Irregular sleep-wake rhythm disorder (ISWRD) is a circadian rhythm sleep disorder, distinct from insomnia, which is characterized by the irregular distribution of sleep bouts across the 24-hour period rather than consolidated sleep at night. ISWRD symptoms are common in patients with Alzheimer’s disease dementia (AD-D). Pathology of ISWRD includes disturbed circadian rhythmicity, neuronal loss in the suprachiasmatic nuclei and pineal gland and decreased amplitude of other circadian rhythms such as melatonin and body temperature. Additionally, recent evidence suggests ISWRD may be due to a dysfunctional orexin system. No adequate pharmacologic or nonpharmacologic treatment for ISWRD is currently available. Lemborexant (LEM) is a dual orexin receptor antagonist in development for the treatment of insomnia and ISWRD. In 2 phase 3 studies for insomnia (SUNRISE-1 [NCT02783729; E2006-G000-304] and SUNRISE-2 [NCT02952820; E2006-G000-303]), LEM demonstrated greater improvements in subject-reported sleep onset and sleep maintenance outcomes vs placebo (PBO) for 1 month and 6 months, respectively. LEM also showed greater improvements in objective measures of sleep onset and sleep maintenance vs zolpidem tartrate extended release over 1 month in SUNRISE-1. In both studies, LEM was well tolerated. This phase 2 proof-of-concept study evaluated the effects of LEM vs PBO on circadian, nighttime, and daytime endpoints in subjects with ISWRD and AD-D.