TOKYO: Eisai Co., Ltd. announced today that it has obtained the manufacturing and marketing approval in Japan for its in-house discovered orexin receptor antagonist DAYVIGO (2.5mg, 5mg, and 10mg tablets, lemborexant) for treatment of insomnia.

DAYVIGO is a dual orexin receptor antagonist that inhibits orexin neurotransmission regulating sleep-wake rhythm by binding competitively to the two subtypes of orexin receptors (OX1R and OX2R). Blocking the binding of wake-promoting neuropeptides orexin to orexin receptors is thought to suppress wake drive by balancing sleep-wake circuitry. DAYVIGO binds to orexin receptors OX1R and OX2R and acts as a competitive antagonist with stronger inhibition effect on OX2R. Higher affinity and faster on/off receptor kinetics of DAYVIGO to OX2R, which also suppresses non-REM sleep, indicate its potential to facilitate the non-sedative onset and maintenance of sleep.

This approval was mainly based on the results of two pivotal Phase 3 clinical studies in adult patients with insomnia, SUNRISE 21 and SUNRISE 12, enrolling approximately 2,000 patients. Approval was also based on important safety studies (Study1083, Study1064), which included assessment of residual next-morning effects via postural stability (falling prediction indicator), memory after middle-of-the-night awakening.

SUNRISE 2 was a placebo-controlled 12-month Phase III clinical study conducted globally, including in Japan, to evaluate the long-term efficacy and safety of DAYVIGO in 949 male or female adult participants 18 to 88 years of age with insomnia. The study evaluated sleep onset latency (primary objective), subjective sleep efficiency and subjective wake after sleep onset (secondary objectives) by using patient-reported (subjective) sleep diaries. From an analysis of results, the primary efficacy endpoint and all secondary endpoints were achieved for both DAYVIGO arms. Statistically significant improvement in sleep onset and sleep maintenance was confirmed for both DAYVIGO arms compared to placebo. Daily functioning, as measured by both of the Insomnia Severity Index and the Fatigue Severity Scale, was also improved by both DAYVIGO 5 mg and 10 mg compared to placebo. The common Adverse Events (AEs) in the DAYVIGO arms were somnolence, nasopharyngitis, headache and influenza.

SUNRISE 1 was a placebo-controlled 1-month Phase III clinical study evaluating the efficacy and safety of DAYVIGO versus zolpidem tartrate extended-release (zolpidem ER) in 1,006 male or female adult patients 55 years and older (45% of patients were 65 years and older) with insomnia disorder, which was characterized by difficulty staying asleep. The study objectively assessed sleep latency (time taken between going to bed and falling asleep, primary objective), sleep efficiency and wake after sleep onset (effect on maintaining sleep, secondary objectives) using polysomnography. The results of the study showed that DAYVIGO 5 mg and 10 mg had statistically significant improvement compared to zolpidem ER 6.25 mg and placebo in sleep parameters evaluated in primary and key secondary objectives. Daily functioning, as measured by the Insomnia Severity Index, was also improved by both DAYVIGO 5 mg and 10 mg compared to placebo. The most common AEs in the DAYVIGO arms were headache and somnolence.

Across SUNRISE 2 and SUNRISE 1, DAYVIGO was not associated with rebound insomnia following treatment discontinuation and there was no evidence of withdrawal effects following DAYVIGO discontinuation at either dose.

In a SUNRISE 2 sub-population analysis of patients with or without comorbidity of insomnia, there was no difference between these two subgroups in the effect of DAYVIGO. Based on this result, the effect of DAYVIGO is suggested not only for primary insomnia, but also for insomnia associated with other diseases, such as depression.

In addition, the effects of DAYVIGO on next-day postural stability and memory were evaluated in two randomized, placebo- and active-controlled trials in healthy subjects and insomnia patients age 55 and older (Study 108 and SUNRISE1). There were no meaningful differences between DAYVIGO (5 mg or 10 mg) and placebo on next-day postural stability or memory compared to placebo. These results showed DAYVIGO had no meaningful residual next-morning effects.

In December 2019, the United States Food and Drug Administration (FDA) approved DAYVIGO for the treatment of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. In the United States, DAYVIGO will be commercially available in 5 mg and 10 mg tablets following scheduling by the U.S. Drug Enforcement Administration (DEA), which is expected to occur within 90 days. In addition, Eisai submitted a new drug application seeking approval of DAYVIGO in Canada in August 2019.

Insomnia is characterized by difficulty falling asleep, staying asleep or both, despite an adequate opportunity to sleep, that can lead to daytime consequences, such as fatigue, difficulty concentrating and irritability.5,6 Insomnia is one of the most common sleep-wake disorders. Approximately 30% of adults worldwide have symptoms of insomnia.(7),(8) In particular, older adults tend to have a higher prevalence rate with many experiencing insomnia symptoms for months to years. As a result, insomnia causes various social losses, such as long absences and reduced productivity. It can increase the risk of falling in older adults.(9)

Through DAYVIGO’s ability to provide fast sleep onset and good quality sleep to many patients suffering from insomnia, Eisai aims to contribute to patients’ ability to have an active daytime lifestyle.