Lack of residual morning effects of lemborexant treatment for insomnia: summary of findings across 9 clinical trials

Abstract

Objectives: Residual next-day effects of sleep-promoting drugs are common and an important safety issue. Lemborexant is a dual orexin receptor antagonist approved in the United States and Japan for treatment of insomnia in adults. We evaluated the potential of lemborexant for residual morning and next-day effects, including somnolence, based on lemborexant clinical study findings. Methods: This paper reports findings from 9 lemborexant clinical studies that incorporated next-day assessments of residual drug effects, based on published findings and data on file. Results are reported for healthy subjects or subjects with insomnia disorder treated with lemborexant 5 mg/day or 10 mg/day, placebo, or active comparator before bedtime. Outcomes assessed included next-morning postural stability (body sway measured by ataxiameter), cognitive performance (Cognitive Performance Assessment Battery), impact on driving (standard deviation of lateral position during highway driving test), subjective sleepiness (sleep diary entries), and adverse events of somnolence. Results: Change from baseline in postural stability the morning after lemborexant administration did not differ from placebo. Among 4 Cognitive Performance Assessment Battery measures, only power of attention declined significantly more with lemborexant treatment compared with placebo in 1 of 2 studies, whereas zolpidem differed from placebo on multiple measures. On the highway-driving test, lemborexant did not significantly impair driving performance versus placebo, however, zopiclone did differ. In large phase 3 trials, next-morning sleep diary ratings showed significantly greater alertness with lemborexant compared with placebo after up to 6 months of treatment. As expected, somnolence was the most common adverse event reported with lemborexant treatment. Somnolence was typically mild to moderate in severity and rarely caused discontinuation of study drug. Conclusion: Across 9 clinical studies, lemborexant did not substantially impair next-day functioning among healthy subjects and subjects with insomnia.

Comparative efficacy of lemborexant and other insomnia treatments: a network meta-analysis

“…More somnolence was observed with higher lemborexant doses. 14 However, there was no statistical difference in objective measures such as reaction time between lemborexant and placebo or other assessments of the potential for residual morning sleepiness, 60,78 indicating that lemborexant was not associated with clinically meaningful residual morning sleepiness. comparison-adjusted funnel plots for 4-week efficacy and safety endpoints reported by more than 10 studies (Supplementary Figures 11-13, available in online article).…”

Physiologically‐based pharmacokinetic modeling to predict drug interactions of lemborexant with CYP3A inhibitors

“…The clinical consequence of the observed and predicted increases in lemborexant exposures in the presence of CYP3A inhibitors was evaluated in the context of the efficacy and safety profile of lemborexant across its therapeutic range, evaluated across a phase II study (E2006‐G000‐201 [NCT01995838] 33 ), two phase III studies (E2006‐G000‐304, SUNRISE‐1 [NCT02783729] 3 ; and E2006‐G000‐303, SUNRISE‐2 [NCT02952820] 4 ), and safety studies assessing next‐day performance (residual effects) of lemborexant 34,35 . These studies demonstrated that doses of 5 mg and above provide clinically meaningful sleep benefits, and that lemborexant exposures greater than 10 mg were associated with an increased risk of somnolence adverse events 33,36 . With somnolence emerging as the most frequently occurring treatment‐emergent adverse event, PK/pharmacodynamic analyses of late‐stage trials indicated that this, and other adverse events of interest, are exposure‐independent over the 5–10 mg therapeutic dose range of lemborexant 37 …”

“…The clinical consequence of the observed and predicted increases in lemborexant exposures in the presence of CYP3A inhibitors was evaluated in the context of the efficacy and safety profile of lemborexant across its therapeutic range, evaluated across a phase II study (E2006-G000-201 [NCT01995838] 33 ) 34,35 These studies demonstrated that doses of 5 mg and above provide clinically meaningful sleep benefits, and that lemborexant exposures greater than 10 mg were associated with an increased risk of somnolence adverse events. 33,36 With somnolence emerging as the most frequently occurring treatment-emergent adverse event, PK/pharmacodynamic analyses of late-stage trials indicated that this, and other adverse events of interest, are exposure-independent over the 5-10 mg therapeutic dose range of lemborexant. 37 Therefore, lemborexant exposures in a DDI scenario that are equivalent or above those achieved with lemborexant 10 mg alone are not expected to balance clinical benefit with Abbreviations: AUCR, ratio between the area under the concentration-time curve in the presence and absence of an inhibitor or inducer; C max R, ratio between the maximum concentration in the presence and absence of an inhibitor or inducer; CV%, percent coefficient of variation; DDI, drug-drug interaction; FDA, US Food and Drug Administration.…”

Advances in the Treatment of Chronic Insomnia: A Narrative Review of New Nonpharmacologic and Pharmacologic Therapies

“… 137 Lemborexant treatment was associated with significantly greater alertness for up to 6 months versus placebo as determined by next-morning sleep diary ratings. 137 In addition, whereas zolpidem differed from placebo on multiple measures of the Cognitive Performance Assessment Battery, power of attention was the only measure that found significantly decreased performance with lemborexant compared with placebo, and only in one of two studies. 137 Similarly, lemborexant treatment was also not associated with statistically significant or clinically meaningful next-day impairment in a randomized, double-blind, double-dummy, placebo- and active-controlled, four-period, incomplete crossover study conducted in healthy volunteers to determine effects on driving performance during a standardized highway driving test in normal traffic.…”

“… 137 In addition, whereas zolpidem differed from placebo on multiple measures of the Cognitive Performance Assessment Battery, power of attention was the only measure that found significantly decreased performance with lemborexant compared with placebo, and only in one of two studies. 137 Similarly, lemborexant treatment was also not associated with statistically significant or clinically meaningful next-day impairment in a randomized, double-blind, double-dummy, placebo- and active-controlled, four-period, incomplete crossover study conducted in healthy volunteers to determine effects on driving performance during a standardized highway driving test in normal traffic. 138 However, while there were no stopped drives during the lemborexant conditions, driving ability was impaired in 2 of the 32 participants receiving lemborexant 10 mg, and the product label recommends that patients who take the 10-mg dose should be advised about the possibility of next-morning driving impairment due to individual variation in lemborexant sensitivity; of note, the recommended starting dose of lemborexant is 5 mg. 139 The effects of lemborexant, zolpidem, and placebo on auditory awakening threshold and postural stability in the middle of the night and upon morning awakening were assessed in healthy females (≥55 years of age) and males (≥65 years of age).…”