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Preclinical in vivo characterization of lemborexant (E2006), a novel dual orexin receptor antagonist for sleep/wake regulation.

ABSTRACT: STUDY OBJECTIVES:To present results from in vivo studies underlying the preclinical development of lemborexant (E2006), a novel dual orexin (hypocretin) receptor antagonist for sleep/wake regulation. METHODS:Rodent (wild-type rats and wild-type and orexin neuron-deficient [orexin/ataxin-3 Tg/+] mice) studies were performed to evaluate the effects of single-dose oral lemborexant (1-300 mg/kg) on orexin-induced increases in plasma adrenocorticotropic hormone (ACTH), locomotor activity, vigilance state measures (wakefulness, nonrapid eye movement [non-REM] sleep, rapid eye movement [REM] sleep), ethanol-induced anesthesia, and motor coordination, and the effects of multiple-dose oral lemborexant (30 mg/kg) on vigilance state measures. Active comparators were almorexant and zolpidem. Pharmacokinetics were assessed after single-dose lemborexant in mice and rats. RESULTS:Lemborexant prevented the orexin-promoted increase in ACTH in rats, therefore demonstrating inhibition of the orexin signaling pathway. Furthermore, lemborexant promoted sleep in wild-type mice and rats. Lemborexant promoted REM and non-REM sleep at an equal rate (there was no change in the REM sleep ratio). In contrast, zolpidem reduced REM sleep. The sleep-promoting effect of lemborexant was mediated via the orexin-peptide signaling pathway as demonstrated by a lack of sleep promotion in orexin neuron-deficient mice. Chronic dosing was not associated with a change in effect size or sleep architecture immediately postdosing. Lemborexant did not increase the sedative effects of ethanol or impair motor coordination, showing good safety margin in animals. Pharmacokinetic/pharmacodynamic data for mice and rats were well aligned. CONCLUSIONS:These findings supported further clinical evaluation (ongoing at this time) of lemborexant as a potential candidate for treating insomnia and other sleep disorders.

SUBMITTER: Beuckmann CT

PROVIDER: S-EPMC6559177 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Preclinical in vivo characterization of lemborexant (E2006), a novel dual orexin receptor antagonist for sleep/wake regulation.

Beuckmann Carsten Theodor CT Ueno Takashi T Nakagawa Makoto M Suzuki Michiyuki M Akasofu Shigeru S

Sleep 20190601 6

<h4>Study objectives</h4>To present results from in vivo studies underlying the preclinical development of lemborexant (E2006), a novel dual orexin (hypocretin) receptor antagonist for sleep/wake regulation.<h4>Methods</h4>Rodent (wild-type rats and wild-type and orexin neuron-deficient [orexin/ataxin-3 Tg/+] mice) studies were performed to evaluate the effects of single-dose oral lemborexant (1-300 mg/kg) on orexin-induced increases in plasma adrenocorticotropic hormone (ACTH), locomotor activi ...[more]

PMID: 30923834

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Project description:To identify dose(s) of lemborexant that maximize insomnia treatment efficacy while minimizing next-morning residual sleepiness and evaluate lemborexant effects on polysomnography (PSG) measures (sleep efficiency [SE], latency to persistent sleep [LPS], and wake after sleep onset [WASO]) at the beginning and end of treatment.Adults and elderly subjects with insomnia disorder per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition were enrolled in a multicenter, randomized, double-blind, placebo-controlled, Bayesian, adaptive, parallel-group study, receiving lemborexant (1, 2.5, 5, 10, 15, 25 mg) or placebo for 15 nights. Efficacy assessments included a utility function that combined efficacy (SE) and safety (residual morning sleepiness as measured by Karolinska Sleepiness Scale [KSS]), PSG measures, and sleep diary. Safety assessments included KSS, Digit Symbol Substitution Test, computerized reaction time tests, and adverse events (AEs).A total of 616 subjects were screened; 291 were randomized. Baseline characteristics were similar between lemborexant groups and placebo (?63% female, median age: 49.0 years). The study was stopped for early success after the fifth interim analysis when the 15-mg dose met utility index/KSS criteria for success; 3 other doses also met the criteria. Compared with placebo, subjects showed significant improvements in SE, subjective SE, LPS, and subjective sleep onset latency at the beginning and end of treatment for lemborexant doses ? 5 mg (P < .05). WASO and subjective WASO showed numerically greater improvements for doses > 1 mg. AEs, mostly mild to moderate, included dose-related somnolence.Lemborexant doses ranging from 2.5-10 mg provided efficacy for the treatment of insomnia while minimizing next-morning residual sleepiness.Title: A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Bayesian Adaptive Randomization Design, Dose Response Study of the Efficacy of E2006 in Adults and Elderly Subjects With Chronic Insomnia; URL: https://clinicaltrials.gov/ct2/show/NCT01995838; Identifier: NCT01995838.

Dataset Information

Preclinical in vivo characterization of lemborexant (E2006), a novel dual orexin receptor antagonist for sleep/wake regulation.

Publications

Preclinical in vivo characterization of lemborexant (E2006), a novel dual orexin receptor antagonist for sleep/wake regulation.

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