Narcolepsy type 1 (NT1), caused by loss of
orexin neurons, is a
neurological disorder characterized by
excessive daytime sleepiness,
cataplexy, disrupted nighttime sleep, hypnagogic/hypnopompic
hallucinations and
sleep paralysis, as well as a high risk of
obesity. Danavorexton (TAK-925) is a novel brain-penetrant
orexin 2 receptor (OX2R)-selective agonist currently being evaluated in clinical trials for the treatment of
hypersomnia disorders including NT1. Thus, detailed characterization of danavorexton is critical for validating therapeutic potential of OX2R-selective agonists. Here, we report preclinical characteristics of danavorexton as a therapeutic
drug for NT1. Danavorexton showed rapid association/dissociation kinetics to OX2R. The activation mode of endogenous OX2R by danavorexton and
orexin peptide was very similar in an electrophysiological analysis. In
orexin/
ataxin-3 mice, a mouse model of NT1, danavorexton promoted wakefulness, and ameliorated fragmentation of wakefulness during the active phase after both acute and repeated administration, suggesting a low risk of receptor desensitization. Electroencephalogram (EEG) power spectral analysis revealed that danavorexton, but not
modafinil, normalized dysregulated EEG power spectrum in
orexin/
ataxin-3 mice during the active phase. Finally, repeated administration of danavorexton significantly suppressed the
body weight gain in
orexin/
ataxin-3 mice. Danavorexton may have the potential to treat multiple symptoms of NT1. These preclinical findings, together with upcoming clinical observations of danavorexton, could improve our understanding of the pathophysiology of NT1 and therapeutic potential of OX2R agonists.