni J, Shelton J, et al. Effects of thyrotropin-releasing hormone and its analogs on daytime sleepiness and cataplexy in canine narcolepsy. J Neurosci. 1997;17:6401–6408.
  • Riehl J, Honda K, Kwan M, et al. Chronic oral administration of CG-3703, a thyrotropin releasing hormone analog, increases wake and decreases cataplexy in canine narcolepsy. Neuropsychopharmacology. 2000;23:34–45.
  • Dauvilliers Y, Siegel JM, Lopez R, et al. Cataplexy – clinical aspects, pathophysiology and management strategy. Nat Rev Neurol. 2014;10:386–395.
  • Dauvilliers Y, Abril B, Mas E, et al. Normalization of hypocretin-1 in narcolepsy after intravenous immunoglobulin treatment. Neurology. 2009;73:1333–1334.
  • Knudsen S, Mikkelsen JD, Bang B, et al. Intravenous immunoglobulin treatment and screening for hypocretin neuron-specific autoantibodies in recent onset childhood narcolepsy with cataplexy. Neuropediatrics. 2010;41:217–222.
  • Black SW, Yamanaka A, Kilduff TS. Challenges in the development of therapeutics for narcolepsy. Prog Neurobiol. 2017;152:89–113.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.