0142 TAK-925, an Orexin 2 Receptor-Selective Agonist, Enhanced Cortical Arousal in a Narcolepsy Mouse Model Different from Effects of Modafinil

Abstract

Abstract Introduction Patients with narcolepsy type 1 (NT1) suffer from distressing symptoms such as excessive daytime sleepiness (EDS) and cataplexy. Modafinil is widely used as a therapy for NT1; however, it has limited efficacy for EDS and no efficacy for cataplexy. TAK-925 is an orexin 2 receptor (OX2R)-selective agonist which improves multiple symptoms of narcolepsy such as fragmentation of wakefulness and cataplexy-like episodes, and also reduces weight gain, in orexin/ataxin-3 mice, a narcolepsy mouse model. An early proof of concept study showed TAK-925 increased wakefulness compared to placebo in individuals with NT1; however, a head-to-head comparison between TAK-925 and modafinil in NT1 has not been performed to date. In this study, we carefully compared the wake-promoting effects of TAK-925 and modafinil in orexin/ataxin-3 mice. Methods TAK-925 or modafinil was administered to orexin/ataxin-3 mice at zeitgeber time 12, and the sleep/wakefulness states were evaluated based on electroencephalogram (EEG) and electromyogram measurements. EEG spectral analysis was performed by fast Fourier transform during wakefulness. EEG frequency band was divided into five frequency bands: delta, theta, alpha, beta, and gamma. Results Both TAK-925 and modafinil significantly increased wakefulness time, and ameliorated fragmentation of wakefulness, in orexin/ataxin-3 mice during active phase. In contrast, TAK-925, but not modafinil, significantly decreased delta power, and increased alpha and gamma power during wakefulness in orexin/ataxin-3 mice, suggesting a shift in EEG power density toward higher frequencies. Conclusion TAK-925, but not modafinil, enhanced cortical arousal and suppressed signs of somnolence and drowsiness. In a phase 1 study in individuals with NT1, TAK-925 was found to have pronounced effects on the maintenance of wakefulness test, reaching a total duration of 40 minutes wake time at some doses tested. Spectral analysis will be evaluated in future studies in NT1 patients. Support This work was conducted by Takeda Pharmaceutical Company Limited.