A Comprehensive Review of Lemborexant to Treat Insomnia

Abstract

Purpose of Review

This is a comprehensive review of the literature regarding Lemborexant for the treatment of insomnia. It covers the background and management of insomnia and then reviews the body of existing evidence evaluating the use of Lemborexant for this purpose.

Recent Findings

Insomnia leads to significant decreased in quality of life and economic burden due to decreased workplace performance and increased health care costs. Insomnia manifests as a single common pathway of hyperarousal due to a highly complex network of interactions between activation of the sympathetic system and the endocrine system. Lemborexant is a dual orexin 1/2 antagonist that blocks cortical arousal and promotes sleep state transition. Lemborexant was approved by the FDA in 2019 for use in insomnia. It belongs to a class of orexin neuropeptide inhibitors that is growing in popular clinical application.

Summary

Insomnia is a crippling disorder of the sleep wake cycle that drives significant morbidity and mortality in the United States. It carries a high societal and economic toll due to direct and indirect effects to the healthcare system. Lemborexant is a new addition to the orexin antagonist class of drugs that already includes Almorexant and Suvorexant that has superior pharmacokinetic properties. While Lemborexant does have a mild side effect profile, its clinical safety and efficacy make it a promising insomnia drug of the future.

Introduction

Insomnia is the most common sleep disorder among adults and results in a plethora of negative outcomes. The total cost of insomnia surpasses $100 billion dollars annually wherein most of the cost is indirectly from decreased workplace performance and directly from health care utilization.¹ The clinicians arsenal for treatment of chronic insomnia includes cognitive behavioral therapy, music, exercise, light therapy, and pharmacotherapy altering multiple neurobiologic systems (i.e.: benzodiazepines, nonbenzodiazepine “z” drugs, antidepressants, melatonin agonists and antipsychotics).² Literature has shown significant improvement in symptoms with these approaches, but there are unreconcilable consequences to current treatment regiments.³ For example, long term benzodiazepine use has a negative withdrawal profile and is associated with a range of neuropsychological impairment.⁴ Additionally, antidepressants and antipsychotics have a vast side effect profile of their own and are only indicated in cases with comorbid conditions. Due to the various limitations of current approaches, there is need for more well tolerated insomnia therapies. Recent advances in an emerging class of drugs called orexin antagonists have been showing great promise as an insomnia treatment of the future. Orexins are naturally occurring neuropeptides that regulate sleep, cognition, emotion, pain and acute stress.⁵ Lemborexant is a dual orexin OX1/OX2 receptor antagonist that works in insomnia to mitigate sleep wake cycle disturbances. Since FDA approval in 2019 there has been a myriad of studies showing a mild side effect profile and preferable drug properties compared to alternative approaches. This review will investigate Lemborexant as an emerging insomnia pharmacotherapy.

Insomnia Epidemiology, Pathophysiology, Risk Factors and Presentation

Epidemiology

The American Insomnia Survey estimated the prevalence of insomnia by a survey conducted from 2008–2009 through different diagnostic criteria that resulted in prevalence’s of 22.1% via DSM–IV-TR, 3.9% through ICD-10 criteria, and 14.7% by ICSD-2 standards.⁶ Although these results vary due to differences in diagnostic criteria, the consensus is that insomnia is a highly widespread disorder. Physician diagnosed insomnia has risen from 3.9% to 6.2% from 2006 to 2013.⁷ The risk of insomnia varies between numerous sociodemographic factors. According to the AAP (American Academy of Pediatrics) the median age of onset of insomnia is 11 with a 2.75-fold increase risk of insomnia at menses.⁸ Furthermore, women are at a 25–27.1% risk, while men’s associated risk is 15–19.7% for developing insomnia.^9,10 Lowered socioeconomic status including income and education are also associated with an increase prevalence of insomnia.^11,12

Pathophysiology

Insomnia is characterized by a dissatisfaction in the quality and/or quantity of sleep due to a noticeable difficulty initiating sleep, maintaining sleep, and/or early morning awakening with struggles falling back to sleep.^13,14 The pathophysiology of insomnia is a complex condition with numerous underlying contributories to its manifestation with a common motif of hyperarousal.¹⁵ Physiologic hyperarousal has been analyzed by finding variances in specific markers between individuals with insomnia compared to good sleepers, such as: sympathetic activation, increased 24-hour metabolic rate (measured by oxygen consumption), elevated adrenocortical hormones such as cortisol levels, and heart rate elevations.^16–19 Insomnia and its’ genetic relationship has been extensively studied and supported through numerous physiologic processes.²⁰ For instance, familial aggregation of insomnia in clinical and population based studies have observed an increased risk in those with an identifiable family history of insomnia.^21,22 Individuals with the CLOCK allele variant 311C and other single nucleotide polymorphisms, such as a mutation in the beta3 subunit (R192H) of GABA, resulting in decrease GABAergic inhibition may be conducive in insomnia’s presentation.^23–25 Furthermore, the “3-Ps” is a psychological behavioral model that illustrates the predisposing, precipitating, and perpetuating factors of insomnia development and maintenance.²⁶ These may include sex or age as predisposing factors and a stressful life event as a precipitating factor. Perpetuating factors include inapt behaviors, thoughts, and coping patterns which reinforce your insomnia, even with resolution of the initial trigger.²⁷ This complex pathophysiology is fundamental to the development and clinical presentation of chronic and acute Insomnia.

Clinical Presentation

Comparably, subtypes of insomnias umbrella similar presenting features, including; (1) Difficulty initiating and/or maintaining sleep, early awakening, or non-restorative sleep. (2) Daytime sequala such as cognitive impairment (e.g. focus or memory) fatigue, or mood disruption (e.g. dyspeptic or dysphoria).²⁸ Insomnia is diagnostically distinguishable from sleep deprivation due to adequate time for sleep. Acute insomnia is defined as: “Sleep continuity disturbance occurring for three days per week for anywhere between one week and three months,” consequently from a precipitating triggered event including current distress (medication change, illness, circumstance) or a lifetime event(s) resulting in an inadequate QOL in regard to one’s own standards. Symptomatically, CI (chronic insomnia) resembles AI (acute insomnia) with its’ presentation persisting for ⩾ 3 months.^28,29 Those experiencing AI predominately recover, a minority progress to CI, and 20% developing a sleep disturbance pattern which does not fit within the diagnosis of AI or CI. CI is present up to 10% of the population and 30% experience a new onset or AI annually.²⁸

Risk Factors

Copious amounts of research has linked insomnia’s impact on individual’s health such as mental illness and comorbidities, along with socioeconomic consequences.³⁰ Quality of life is a multifactorial assessment that has been inversely associated with increasing insomnia severity. Impaired physical (activities of daily living), emotional or psychological, and social domains may all be affected by insomnia. For example, in comparison to good-sleepers, insomniacs reported an overall health status and bodily pain as decreased and increased, respectively.³¹ Furthermore, SwePain, a longitudinal population study found that the risk of localized pain disseminating is associated in a dose-dependent manner with moderate to severe insomniacs.³² Cardiometabolic risks including type 2 diabetes, cardiovascular disease, hypertension, cerebrovascular disease, impaired heart rate variability, and blood pressure dripping are associate with insomniac patients.³³ Other individual risk factors associated with insomnia include, chronic headaches, cognitive aging, osteoarthritis and hip dysfunction, gastrointestinal complications, renal disease, depression and neurodegenerative disease.^34,35 For instance, chronic insomnia catalyzes brain changes in Alzheimer’s disease resulting in accumulation amyloid plaques and Tau proteins.³⁵ A systemic review with a longitudinal design further provides evidence to the hypothesis that insomnia is a predictor of mental illness, including depression, anxiety, and bipolar disorder.³⁶ Sleep continuity disturbances and its subsequent symptoms are also associated with indirect health risks, such as smoking cessation failure and significant financial burdens.³⁷ Patient’s with insomnia have more health care visits, diagnostic tests, and prescription drug use, resulting in a 60% higher mean total healthcare cost in comparison of those without insomnia.^38,39 Furthermore, the daytime consequences of insomnia results in indirect costs such as: increased work absences, mistakes and accidents, and a lesser self-rated job performance in contrast to their non-insomnia counterparts.^40,41

Current Treatment of Insomnia

There are a variety of therapies that can be used to treat insomnia. Cognitive behavioral therapy (CBT) is well known to be the first line treatment in chronic insomnia due to the great efficacy.^42–44 The use of medications has been the mainstay treatment modality due to system barriers such as a lack of CBT providers resulting in lower accessibility paired with cost effectiveness means many individuals do not benefit from this treatment.^45,46

Pharmacologic Treatment

Current pharmacologic treatment of chronic insomnia is broken up into four pharmacologic classes: benzodiazepine receptor agonists, melatonin receptor agonists, selective histamine receptor antagonists, and dual orexin/hypocretin receptor antagonists.⁴⁷ These pharmacotherapies have different uses based off of individual patient’s associated comorbidities.⁴⁸ Benzodiazepine receptor agonists have been shown to be associated with increase sleep duration, but are countered by a number of adverse effects such as drowsiness, ataxia, and cognitive impairment, particularly in the elderly.^49,50 Melatonin receptor agonists have been shown to be beneficial in comorbid neurological, psychiatric, cardiovascular, and metabolic symptomatology with a low side effect profile.⁵¹ Over-the-counter antihistamines can be used for treatment in younger adults, but tolerance develops rapidly.⁵² One of the newer molecules for the treatment of insomnia are the dual orexin/hypocretin receptor antagonists which have shown potential in being a therapeutic treatment with minimal adverse effects.⁵³ Suvorexant is the first approved orexin/hypocretin receptor antagonist and has shown to have daytime somnolence, driving impairment, and possible narcolepsy-like symptoms causing it to be unlikely to proven as superior to currently available hypnotics.⁵⁴

Non-Pharmacologic Treatment

Furthermore, there are several modalities of non-pharmacologic treatment in addition to CBT such as sleep restriction, stimulus control, sleep hygiene, and relaxation training that have shown some form of benefit in treating insomnia with varying levels of efficacy.⁵⁵ Sleep restriction is when the number of hours of sleep and time in bed limited and slowly increased. This has shown to indicate a small improvement; however, studies are insufficient to evaluate the full impact on objective sleep variables such as daytime functioning in response to sleep restriction.⁵⁶ Stimulus control is when cues for sleep and arousal are tightly monitored to develop a consistent sleep-wake schedule for improvement.⁵⁷ This has been shown to be more effective than no treatment in reducing both the frequency and duration of nighttime awakenings in sleep-maintenance insomniacs.⁵⁸ Sleep hygiene includes educating patients about lifestyle modifications such as electronic use, meal times, caffeine consumption, and naps.⁵⁹ Sleep hygiene independently has been shown to be ineffective in managing patients with chronic insomnia.^59,60 Relaxation therapy such as meditation or yoga has also been shown to reduce underlying anxiety and stress to improve pre-sleep arousal in insomnia patients.⁶¹ Additionally, light therapy has become a newer promising treatment modality and has shown to be effective in insomnia, especially when using a higher light intensity.⁶²

Lemborexant Drug Information

Lemborexant, brand name Davigo, is a Dual Orexin Receptor Antagonist (DORA) that has been approved for the treatment of insomnia in the US and Japan. Lemborexant and other DORAs treat the principal pathology of insomnia, the inability to extinguish arousal, while exhibiting little effect on sleep-related circuits.^63,64 Lemborexant promotes fast sleep onset and maintains sleep throughout the night, with little disturbances in normal sleep architecture.^5,63,65,66 Generally, lemborexant is well tolerated and does not increase next day morning somnolence to any clinically significant degree.⁶⁵ There is no significant impairment in next-morning driving or next day memory.⁶⁷ However, there does appear to be a dose dependent relationship with next day morning somnolence.^5,65,66

Lemborexant comes in an oral formulation in doses of either 5mg or 10 mg. It is recommended that patients should allow for at least 7 hours or sleep when taking the medication. If a patient expects to wake earlier that 7 hours after administration, it is not recommended that they take Lemborexant as there is a chance that they will experience somnolence and possibly balance and memory impairment. There is little concern of Lemborexant toxicity as there has been zero reported overdoses. Some studies have reportedly administered 7.5 times the recommended dose with no sings of toxicity.⁶⁸ Lemborexant does not appear to causes any dependance and its abuse liability is low.⁶⁷ Drug tolerance does not seem to be an issue with Lemborexant, as patients in a month-long study responded equally to treatment at the end of the study as they did at the beginning.⁴ There has been no rebound insomnia reported.⁴

The most common adverse effect reported is next day morning somnolence.^67,66 The risk was found to be about 10% for those taking the 10mg preparation and 7% for those taking 5mg. The risk is reduced by extending the period of sleep beyond 7 hours. A minority of patient also report headaches when taking Lemborexant. There does not appear to be a dose dependent relationship with this adverse effect, with 5.9% of patients on 5mg resorting headaches and 4.5% of patients on 10 mg. Nightmares were reported more frequently by those taking 10 mg of Lemborexant when compared to the control. There also appears to be a slightly greater risk of sleep paralysis and hypnagogic hallucinations in patients on Lemborexant. Finally, Lemborexant is associated with decreased middle of the night postural stability, attention, and memory when measured 4 hours after administration. None of these middle of the night effects have been demonstrated to be clinically significant when measured in the morning of the next day if the drug is taking correctly.⁶⁷

As a class, orexin receptor antagonists seem to have less drug-drug interactions when compared to traditional therapies that exude their effects through GABA_A modulation.⁶⁹ However there are still plenty of interactions that clinicians and patients should be aware of. Lemborexant metabolism is CYP3A mediated. Concomitant use of Lemborexant with any moderate or strong CYP3A inhibitors should be avoided and concomitant use with weak inhibitors should be limited to 5 mg.⁶⁷ Reciprocally, Lemborexant is thought to be an inducer of CYP2B6 and drugs that are metabolized by this cytochrome may require monitoring to ensure appropriate levels. Alcohol should be avoided while taking Lemborexant as increases the availability and concentration of bioavailable drug.

Lemborexant is contraindicated with patients with narcolepsy. It is also not recommended for use in patients with severe hepatic impairment and should be limited to 5 mg in patients with moderate hepatic impairment. As of yet, there is no widely available data on Lemborexant use in pediatric population nor the pregnant population. In fact the majority of studies have only included patients older than 55. Any use of outside of this population should be done with caution.⁶⁷

Lemborexant Mechanism of Action

Unlike the majority of pharmacological treatments of insomnia, like benzodiazepines, which modulate γ-aminobutyric acid-A (GABA) and histamine signaling in the hypothalamus and forebrain, Lemborexant inhibits the receptors for orexins (hypocretins). Orexins are stimulatory neuropeptides which exhibit effects a broad range of CNS nuclei ultimately culminating in arousal and wakefulness.

There are two known types of orexin peptides, Orexin A and Orexin B, and both are produced exclusively by a relatively small number of neurons in the lateral hypothalamus (LH). These two peptides exhibit effects on a wide distribution of nuclei throughout the brain by interacting with neurons that express their cognate (complementary/corresponding) receptors. There are two known orexin receptors OX1R and OX2R. OX2R is thought to be associated with cortical arousal while OX1R is associated with sleep state transitions.⁷⁰ Orexin B exhibits some specificity for the OX2R, while orexin A exhibits a similar affinity for both orexin receptors.^63,70,71 The release of orexins from neurons in the LH produces noradrenergic, serotonergic, cholinergic, and histaminergic effects through their interactions with the locus coeruleus, dorsal raphe nucleus, laterodorsal/pedunculopontine tegmental nuclei, and tuberomammillary nucleus respectively.^63,68,69,72 The cumulative effects of this widespread stimulation is arousal and wakefulness.^69,70

Inhibition or obliteration of the orexin producing neurons leads to decreased arousal and sleepiness. Multiple studies have demonstrated that orexins are involved in a variety of sleep pathologies.^73,74 The correlation between narcolepsy and the loss of orexin producing neurons has been well defined, so much so that the absence of orexin is now diagnostic of Type 1 narcolepsy.^69,75 Reciprocally, aberrant orexin activity has been implicated in insomnia.^76–78 Because of the implication between orexins and arousal, targeting the orexin pathway has become a promising approach to treating arousal pathologies, particularly insomnia. The development of therapeutic dual orexin receptor antagonists (DORAs), like suvorexant, has shown proof of concept and clinical success. Additionally, single receptor orexin antagonists are currently being studied. On a basic science level, these single orexin blockade studies seek to delineate the discrete functions of OX1R and OX2R. Furthermore, these experiments with single orexin receptor modulators may identify a more targeted therapy for specific sleep pathologies.⁶⁹

Being that Lemborexant is a dual orexin receptor antagonist, it has a common mechanism of action with Suvorexant. It competitively binds to both orexin receptors with only a slightly higher affinity for the OX2R.⁶³ Despite this shared mechanism of action, Lemborexant seems to both bind and dissociate quicker than suvorexant and other orexin receptor antagonists.^63,79 Lemborexant has been shown to be more effective in treating patients who have trouble falling asleep when compared to suvorexant and zolpidem, and this is likely to its rapid binding. However, Lemborexant has not been shown to have less risk of next day somnolence than other DORAs as one might expect due to its rapid dissociation.⁷⁹

Lemborexant Pharmacodynamics and Pharmacokinetics

Pharmacodynamics

Lemborexant is a dual antagonist of the orexin 1 (OX1R) and orexin 2 (OX2R) receptors.⁸⁰ Orexin peptides are produced in the hypothalamus and have projections to many brain regions.^72,81,82 The orexin peptides bind selectively to OX1R and OX2R.⁷¹ These are G protein-coupled receptors with 7 transmembrane domains strongly conversed across mammals.^71,83 OXR1 binds orexin-A with high affinity and lesser affinity for orexin-B.⁸³ OX2R is less selective than OX1R and binds both orexin-A and orexin-B with high affinity.⁷¹ When bound, these orexin receptors induce a rapid increase in intracellular calcium through voltage-gated calcium channels to excite target neurons.⁷¹ This causes the release of GABA or glutamate to continue a downstream cascade.⁸⁴ Orexins can also cause N-methyl-D-aspartate (NMDA) receptors in the membrane to increase in number, creating excitatory effects which is suspected to cause an increase in arousal.^85,86 Some of the most potent effects come arousal and sleep where orexin can markedly increase wakefulness for several hours.⁸³ It has also been shown that disruption of OXR2 produces moderate sleepiness without cataplexy and mice lacking both OXR 1 and OXR2 receptors have severe sleepiness with some cataplexy.^87,88 These same receptors are also thought to play a role in the control of appetite by heling to arouse hunger, play a role in stressful situations, and play a role in increasing excitability throughout regulating the autonomic nervous system.^89–91 These factors all mediate wakefulness, and when blocked can lead to sleepiness as well as reduce arousal.

Pharmacokinetics

Lemborexant is commonly prescribed in doses ranging from 2.5 to 25 mg. Lemborexant’s absorption time to peak concentration takes approximately one to three hours.^67,92 When it is taken with food, the maximum concentration is decreased by 23% with the AUC0-24h increased by 18% with the time to peak concentration delayed by approximately two hours.^67,93 The volume of distribution of Lemborexant is 1970 L.⁶⁷ Protein binding of Lemborexant is 94% in vitro.⁶⁷ The blood to plasma concentration ratio of Lemborexant is .65.^67,93 Lemborexant is eliminated through metabolism as well as excretion. It is primarily metabolized by CYP3A4 and slightly by CYP3A5.^67,93 The major resulting metabolite is M10.^67,94 Through excretion, 57.4% of the dose was recovered in feces and 29.1% in urine.^67,93 The effective half-life for Lemborexant 5 mg and 10 mg is 17 and 19 hours, respectively.^67,92 The plasma concentration at 0 hours post dose was 27% of the maximum concentration following multiple dosing with Lemborexant 10 mg.^67,92 It was found that there were no clinically significant differences in the pharmacokinetics of Lemborexant based on age, sex, race/ethnicity, or body mass index.⁹² It was initially demonstrated that Lemborexant and M10 have the ability to induce CYP3A and the weak potential to inhibit CYP3A and induce CYP2B6, but do not inhibit other isoforms or molecular transporters.^67,93 It can be a potential poor substrate of P-gp. Physiologically-based pharmacokinetic modeling showed that the use of weak CYP3A inhibitors increased Lemborexant exposure by less than 2-fold.^67,93 It further showed that interactions between strong CYP3A inducers, strong CYP3A inhibitors, moderate CYP3A inhibitors, and CYP2B5 substrates are clinically significant.^67,93 It is also shown that Lemborexant interacts with Bupropion, a CYP2B6 substrate clinically significantly.^67,93 These studies have shown that Lemborexant at doses through 25mg provides an overall pharmacokinetic, pharmacodynamic, and safety profile suitable for achieving pharmacologic effect while supporting treatment of insomnia while minimizing residual effects during wake time.^67,92

Clinical Studies: Safety and Efficacy

Safety

Insomnia medications frequently used today, including gamma-Aminobutyric acid (GABA) agonists, benzodiazepines, and nonbenzodiazepines such as zolpidem, have been associated with multiple safety concerns. These include daytime sleepiness, abuse potential, and tolerance. In addition, melatonin agonists have largely been unsuccessful in adequately managing insomnia. Lemborexant, a novel dual orexin receptor antagonist (DORA) has recently been approved in the United States and Japan for use in elderly patients with insomnia. It has been studied in multiple randomized control trials regarding its clinical use in both safety and efficacy.^95,96

Rosenberg et al. investigated the safety of Lemborexant over a 1-month period on 1006 randomized patients, with 45% being 65 years or older. They had 8 patients discontinue the trial due to adverse effects, with 1 being in the placebo (PBO) group, 3 taking zolpidem, 2 taking 5 mg of Lemborexant (LEM5), and 2 taking 10mg of Lemborexant (LEM10). They also reported 4 falls in the LEM5 group, however expert review determined none to be severe and none were considered treatment related. In addition, postural sway showed no difference between PBO and Lemborexant group, while the zolpidem group did exhibit significant body sway compared to PBO and Lemborexant. In summary, the trial determined Lemborexant to be tolerated well and may prove to be advantageous as a novel and robust treatment option for elderly patients with insomnia.⁹⁵

Other concerns that arise with current insomnia medications include an increased auditory awakening threshold (AAT), and decreased cognitive performance (CP) in the morning, after taking medications the prior evening, due to delayed drug wearing off. These effects can be magnified in the elderly population as drug metabolism is altered. This is significant, as this population bears a large burden of insomnia diagnoses. Murphy et al. compared zolpidem to Lemborexant at 5 and 10 mg doses both after awakening patients in the middle of the night, and in the morning. They found significantly increased change from baseline in body sway in zolpidem compared to Lemborexant with midnight awakening, and no change in AAT when comparing LEM5 or LEM10 to PBO. Additionally, LEM5 had no statistical difference compared to PBO on CP. Upon morning awakening, there was no difference between LEM5 or LEM10 and PBO in body sway or CP, while zolpidem had significantly increased body sway. These findings suggest that Lemborexant may be better tolerated than zolpidem, with fewer adverse effects and a faster wearing off period.⁹⁷

Sleep-promoting medications are also known to negatively affect the user’s ability to operate motor vehicles the morning after bedtime doses due to residual effects. While the results of prior studies suggest that Lemborexant has minimal residual effects in the morning after bedtime dosing, support for safety while operating motor vehicles is useful for safe prescribing. Vermeeeren et al. assessed next-morning side effects ~9 hours after administration of Lemborexant 2.5 mg, 5 mg, and 10 mg, and compared results to PBO and zopiclone 7.5 mg. They found no statistically significant or clinically relevant effects on driving ability for Lemborexant at any dose compared to PBO. However, zopiclone resulted in increased driving impairment, as well as three incidences of driving tests being terminated prematurely by the investigators due to study participant not operating safely. Thus Lemborexant seems to be as safe as PBO the morning after taking it, with a decreased side effect profile compared to zopiclone.⁹⁸

While Lemborexant has recently gained FDA approval for use in the United States, another DORA, Suvorexant, was approved in 2014 for treatment of insomnia. Similar to Lemborexant, suvorexant has increased specificity for the orexin 2 receptor (OXR2) compared to the orexin 1 receptor (OX1R) and is predicted to increase time in non-REM sleep. Compared to other DORAs, Lemborexant is predicted to dissociate more rapidly from its receptors, thus promoting sleep while having less risk of somnolence the morning after dosing. However, their data suggested that LEM10 has a greater risk of somnolence when compared to SUV20/15 and LEM10. Additionally, LEM10 has a higher discontinuation rate than SUV20/15 and may be more poorly tolerated than SUV20/15. Thus, Lemborexant is generally well-tolerated for insomnia treatment but starting doses should not exceed 5 mg, especially in elderly populations.⁷⁹

Efficacy

Insomnia is a very prevalent condition, affecting 30% of the population and costing roughly $62 billion annually. Additionally, symptoms of insomnia are risk factors for other conditions including mental health, cerebrovascular disease, ischemic heart disease, and ischemic stroke.^10,99,100 Currently, there is a need for medical therapeutics which have high efficacy at reducing wakefulness, decreasing sleep onset, and promoting sleep maintenance. Critically, while also reducing residual feelings of somnolence in the morning compared to current therapies.

Lemborexant, a novel DORA, thought to alter sleep/wake regulation, targets hypothalamic postsynaptic G-protein-coupled receptors orexin-1 and orexin-2 for the neuropeptide’s orexin-A and orexin-B.¹⁰¹ Prior animal studies have shown the importance of these receptors in sleep/wake regulation, and humans with narcolepsy type-1 have been shown to have deficits in orexin signaling.¹⁰² In vivo studies performed by Beuckmann et al. determined that Lemborexant affects the sleep/wake cycle regulation, and notably may enable both REM and non-REM sleep equally, via the signaling pathway involving orexin peptide and receptors. Additionally, Lemborexant did not agonize sedative effects felt from alcohol or result in decreased motor coordination.¹⁰³

Kärppä et al. sought to establish the degree of improvement patients taking Lemborexant experienced. Subjective sleep onset latency (sSOL) and subjective wake after sleep onset (sWASO) were reported on 750 patients over the age of 18, taking either 5 mg or 10 mg of Lemborexant. Results were calculated at 6 and 12 months. Improvements in sSOL at 6 months of 20 minutes or more were reported in 45.5% on LEM5, and 44.9% in LEM10. Results at 12 months were similar (LEM5 40.4%; LEM10 43.3%). PBO reported 30.4% improving greater than 20 minutes from baseline. Similarly, Lemborexant showed an improvement of 60 minutes or more in sWASO compared to PBO at 6 months, with 27.8% reporting improvement on LEM5 and 30.2% on LEM10, at 12 months. PBO reported an improvement of 24.2%. Similar results were reported at 12 months (LEM5, 27.8%; LEM10 27.7%). Thus, while PBO did improve all measurements of sleep, Lemborexant has shown statistically significant improvement in efficacy compared to PBO at 6 and 12 months, both for patients taking 5 mg or 10 mg doses.^96,104

Kishi et al. compared Lemborexant to suvorexant and zolpidem for its use in insomnia, at 1 week and at 1 month. In their study, LEM5, LEM10, and SUV20/15 were all superior in efficacy to PBO for improving SOL. Additionally, LEM10 was superior to SUV20/15 at 1 week for both total sleep time and sWASO, however this benefit disappeared at 1 month of medication use, suggesting there is some development of tolerance for Lemborexant. LEM10 showed an improvement in all measures of sleep compared to LEM5 at 1 week, and at 1 month. This suggests that Lemborexant effective at maintaining sleep in a dose-dependent manner. Utilizing polysomnography measurements, LEM10, LEM5 and SUV20/15 were all superior to PBO for decreasing latency to persistent sleep and increasing WASO. In this experiment, LEM10 was found to be superior to LEM5 and zolpidem, but not to SUV20/15. Interestingly, LEM10 was superior to SUV20/15 at 1 day when measuring WASO but this effect disappeared by 1 month, again suggesting the potential for tolerance development to Lemborexant. The results of this study are that Lemborexant is effective at treating symptoms of insomnia, including SOL, WASO, sleep maintenance, and latency to persistent sleep, however there may be a slightly increased risk of adverse effects than SUV20/15 at higher doses (i.e. Lemborexant 10 mg).⁷⁹

Murphy et al. evaluated multiple Lemborexant doses, from 1 mg to 25 mg for their improvement in sleep efficiency (SE) over a 15-day period. SE was improved 5% on 1 mg and 10% on 25 mg of Lemborexant, based on a decrease in SOL and increased time to WASO. Lemborexant outperformed placebo at all doses, with a dose-dependent effect observed for SE improvement. Importantly, both the objective and subjective measurements of SE were in alignment for improvement. This is valuable as insomnia is a multifaceted disorder, including a significant psychological component. Thus, the subjective component of improved SE is an important measurement for confirmation of adequate pharmacotherapy. All effects were maintained throughout the duration of the experiment, but longer term effects were not distinguishable based on this study.⁶⁵

In another study, subjective effects of Lemborexant were reported based on the Patient Global Impression—Insomnia (PGI-I) after 6 months of medication use. The PGI-I contains three measures of medication effect: helped/worsened sleep, decreased/increased time to fall asleep; and increased/decreased total sleep. All measures are recorded on a three-point scale with 1 being positive, 2 being neutral, and 3 being negative. The PGI-I does not have a baseline, and thus outcome is based on patient impression of medication effects. All patients were given PGI-I months 1, 3, 6, 9, ad 12 after a PBO-controlled treatment period. All subjects were also asked whether the medication strength was “just right,” “too strong,” or “too weak.” Patients self-reported an increase in total sleep vs PBO at month 6 and a greater percentage of patients reported medication strength as being “just right” when compared to PBO at month 6.¹⁰⁵

Summary

Insomnia is a highly dynamic disturbance of the sleep wake cycle that often has many comorbidities. Given the complex nature of insomnia, the next best option for treatment must be individualized to the patient. Lemborexant is a new FDA approved pharmacotherapy for insomnia that boasts a mild side effect profile and superior efficacy and safety in multiple high-quality clinical trials. Lemborexant has even shown superior pharmacokinetic properties compared to drugs in the same class of orexin receptor antagonists such as Suvorexant. Research should continue to investigate the long-term effects of Lemborexant considering insomnia mitigation requires long term treatment. In addition, Lemborexant should be weighed against current treatment regimens such as benzodiazepines, “z” drugs, antidepressants, antipsychotics, melatonin agonists and the non-pharmacotherapies including light therapy, music, and cognitive behavioral therapy.

Table 1. Studies Reviewing the Clinical Efficacy and Safety of Lemborexant for Insomnia.

Author (Year)		Groups Studied and Intervention		Results and Findings		Conclusions
Rosenberg et al. (2019) Rosenberg R, Filippov G, LoPresti A, Kumar D, Murphy P, Moline M. Safety of lemborexant in elderly subjects with insomnia: Results from a phase 3 study (SUNRISE 1). Am J Geriatr Psychiatry. 2019;27(3):S196–S197.		SUNRISE 1 group. N = 1006, females > 55yo, males > 65 yo Lemborexant 5 mg vs. Lemborexant 10 mg vs. Zolpidem 6.25 mg for 1 month		No difference in body sway upon awakening and falls for Lemborexant 10 compared to placebo. Zolpidem had increase in body sway upon awakening.		Lemborexant is well tolerated in elderly population and may offer an optimal treatment in this population.
Karppa et al. (2020) Kärppä M, Yardley J, Pinner K, Filippov G, Zammit G, Moline M, et al. Long-term efficacy and tolerability of lemborexant compared with placebo in adults with insomnia disorder: Results from the phase 3 randomized clinical trial SUNRISE 2. Sleep. 2020;XX.		SUNRISE 2 group. N = 949, age > 18 yo Lemborexant 5 mg vs. Lemborexant 10 mg vs. placebo		Lemborexant 5/10 mg showed improvements in subjective wake after sleep onset and subjective sleep onset latency compared to placebo consistently over 6-month period.		Lemborexant has superior efficacy compared to placebo throughout 6-month use in general public age > 18 yo.
Murphy et al. (2020) Murphy P, Kumar D, Zammit G, Rosenberg R, Moline M. Safety of lemborexant versus placebo and zolpidem: effects on auditory awakening threshold, postural stability, and cognitive performance in healthy older participants in the middle of the night and upon morning awakening. J Clin Sleep Med. 2020;16(5):765–73.		N = 60, females > 55 yo, males > 65 yo Lemborexant 5 mg vs. Lemborexant 10 mg vs. ER Zolpidem 6.25 mg vs. placebo in crossover study		Zolpidem had significantly increased middle of the night body sway compared to Lemborexant 5/10 mg and placebo. Lemborexant 5/10 mg showed no difference in body sway upon awakening compared to placebo. Lemborexant 10 mg and Zolpidem showed decreased performance of attention and/or memory. Lemborexant 5 mg showed no change in performance of attention and/or memory. No difference in decibels required to awaken participants in all interventions.		Lemborexant does not impair ability to awaken by auditory signaling. High dose Lemborexant may have negative cognitive performance outcomes. Lemborexant causes less postural instability than Zolpidem.
Vermeeren et al. (2018) Vermeeren A, Jongen S, Murphy P, Moline M, Filippov G, Pinner K, et al. On-the-road driving performance the morning after bedtime administration of lemborexant in healthy adult and elderly volunteers. Sleep. 2019;42(4):1–9.		N = 48, 22 females, 23 yo–78 yo Lemborexant (2.5 mg, 5 mg, 10 mg) vs. Zopiclone 7.5 mg vs. placebo for 8 nights		Driving performance in the morning showed mean standard deviation of lateral position of 0.74 cm or less (95% CI included 0) for all intervention groups.		Lemborexant has no clinically or statistically significant impairment of driving performance the morning after nighttime dosing.
Murphy et al. (2017) Murphy P, Moline M, Mayleben D, Rosenberg R, Zammit G, Pinner K, et al. Lemborexant, a dual orexin receptor antagonist (DORA) for the treatment of insomnia disorder: Results from a Bayesian, adaptive, randomized, double-blind, placebo-controlled study. J Clin Sleep Med. 2017;13(11):1289–1299.		N = 616, 63% female, 49.0 yo mean age Lemborexant (1 mg, 2.5 mg, 5 mg, 10 mg, 15 mg, 25 mg) vs. placebo for 15 nights		Lemborexant doses > 5 mg were associated with significantly improved sleep efficiency, latency to persistent sleep and subjective sleep onset latency. Lemborexant doses > 1 mg showed significantly improved wake after sleep onset.		Lemborexant ranging from 2.5 mg–10 mg proved efficacious for treatment of insomnia.

Table 2. Studies Comparing Lemborexant to Alternative Pharmacotherapies for Insomnia.

Author (Year)		Groups Studied and Intervention		Results and Findings		Conclusions
Kishi et al. (2020) Kishi T, Nomura I, Matsuda Y, Sakuma K, Okuya M, Ikuta T, et al. Lemborexant vs suvorexant for insomnia: A systematic review and network meta-analysis. J Psychiatr Res. 2020;128:68–74.		N = 3237, 72% female, 58.0 yo mean age Lemborexant 5 mg vs. Lemborexant 10 mg vs. ER Zolpidem 6.25 mg vs. Suvorexant 20/15 mg/d vs. placebo for 1 week		Lemborexant 10 mg outperformed alternative drugs in subjective time to sleep onset, subjective total sleep time and subjective wake-after-sleep onset with 95% confidence interval at one week. All pharmacotherapies outperformed placebo at one week.		Lemborexant 10 mg and Suvorexant 20/15 mg/d are associated with somnolence compared to placebo. Lemborexant 10 mg has largest effect size compared to all alternatives.
Rosenberg et al. (2019) Rosenberg R, Filippov G, LoPresti A, Kumar D, Murphy P, Moline M. Safety of lemborexant in elderly subjects with insomnia: Results from a phase 3 study (SUNRISE 1). Am J Geriatr Psychiatry. 2019;27(3):S196–S197.		SUNRISE 1 group. N = 1006, Females > 55yo, males > 65 yo Lemborexant 5 mg vs. Lemborexant 10 mg vs. Zolpidem 6.25 mg for 1 month		No difference in body sway upon awakening and falls for Lemborexant 10 compared to placebo. Zolpidem had increase in body sway upon awakening.		Lemborexant is well tolerated in elderly population and may offer an optimal treatment in this population.
Beuckmann et al. (2019) Beuckmann CT, Ueno T, Nakagawa M, Suzuki M, Akasofu S. Preclinical in vivo characterization of lemborexant (E2006), a novel dual orexin receptor antagonist for sleep/wake regulation. SLEEPJ. 2019;42(6):1–14.		Rat study in wild type and orexin receptor neuron deficient type. Single and multiple dose Lemborexant vs. Almorexant vs. Zolpidem		Lemborexant prevented orexin-promoted ACTH in rats. Lemborexant promoted sleep in wild type rodents. Lemborexant promoted non-REM and REM sleep in constant ratio. Lemborexant did not increase sedative effects of ethanol or impair motor function.		Lemborexant positively impacts sleep and does not worsen sedative effects of ethanol in rodent models.