Narcolepsy, recognized since the 19th century, was first described as chronic excessive daytime sleepiness, sleep attacks, sleep paralysis, and cataplexy.1 It is estimated to affect approximately 1 in 2,000 individuals in the general population.2 Following the discovery of the neuropeptide orexin in 1998 and subsequent findings that patients with narcolepsy have deficient orexin (or hypocretin) levels, the classification system was revised. In 2014, the International Classification of Sleep Disorders, Third Edition introduced the term narcolepsy type 1 (NT1). NT1 is characterized by the loss of hypothalamic neurons that produce orexin, resulting in low or absent cerebrospinal fluid orexin levels associated with cataplexy, which is the hallmark sign of NT1.
Excessive daytime sleepiness is commonly treated with wake-promoting agents and stimulants such as modafinil, armodafinil, methylphenidate, and amphetamine derivatives, which enhance dopaminergic and noradrenergic signaling to promote alertness. Cataplexy and disrupted nighttime sleep are often managed with sodium oxybate, which act through gamma aminobutyric acid type B-related mechanisms to consolidate nocturnal sleep and reduce cataplexy frequency. Additional therapies, including serotonin-norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors, suppress rapid eye movement (REM) sleep and thereby help control cataplexy, sleep paralysis, and hypnagogic hallucinations. However, these therapies do not address the core pathophysiology, which is the deficiency of orexin signaling. Orexin exerts its effects through two G protein-coupled receptors, OX1R and OX2R, which have overlapping but distinct distributions in the brain. Evidence from animal models suggests that OX2R plays a central role in maintaining wakefulness, regulating sleep, and suppressing cataplexy.3
Early preclinical and clinical studies demonstrated that intravenous administration of the OX2R agonist danavorexton (TAK-925) increased wakefulness and suggested a reduction in cataplexy in patients with NT1.4 This was followed by studies of the oral OX2R agonist, TAK-994, which improved wakefulness and cataplexy compared with placebo but was associated with hepatotoxicity.5 Subsequently, TAK-861 (oveporexton), another oral selective OX2R agonist, was evaluated.6 In a phase 2, double-blind, randomized, placebo-controlled trial, patients with NT1 received once or twice daily oveporexton or placebo for eight weeks. Treatment led to significant improvements in objective measures of wakefulness and patient-reported daytime sleepiness compared with placebo. Additional benefits included reduced cataplexy frequency, increased sleep latency by week 4 (sustained through week 8), and improved Epworth Sleepiness Scale scores. Common adverse effects included insomnia and urinary urgency/frequency, without the hepatotoxicity observed with TAK-994.
These findings led to two global, multicenter, placebo-controlled trials (FirstLight [NCT06470828] and RadiantLight [NCT06505031]) to further evaluate the efficacy, safety, and tolerability of oveporexton. Both studies reported significant improvements in subjective and objective measures of wakefulness, sleepiness, and cataplexy frequency, with generally good tolerability.7–8 Common adverse effects were pollakiuria and insomnia.
Based on these results, the US Food and Drug Administration accepted a new drug application for oveporexton and has granted it priority review for the treatment of NT1, with a decision expected later this year. Overall, this therapy and direction in treatment represents a promising and exciting step toward a precision medicine approach that directly targets the underlying deficiency of orexin signaling in NT1.
References
1. Schenck CH, Bassetti CL, Arnulf I, Mignot E. English translations of the first clinical reports on narcolepsy and cataplexy by Westphal and Gélineau in the late 19th century, with commentary. J Clin Sleep Med. 2007;3(3):301-311.
2. National Organization for Rare Disorders. Narcolepsy. Accessed April 30, 2026.
3. Sun Y, Tisdale RK, Kilduff TS. Hypocretin/orexin receptor pharmacology and sleep phases. Front Neurol Neurosci. 2021;45:22-37. doi:10.1159/000514963
4. Evans R, Kimura H, Alexander R, et al. Orexin 2 receptor-selective agonist danavorexton improves narcolepsy phenotype in a mouse model and in human patients. Proc Natl Acad Sci U S A. 2022;119(35):e2207531119. doi:10.1073/pnas.2207531119
5. Dauvilliers Y, Mignot E, Del Río Villegas R, et al. Oral orexin receptor 2 agonist in narcolepsy type 1. N Engl J Med. 2023;389:309-321. doi:10.1056/NEJMoa2301940
6. Dauvilliers Y, Plazzi G, Mignot E, et al. Oveporexton, an oral orexin receptor 2–selective agonist, in narcolepsy type 1. N Engl J Med. 2025;392(19):1905-1916. doi:10.1056/NEJMoa2405847
7. World Sleep Society. World Sleep 2025 Abstracts, pg. 443. Accessed April 30, 2026.
8. World Sleep Society. World Sleep 2025 Abstracts, pg. 444. Accessed April 30, 2026.
