Insomnia pharmacotherapy update: Dual orexin receptor antagonists

06 May 2021

Chronic insomnia, defined as trouble falling or staying asleep ≥3 times per week for ≥3 months, is prevalent among adults in Hong Kong and associated with health and social problems. Cognitive behavioural therapy for insomnia (CBT-I) is recommended as first-line therapy. Nevertheless, pharmacological therapy remains the mainstay of treatment due to limited availability and accessibility of CBT-I in most parts of the world. γ-aminobutyric acid type-A (GABA-A) receptor agonists, such as sedative-hypnotic benzodiazepines and nonbenzodiazepines (Z-drugs), and sedating antidepressants have traditionally been used to treat insomnia. However, they have been inadequate in addressing both sleep initiation and maintenance symptoms, and treatment-emergent adverse events (TEAEs) are common. Novel agents, such as the dual orexin receptor antagonist (DORA), lemborexant (Dayvigo®, Eisai), recently approved in Hong Kong, may be useful alternatives to existing insomnia pharmacotherapies.


Novel pharmacotherapeutic approach to insomnia treatment

Insomnia is common among adults in Hong Kong, with the prevalence increasing with age. [J Psychosom Res 2002;53:601-609; J Sleep 2011;20:117-126; Sleep Med 2012;13:455-462] Older adults tend to have relatively greater difficulty with sleep maintenance and experience early morning awakening. [Sleep 1994;17:551-554] Benzodiazepines and other sedative-hypnotic medications, commonly prescribed to treat insomnia in older adults, may be unable to adequately address both sleep initiation and maintenance symptoms, and may be associated with falls, hip fractures and risk of unintentional injury. DORAs, by competitively and reversibly binding and blocking wake-promoting orexin neuropeptides to orexin receptors, suppress the wake drive. As such, DORAs are effective in sleep induction and maintenance and have fewer side effects. [BMJ 2005;331:1169; Clin Ther 2016;38:2340-2372; Int J Neuropsychopharmacol 2014;17:157-168] (Figure 1)

Orexin-A (OXA) and orexin-B (OXB) are hypothalamic neuropeptides that play critical roles in maintaining wakefulness. Their actions are mediated by postsynaptic G-protein–coupled orexin-1 and orexin-2 receptors (OX1R and OX2R). [Nat Rev Neurosci 2007;8:171-181; J Neurosci 2011;31:6518-6526] (Figure 1)


The orexin (hypocretin) signalling pathway regulates sleep and wakefulness through interactions with central nervous system pathways that participate in emotion processing, reward recognition and energy homeostasis. Furthermore, a causal link between loss of orexin signalling and narcolepsy has been discovered, while recent neuro imaging evidence suggests that insomnia is likely to be inappropriately timed hyperarousal or wakefulness rather than the brain’s inability to sleep. This combined evidence supports the novel therapeutic approach of dampening the excessive wakefulness in insomnia as opposed to the sleep-promoting GABA-agonistic action of traditional agents. [Int J Neuropsychopharmacol 2014;17:157-168; Am J Psychiatry 2004;161;2126-2129; J Neurosci 2011;31:6518-6526; J Pharmacol Exp Ther 2017;362:287-295; Sleep 2019;42:1-14]

Lemborexant: DORA for insomnia

Lemborexant is a DORA recently approved in Hong Kong for treating insomnia in adults, following approval in the US and Japan, based on findings of the pivotal phase III SUNRISE 1 and SUNRISE 2 studies in nearly 2,000 adult patients with insomnia. Lemborexant is contraindicated in patients with narcolepsy. [JAMA Netw Open 2019;2:e1918243; Sleep 2020;43:1-11; Neurology 2020;94(15 Suppl):420; Dayvigo Prescribing Information]

SUNRISE 1: Safety and efficacy in older adults

SUNRISE 1 was a 1-month, randomized, double-blind, parallel-group, placebo-controlled active-comparator phase III study that included 1,006 adults ≥55 years of age with insomnia disorder in North America and Europe. Orally administered lemborexant 5 mg or 10 mg was shown to significantly improve both laten-cy to persistent sleep, sleep efficiency, and wake-after-sleep onset  (WASO), including in the second half of the night,  objectively measured via polysomnography, compared with both placebo and zolpidem extended release 6.25 mg. Efficacy was also demonstrated in the endpoints of sleep onset, sleep efficiency and WASO for both does of lemborexant compared with placebo. There was no evidence of withdrawal symptoms or rebound insomnia upon lemborexant withdrawal. [JAMA Netw Open 2019;2:e1918243]

Both doses of lemborexant were effective in the first two and last two nights of treatment, indicating immediate and sustained efficacy. In contrast, zolpidem therapy improved sleep onset initially (nights 1 and 2), but became less effective over time, with no difference vs placebo in latency to persistent sleep after the first month of treatment. Most patients in the lemborexant group fell asleep in <20 minutes, which is typical for those without insomnia, and also gained >60 minutes of sleep per night than they had before treatment.

Lemborexant therapy was generally well tolerated in the elderly, with nearly all patients completing the treatment period. Consistent with earlier studies, a dose-dependent somnolence response was observed. The overall incidence of TEAEs in the lemborexant groups was similar to that in the zolpidem group. Six participants (four in the zolpidem group and two in the lemborexant 5 mg group) reported serious adverse events (AEs), none of which were treatment-related. Other AEs were mostly mild or moderate.

SUNRISE 2: Long-term safety and efficacy in adults

SUNRISE 2 was a 12-month, global, multicentre, randomized, double-blind, parallel-group phase III study comprising a 6-month placebo-controlled period (reported here) followed by a 6-month active-treatment-only period (results to be published later). It included 949 participants aged ≥18 years with insomnia, who were randomized to receive treatment with an oral dose of placebo or lemborexant 5 mg or 10 mg. [Sleep 2020;43:1-11; Neurology 2020;94(15 Suppl):420]

Lemborexant treatment resulted in significant decreases from baseline in patient-reported (subjective) sleep onset latency and subjective WASO, as well as a significant increase from baseline in subjective sleep efficiency during the first 7 nights and throughout 6 months of treatment. At the end of month 6, significantly greater proportions of patients in the lemborexant groups were sleep-onset and sleep-maintenance responders vs the placebo group, and the mean subjective sleep efficiency approached 80 percent with lemborexant treatment. This threshold has clinical importance as the American Academy of Sleep Medicine guidelines indicate that achieving a sleep efficiency of >80–85 percent is an important goal of insomnia treatment. (Figure 2) [Sleep 2020;43:1-11; J Clin Sleep Med 2008;4:487-504]


Lexborexant was generally well tolerated over the 6-month treatment period in the SUNRIES 2 study population. Consistent with previous studies of lemborexant, a similar incidence of TEAEs was re-ported across the placebo, lemborexant  5 mg, and lemborexant 10 mg treatment groups, and the majority of TEAEs in all treatment groups were mild or moderate in severity. The most common TEAE was somnolence, which appeared to show a dose-response in incidence.


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