Eisai's Dual Orexin Receptor Antagonist Dayvigo (Lemborexant) Approved in Japan for Insomnia Treatment

January 26, 2020 /BioonBIOON/ -- Eisai recently announced that Dayvigo (lemborexant) has been approved in Japan. This drug, an orexin receptor antagonist discovered and developed internally by Eisai, is indicated for the treatment of insomnia in adults, a sleep-wake disorder characterized by difficulty with sleep onset and/or sleep maintenance. Dayvigo is available in three tablet strengths (2.5 mg, 5 mg, and 10 mg).

In late December 2019, Dayvigo was first approved in the United States. According to the U.S. Drug Enforcement Administration (DEA) scheduling, Dayvigo will be marketed as 5 mg and 10 mg tablets, with an expected market launch within 90 days. Additionally, Eisai submitted a marketing application for Dayvigo to Canadian regulatory authorities in August 2019.

It is estimated that insomnia affects one in three adults. However, because safety is a major concern with sleep medications, new therapies face a difficult path to gaining acceptance among physicians and patients. Earlier in 2019, the United StatesFDABlack box warnings were issued for a class of insomnia medications, including Lunesta, Sonata, and Ambien, due to reports of injuries and fatalities resulting from hazardous activities such as sleepwalking and sleep-driving in patients taking these drugs.

Due to concerns regarding efficacy and safety, there remains a significant unmet medical need in the treatment of insomnia. Dayvigo is a therapeutic agent that addresses both sleep onset and sleep maintenance issues; its mechanism of action does not impair morning postural stability or cognitive function.

The mechanism of action of Dayvigo in the treatment of insomnia is believed to be mediated through antagonism of orexin receptors. Orexin is a neuropeptide naturally produced by the hypothalamus and is involved in regulating the sleep-wake cycle. The orexin neuropeptide signaling system plays a role in promoting wakefulness. Blocking the binding of the wake-promoting neuropeptides orexin A and orexin B to their receptors, OX1R and OX2R, is thought to inhibit wake-driving signals. Dayvigo binds to both orexin receptors OX1R and OX2R, acting as a competitive antagonist with greater inhibitory potency at OX2R.

This approval is based on data from the clinical development program evaluating lemborexant for the treatment of insomnia, which included two pivotal Phase III clinical studies, SUNRISE-1 (Study 304) and SUNRISE-2 (Study 303), enrolling approximately 2,000 patients. The SUNRISE-1 study was conducted in 1,006 patients aged ≥55 years (45% of whom were aged ≥65 years) with difficulty initiating sleep, and evaluated the efficacy and safety of lemborexant versus placebo and the active control zolpidem tartrate extended-release. The data showed that the study met its primary and secondary endpoints, and the most commonly reported adverse events in the lemborexant treatment group were headache and somnolence. The SUNRISE-2 study was conducted in 949 adult patients (aged 18–88 years) with insomnia disorder and evaluated the efficacy and safety of lemborexant versus placebo. The data showed that this study also met its primary and key secondary endpoints. The most commonly reported adverse events in the lemborexant treatment group were somnolence, nasopharyngitis, headache, and influenza.

In addition to these pivotal trials, Eisai conducted further studies to evaluate the safety profile of Dayvigo, including assessments of the impact of lemborexant on arousal from auditory stimuli, next-day postural stability and memory, and next-morning driving performance. The data indicated that while there was no significant difference between lemborexant and placebo in the ability to arouse from auditory stimuli, lemborexant was associated with dose-dependent impairments in attention and memory compared to placebo. Furthermore, no significant differences were observed between lemborexant and placebo regarding next-day postural stability or memory. Although neither the 5 mg nor the 10 mg dose of lemborexant caused statistically significant impairment in next-morning driving performance in adult or elderly subjects compared to placebo, driving performance was impaired in some subjects receiving the 10 mg dose of lemborexant.

Molecular structure of lemborexant (Image source: Wikipedia)

Lemborexant is a dual orexin receptor OX1 and OX2 antagonist discovered and developed internally by Eisai. This compound inhibits orexin by competitively binding to the two subtypes of orexin receptors (orexin receptor 1 and orexin receptor 2). In individuals with insomnia disorder, the orexin system, which regulates sleep and wakefulness, may not function properly. During a normal sleep cycle, activity of the orexin system is suppressed; this suggests that lemborexant may promote the initiation and maintenance of sleep by intentionally interfering with orexinergic neurotransmission.

Orexin signaling is associated with other physiological functions, such as memory, mood, motivation, and attention. Therefore, in addition to idiopathic sleep-wake rhythm disorder (ISWRD), Eisai is also testing lemborexant for its application in Alzheimer’s disease (AD). Previously, the drug was developed jointly by Eisai and Purdue Pharma; however, in early 2019, Eisai repurchased all rights to the drug. (Bioon.com)

Original Source: Eisai: Dayvigo (Lemborexant)approved for Treatment of Insomnia in Japan