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The use of an orexin 2 receptor (OX2R) agonist may be a promising approach for the treatment of narcolepsy type 1. TAK-994 is a novel, orally available OX2R-selective agonist with &amp;gt;700-fold selectivity against orexin 1 receptor. Single administration of TAK-994 ameliorates narcolepsy-like symptoms such as fragmentation of wakefulness and cataplexy-like episodes in orexin/ataxin-3 mice, a narcolepsy mouse model with orexin deficiency. In this study, we evaluated the effect of chronic dosing with TAK-994 on sleep/wakefulness states in orexin/ataxin-3 mice. Methods Orexin/ataxin-3 mice were grouped into two cohorts: a control group and a 14-day treatment group. In the control group, vehicle was administered orally to mice three times a day: zeitgeber time 12 (ZT12), ZT15 and ZT18, for 14 days. In the 14-day treatment group, TAK-994 was administered orally to mice at ZT12, ZT15 and ZT18 for 14 days. Electroencephalogram/electromyogram analysis was performed on day 1 and day 14 (ZT12-ZT21), and the subsequent sleep phase (ZT0-ZT10). Results On day 1, TAK-994 significantly increased wakefulness time, accompanied by a decrease in non-rapid eye movement (NREM) sleep time and rapid eye movement (REM) sleep time, in orexin/ataxin-3 mice compared with the control group. On day 14, TAK-994 also significantly increased wakefulness time, and decreased NREM sleep time and REM sleep time in orexin/ataxin-3 mice. There were no changes in the time spent in wakefulness, NREM sleep and REM sleep during the subsequent sleep phase after chronic dosing with TAK-994. Conclusion Wake-promoting effects of TAK-994 were observed following chronic dosing for up to 14 days in orexin/ataxin-3 mice with no rebound of sleep. Overall, there was no clear difference in efficacy between the single and repeated administration of TAK-994 in orexin/ataxin-3 mice. Support This work was conducted by Takeda Pharmaceutical Company Limited.

sleep

0141 A Novel, Orally Available Orexin 2 Receptor-Selective Agonist, TAK-994, Shows Wake-Promoting Effects Following Chronic Dosing in an Orexin-Deficient Narcolepsy Mouse Model