Enhancing the Management of Hypersomnia: Examining the Role of the Orexin System

Abstract

Excessive daytime sleepiness (EDS) is common. However, clinical features of excessive sleepiness can have broad and variable presentations. In addition, there can be an increased likelihood of medical or psychiatric comorbidity. Examination of the networks that regulate sleep–wake and circadian control reveals a complex and intricately designed integration system. Dysregulation in the coordination, effectiveness, or efficiency of these systems can contribute to developing EDS, and inform on the endotypes observed and pharmacologic considerations for treatment. The discovery and characterization of the diurnal expression and function of orexin (hypocretin) have led to a transformed understanding of sleep–wake control and EDS, as well as its role beyond sleep. As a result, a novel drug class, orexin agonists, is anticipated to emerge for clinical use in the near future. An understanding of orexin physiology and its transdisciplinary impact is necessary to best prepare for patient selection, use, and anticipated benefit and monitoring of both expected benefits and any other health change. This study provides a review of the range of clinical features and impact of EDS, the relationship between sleep–wake, circadian and other health networks, and an examination of orexin physiology with anticipatory guidance on the potential transdisciplinary role and impact of orexin agonists.

Keywords

narcolepsy - orexin - orexin agonists - sleepiness - cognition - hypersomnolence - idiopathic hypersomnia

The sleep–wake cycle is a centrally derived homeostatic process. The two-process model is a basic conceptual framework commonly used to illustrate sleep–wake regulation. This model demonstrates a synchronized interaction between the homeostatic sleep drive (process S) and the circadian drive for arousal (process C) across a near 24-hour cycle ([Fig. 1]).[1] Physiologic sleepiness is distinct from excessive daytime sleepiness (EDS).[2] [3] Physiologic sleepiness is normal and generally attributed to the expected accumulation of homeostatic or sleep pressure to fall back to sleep that is combined with a reduced circadian drive for arousal.[2] [3] Increasing sleep pressure has been suggested to be primarily based on increasing amounts of adenosine.[4] Based on this conceptual framework, there is an optimal difference that must be achieved between processes C and S that will allow the sleep gate to open and allow for the subsequent return to sleep.[5] The homeostatic sleep drive facilitates the first part of sleep in the night but is rapidly diminished, with the remaining hours of sleep for the remaining sleep time being supported by endogenous melatonin production.[5] Unfortunately, in this model there is a failure to include the role of other critical endogenous factors that influence these processes like genetics, inflammatory signaling (i.e., IL-6, TNF-α, and NO), microbiome, or other network factors that are independent of these processes, such as orexin or melanin-concentrating hormone.[6] [7] [8] [9] [10] [11]

Fig. 1 Two process sleep–wake models: the circadian drive for arousal (process C) and the homeostatic sleep drive (process S).

EDS is typically described as sleep needs beyond age-appropriate duration, inappropriate lapses to sleep or desire to sleep at inappropriate times, or sleepiness interfering with daily functioning.[12] However, clinical presentations can vary widely, with increasing recognition of various contributing factors, functional impact, and compensatory actions or consequences ([Table 1]).[13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] Beyond functional impairment there is also increasing evidence that the presence of EDS may positively correlate with increased morbidity and mortality, and may have differential risk stratification based on age or gender.[23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] This highlights the age, gender, and transdisciplinary considerations related to sleep and circadian health that may be important in examining the approach to EDS.

Table 1 Clinical features, functional impact, and compensatory of excessive daytime sleepiness

Clinical features	Functional impact	Compensatory actions or related outcomes
• Sleep inertia and oversleeping • Elongated nocturnal sleep • Napping • Unintentional lapses in sleep • Impulsiveness • Hyperkinesis • Impaired attention or lapses of awareness • Cognitive slowing • Appearance of depressed mood (i.e., reduced interest or participation in activities) • Obsessive-compulsive behavior (maybe compensatory to cope with lack of predictability and reduced functioning) • Appearance of anxiety (i.e., driven by lack of predictability in the day and inability to consistently perform at ability level) • Irritability or emotional volatility	• Absences or tardiness • Sleep-related anxiety • Perception of time management difficulties • Automatic behaviors • Poor presenteeism • Impaired academic or occupational performance • Withdrawn or social isolation • Stigma and embarrassment • Personal and social perceptions of not trying hard enough or being at fault • Injury • Driving impairment • Risk-taking behavior • Reduced academic and occupational success • Reduced earnings • Depressed mood • Risk of suicidal ideation • Poor self-esteem, self-worth, or guilt	• Homeschooling or discontinuation of higher education • Job loss due to poor presenteeism or absenteeism • Partial employment or unemployment • Employment in a position that may be less than capabilities (potentially due to flexibility in schedule or less expectation that accommodates disabilities experienced) • Few or no friends ± reduced social interactions • No romantic relationships or less than age typical romantic partners ± intimacy avoidance • Family estrangement (potentially related to poor understanding, disappointment, frustration from family, or self-preservation on behalf of the individual) • Self-characterize EDS features as depression, anxiety, or obsessive behaviors (i.e., “I need to have everything scheduled so I can do it before I get too tired,” “I don't like going out I am too tired to,” “I get to anxious about making plans because I worry about being too fatigued while out or having to cancel because I am too tired”) • Avoid spontaneous reporting of napping or sleep attacks (potentially related to feelings of guilt or fear of judgment)

EDS is common, but never normal. In fact, pediatric prevalence for EDS has been reported to range from 10 to 12% to upward of 50%, with advancing chronological age increasing the likelihood of EDS.[45] [46] [47] [48] [49] [50] [51] In 2020, it was found that a third of adults in a large general population sample had EDS.[23] The presence of EDS with age-appropriate duration of sleep is hypersomnolence. EDS with the need for more than age-appropriate duration of sleep is still categorized as a hypersomnolence disorder but is more specifically considered hypersomnia.

Hypersomnolence disorders are characterized by either chronic or episodic features of EDS. The International Classification of Sleep Disorders-3 Text Revision (ICSD-3TR) classifies central disorders of hypersomnolence as: (1) narcolepsy type 1 (previously narcolepsy with cataplexy); (2) narcolepsy type 2 (previously narcolepsy without cataplexy; (3) idiopathic hypersomnia; (4) Kleine–Levin syndrome (KLS); (5) hypersomnia due to a medical disorder; (6) hypersomnia due to medication or substance abuse; (7) hypersomnia due to a psychiatric disorder; and (8) insufficient sleep syndrome.[52] These conditions should be considered as part of the differential diagnosis in any individual with EDS at the time of presentation, and when EDS persists despite adequate treatment for alternative etiologies. An understanding of the neuroanatomy, neurochemistry, neurophysiology, related connectome, and contributing genetic factors that are involved in the orchestration of the sleep–wake and circadian cycles may enhance the ability to more optimally identify and address EDS, as well as its impact in a transdisciplinary manner.

Sleep–Wake and Circadian Cycles

There is an expected ontogeny of the sleep–wake and circadian cycle that is representative of neurodevelopmental or degenerative changes over time. This can be observed in the evolution of sleep–wake and circadian features that correspond with advancing age, such as sleep duration, circadian distribution, and timing of sleep, as well as sleep stage expression and cycling. For instance, neonates require on average 14 to 17 hours of sleep that is fragmented across 24 hours and lacks the mature features of nonrapid eye movement (NREM) and REM sleep with cycling every 50 to 60 minutes. As an individual age, there is a progressive reduction in total sleep duration with a corresponding circadian maturity and consolidation of nocturnal sleep. Additionally, sleep stage morphology denotes NREM and REM sleep and their corresponding percentage of time spent in each also evolves.

Sleep–wake control has previously been described as a “Flip Flop” switch, providing a rudimentary and binary on–off illustration of control ([Fig. 2A, B]).[53] Orexin is a pivotal component in this model, serving as the fulcrum or main modulatory factor of the on–off the expression of sleep–wake. However, more advanced models of continuous activation of modulatory communication have been proposed to better represent the intricate interactions across multiple neuroanatomical structures and various neurotransmitters resulting in a complex connectome ([Fig. 2C])[54] that also has significant influence on nonsleep–wake systems, such as cardiovascular or metabolic ([Fig. 2D]).[54] [55] [56] [57] [58] [59] An additional layer to this already intricate concept is the consideration of genetic contributions to both homeostatic and circadian function, as well as the development and stability of these networks.[9]

Fig. 2 (A) Sleep–wake flip-flop switch promoting wakefulness. (B) Sleep–wake flip-flop switch promoting sleep. (C) Flip Flop switch including orexin and its circadian interaction with a suprachiasmatic nucleus. (D) Orexin modulates sleep–wake and other organ systems as an integrator. Ach, acetylcholine; BF, basal forebrain; cSPVZ, subparaventricular zone; DA, dopamine; DMH, dorsomedial hypothalamus; DRN, dorsal raphe nucleus; GABA, gamma-aminobutyric acid; Glu, glutamate; His, histamine; LC, locus coeruleus; LH, lateral hypothalamus; mPOA, medial preoptic area; NAc, nucleus accumbens; NE, norepinephrine; SCN, suprachiasmatic nucleus; SN, substantia nigra; TMN, tuberomammillary nuclei; VLPO; VTA, ventral tegmental area; vSPVZ, ventral subparaventricular zone.

EDS can be due to dysfunction within these networks and result in an exaggerated expression of sleep drive, inadequate wake promotion, misalignment, loss of coordination of signaling, or a combination of these.[2] [3] [12] The variation in possible network dysfunction may contribute to phenotypic variability in the expression of EDS observed.[60] Historically, attempts at modifying the expression of EDS have been based on pharmacologic strategies that enhance or stabilize the expression and utilization of neurotransmitters like dopamine, serotonin, GABA (or GHB), norepinephrine, and histamine.[60] However, most recent attention has been more upstream in the signaling cascade, with a specific focus on orexin and its role in sleep–wake modulation.[7] [57] [59] [61] An understanding of these relationships provides a basis for delineating an approach for treatment considerations and an entry point to explore the bidirectional transdisciplinary impact that may relate to the increased health risks that can be observed in individuals with EDS.

The Role of Orexin

Orexin, also known as hypocretin, is expressed in the central nervous system and throughout the body as orexin-A/hypocretin-1 and orexin-B/hypocretin-2.[62] [63] They are a result of proteolytic cleavage of the polypeptide precursor prepro-orexin and results in these two unique neuropeptides with independent but overlapping function.[61] [62] [63]. The preprepro-orexin gene is located on chromosome 17q21.[61] [62] [63] Orexins 1 and 2 receptors are G-protein-coupled receptors (GPCRs) that lead to the activation of a cascade of complex downstream signaling ([Fig. 3]).[7] [57] [59] [61] [64] Most typically, GPCRs are monomers, however, orexin receptors form homo- and heterodimers[65] [66] and have the potential for multimerization, or variations in the receptor combinations with orexin and nonorexin receptor subunits.[67] These dimers have distinct effects on the signaling pathways induced by the corresponding monomers that contribute to their development.[67]

Fig. 3 Orexin signaling pathways. 2-AG, 2-arachindonoyl glycerol; AA, arachidonic acid; AC, adenylyl cyclases; AKT, protein kinase B; ATP, adenosine triphosphate; Ca²⁺, calcium; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element protein; DAG, diacylglycerol; ERK, extracellular signal related kinase; Gq/Gs/Gi, G-protein subtypes; IP3, inositol trisphophate; NSCC, nonselective calcium channel; OX1R, orexin receptor 1; OX2R, orexin receptor 2; P38 MAPK, P38 mitogen-activated protein kinase; PIP2, phosphatidylinositol bisphosphate; PLA, phospholipase A; PLC, phospholipase C; PLD, phospholipase D; PKC, protein kinase C.

Centrally, these neuropeptides are synthesized in orexin neurons in the lateral hypothalamus and perifornical area[59] [62] [63] in response to environmental, physiological, and emotional signaling, and then project broadly across the entire CNS.[61] In fact, significant adaptive changes occur with orexin neurons resulting in remodeling of signaling paths in response to changes in feeding or nutrition and prolonged wakefulness resulting in diurnal variation of expression of orexin. However, similar connectivity changes and diurnal variation occur even without such provoking factors, and have been suggested to potentially represent a “chronoconnectivity” or “synaptic rearrangement of inputs to orexin neurons over the course of the day in relation to sleep and wake states.”[68] In addition to the diurnal expression of orexin there has also been the illustration of endocannabinoid and hormonal (i.e., leptin, estradiol, GLP-1, and CGRP) influence on the expression of orexin and its receptors.[55] [56] [57] [61] [67] [69] [70] [71]

Interestingly, orexin neurons themselves rarely express orexin receptors, suggesting that they may lack a significant autoreceptor feedback mechanism.[60] Orexins A and B both interact with orexin 1 and 2 receptors (OX1R and OX2R).[60] Initial studies suggested different affinities for orexins A and B for the respective receptors.[72] More recent data suggests that orexin-A preferentially binds OX1R, with 5 to 100 times greater affinity than orexin-B, whereas both neuropeptides now are reported to likely have similar affinities for OX2R.[60]

Centrally, OX1R and OX2R are found in the brain and spinal cord and exhibit distinct, but partially corresponding distribution patterns.[57] [61] [62] [63] [72] OX1R is more concentrated in the locus coeruleus (LC), prefrontal cortex, CA2 region of the hippocampus, and in the dorsal raphe and lateral tegmental area within the brainstem.[57] [61] [62] [63] [72] OX2R are primarily found in the tuberomammillary nucleus (TMN), nucleus accumbens (NAc), the paraventricular nucleus and the arcuate nucleus of the hypothalamus, and subthalamic nuclei.[57] [61] [62] [63] [72] With this stated, in 2024 a further understanding of the distribution of these receptors was informed by a study of whole brain mapping in mice of orexin receptor mRNA expression with neuron subtype markers via a novel approach called branched in situ hybridization chain reaction (bHCR).[73] In this study, it was found that although both Ox1r and Ox2r mRNAs are expressed across the brain it was not common for both Ox1r and Ox2r mRNAs to be expressed in the same cell. With this stated, the brain regions that are expressing both receptors include the dorsal raphe nucleus (DRN), lateral mammillary nucleus (LM), Barrington's nucleus (BAR, also known as the pontine micturition center), a compact part of the nucleus ambiguous (AMBc), ventromedial hypothalamic nucleus (VMH), and dorsal motor nucleus of the vagus nerve (DMN).[73] The majority of these nuclei have a direct impact on sleep–wake regulation and ultradian cycling (e.g., DRN, LM, and BAR).[54] However, although the other may not have a direct role in sleep–wake regulation, they may have either an indirect or proposed role (e.g., VMH and its network with VLPO[74]; DMN and its role controlling the gastrointestinal tone and secondary sleep impact[75]). Only the AMBc has no described relationship with sleep–wake regulation but does influence swallowing and upper airway muscle stability.[76] Downstream signaling within double versus single receptor expressed cells may differ, but this needs to be characterized as it is unclear at this time based on current research.[73]

In sleep, most attention and learning about orexin has been related to the orexin deficiency that has been characterized as being causative for the pentad symptoms (e.g., EDS, cataplexy, disturbed nocturnal sleep, sleep-related hallucinations, and sleep paralysis) experienced by many individuals with Narcolepsy type 1 (NT1) who are characterized to have a deficiency of measures orexin-A in the cerebrospinal fluid (CSF).[77] However, it is also recognized that narcolepsy type 1 has been characterized in individuals without CSF deficiency of Orexin-A. The current CSF testing available has limitations. It is a radioimmunoassay (RIA) that measures orexin and its byproducts using competitive RIA, but is subject to poor inter-batch intermediate precision, and is at risk for interference and potential to cross-react with metabolized fragments of other proteins, resulting in false-positive or negative results.[78] A new method to measure CSF orexin-A with mass spectroscopy has been evaluated and suggested to be superior.[78] A new method to measure CSF orexin-A with mass spectroscopy has been evaluated and suggested to be superior.[78] However, there is no study or proposed methodology of CSF orexin-B levels in people with or without narcolepsy. Improved understanding of the interaction of the orexin neuropeptides may provide additional insights. Exploration of how CSF orexins A and B concentrations influence each other's timing or amplitude of one another's diurnal expression may be useful, as there are overlapping roles in function, as well as receptor affinities. Beyond these neuropeptides would be an understanding of the impact of OX1R or OX2R regulation of receptor expression, various dimerization possibilities, and allosteric or other modifications that may result in either enhanced, reduced, or even null affinity for typical binding ligands. Evaluation of changes in downstream signaling after appropriate ligand-receptor binding may give insights into causation of other hypersomnolence disorders, as well as in individuals with a narcolepsy type 1 phenotype and CSF orexin-A. Orexin's role across other organ systems may be best illustrated in the increased risk for medical and psychiatric comorbidity that is observed in individuals with narcolepsy and known orexinergic dysfunction, and may also be related to the increased morbidity and mortality observed in other conditions with EDS.[23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] Orexin neurons have an influence on feeding behavior, energy homeostasis, reward systems, cognition, and mood.[55] [56] [57] [59] [61] [79] An important relationship to underscore is Orexin's interaction with Leptin and Ghrelin. Ghrelin is considered the most potent appetite-enhancing hormone and acts via the growth hormone secretagogue receptor (GHSR).[80] Signaling occurs through the hypothalamic arcuate nucleus (ARH) neurons producing neuropeptide Y (NPY) and agouti-related protein (AgRP), which highly express GHSR and serve in sensing plasma ghrelin levels, facilitating a feedback loop. Additional signaling occurs via the mesolimbic pathway through dopamine neurons in the ventral tegmental area (VTA) and is more representative of a hedonic pathway or reward-related behavior.[80] On the other hand, Leptin modulates food reward via the leptin receptor (LepRb). Although LepRb neurons are distinct from orexin neurons they directly innervate orexin neurons.[81] This results in indirect orexin action with the modulation of the rewarding value and consumption associated with hedonic eating. Leptin has been shown to strongly inhibit orexin neurons resulting in hyperpolarization and decreased firing frequency.[82] Whereas, Ghrelin has been shown to activate isolated orexin neurons resulting in depolarization and increased firing frequency[82] and participation in augmented food-seeking behavior.

Orexins enhance hippocampal neurogenesis and improve spatial learning, memory abilities, and mood, and maybe a result of their network involved in cognition and mood regulation, including the hippocampus.[61] Additionally, ectopic expression of orexin and its receptors have been found in many diseases,[83] [84] [85] [86] emphasizing the significance of their role beyond sleep.

The Role of Orexin Pharmacology

The understanding of the bidirectional transdisciplinary relationship with sleep–wake and circadian health continues to develop, and experience with various pharmacologic treatments is adding to this understanding, especially in regard to orexin. In 2014, the first FDA-approved dual orexin receptor antagonist (DORA), suvorexant, became available as a Schedule IV medication for the treatment of insomnia in adults.[87] Since that time, two additional DORAs, lemborexant and daridorexant, have also been FDA-approved as well.[88] Schedule IV classification of these medications is due to the suggestion of risk of dependence, misuse, and abuse similar to benzodiazepines and benzodiazepine receptor agonists.[89] However, postmarketing surveillance data, federal surveillance systems, and a re-analysis of the Eight Factors of the Controlled Substances Act do not support this. To further this point, there is even data to demonstrate the effective use of these medications as a treatment for substance use disorder, resulting in improved sleep normalizing sleep, executive control over drug-seeking, and reduced drug craving.[90] [91] [92]

Studies evaluating alternative uses of orexin antagonists have revealed additional sleep- and nonsleep-related information. Studies evaluating DORAs as a treatment for mild or mild-to-moderate obstructive sleep apnea (OSA) were performed based on the knowledge of orexins' role in modifying upper airway muscle tone and dilator function.[93] These studies did not show worsening or benefit that was statistically significant.[94] A randomized, double-blind, crossover, and placebo-controlled study of suvorexant for patients with restless leg syndrome (RLS) demonstrated proof of concept benefit in sleep, as well as sensory and motor symptoms, and posed the possibility that this was achieved via orexin-related sleep–wake pathways as well as their nociceptive pathways.[95] Selmorexant is a selective orexin agonist (SORA-) currently in phase 3 studies for the treatment of depression and insomnia and suggesting favorable antidepressant properties.[96]

After 10 years of clinical experience with orexin antagonists demonstrating safety and a growing body of evidence for transdisciplinary use with variable benefits, there is great anticipation for the clinical use of orexin agonists. Several first-in-class orexin agonists are currently in phase 1 to 3 studies, with the anticipation of a successful entry to the market of at least one of these within the next few years for the treatment of narcolepsy type 1, and possibly hypersomnolence disorders as well. Thus, a call to action to develop a framework of potential sleep and nonsleep factors to characterize as an initial step for anticipatory guidance for future clinical practice.

In July 2023, the first study to document findings from a phase 2 trial of an oral selective orexin 2 agonist (SORA2 + ) was published, but unfortunately, the study was terminated early due to safety concerns related to hepatotoxicity.[97] This was a randomized, placebo-controlled trial of TAK-994, danavorexton, a twice-daily oral SORA2+ in patients with narcolepsy type 1 that had the primary endpoint of the mean change of average sleep latency (SL) on the Maintenance of Wakefulness Test (MWT) from baseline to week 8; secondary endpoints included the change in the Epworth Sleepiness Scale (ESS) score and the weekly cataplexy rate (WCR).[97] Despite early termination of the study, the findings demonstrated unprecedented impact with normalization of ESS across all dose ranges, marked to near complete cataplexy freedom, and a gain of 25 minutes or more on the MWT, with the ability to remain awake for the entire test observed in some patients.[97] The most common side effect observed was urinary urgency, which had been postulated to be a possible on-target effect related to OX2R signaling in the pons.[97]

Hy's Law criteria indicate the likelihood of drug-induced liver injury and is based on liver enzymes, AST or ALT, being at least three times the upper limit of normal (ULN), bilirubin is at least twice the ULN, and there is no alternative explanation.[98] In this study, early termination was based on the observation that eight patients had elevated liver enzymes, with three meeting Hy's Law criteria. The authors theorized that drug-induced liver injury occurred as a consequence of reactive metabolites, rather than an on-target effect of OX2R activation, as orexin receptors are not expressed on human hepatocytes or on most immune cells.[97] Although the findings in the study are based on a limited number of patients and had early termination, the positive impact found remains impressive and has now laid the foundational expectations for class effect.

Oveporexton, TAK-861, is long-acting SORA2+ administered as BID dosing that has a pharmacokinetic profile that simulates diurnal CSF orexin-A fluctuation and is currently in phase 3 clinical trials. Phase 2b and long-term evaluation (LTE) study evaluating the safety and efficacy of Oveporexton in 4 doses (0.5 mg twice daily 3 hours apart, 2 mg twice daily 3 hours apart, 2 mg followed by 5 mg daily 3 hours apart, and 7 mg once daily) in NT1 demonstrated normalization of sleep latency (wakefulness for greater than 20 minutes) on MWT, normalization of the ESS, and a significant reduction in WCR that was sustained in a 6-month open-label period.[99] In addition, statistically significant improvements in sustained attention as measured by psychomotor vigilance testing (PVT) and reduction in disturbing dreams and hallucinations were found in the phase 2 study.[99] Most optimal dosing was twice daily versus once daily. There were no cases of hepatotoxicity or visual disturbances reported, and 90% of patients continued into the LTE.[99] The most common side effect was urinary urgency.

TAK-360 is an oral SORA2+ that is chemically distinct from TAK-861 and developed to accommodate for higher and more flexible dosing that may be necessary for orexin normal populations, such as in NT2 or IH.[100] TAK-360 is currently being evaluated in phase 2 dose-finding, adaptive, randomized, double-blinded, placebo-controlled trial to evaluate the safety, tolerability, and efficacy for individuals with IH.[100]

ALKS-2680 is a once daily oral SORA2+ that is currently being evaluated in phase 2 studies as a treatment of NT1, NT2, and IH.[101] The phase 1b study using a randomized crossover design of a single dose of placebo, 1, 3, and 8 mg in 10 individuals with NT1.[101] The results demonstrated similar substantial benefits as has been seen with other SORA2+ compounds with a gain of 18.4 to 34 minutes on the MWT with only a single dose. The compound has an extended-release profile with biphasic distribution and elimination that would provide the ability to maintain daytime wakefulness with once-daily administration.[102] There have been no systematic changes in vital signs, safety laboratory tests, or ECG at any dose level, and no serious or severe adverse events (AEs).[101] AEs that were observed in more than one participant and considered drug-related were insomnia, pollakiuria (small volume and high-frequency urinary voiding), salivary hypersecretion, decreased appetite, dizziness, and nausea.[101] There was one mild transient visual disturbance reported.[101]

ORX-750 is an orally administered once daily extended-release SORA2+ that is currently in phase 2a studies in NT1, NT2, and IH. A phase 1 study of safety, tolerability, and pharmacokinetics of single-ascending and multiple-ascending doses in healthy adult volunteers demonstrated that 2.5, 3.5, and 5.0 mg doses were able to restore normative wakefulness as measured by MWT in acutely sleep-deprived healthy volunteers.[103] No cases of hepatotoxicity, cardiotoxicity, visual disturbances, or hallucinations were observed.[103] AE did include the presence of what appears to be class-related urinary frequency and insomnia.[103]

E2086 is an orally administered once daily extended-release SORA2+ that is now currently enrolling in phase 1 randomized, double-blind, single-dose, 5-period crossover study to evaluate the efficacy, safety, and tolerability of E2086 in individuals with NT1.[104] Preclinical data demonstrate increased wakefulness in both wild type and orexin-deficient transgenic mice when receiving a single oral dose of E2086 at 0.3, 1, and 3 mg/kg.[105] In the orexin-deficient transgenic mice there was a reduction of wake to REM transition and sustained 3 mg/kg dosing for 14 days there was significantly prolonged wakefulness and cataplexy-equivalent episodes prevention.[105] No development of tolerance was observed.

ORX-142 is an orally administered SORA2+ that has favorable preclinical data that demonstrates sustained increases in wakefulness that suppressed NREM and REM sleep at the lowest dose tested, 0.03 mg/kg, and was associated with normal physiological arousal and EEG power spectra signatures of enhanced alertness and attention.[103] ORX-489 is a SORA2+ that is currently in preclinical evaluation. Both ORX-489 and ORX-142 are being developed with the intention of being studied as a treatment for neurological, neurodegenerative, and psychiatric disorders.

TAK-925, Danavorexton, is an intravenous (IV) formulation of a SORA2+ that is or has been evaluated across several conditions, including in healthy sleep-deprived volunteers, IH, narcolepsy, EDS in individuals with OSA despite compliance to CPAP, and adults with OSA after general anesthesia for abdominal surgery.[106] [107] [108] A randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics of a single IV infusion of Danavorexton in people with moderate to severe OSA undergoing general anesthesia for abdominal surgery was terminated for business reasons, no adverse effects.[108] It is unclear at this time if there will be the pursuit of use for TAK-925 for any clinical indications.

Continued progress is being made in the evaluation of SORA2+ as a treatment for NT1, as well as other hypersomnolence disorders, neurologic, psychiatric, and other medical conditions, and demonstrates the potential transdisciplinary impact. The results from the early termination of the phase 2 study on TAK-994 provided foundational knowledge regarding substantial efficacy for SORA2 + , but likely hesitancy about the safety of orexin agonists. Now there are multiple studies across various compounds that provide safety profile reassurance with no severe AEs observed and mostly transient mild AEs. Real-world experience (RWE) will continue to inform on the safety, tolerability, and efficacy of these compounds, especially as relates to co-administration with other medications, impact on medical and psychiatric comorbidities, development of tolerance, and influence on healthcare economics and socioeconomic burden. RWE may also inform on the need for a dual orexin agonist (DORA + ). At this time, there are no DORA + , and this may represent an area of future research.

Conclusion

EDS is a common problem but represents various etiologic contributors. Unfortunately, a complete pathophysiologic understanding of EDS is still lacking. However, a critical step in tying together clinical features, transdisciplinary contributions, and impact that is representative of both day and night is emerging. Existing evidence across medical disciplines prominently showcases the potential of EDS as a clinical feature that may warrant concern for increased morbidity and mortality risk for some, as well as a more robust consideration of orexin beyond its role in sleep–wake control. An improving understanding of orexin physiology and pathophysiology is being further shaped by the experience with both orexin antagonists and agonists, with clear evidence illustrating the need to anticipate both sleep and nonsleep impacts, which based on patient selection may result in enhanced transdisciplinary benefit versus unique adverse event risk profiles. The demand for future study of the potential for broader utility and enhanced patient selection for orexinergic medications is obvious and may represent a transformative milestone for sleep medicine to establish greater transdisciplinary partnership, acceptance, and use to optimize care and outcomes for a person's day and night.

Conflict of Interest

A.M.M. has served as a consultant, speaker, and/or on advisory boards for Apnimed, Avadel Pharmaceuticals, Eisai, Harmony Biosciences, Jazz Pharmaceuticals, Alkermes, Lilly and Takeda Pharmaceutical Co.; has received grant funding from the National Institutes of Health, UCB Pharmaceuticals, Jazz Pharmaceuticals, ResMed Foundation, Coverys Foundation, Harmony Biosciences, and Geisinger Health Plan; is the CEO of DAMM Good Sleep, LLC; and serves as an advisor for Neura Health and Floraworks.

• References

• 1 Borbély AA. A two process model of sleep regulation. Hum Neurobiol 1982; 1 (03) 195-204
• 2 Shen J, Barbera J, Shapiro CM. Distinguishing sleepiness and fatigue: focus on definition and measurement. Sleep Med Rev 2006; 10 (01) 63-76
• 3 Ohayon MM. From wakefulness to excessive sleepiness: what we know and still need to know. Sleep Med Rev 2008; 12 (02) 129-141
• 4 Reichert CF, Deboer T, Landolt HP. Adenosine, caffeine, and sleep-wake regulation: state of the science and perspectives. J Sleep Res 2022; 31 (04) e13597
• 5 Borbély AA, Daan S, Wirz-Justice A, Deboer T. The two-process model of sleep regulation: a reappraisal. J Sleep Res 2016; 25 (02) 131-143
• 6 Verret L, Goutagny R, Fort P. et al. A role of melanin-concentrating hormone producing neurons in the central regulation of paradoxical sleep. BMC Neurosci 2003; 4: 19
• 7 Mieda M. The roles of orexins in sleep/wake regulation. Neurosci Res 2017; 118: 56-65
• 8 Yang Y, Park BY. Differences in structural connectome organization across sleep quality. Heliyon 2023; 9 (12) e23138
• 9 Ashbrook LH, Krystal AD, Fu YH, Ptáček LJ. Genetics of the human circadian clock and sleep homeostat. Neuropsychopharmacology 2020; 45 (01) 45-54
• 10 Smith RP, Easson C, Lyle SM. et al. Gut microbiome diversity is associated with sleep physiology in humans. PLoS One 2019; 14 (10) e0222394
• 11 Krueger JM. The role of cytokines in sleep regulation. Curr Pharm Des 2008; 14 (32) 3408-3416
• 12 Ohayon MM, Dauvilliers Y, Reynolds III CF. Operational definitions and algorithms for excessive sleepiness in the general population: implications for DSM-5 nosology. Arch Gen Psychiatry 2012; 69 (01) 71-79
• 13 Davidson RD, Blattner M, Scammell TE, Zhou ES. The impact of idiopathic hypersomnia on the social lives of young adults. Sleep Health 2025; 11 (01) 113-119
• 14 Davidson R, Biddle K, Scammell T, Nassan M, Zhou E. 498 it makes relationships harder: the role of narcolepsy in social and romantic relationships in young adults. Sleep (Basel) 2021; 44 (Suppl. 02) A196-A197
• 15 Davidson R, Blattner M, Scammell T, Zhou E. 0416 the impact of idiopathic hypersomnia on social and romantic relationships of young adults. Sleep (Basel) 2022; 45 (suppl 1): A186
• 16 O'Hare K, White N, Harding R. et al. Sluggish cognitive tempo and daytime sleepiness mediate relationships between sleep and academic performance. J Dev Behav Pediatr 2021; 42 (08) 637-647
• 17 Mullins HM, Cortina JM, Drake CL, Dalal RS. Sleepiness at work: a review and framework of how the physiology of sleepiness impacts the workplace. J Appl Psychol 2014; 99 (06) 1096-1112
• 18 Owens JA, Babcock D, Weiss M. Evaluation and treatment of children and adolescents with excessive daytime sleepiness. Clin Pediatr (Phila) 2020; 59 (4-5): 340-351
• 19 Melendres MC, Lutz JM, Rubin ED, Marcus CL. Daytime sleepiness and hyperactivity in children with suspected sleep-disordered breathing. Pediatrics 2004; 114 (03) 768-775
• 20 Tsai SY, Lin JW, Wu WW, Lee CN, Lee PL. Sleep disturbances and symptoms of depression and daytime sleepiness in pregnant women. Birth 2016; 43 (02) 176-183
• 21 Nordbakke S, Sagberg F. Sleepy at the wheel: knowledge, symptoms and behaviour among car drivers. Transp Res. Part F Traffic Psychol Behav 2007; 10 (01) 1-10
• 22 Perotta B, Arantes-Costa FM, Enns SC. et al. Sleepiness, sleep deprivation, quality of life, mental symptoms and perception of academic environment in medical students. BMC Med Educ 2021; 21 (01) 111
• 23 Kolla BP, He JP, Mansukhani MP, Frye MA, Merikangas K. Excessive sleepiness and associated symptoms in the U.S. adult population: prevalence, correlates, and comorbidity. Sleep Health 2020; 6 (01) 79-87
• 24 Wang L, Liu Q, Heizhati M, Yao X, Luo Q, Li N. Association between excessive daytime sleepiness and risk of cardiovascular disease and all-cause mortality: a systematic review and meta-analysis of longitudinal cohort studies. J Am Med Dir Assoc 2020; 21 (12) 1979-1985
• 25 Li J, Covassin N, Bock JM. et al. Excessive daytime sleepiness and cardiovascular mortality in US adults: a NHANES 2005–2008 follow-up study. Nat Sci Sleep 2021; 13: 1049-1059
• 26 Mallon L, Broman JE, Hetta J. Restless legs symptoms with sleepiness in relation to mortality: 20-year follow-up study of a middle-aged Swedish population. Psychiatry Clin Neurosci 2008; 62 (04) 457-463
• 27 Merlino G, Lorenzut S, Gigli GL. et al. Insomnia and daytime sleepiness predict 20-year mortality in older male adults: data from a population-based study. Sleep Med 2020; 73: 202-207
• 28 Covassin N, Lu D, St Louis EK. et al. Sex-specific associations between daytime sleepiness, chronic diseases and mortality in obstructive sleep apnea. Front Neurosci 2023; 17: 1210206
• 29 Wang YT, Hsu NW, Lin CH, Chen HC. Concurrence of insomnia and daytime sleepiness predicted 9-year mortality risk in community-dwelling older adults: the Yilan Study, Taiwan. J Gerontol A Biol Sci Med Sci 2023; 78 (12) 2371-2381
• 30 Piovezan RD, Jadczak AD, Tucker G, Visvanathan R. Daytime sleepiness predicts mortality in nursing home residents: findings from the frailty in residential aged care sector over time (FIRST) study. J Am Med Dir Assoc 2023; 24 (10) 1458-1464.e4
• 31 Chen HC, Hsu NW, Lin CH. Different dimensions of daytime sleepiness predicted mortality in older adults: Sex and muscle power-specific risk in Yilan Study, Taiwan. Sleep Med 2024; 113: 84-91
• 32 Li Y, Vgontzas AN, Fernandez-Mendoza J. et al. Objective, but not subjective, sleepiness is associated with inflammation in sleep apnea. Sleep 2017; 40 (02) zsw033
• 33 Kasai T, Taranto Montemurro L, Yumino D. et al. Inverse relationship of subjective daytime sleepiness to mortality in heart failure patients with sleep apnoea. ESC Heart Fail 2020; 7 (05) 2448-2454
• 34 Heybeli C, Soysal P, Oktan MA, Smith L, Çelik A, Kazancioglu R. Associations between nutritional factors and excessive daytime sleepiness in older patients with chronic kidney disease. Aging Clin Exp Res 2022; 34 (03) 573-581
• 35 Maghsoudi A, Azarian M, Sharafkhaneh A. et al. Age modulates the predictive value of self-reported sleepiness for all-cause mortality risk: insights from a comprehensive national database of veterans. J Clin Sleep Med 2024; 20 (11) 1785-1792
• 36 Frohnhofen H, Popp R, Frohnhofen K, Fulda S. Impact of daytime sleepiness on rehabilitation outcome in the elderly. Adv Exp Med Biol 2013; 755: 103-110
• 37 Slater G, Pengo MF, Kosky C, Steier J. Obesity as an independent predictor of subjective excessive daytime sleepiness. Respir Med 2013; 107 (02) 305-309
• 38 Bock J, Covassin N, Somers V. Excessive daytime sleepiness: an emerging marker of cardiovascular risk. Heart 2022; 108 (22) 1761-1766
• 39 Carvalho DZ, St Louis EK, Przybelski SA. et al. Sleepiness in cognitively unimpaired older adults is associated with CSF biomarkers of inflammation and axonal integrity. Front Aging Neurosci 2022; 14: 930315
• 40 Chen YC, Chen KD, Su MC. et al. Genome-wide gene expression array identifies novel genes related to disease severity and excessive daytime sleepiness in patients with obstructive sleep apnea. PLoS One 2017; 12 (05) e0176575
• 41 Amara AW, Chahine LM, Caspell-Garcia C. et al; Parkinson's Progression Markers Initiative. Longitudinal assessment of excessive daytime sleepiness in early Parkinson's disease. J Neurol Neurosurg Psychiatry 2017; 88 (08) 653-662
• 42 Smagula SF, Jia Y, Chang CH, Cohen A, Ganguli M. Trajectories of daytime sleepiness and their associations with dementia incidence. J Sleep Res 2020; 29 (06) e12952
• 43 Van Eycken S, Neu D, Newell J, Kornreich C, Mairesse O. Sex-related differences in sleep-related PSG parameters and daytime complaints in a clinical population. Nat Sci Sleep 2020; 12: 161-171
• 44 Ng WL, Shaw JE, Peeters A. The relationship between excessive daytime sleepiness, disability, and mortality, and implications for life expectancy. Sleep Med 2018; 43: 83-89
• 45 Meyer C, Ferrari GJ, Barbosa DG, Andrade RD, Pelegrini A, Felden ÉPG. Analysis of daytime sleepiniess in adolescents by the pediatric daytime sleepiness scale: a systematic review. Rev Paul Pediatr 2017; 35 (03) 351-360
• 46 Joo S, Shin C, Kim J. et al. Prevalence and correlates of excessive daytime sleepiness in high school students in Korea. Psychiatry Clin Neurosci 2005; 59 (04) 433-440
• 47 van Litsenburg RRL, Waumans RC, van den Berg G, Gemke RJ. Sleep habits and sleep disturbances in Dutch children: a population-based study. Eur J Pediatr 2010; 169 (08) 1009-1015
• 48 Liu Y, Zhang J, Li SX. et al. Excessive daytime sleepiness among children and adolescents: prevalence, correlates, and pubertal effects. Sleep Med 2019; 53: 1-8
• 49 Owens JA, Spirito A, McGuinn M, Nobile C. Sleep habits and sleep disturbance in elementary school-aged children. J Dev Behav Pediatr 2000; 21 (01) 27-36
• 50 Stein MA, Mendelsohn J, Obermeyer WH, Amromin J, Benca R. Sleep and behavior problems in school-aged children. Pediatrics 2001; 107 (04) E60
• 51 Calhoun SL, Vgontzas AN, Fernandez-Mendoza J. et al. Prevalence and risk factors of excessive daytime sleepiness in a community sample of young children: the role of obesity, asthma, anxiety/depression, and sleep. Sleep 2011; 34 (04) 503-507
• 52 American Academy of Sleep Medicine. International classification of sleep disorders. 3rd ed, text revision. Darien, IL: American Academy of Sleep Medicine; 2023
• 53 Saper CB, Chou TC, Scammell TE. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 2001; 24 (12) 726-731
• 54 Eban-Rothschild A, Appelbaum L, de Lecea L. Neuronal mechanisms for sleep/wake regulation and modulatory drive. Neuropsychopharmacology 2018; 43 (05) 937-952
• 55 Stanyer EC, Hoffmann J, Holland PR. Orexins and primary headaches: an overview of the neurobiology and clinical impact. Expert Rev Neurother 2024; 24 (05) 487-496
• 56 Williams DL. Neural integration of satiation and food reward: role of GLP-1 and orexin pathways. Physiol Behav 2014; 136: 194-199
• 57 Dale NC, Hoyer D, Jacobson LH, Pfleger KDG, Johnstone EKM. Orexin signaling: a complex, multifaceted process. Front Cell Neurosci 2022; 16: 812359
• 58 Karnani MM, Schöne C, Bracey EF. et al. Rapid sensory integration in orexin neurons governs probability of future movements. bioRxiv 2019; 620096
• 59 Schöne C, Burdakov D. Orexin/hypocretin and organizing principles for a diversity of wake-promoting neurons in the brain. Curr Top Behav Neurosci 2017; 33: 51-74
• 60 Pérez-Carbonell L, Mignot E, Leschziner G, Dauvilliers Y. Understanding and approaching excessive daytime sleepiness. Lancet 2022; 400 (10357): 1033-1046
• 61 Wang C, Wang Q, Ji B. et al. The orexin/receptor system: Molecular mechanism and therapeutic potential for neurological diseases. Front Mol Neurosci 2018; 11: 220
• 62 Sakurai T, Amemiya A, Ishii M. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998; 92 (04) 573-585
• 63 de Lecea L, Kilduff TS, Peyron C. et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 1998; 95 (01) 322-327
• 64 Mieda M, Tsujino N, Sakurai T. Differential roles of orexin receptors in the regulation of sleep/wakefulness. Front Endocrinol (Lausanne) 2013; 4: 57
• 65 Moreira IS. Structural features of the G-protein/GPCR interactions. Biochim Biophys Acta 2014; 1840 (01) 16-33
• 66 Congreve M, de Graaf C, Swain NA, Tate CG. Impact of GPCR structures on drug discovery. Cell 2020; 181 (01) 81-91
• 67 Thompson MD, Sakurai T, Rainero I, Maj MC, Kukkonen JP. Orexin receptor multimerization versus functional interactions: Neuropharmacological implications for opioid and cannabinoid signalling and pharmacogenetics. Pharmaceuticals (Basel) 2017; 10 (04) 79
• 68 Azeez IA, Del Gallo F, Cristino L, Bentivoglio M. Daily fluctuation of orexin neuron activity and wiring: the challenge of “chronoconnectivity”. Front Pharmacol 2018; 9: 1061
• 69 Frank MG. Circadian regulation of synaptic plasticity. Biology (Basel) 2016; 5 (03) 31
• 70 Challet E. Keeping circadian time with hormones. Diabetes Obes Metab 2015; 17 (Suppl. 01) 76-83
• 71 Huang H, Acuna-Goycolea C, Li Y, Cheng HM, Obrietan K, van den Pol AN. Cannabinoids excite hypothalamic melanin-concentrating hormone but inhibit hypocretin/orexin neurons: implications for cannabinoid actions on food intake and cognitive arousal. J Neurosci 2007; 27 (18) 4870-4881
• 72 Voisin T, Rouet-Benzineb P, Reuter N, Laburthe M. Orexins and their receptors: structural aspects and role in peripheral tissues. Cell Mol Life Sci 2003; 60 (01) 72-87
• 73 Tsuneoka Y, Funato H. Whole brain mapping of orexin receptor mRNA expression visualized by branched in situ hybridization chain reaction. eNeuro 2024; 11 (02) ENEURO.0474 -23.2024
• 74 Prokofeva K, Saito YC, Niwa Y. et al. Structure and function of neuronal circuits linking ventrolateral preoptic nucleus and lateral hypothalamic area. J Neurosci 2023; 43 (22) 4075-4092
• 75 Grabauskas G, Moises HC. Gastrointestinal-projecting neurones in the dorsal motor nucleus of the vagus exhibit direct and viscerotopically organized sensitivity to orexin. J Physiol 2003; 549 (Pt 1): 37-56
• 76 Hopkins DA. Ultrastructure and synaptology of the nucleus ambiguus in the rat: the compact formation. J Comp Neurol 1995; 360 (04) 705-725
• 77 Hungs M, Mignot E. Hypocretin/orexin, sleep and narcolepsy. BioEssays 2001; 23 (05) 397-408
• 78 Hirtz C, Vialaret J, Gabelle A, Nowak N, Dauvilliers Y, Lehmann S. From radioimmunoassay to mass spectrometry: a new method to quantify orexin-A (hypocretin-1) in cerebrospinal fluid. Sci Rep 2016; 6 (01) 25162
• 79 Jagota A. Priyanka, Bussa BR, Gunda V. Sleep and circadian rhythms as modulators of mental health in ageing. In: Brain and mental health in ageing. Berlin: Springer; 2024: 317-335
• 80 Barrile F, Cassano D, Fernandez G. et al. Ghrelin's orexigenic action in the lateral hypothalamic area involves indirect recruitment of orexin neurons and arcuate nucleus activation. Psychoneuroendocrinology 2023; 156: 106333
• 81 Laque A, Yu S, Qualls-Creekmore E. et al. Leptin modulates nutrient reward via inhibitory galanin action on orexin neurons. Mol Metab 2015; 4 (10) 706-717
• 82 Yamanaka A, Beuckmann CT, Willie JT. et al. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 2003; 38 (05) 701-713
• 83 Liguori C, Romigi A, Nuccetelli M. et al. Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. JAMA Neurol 2014; 71 (12) 1498-1505
• 84 Feng Y, Liu T, Li XQ. et al. Neuroprotection by orexin-A via HIF-1α induction in a cellular model of Parkinson's disease. Neurosci Lett 2014; 579: 35-40
• 85 Imperatore R, Palomba L, Cristino L. Role of orexin-A in hypertension and obesity. Curr Hypertens Rep 2017; 19 (04) 34
• 86 Perez MV, Pavlovic A, Shang C. et al. Systems genomics identifies a key role for hypocretin/orexin receptor-2 in human heart failure. J Am Coll Cardiol 2015; 66 (22) 2522-2533
• 87 Yang LP. Suvorexant: first global approval. Drugs 2014; 74 (15) 1817-1822
• 88 Giliberto S, Shishodia R, Nastruz M. et al. A comprehensive review of novel FDA-approved psychiatric medications (2018–2022). Cureus 2024; 16 (03) e56561
• 89 Scott L. The pleasure principle: A critical examination of federal scheduling of controlled substances. Sw. UL Rev. 1999; 29: 447
• 90 James MH, Fragale JE, Aurora RN, Cooperman NA, Langleben DD, Aston-Jones G. Repurposing the dual orexin receptor antagonist suvorexant for the treatment of opioid use disorder: why sleep on this any longer?. Neuropsychopharmacology 2020; 45 (05) 717-719
• 91 Huhn AS, Finan PH, Gamaldo CE. et al. Suvorexant ameliorated sleep disturbance, opioid withdrawal, and craving during a buprenorphine taper. Sci Transl Med 2022; 14 (650) eabn8238
• 92 Gyawali U, James MH. Sleep disturbance in substance use disorders: the orexin (hypocretin) system as an emerging pharmacological target. Neuropsychopharmacology 2023; 48 (01) 228-229
• 93 Boof ML, Ufer M, Fietze I. et al. Assessment of the effect of the dual orexin receptor antagonist daridorexant on various indices of disease severity in patients with mild to moderate obstructive sleep apnea. Sleep Med 2022; 92: 4-11
• 94 Born S, Gauvin DV, Mukherjee S, Briscoe R. Preclinical assessment of the abuse potential of the orexin receptor antagonist, suvorexant. Regul Toxicol Pharmacol 2017; 86: 181-192
• 95 Garcia-Borreguero D, Aragón AG, Moncada B. et al. Treatment of sleep, motor and sensory symptoms with the orexin antagonist suvorexant in adults with idiopathic restless legs syndrome: A randomized double-blind crossover proof-of-concept study. CNS Drugs 2024; 38 (01) 45-54
• 96 Recourt K, de Boer P, Zuiker R. et al. The selective orexin-2 antagonist seltorexant (JNJ-42847922/MIN-202) shows antidepressant and sleep-promoting effects in patients with major depressive disorder. Transl Psychiatry 2019; 9 (01) 216
• 97 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 (04) 309-321
• 98 Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 2006; 15 (04) 241-243
• 99 Takeda Pharmaceuticals. Takeda pharmaceutical company 43rd annual J.P. morgan healthcare conference. Accessed February 27, 2025 at: chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/ https://assets-dam.takeda.com/image/upload/Global/Investor/events/2025/documents/JPMHC_2025_presentation.pdf
• 100 Takeda Pharmaceuticals. A study of TAK-360 in adults with idiopathic hypersomnia. Accessed February 2, 2025 at: https://clinicaltrials.gov/study/NCT06812078?intr=tak-360&rank=1
• 101 Alkermes. Alkermes 2025. Accessed February 27, 2025 at: https://chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://investor.alkermes.com/static-files/a779844f-db8b-4859-8dac-775d11142f8f
• 102 Yee B, Chapman J, Grunstein R. et al. O013 preliminary results from a phase 1 study of ALKS 2680, an orexin-2 receptor agonist, in healthy participants and patients with narcolepsy or idiopathic hypersomnia. Sleep Adv 2023; 4 (Suppl. 01) A5-A6
• 103 Centessa pharmaceuticals. Accessed February 27, 2025 at: https://chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://investors.centessa.com/static-files/04030d63-c59d-488d-862e-9f9b2158a35e
• 104 Eisai Pharmaceuticals. A study to evaluate the efficacy, safety, and tolerability of E2086 compared to placebo and active comparator in adult participants with narcolepsy type 1. Accessed February 27, 2025 at: https://clinicaltrials.gov/study/NCT06462404?cond=E2086&rank=3
• 105 Hatanaka K, Suzuki H, Michikawa F. et al A novel orally-available selective orexin 2 receptor agonist, E2086, enhances wake-promotion and treats narcolepsy-like symptoms in narcolepsy model mice. Neuropsychopharmacology 2022; 47: S401-S402
• 106 Takeda Pharmaceuticals. A study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-925 in healthy volunteers and participants with narcolepsy. Accessed February 25, 2020 at: https://clinicaltrials.gov/study/NCT03748979?intr=tak-925&rank=4
• 107 Takeda Pharmaceuticals. A study of a single intravenous infusion dose of TAK-925 in participants with idiopathic hypersomnia. Accessed February 25, 2023 at: https://clinicaltrials.gov/study/NCT04091438?intr=tak-925&rank=1
• 108 Takeda Pharmaceuticals. A study of danavorexton in people with obstructive sleep apnea after general anesthesia for abdominal surgery. Accessed February 25, 2024 at: https://clinicaltrials.gov/search?intr=tak-925

Publication History

Accepted Manuscript online:
16 April 2025

Article published online:
12 May 2025