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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.)

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.)