Safety and pharmacodynamics of a single infusion of danavorexton in adults with obstructive sleep apnea experiencing excessive daytime sleepiness despite adequate use of CPAP.

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.
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