List of investigational narcolepsy and hypersomnia drugs

Preregistration

• Sodium oxybate controlled release (TRN-257) – GABA_B receptor agonist and GHB receptor agonist – narcolepsy, idiopathic hypersomnia
• Oveporexton (TAK-861) – orexin OX₂ receptor agonist – narcolepsy
• Reboxetine (AXS-12) – norepinephrine reuptake inhibitor (NRI) – narcolepsy

Phase 3

• Sodium oxybate micropump (FT-218; Lumryz; ON-SXB) – GABA_B receptor agonist and GHB receptor agonist – idiopathic hypersomnia
• 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

Phase 2

• Alixorexton (ALKS-2680) – orexin OX₂ receptor agonist – idiopathic hypersomnia
• Balumorexton (TAK-360) – orexin OX₂ receptor agonist – narcolepsy, 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) – 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

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
• 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

No development reported

• 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) – 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
• 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
• 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-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]

Approved drugs

Discontinued drugs

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