Lemborexant. Dual orexin receptor antagonist, Treatment of insomnia

Eisai's lemborexant, or E-2006, is a dual orexin OX1/OX2 receptor antagonist (DORA)in codevelopment withPurdue Pharma. Functionally, lemborexant is about 10-fold selective for OX2 over OX1, whereas it is almost nonselective in recombinant human, rat and mouse receptor binding assays. Lemborexant binds and dissociates rapidly from orexin receptors in contrast to other DORAs, which are typically slow to dissociate. It is relatively stable, shows good bioavailability and brain penetration. In mice, lemborexant enhanced sleep for 4-5 h with effects on both non-REM and REM sleep. Lemborexant is currently in phase II/III clinical studies for the treatment of insomnia. A phase II proof-of-concept study investigated six doses from 1 to 25 mg or placebo administered for 15 nights with polysomnography conducted at baseline and on treatment days 1/2 and 14/15. At all doses, lemborexant induced sleep, reduced latency to sleep and wake after sleep onset. Results of other studies have been reported either in abstract form or as corporate press releases. Lemborexant is apparently well tolerated with moderate adverse events, primarily headache and dose-related somnolence. Some studies are placebo controlled, others against active comparators including flurazepam, zolpidem and/or zopiclone where lemborexant was reported as superior to the latter two drugs, especially with respect to next-morning somnolence, driving performance and balance control. Lemborexant is expected to be submitted to regulatory authorities by 2019 and if registered, market forces will tell whether lemborexant fares better than the first-in-class DORA suvorexant and/or selective OX2 receptor antagonists currently in clinical investigation such as seltorexant (JNJ-54717793/MIN-202) or MK-1064.