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List of investigational narcolepsy and hypersomnia drugs

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This is a list of investigational narcolepsy and hypersomnia drugs, or drugs that are currently under development for clinical use for the treatment of narcolepsy and/or hypersomnia (e.g., excessive daytime sleepiness, idiopathic hypersomnia) but are not yet approved. Many of them may also be referred to as investigational wakefulness-promoting agents (WPAs).

Chemical/generic names are listed first, with developmental code names, synonyms, and brand names in parentheses. The format of list items is "Name (Synonyms) – Mechanism of Action – Indication [Reference]".

This list was last comprehensively updated in September 2025. It is likely to become outdated with time.

Under development

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Preregistration

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  • Reboxetine (AXS-12) – norepinephrine reuptake inhibitor (NRI) – narcolepsy
  • Sodium oxybate (Xyrem) controlled release (TRN-257) – GABAB receptor agonist and GHB receptor agonist – narcolepsy, idiopathic hypersomnia

Phase 3

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  • Alixorexton (ALKS-2680) – orexin OX2 receptor agonist – narcolepsy
  • Pitolisant (BF-2.649; BF-2649; HBS-201; Ozawade; tiprolisant; Wakix) – histamine H3 receptor antagonist – idiopathic hypersomnia
  • Sodium oxybate micropump (FT-218; Lumryz; ON-SXB) – GABAB receptor agonist and GHB receptor agonist – idiopathic hypersomnia

Phase 2/3

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  • Balumorexton (TAK-360) – orexin OX2 receptor agonist – narcolepsy, idiopathic hypersomnia

Phase 2

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  • Alixorexton (ALKS-2680) – orexin OX2 receptor agonist – idiopathic hypersomnia
  • Cleminorexton (ORX750; ORX-750) – orexin OX2 receptor agonist – narcolepsy, idiopathic hypersomnia
  • Firazorexton (TAK-994) – orexin OX2 receptor agonist – narcolepsy
  • Flecainide/modafinil (THN-102) – combination of flecainide (sodium channel blocker) and modafinil (atypical dopamine reuptake inhibitor) – narcolepsy
  • Ledasorexton (E-2086) – orexin OX2 receptor agonist – narcolepsy
  • Mazindol controlled release (NLS-0; NLS-1; NLS-10; NLS-13; NLS-2; Nolazol; Quilience) – serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) – narcolepsy, idiopathic hypersomnia
  • Pentylenetetrazole (BTD-001; pentetrazol; PTZ) – GABAA receptor antagonist – narcolepsy, idiopathic hypersomnia
  • Samelisant (SUVN-G3031) – histamine H3 receptor antagonist – narcolepsy
  • Serdexmethylphenidate (KP-484; KP-1077; KP-879) – norepinephrine–dopamine reuptake inhibitor (NDRI) – idiopathic hypersomnia

Phase 1/2

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  • Serdexmethylphenidate (KP-484; KP-1077; KP-879) – norepinephrine–dopamine reuptake inhibitor (NDRI) – narcolepsy

Phase 1

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  • Lu-AH69593 – undefined mechanism of action – narcolepsy
  • MK-6552 – undefined mechanism of action – narcolepsy
  • ORX-142 – orexin OX2 receptor agonist
  • Sodium oxybate once-nightly – GABAB receptor agonist and GHB receptor agonist – narcolepsy
  • Valiloxybate (XW-10172) – GABAB receptor agonist and GHB receptor agonist – narcolepsy

Preclinical

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  • AEX-2 – orexin OX1 and OX2 receptor agonist – narcolepsy
  • HBS-102 (CSTI-100) – melanin-concentrating hormone receptor 1 (MCHR1) antagonist – narcolepsy
  • Methylphenidate transdermal (Defent) – norepinephrine–dopamine reuptake inhibitor (NDRI) – narcolepsy
  • NLS-11 – undefined mechanism of action – Kleine–Levin syndrome

Research

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  • AEX-19 – orexin OX1 and OX2 receptor agonist – narcolepsy, idiopathic hypersomnia
  • SPN-446 – undefined mechanism of action – narcolepsy

Not under development

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No development reported

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  • Armesocarb (MLR-1019; (R)-mesocarb) – atypical dopamine reuptake inhibitor (DRI) – sleep disorders
  • Danavorexton (TAK-925) – orexin OX2 receptor agonist – idiopathic hypersomnia
  • Flecainide/modafinil (THN-102) – combination of flecainide (sodium channel blocker) and modafinil (atypical dopamine reuptake inhibitor (DRI)) – hypersomnia
  • Flmodafinil (CRL-40,940; NLS-14; NLS-4; JBG01-41; bisfluoromodafinil; lauflumide) – atypical dopamine reuptake inhibitor (DRI) – idiopathic hypersomnia
  • Golexanolone (GR-3027) – GABAA receptor negative allosteric modulator and neurosteroid – idiopathic hypersomnia
  • GSK-189254 (GSK-189254A) – histamine H3 receptor antagonist – narcolepsy
  • JZP-386 (C-10323; deuterated sodium oxybate; deuterated GHB) – GABAB receptor agonist and GHB receptor agonist – narcolepsy
  • Research programme: neurological diseases therapies - Inexia/Nxera Pharma – orexin OX1 and OX2 receptor agonists – narcolepsy
  • Research programme: small molecule therapeutics - Orexia/X-Chem – orexin OX2 receptor agonists
  • SLS-010 – histamine H3 receptor antagonist – narcolepsy
  • Sodium oxybate controlled release (GHB) – GABAB receptor agonist and GHB receptor agonist – narcolepsy
  • Solriamfetol (YKP-10A; YKP10A; R–228060) – undefined mechanism of action – narcolepsy
  • Valiloxibic acid (XWL-008) – undefined mechanism of action – narcolepsy

Discontinued

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  • ABT-652 – histamine H3 receptor modulator – sleep disorders
  • Bavisant (BEN-2001; JNJ-1074; JNJ-31001074) – histamine H3 receptor antagonist – narcolepsy
  • Cipralisant (GT-2331; Perceptin) – histamine H3 receptor antagonist – sleep disorders
  • Danavorexton (TAK-925) – orexin OX2 receptor agonist – narcolepsy
  • Enerisant (TS-091; TS-0911; TS091) – histamine H3 receptor antagonist – narcolepsy and hypersomnia
  • Flmodafinil (CRL-40,940; NLS-14; NLS-4; JBG01-41; bisfluoromodafinil; lauflumide) – atypical dopamine reuptake inhibitor (DRI) – narcolepsy
  • JNJ-17216498 – histamine H3 receptor antagonist – narcolepsy
  • Lisdexamfetamine (LDX; Elvanse; NRP-104; S-877489; SHP-489; SPD-489; Tyvense; Venvanse; Vyvanse) – norepinephrine–dopamine releasing agent (NDRA) – sleep disorders
  • LML-134 (LML134) – histamine H3 receptor antagonist – sleep disorders
  • Oveporexton (TAK-861) – orexin OX2 receptor agonist – idiopathic hypersomnia
  • Phacetoperane (NLS-3) – norepinephrine–dopamine reuptake inhibitor (NDRI) – narcolepsy [1]
  • Research programme: sleep disorder therapeutics - Servier (S-41150) – histamine H3 receptor antagonist – sleep disorders
  • SAR-152954 (SAR152954) – histamine H3 receptor antagonist – sleep disorders
  • Ulotaront (SEP-363856; SEP-856) – trace amine-associated receptor 1 (TAAR1) agonist and serotonin 5-HT1A and 5-HT1D receptor partial agonist – narcolepsy

Formal development never or not yet started

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  • Mevidalen (LY-3154207; D1 PAM) – dopamine D1 receptor positive allosteric modulator [2][3]

Clinically used drugs

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Approved drugs

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Catecholaminergic agents

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  • Armodafinil (CEP-10953; Nuvigil; (R)-modafinil) – atypical dopamine reuptake inhibitor (DRI) – hypersomnia
  • Modafinil (AFT-801; Alertec; Attenace; CN-801; CRL-40476; Modasamil; Modasonil; Modavigil; Modiodal; Provigil; Sparlon; Vigil) – atypical dopamine reuptake inhibitor (DRI) – narcolepsy, hypersomnia
  • Solriamfetol (ADX-N05; ARL-N05; JZP-110; SKL-N05; Sunosi) – atypical norepinephrine–dopamine reuptake inhibitor (NDRI) and trace amine-associated receptor 1 (TAAR1) agonist – hypersomnia

Oxybate/GHB drugs

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  • Calcium/magnesium/potassium/sodium oxybates (GHB; JZP-258; Xywav; oxybate mixed salt solution; lower-sodium oxybate) – GABAB receptor agonist and GHB receptor agonist – narcolepsy and idiopathic hypersomnia
  • Sodium oxybate (GHB; JZP-6; KEY-10; Xyrem) – GABAB receptor agonist and GHB receptor agonist – narcolepsy
  • Sodium oxybate (GHB; FT-218; Lumryz; ON-SXB) – GABAB receptor agonist and GHB receptor agonist – narcolepsy

Histamine H3 receptor antagonists

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  • Pitolisant (BF-2.649; BF-2649; HBS-201; Ozawade; tiprolisant; Wakix) – histamine H3 receptor antagonist – narcolepsy, hypersomnia

Orexin receptor agonists

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  • Oveporexton (Orzeyful; TAK-861) – orexin OX2 receptor agonist – narcolepsy [4]

Discontinued drugs

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  • Adrafinil (Olmifon; CRL-40028; N-hydroxymodafinil) – atypical dopamine reuptake inhibitor (DRI) (modafinil prodrug) – hypersomnia

Off-label drugs

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See also

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References

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  1. ↑ Konofal E, Lecendreux M, Bizot JC, Lormier AT, Figadère B (2024). "NLS-3 (Levophacetoperane or (R,R) Phacetoperane): A Reverse Ester of Methylphenidate: A Literature Review". Curr Med Chem. 31 (9): 1069–1081. doi:10.2174/0929867330666230120161837. PMID 36683369.
  2. ↑ Jones-Tabah J, Mohammad H, Paulus EG, Clarke PB, Hébert TE (2021). "The Signaling and Pharmacology of the Dopamine D1 Receptor". Frontiers in Cellular Neuroscience. 15 806618. doi:10.3389/fncel.2021.806618. PMC 8801442. PMID 35110997.
  3. ↑ McCarthy AP, Svensson KA, Shanks E, Brittain C, Eastwood BJ, Kielbasa W, et al. (March 2022). "The Dopamine D1 Receptor Positive Allosteric Modulator Mevidalen (LY3154207) Enhances Wakefulness in the Humanized D1 Mouse and in Sleep-Deprived Healthy Male Volunteers". The Journal of Pharmacology and Experimental Therapeutics. 380 (3): 143–152. doi:10.1124/jpet.121.000719. PMID 34893551. S2CID 247363215.
  4. ↑ Research, Center for Drug Evaluation and (2026-08-05). "FDA Approves First Drug to Treat the Full Range of Narcolepsy Type 1 Symptoms". FDA. Retrieved 2026-08-05.
  5. 1 2 3 4 Nishino S, Kotorii N (2016). "Modes of Action of Drugs Related to Narcolepsy: Pharmacology of Wake-Promoting Compounds and Anticataplectics". Narcolepsy. Cham: Springer International Publishing. pp. 307–329. doi:10.1007/978-3-319-23739-8_22. ISBN 978-3-319-23738-1.
  6. 1 2 3 4 Nishino S, Okuro M (March 2010). "Emerging treatments for narcolepsy and its related disorders". Expert Opin Emerg Drugs. 15 (1): 139–158. doi:10.1517/14728210903559852. PMID 20166851.
  7. 1 2 Konofal E (August 2024). "From past to future: 50 years of pharmacological interventions to treat narcolepsy". Pharmacol Biochem Behav. 241 173804. doi:10.1016/j.pbb.2024.173804. PMID 38852786.
  8. ↑ Billiard M (June 2008). "Narcolepsy: current treatment options and future approaches". Neuropsychiatr Dis Treat. 4 (3): 557–566. PMC 2526380. PMID 18830438.
  9. 1 2 Thorpy MJ (May 2015). "Update on therapy for narcolepsy". Curr Treat Options Neurol. 17 (5) 20: 347. doi:10.1007/s11940-015-0347-4. PMID 25854650.
  10. ↑ Nishino S (2007). "Narcolepsy: pathophysiology and pharmacology". The Journal of Clinical Psychiatry. 68 (13): 9–15. PMID 18078360.
  11. ↑ Thorpy MJ, Dauvilliers Y (January 2015). "Clinical and practical considerations in the pharmacologic management of narcolepsy". Sleep Med. 16 (1): 9–18. doi:10.1016/j.sleep.2014.10.002. PMID 25458251.
  12. ↑ Abad VC, Guilleminault C (2017). "New developments in the management of narcolepsy". Nat Sci Sleep. 9: 39–57. doi:10.2147/NSS.S103467. PMC 5344488. PMID 28424564.
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