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 It is likely to become outdated with time.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

Phase 3

• Oveporexton (TAK-861) – orexin OX₂ receptor agonist – narcolepsy
• Reboxetine (AXS-12) – norepinephrine reuptake inhibitor (NRI) – narcolepsy
• Sodium oxybate (FT-218; Lumryz; ON-SXB) – GABA_B receptor agonist and GHB receptor agonist – idiopathic hypersomnia

Phase 2

• Alixorexton (ALKS-2680) – 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
• Mazindol controlled release (NLS-0; NLS-1; NLS-10; NLS-13; NLS-2; Nolazol; Quilience) – serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) – narcolepsy, idiopathic hypersomnia
• ORX-750 – orexin OX₂ receptor agonist – narcolepsy, idiopathic hypersomnia
• Pentylenetetrazole (BTD-001; pentetrazol; PTZ) – GABA_A 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
• TAK-360 – orexin OX₂ receptor agonist – narcolepsy, idiopathic hypersomnia
• TRN-257 – undefined mechanism of action – narcolepsy

Phase 1/2

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

Phase 1

• Danavorexton (TAK-925) – orexin OX₂ receptor agonist – narcolepsy
• E-2086 – orexin OX₂ receptor agonist – narcolepsy
• Lu-AH69593 – undefined mechanism of action – narcolepsy
• MK-6552 – undefined mechanism of action – narcolepsy
• Sodium oxybate once-nightly – GABA_B receptor agonist and GHB receptor agonist – narcolepsy
• Valiloxybate (XW-10172) – GABA_B receptor agonist and GHB receptor agonist – narcolepsy

Preclinical

• 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
• ORX-142 – orexin OX₂ receptor agonist

Research

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

Not under development

No development reported

• Armesocarb (MLR-1019; (R)-mesocarb) – atypical dopamine reuptake inhibitor (NDRI) – 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) – GABA_A 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) – GABA_B receptor agonist and GHB receptor agonist – narcolepsy
• Oveporexton (TAK-861) – orexin OX₂ receptor agonist – idiopathic hypersomnia
• 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) – GABA_B 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

• 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
• 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
• 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
• TS-091 (TS-0911; TS091) – undefined mechanism of action – narcolepsy and hypersomnia
• Ulotaront (SEP-363856; SEP-856) – trace amine-associated receptor 1 (TAAR1) agonist and serotonin 5-HT_1A and 5-HT_1D receptor partial agonist – narcolepsy

Formal development never or not yet started

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

Clinically used drugs

Approved drugs

Catecholaminergic agents

• 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

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

Histamine H₃ receptor antagonists

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

Off-label drugs

• Adenosine receptor antagonists (e.g., caffeine) ^{[4] [5] [6]}
• Norepinephrine releasing agents (NRAs) (e.g., ephedrine, selegiline (via metabolites)) ^{[4] [6]}
• Norepinephrine reuptake inhibitors (NRIs) (e.g., atomoxetine, reboxetine, viloxazine) ^{[7] [8]}
• Norepinephrine–dopamine reuptake inhibitors (NDRIs) (e.g., bupropion, nomifensine, amineptine) ^{[4] [5] [9]}
• Serotonin–norepinephrine–dopamine reuptake inhibitors (SNDRIs) (e.g., mazindol) ^{[4] [5]}
• Stimulants (norepinephrine–dopamine releasing agents and/or reuptake inhibitors (NDRAs/NDRIs)) (e.g., amphetamine, methamphetamine, lisdexamfetamine, methylphenidate, pemoline) ^{[10] [11] [5] [8]}

See also

• List of investigational drugs
• List of investigational insomnia drugs
• List of investigational chronobiotics
• Wakefulness-promoting agent
• Stimulant

References

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. 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.
5. 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.
6. 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.
7. Billiard M (June 2008). "Narcolepsy: current treatment options and future approaches". Neuropsychiatr Dis Treat. 4 (3): 557–566. PMC   2526380 . PMID   18830438.
8. 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.
9. Nishino S (2007). "Narcolepsy: pathophysiology and pharmacology". The Journal of Clinical Psychiatry. 68 (13): 9–15. PMID   18078360.
10. 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.
11. 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.

External links

• AdisInsight - Springer