002 Daridorexant, a dual orexin receptor antagonist, improves age-related insomnia in rats

Abstract Introduction Sleep disturbances develop with age, and prevalence of insomnia is higher in the elderly. Daridorexant is a new medication in development for the treatment of insomnia. Our aim was to investigate whether an insomnia-like phenotype develops in old rats, and then to assess the effect of repeated administration of daridorexant in these animals. Methods We recorded the electroencephalogram and electromyogram of freely moving male Wistar rats implanted with telemetry transmitters. Time spent sleeping during the inactive phase was measured at the ages of 4 (n=50), 6 (n=55), 8 (n=37), 12 (n=44), 18 (n=22) and 24 (n=9) months. The age at which the rats’ time spent sleeping started to be significantly reduced compared to that of 4-month-old rats was when the insomnia-like phenotype would start to occur. The impact of 100 mg/kg daridorexant, given orally at the beginning of the inactive phase, was evaluated in 16-month-old rats (n=8). Rats were consecutively treated daily for 6 days with vehicle (baseline period), for 3 weeks with daridorexant, and again for 1 week with vehicle (wash-out period). Results The total time spent sleeping during the 12-h inactive period decreased from 51.3±1.1% (mean ± SEM) at 4-months old to 39.3±4.4% at 24-months, with a significant decrease starting from 8-months (p<0.05). Whereas the time spent in rapid-eye-movement (REM) sleep (~10%) was not affected by age (p=0.64), the time spent in non-REM sleep decreased from 41.7±0.8% at 4 months to 28.7±3.2% at 24 months (p<0.001). In 16-month-old rats daridorexant increased the time spent in non-REM sleep over the first 6-h following administration (p<0.001). The time spent in REM sleep was unaffected (p=0.47). The average time spent in non-REM sleep over those 6h was 37.2±2.5% at baseline, and 43.8±2.4%, 44.6±2.7% and 44.5±3.0% in the 1st (p<0.05 vs baseline), 2nd (p<0.001) and 3rd (p<0.01) week of treatment, respectively. During the wash-out period, the non-REM sleep time returned to baseline levels (35.6±2.7%; p=0.06). Conclusion In rats, an insomnia-like phenotype, characterized by reduced non-REM sleep time, develops with age. Daridorexant improves this phenotype and its effect is maintained upon repeated administration over three weeks. Support (if any) Funded by Idorsia Pharmaceuticals Ltd