Impact of Lemborexant on Fatigue Severity and Sleep Outcomes in Older Adults With Clinically Significant Fatigue at Baseline

Abstract

<h3>Introduction</h3> In addition to sleep onset and/or maintenance difficulties, sleep-related daytime impairments must be acknowledged by patients to meet DSM-5 insomnia disorder diagnostic criteria. Daytime functioning impairments of insomnia disorder may include mood disturbances, decreased energy and fatigue. Given higher insomnia disorder prevalence and negative fatigue health and function impacts in older adults, treatment may require monitoring and managing sleep-related fatigue. Lemborexant (LEM) is a dual orexin receptor antagonist, approved in the US, Canada and Japan for the treatment of insomnia in adults. In the pivotal Phase 3 Study E2006-G000-303 (Study 303; SUNRISE-2; NCT02952820), LEM provided significant benefit on subjective sleep and fatigue severity outcomes vs placebo (PBO). In this post-hoc analysis, these outcomes were analyzed in subjects aged ≥65y with baseline Fatigue Severity Scale (FSS) total score ≥36 indicating clinically significant fatigue (analysis subgroup). <h3>Methods</h3> Study 303 was a 12-month, randomized, double-blind study in subjects aged ≥18y (n=949). For the first 6 months (Treatment Period 1), subjects received PBO or LEM (5mg [LEM5]; 10mg [LEM10]). During the second 6 months (Treatment Period 2), PBO subjects were rerandomized to LEM5 or LEM10 (reported separately) while LEM subjects remained on their original doses. The FSS is a self-report questionnaire that evaluates the impact of fatigue on quality of life and daily functioning. FSS total score (TS) ≥36 indicates clinically significant fatigue, and baseline FSS-TS ≥36 was used to select the analysis subgroup in subjects aged ≥65y. Changes from baseline in FSS-TS, subjective sleep onset latency (sSOL), subjective sleep efficiency (sSE) and subjective wake after sleep onset (sWASO) for LEM vs PBO, assessed during Treatment Period 1 are presented. <h3>Results</h3> For the analysis subgroup (Total, n=134; PBO, n=41; LEM5, n=44; LEM10, n=49), mean FSS-TS (SD) at baseline was 44.1 (6.8), 46.2 (7.6), and 44.9 (6.3) in PBO, LEM5, and LEM10, respectively. At 6 months, mean (SD) decreases from baseline (improvement) in FSS-TS were significantly greater with LEM vs PBO (PBO: −8.7 [10.0]; LEM5: −18.3 [12.9], <i>P</i>=0.006 vs PBO; LEM10: −17.4 [11.6], <i>P</i>=0.003 vs PBO).Median decreases from baseline in sSOL (min) were significantly greater with LEM5 and numerically greater with LEM10 vs PBO (PBO: −9.0; LEM5: −20.1, <i>P</i>=0.0008 vs PBO); LEM10: −19.8) at 6 months. At baseline, mean (SD) sSE was 61.8% (18.1%), 65.2% (14.3%) and 61.0% (14.6%) for PBO, LEM5 and LEM10, respectively. Mean (SD) increases (improvement) from baseline in sSE were significantly greater with LEM5 and numerically greater with LEM10 vs PBO at 6 months (PBO: 5.8% [10.3%]; LEM5: 17.1% [14.3%], <i>P</i>=0.0012 vs PBO; LEM10, 13.1% [14.0%]). Lastly, mean sWASO (min) at baseline was 134.9 (82.3), 126.8 (65.1) and 166.4 (91.0) for PBO, LEM5 and LEM10, respectively. At 6 months, mean (SD) decreases (improvement) from baseline in sWASO (min) were significantly greater with LEM for both doses vs PBO (PBO: −9.9 [47.2]; LEM5: −58.3 [79.9], <i>P</i>=0.004 vs PBO; LEM10, −50.6 [56.6], <i>P</i>=0.03 vs PBO). Overall, treatment –emergent adverse events (AE) rates were similar across treatment groups (58.5%, 65.9%, 53.1% for PBO, LEM5 and LEM10, respectively). The most common AEs (≥5% in any LEM group and >PBO) were somnolence (0%, 11.4%, 22.4%), nasopharyngitis (4.9%, 6.8%, 8.2%), gastroenteritis (0%, 2.3%, 8.2%), upper abdominal pain (0%, 2.3%, 6.1%), diarrhea (0%, 0%, 6.1%), and vomiting (0%, 0%, 6.1%) in PBO, LEM5, LEM10, respectively. <h3>Conclusions</h3> In this post hoc analysis from Study 303, subjects aged ≥65y with clinically significant fatigue at baseline had greater improvements in FSS-TS and all sleep parameters with LEM vs PBO at 6 months. Reductions in fatigue severity generally paralleled the time course of sleep parameter improvements. <h3>Funding</h3> Eisai Inc.