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BACKGROUND Narcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides. METHODS We conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2-seIective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, >20 minutes). Secondary end points included the change in the Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and the weekly cataplexy rate. RESULTS Of the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and -2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P<0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were -12.2 in the 30-mg group, -13.5 in the 90-mg group, -15.1 in the 180-mg group, and -2.1 in the placebo group (difference vs. placebo, -10.1 in the 30-mg group, -11.4 in the 90-mg group, and -13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy's law criteria occurred in 3 patients. CONCLUSIONS In a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.). [ABSTRACT FROM AUTHOR]

Study Objectives: Idiopathic hypersomnia (IH) is a chronic disorder characterized by excessive daytime sleepiness unexplained by another disorder or drug/medication use. Although the orexin system plays a role in sleep-wake regulation, orexin A levels in the cerebrospinal fluid are normal in people with IH. This phase 1b, randomized, placebo-controlled, crossover study aimed to investigate the safety, pharmacokinetics, and pharmacodynamics of danavorexton, a small-molecule orexin-2 receptor agonist, in adults with IH., Methods: Adults with IH aged 18-75 years were randomized to one of two treatment sequences of single intravenous infusions of danavorexton 112 mg and placebo. Pharmacodynamic endpoints included the maintenance of wakefulness test (MWT), the Karolinska Sleepiness Scale (KSS), and the psychomotor vigilance task (PVT). Adverse events were monitored throughout the study period., Results: Of 28 randomized participants, 12 (44.4%) had a treatment-emergent adverse event (TEAE) and 10 (37.0%) had a TEAE considered related to study drug, most of which were mild or moderate. Four participants (18.2%) had urinary TEAEs while receiving danavorexton, all of which were mild in severity. There were no deaths or TEAEs leading to discontinuation. Improvements in MWT, KSS, and PVT scores were observed with danavorexton compared to placebo. Following drug administration, a mean sleep latency of 40 min (maximum value) was observed during the MWT within 2 h of danavorexton infusion in most participants., Conclusions: A single infusion of danavorexton improves subjective and objective excessive daytime sleepiness in people with IH with no serious TEAEs, indicating orexin-2 receptor agonists are promising treatments for IH. Clinical Trial: Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT04091438., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society.)

Background: Sleep disruptions experienced by patients with obstructive sleep apnea (OSA) can lead to excessive daytime sleepiness (EDS) and significantly impact patients' quality of life. EDS may persist despite use of continuous positive airway pressure (CPAP) therapy. Small molecules that target the orexin system, which has a known role in sleep-wake regulation, show therapeutic potential for the treatment of EDS in patients with hypersomnia. This randomized, placebo-controlled, phase 1b study aimed to investigate the safety of danavorexton, a small-molecule orexin-2 receptor agonist, and its effects on residual EDS in patients with OSA., Methods: Adults with OSA aged 18-67 years with adequate CPAP use were randomized to one of six treatment sequences of single IV infusions of danavorexton 44 mg, danavorexton 112 mg, and placebo. Adverse events were monitored throughout the study. Pharmacodynamic assessments included maintenance of wakefulness test (MWT), Karolinska Sleepiness Scale (KSS), and the psychomotor vigilance test (PVT)., Results and Conclusion: Among 25 randomized patients, 16 (64.0%) had treatment-emergent adverse events (TEAEs) and 12 (48.0%) had TEAEs considered related to treatment, all mild or moderate. Seven patients (28.0%) had urinary TEAEs: three, seven, and none while taking danavorexton 44 mg, danavorexton 112 mg, and placebo, respectively. There were no deaths or TEAEs leading to discontinuation. Improvements in mean MWT, KSS, and PVT scores were observed with danavorexton 44 mg and 112 mg vs placebo. These findings show that danavorexton can improve subjective and objective measures of EDS in patients with OSA and residual EDS despite adequate CPAP use., Competing Interests: Declaration of competing interest RKB is a shareholder of Healthy Humming, LLC and WaterMark Medical, and is on the board of directors for WaterMark Medical. He is also a consultant to Avadel Pharmaceuticals, Harmony Biosciences, Jazz Pharmaceuticals, Oventus Medical, and Takeda Pharmaceutical Company Limited, and has Speakers Bureau involvement for Eisai, Harmony Biosciences, Idorsia, and Jazz Pharmaceuticals. He reports industry-funded research for Apnimed, Avadel Pharmaceuticals, Balance, BresoTec Medical, Eisai, Fresca Medical, Idorsia, Jazz Pharmaceuticals, LivaNova, Merck, NLS Pharmaceutics, Philips, Roche, Sanofi, Sommetrics, Suven Life Sciences, Takeda Pharmaceutical Company Limited, and Vanda Pharmaceuticals. JPM has no conflicts of interest to disclose. RN, HF, TS, and TO are employees of, and stockholders in, Takeda Pharmaceuticals Company Limited., (Copyright © 2023 Takeda Pharmaceuticals. Published by Elsevier B.V. All rights reserved.)

Introduction: Narcolepsy patients report lower health-related quality of life (HRQoL) than the general population, as measured by the Short Form-36 Health Survey (SF-36). This analysis evaluated whether changes in SF-36 correlated with physician-rated Clinical Global Impression of Change (CGI-C)., Methods: Data were from 209 of 228 narcolepsy patients participating in an 8-week clinical trial of sodium oxybate. Changes from baseline for SF-36 subscales (Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health) and the summary scores were evaluated for correlation with CGI-C overall and by treatment group. Correlations were calculated using the Pearson product-moment correlation coefficient (r)., Results: Correlations described an inverse relationship in scores, but a direct relationship in improvement; lower CGI-C scores (i.e., better) were associated with higher SF-36 subscale scores (i.e., improved HRQoL). Moderate and significant correlations were observed for Vitality (r = -0.464; P < 0.0001) and Role Physical (r = -0.310; P < 0.0001) subscales, but weak correlations were observed with other subscales including summary scores. Correlations were stronger at higher sodium oxybate doses for most SF-36 subscales., Conclusion: Some aspects of HRQoL, measured by the SF-36, may be associated with narcolepsy. In particular, Vitality (indicative of energy and tiredness) and Role Physical (impact of physical function on daily roles) moderately correlated with overall change in status observed by clinicians. However, lack of strong correlations between SF-36 and CGI-C indicates differences in patient and clinician perspectives of disease, and suggest a need for broader assessment of the impact of narcolepsy and its treatment on patients., Funding: Jazz Pharmaceuticals.

Introduction: The present post hoc analysis was designed to evaluate health-related quality of life (HRQoL) using the 36-item Short Form Health Status Survey (SF-36) during an 8-week trial of sodium oxybate (SXB)., Methods: SF-36 was assessed in a phase 3 placebo-controlled trial in patients with narcolepsy (N = 228) randomized to placebo or SXB in doses of 4.5, 6, or 9 g nightly for 8 weeks. Changes from baseline in SF-36 (last observation carried forward) were compared between SXB and placebo, and effect sizes (ES) were estimated., Results: Baseline SF-36 values were lower than normative values for the US general population. After 8 weeks of treatment, mean (±standard deviation) improvement from baseline on the Physical Component Summary (PCS) was significantly greater with SXB 9 g/night than placebo (6.3 ± 9.1 vs. 1.5 ± 6.2; p = 0.005), with moderate ES; no significant difference was found between the SXB and placebo groups on the Mental Component Summary. SXB 9 g/night resulted in significantly (p < 0.05) greater improvements than placebo in Physical Functioning (4.4 ± 9.2 vs. 1.0 ± 8.0), General Health (GH; 3.1 ± 7.0 vs. 0.4 ± 6.8), and Social Functioning (6.8 ± 16.8 vs. 1.1 ± 9.6). All SXB doses resulted in significant improvement (p < 0.05) relative to placebo for Vitality, with moderate ES. No significant differences versus placebo were observed for Role-Physical, Role-Emotional, or Mental Health domains., Conclusion: Treatment with SXB was associated with a dose-dependent improvement in HRQoL, with the 9-g nightly dose demonstrating a positive impact on PCS and individual SF-36 domains of Vitality, GH, and Physical and Social Functioning., Trial Registration: NCT00049803., Funding: Jazz Pharmaceuticals.

Background: Effects of sodium oxybate (SXB) on patients with narcolepsy with cataplexy (NC) or without cataplexy (NWOC) have not been separately evaluated in clinical trials., Methods: Retrospective analysis evaluated data from a phase 3, randomized, placebo-controlled trial of SXB, modafinil, and SXB + modafinil versus placebo in adult NC patients (n = 95) or NWOC patients (n = 127). NC patients were identified based on medical history, concomitant medications, and sleep-onset REM periods on nocturnal polysomnography. The studied outcomes were changes from baseline at eight weeks on the Epworth Sleepiness Scale (ESS), the Maintenance of Wakefulness Test (MWT), and the Clinical Global Impression of Change (CGI-C)., Results: Among NC and NWOC patients, ESS improvement was significantly greater with SXB and SXB + modafinil versus placebo. In NC patients, mean MWT sleep latency was significantly increased with SXB + modafinil versus placebo. In NWOC patients, mean MWT sleep latency significantly increased in all groups versus placebo. Higher percentages of patients in the SXB and SXB + modafinil groups were "very much improved" or "much improved" on the CGI-C versus placebo in both NC and NWOC populations, although the difference did not reach statistical significance in the NWOC populations. Adverse events were consistent with previously-reported profiles for modafinil and SXB. Nausea was more common in the SXB and SXB + modafinil groups. Dizziness and tremor were more common in the SXB + modafinil group only., Conclusions: SXB alone and in combination with modafinil improved subjective ratings of excessive sleepiness and an objective measure of the ability to stay awake to similar extents in NC patients and NWOC patients., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: This study aimed to evaluate safety and efficacy of sodium oxybate (SXB) titrated to effect., Methods: SXB-naive patients who had participated in a randomized SXB clinical trial and had not been titrated to adequate clinical effect were initiated on open-label SXB at 4.5 g/night and titrated in 1.5-g increments to 6, 7.5, or 9 g/night or down to 3 g/night, based on individual clinical response. Treatment was 12 weeks; safety was the primary outcome. Efficacy was evaluated using the Narcolepsy Symptom Assessment Questionnaire (NSAQ), a five-point scale ("much improved" to "much worse") that assessed changes from baseline in specific symptoms. Response was defined as "much improved" or "somewhat improved" overall at weeks 6 and 12., Results: Of 202 patients, 171 (85%) completed treatment; final doses were 3 g (n = 5), 4.5 g (n = 29), 6 g (n = 80), 7.5 g (n = 66), and 9 g (n = 22). Adverse events (AEs) were reported in 114 patients (56%), serious AEs in five (2%). The most common AEs were nausea (10%), headache (7%), and dizziness (5%). Response rate was 92% at week 6 and 90% at week 12; most patients reported improvements in all individual symptoms. Overall, 60% of patients rated their symptoms at 12 weeks as "much improved," and this improvement was dose dependent., Conclusions: The SXB safety profile was consistent with parent trials. Ninety percent of patients reported improvements as measured by the NSAQ., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Study Objectives: Characterize disrupted nighttime sleep (DNS) in narcolepsy, an important symptom of narcolepsy., Methods: A panel of international narcolepsy experts was convened in 2011 to build a consensus characterization of DNS in patients with narcolepsy. A literature search of the Medline (1965 to date), Medline In-Process (latest weeks), Embase (1974 to date), Embase Alert (latest 8 weeks), and Biosis (1965 to date) databases was conducted using the following search terms: narcolepsy and disrupted nighttime sleep, disturbed nighttime sleep, fragmented sleep, consolidated sleep, sleep disruption, and narcolepsy questionnaire. The purpose of the literature search was to identify publications characterizing the nighttime sleep of patients with narcolepsy. The panel reviewed the literature. Nocturnal sleep can also be disturbed by REM sleep abnormalities such as vivid dreaming and REM sleep behavior disorder; however, these were not reviewed in the current paper, as we were evaluating for idiopathic sleep disturbances., Results: The literature reviewed provide a consistent characterization of nighttime sleep in patients with narcolepsy as fragmented, with reports of frequent, brief nightly awakenings with difficulties returning to sleep and associated reports of poor sleep quality. Polysomnographic studies consistently report frequent awakenings/arousals after sleep onset, more stage 1 (S1) sleep, and more frequent shifts to S1 sleep or wake from deeper stages of sleep. The consensus of the International Experts' Panel on Narcolepsy was that DNS can be distressing for patients with narcolepsy and that treatment of DNS warrants consideration., Conclusions: Clinicians involved in the management of patients with narcolepsy should investigate patients' quality of nighttime sleep, give weight and consideration to patient reports of nighttime sleep experience, and consider DNS a target for treatment.

Background: Many patients with Parkinson disease (PD) have excessive daytime sleepiness and numerous nocturnal sleep abnormalities., Objective: To determine the safety and efficacy of the controlled drug sodium oxybate in a multicenter, open-label, polysomnographic study in subjects with PD and sleep disorders. Design, Setting, and Patients Inclusion required an Epworth Sleepiness Scale (ESS) score greater than 10 and any subjective nocturnal sleep concern, usually insomnia. An acclimation and screening polysomnogram was performed to exclude subjects with sleep-disordered breathing. The following evening, subjects underwent another polysomnogram, followed by an evaluation with the Unified Parkinson Disease Rating Scale (UPDRS) while practically defined off ("off") PD medications, ESS (primary efficacy point), Pittsburgh Sleep Quality Inventory, and Fatigue Severity Scale. Subjects then started sodium oxybate therapy, which was titrated from 3 to 9 g per night in split doses (at bedtime and 4 hours later) across 6 weeks, and returned for subjective sleep assessments. They then returned at 12 weeks after initiating therapy for a third polysomnogram, an off-medication UPDRS evaluation, and subjective sleep assessments. Data are expressed as mean (SD)., Results: We enrolled 38 subjects. At screening, 8 had sleep apnea (n = 7) or depression (n = 1). Twenty-seven of 30 subjects completed the study. Three dropped out owing to dizziness (n = 3) and concurrent depression (n = 1). The mean dose of sodium oxybate was 7.8 (1.7) g per night. The ESS score improved from 15.6 (4.2) to 9.0 (5.0) (P < .001); the Pittsburgh Sleep Quality Inventory score, from 10.9 (4.0) to 6.6 (3.9) (P < .001); and the Fatigue Severity Scale score, from 42.9 (13.2) to 36.3 (14.3) (P < .001). Mean slow-wave sleep time increased from 41.3 (33.2) to 78.0 (61.2) minutes (P = .005). Changes in off-medication UPDRS scores were not significant, from 28.4 (10.3) to 26.2 (9.6)., Conclusion: Nocturnally administered sodium oxybate improved excessive daytime sleepiness and fatigue in PD., Trial Registration: clinicaltrials.gov Identifier: NCT00641186.

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