092 Effect of the dual orexin receptor antagonist (DORA) daridorexant on behaviour upon awakening in rats and dogs

Abstract

Abstract Introduction The ability to be fast alert and to interact with the environment without motor impairment upon waking up, is a critical feature of natural sleep. DORAs represent a new class of insomnia medications that specifically inhibit the wake-promoting effects of orexin neuropeptides. Daridorexant is a potent and selective DORA under late stage development for the treatment of insomnia. Here, we assessed the impact of sleep-promoting doses of daridorexant on rats’ and dogs’ behaviour upon forced awakening. Zolpidem (a positive GABAA receptor modulator) was used as active comparator in rats because of its known negative impact on motor functions. Methods Rats were woken up at different time points after oral administration of daridorexant (10, 30, 100 mg/kg) or zolpidem (30, 100 mg/kg) during their inactive phase, and repeatedly subjected to two motor tasks: 1) the rotating rod test (lasting 120 sec, at each time point) assessing gross motor skills and coordination, and 2) the forepaw grip strength test assessing fine motor skills and muscle strength. Dogs were presented with food as an external, salient stimulus, three hours after administration of daridorexant in gelatin capsules (10, 30 or 90 mg/dog) during their active phase. Behaviour and signs of muscle weakness, after having woken up, were assessed by manual inspection of video recordings and concomitant electroencephalogram/electromyogram recordings. Results In both the rotarod and grip tests, daridorexant treatment had no effect on motor behavior at any dose or time point tested, while zolpidem significantly reduced the time spent on the rotarod and the grip strength in a dose and time-dependent manner (N=12/group; p<0.001;) (e.g. at 30 min post-dose, time spent on the rotarod was 84, 79–89 and 10–19 sec for vehicle, daridorexant and zolpidem, respectively). Dogs treated with daridorexant were able to wake up easily upon food presentation. They behaved and ate normally and did not show any signs of muscle weakness. Conclusion The type of sleep promoted by daridorexant is surmountable in rats and dogs and similar to physiological sleep. It allows animals to easily wake up, to behave normally without motor impairment and to respond efficiently to the environmental conditions. Support (if any) Funded by Idorsia Pharmaceuticals Ltd