Orexin antagonist

An orexin receptor antagonist, or orexin antagonist, is a drug that inhibits the effect of orexin by acting as a receptor antagonist of one (selective orexin receptor antagonist or SORA) or both (dual orexin receptor antagonis or DORA) of the orexin receptors, OX₁ and OX₂.^[1] Medical applications include treatment of sleep disorders such as insomnia.^[2][3]

• Daridorexant (nemorexant; Quviviq) – dual OX₁ and OX₂ antagonist – approved for insomnia in January 2022,^[4] formerly under development for sleep apnea^[5] – half-life 8 hours^[6]
• Lemborexant (Dayvigo) – dual OX₁ and OX₂ antagonist – approved for insomnia in December 2019^[4] and released June 1 2020, under development for circadian rhythm sleep disorders, chronic obstructive pulmonary disease, and sleep apnea – half-life 17–55 hours^[7][8]
• Suvorexant (Belsomra) – dual OX₁ and OX₂ antagonist – approved for insomnia in August 2014,^[4] under development for delirium^[9][10] – half-life 12 hours^[7][11]

• Fazamorexant (YZJ-1139) – dual OX₁ and OX₂ antagonist – under development for insomnia, up to phase 3 ^[12]
• Nivasorexant (ACT-539313) – selective OX₁ antagonist – under development for binge eating disorder and previously for anxiety disorders, up to phase 2 – half-life 3–7 hours ^[13]
• Seltorexant (MIN-202, JNJ-42847922, JNJ-922) – selective OX₂ antagonist – under development for major depressive disorder, insomnia, and sleep apnea, up to phase 3 – half-life 2–3 hours ^[14]
• Tebideutorexant (JNJ-61393215, JNJ-3215) – selective OX₁ antagonist – under development for major depressive disorder, no development reported for anxiety disorders and panic disorder, up to phase 2^[15]
• Vornorexant (ORN-0829, TS-142) – dual OX₁ and OX₂ antagonist – under development for insomnia and sleep apnea, up to phase 2 – half-life 1.5–3 hours^[16]

• ACT-335827 – selective OX₁ antagonist
• Almorexant (ACT-078573) – dual OX₁ and OX₂ antagonist – development of the drug was abandoned in January 2011 ^[17]
• EMPA – selective OX₂ antagonist
• Filorexant (MK-6096) – dual OX₁ and OX₂ antagonist – development was discontinued in 2015 ^[18]
• GSK-649868 (SB-649868) – dual OX₁ and OX₂ antagonist – was in development for potential use in sleep disorders
• JNJ-10397049 – selective OX₂ antagonist
• RTIOX-276 – selective OX₁ antagonist
• SB-334867 – first non-peptide selective OX₁ antagonist – has been shown to produce sedative and anorectic effects in animals^[19]
• SB-408124 – selective OX₁ antagonist
• TCS-OX2-29 – first non-peptide selective OX₂ antagonist

Orexin receptor antagonists dose-dependently improve sleep parameters including latency to persistent sleep (LPS), wake after sleep onset (WASO), sleep efficiency (SE), total sleep time (TST), and sleep quality (SQ).^{[20][21][22][23][24]}

Orexin receptor antagonists are not currently used as first-line treatments for insomnia due to cost and concerns about possible misuse liability.^[25]

Suvorexant appears to be effective in the prevention of delirium.^[9][10]

Side effects of orexin receptor antagonists include somnolence, daytime sleepiness and sedation, headache, abnormal dreams, fatigue, and dry mouth.^{[20][21][22][24][23]}

Rates of somnolence or fatigue with orexin receptor antagonists in clinical trials were 7% (vs. 3% with placebo) for suvorexant 15 to 20 mg,^[26] 7 to 10% (vs. 1.3% for placebo) for lemborexant 5 to 10 mg,^[27] and 5 to 6% (vs. 4% with placebo) for daridorexant 25 to 50 mg.^[28]

Narcolepsy, a neurological disorder caused by orexin deficiency, is a contraindication to the use of orexin antagonists.^[29]

The elimination half-lives of clinically used orexin receptor antagonists are 12 hours for suvorexant, about 17 to 19 hours ("effective" half-life) or 55 hours (terminal elimination half-life) for lemborexant, and 6 to 10 hours for daridorexant.^[8] The elimination half-lives of investigational orexin receptor antagonists are 2 to 3 hours for seltorexant and about 1.5 to 3 hours for vornorexant.^[8][30]

The pharmacokinetics of suvorexant are significantly affected by age, sex, and other factors, leading to increased blood concentrations in female, obese, and older patients.^[7] These factors do not significantly affect the pharmacokinetics of lemborexant^[7] or daridorexant.^[31]

All three marketed orexin antagonists do not need to be dose adjusted in patients with reduced renal function, as the pharmacokinetic profiles of these medications are not significantly affected.^[32][31][33] In patients with moderate to severe hepatic impairment, dose adjustments of these medications may be necessary.^[34]

Filorexant was studied for but was not found to be effective in the treatment of diabetic neuropathy, migraine, and major depressive disorder in phase 2 clinical trials.^[35][36][37] Seltorexant is under development for treatment of major depressive disorder however and is in phase 3 trials for this indication.^[38] Also, suvorexant is in a phase 4 trial for use as an adjunct to antidepressant therapy in people with major depressive disorder and residual insomnia.^[38][39][40]

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