Out of the Pipeline Lemborexant for insomnia David N. Neubauer, MD emborexant, FDA-approved for the Table 1 New agent treatment of insomnia, has demon- Fast facts about lemborexant promotes sleep strated efficacy in improving both sleep by suppressing L 1 Brand name: Dayvigo onset and sleep maintenance. This novel the wake drive compound is now the second approved Class: Dual orexin receptor antagonist supported by the insomnia medication classed as a dual orexin Indication: Insomnia characterized by difficulties with sleep onset and/or sleep orexin system receptor antagonist (Table 1). This targeted maintenance mechanism of action aims to enhance sleep Approval date: December 20, 2019 while limiting the adverse effects associated Availability date: June 2020 with traditional hypnotics. Manufacturer: Eisai Inc., Woodcliff Lake, New Jersey Clinical implications Dosage forms: 5-mg and 10-mg tablets Insomnia symptoms affect approximately Recommended dosage: 5 mg taken one-third of the general population at least immediately before going to bed with at least occasionally. Approximately 10% of indi- 7 hours remaining before the planned time viduals meet DSM-5 criteria for insomnia of awakening, no more than once per night. The dosage may be increased to 10 mg taken disorder, which require nighttime sleep once per night based on clinical response and difficulty and daytime consequences tolerance persisting for a minimum of 3 months.2 The prevalence is considerably higher in patients with chronic medical disorders and comorbid psychiatric conditions, especially similar mechanisms of action. There is 1 mood, anxiety, substance use, and stress- melatonin receptor agonist (ramelteon) and and trauma-related disorders. Clinical 1 histamine receptor antagonist (low-dose guidelines for treating insomnia disorder doxepin). Joining suvorexant (approved typically recommend cognitive-behavioral in 2014), lemborexant is the second dual therapy for insomnia as a first choice and orexin receptor antagonist. FDA-approved insomnia medications as The orexin (also called hypocretin) secondary options.3 system was first described in 1998 and Currently approved insomnia medi- its fundamental role in promoting and cations fall into 4 distinct pharmaco- coordinating wakefulness was quickly dynamics categories.4 Benzodiazepine established.5 A relatively small number of receptor agonist hypnotics include 5 hypothalamic neurons located in the lateral medications with classic benzodiazepine structures (estazolam, flurazepam, quaz- The author is Associate Professor, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland. epam, temazepam, and triazolam) and 3 Disclosure compounds (eszopiclone, zaleplon, and The author is a consultant to Eisai Inc. Current Psychiatry zolpidem) with alternate structures but doi: 10.12788/cp.0060 Vol. 19, No. 11 43 Out of the Pipeline and perifornical regions produce 2 similar Pharmacokinetics orexin neuropeptides (orexin A and orexin Lemborexant is available in immediate- B) with widespread distributions, notably release tablets with a peak concentration reinforcing the wake-promoting activity of time (Tmax) of approximately 1 to 3 hours histamine, acetylcholine, dopamine, sero- after ingestion. When taken after a high-fat tonin, and norepinephrine. Consistent with and high-calorie meal, there is a delay in the the typical sleep-wake cycle, orexin release Tmax, a decrease in the maximum plasma con- is limited during the nighttime. The orexin centration (Cmax), and an increase in the con- 1 neuropeptides interact with 2 G-protein- centration area under the curve (AUC0-inf). coupled orexin receptors (OX1R, OX2R). Metabolism is primarily through the cyto- Animal studies showed that impairment chrome P450 (CYP) 3A4 pathway, and to a in orexin system activity was associated lesser extent through CYP3A5. Concomitant Clinical Point with symptoms characteristic of narcolepsy, use with moderate or strong CYP3A inhibi- Modulating orexin including cataplexy and excessive sleep epi- tors or inducers should be avoided, while sodes. Soon after, it was found that humans use with weak CYP3A inhibitors should be activity with a diagnosed with narcolepsy with cataplexy limited to the 5-mg dose of lemborexant. receptor antagonist had markedly low CSF orexin levels.6 This Lemborexant has the potential to induce might reduce the recognition that excessively sleepy people the metabolism of CYP2B6 substrates, such excessive arousal with narcolepsy had a profound decrease in as bupropion and methadone, possibly lead- orexin production led to the hypothesis that ing to reduced efficacy for these medica- associated with pharmacologically decreasing orexin activ- tions. Accordingly, the clinical responses to insomnia ity might be sleep-enhancing for insomnia any CYP2B6 substrates should be monitored patients, who presumably are excessively and dosage adjustments considered. aroused. Numerous compounds soon Concomitant use of lemborexant with were evaluated for their potential as orexin alcohol should be avoided because there receptor antagonists. The efficacy of treat- may be increased impairment in postural ing insomnia with a dual orexin receptor stability and memory, in part due to increases antagonist in humans was first reported in the medication’s Cmax and AUC, as well as in 2007 with almorexant, a compound that the direct effects of alcohol. remains investigational.7 Research con- tinues to investigate both single and dual Efficacy orexin antagonist molecules for insomnia In randomized, placebo-controlled trials, and other potential indications. lemborexant demonstrated both objective and subjective evidence of clinically sig- How it works nificant benefits for sleep onset and sleep Unlike most hypnotics, which have wide- maintenance in patients diagnosed with spread CNS depressant effects, lemborex- insomnia disorder.1 The 2 pivotal efficacy ant has a more targeted action in promoting studies were: sleep by suppressing the wake drive sup- • Sunrise 1, a 4-week trial with older ported by the orexin system.8 Lemborexant adults that included laboratory polysom- is highly selective for the OX1R and OX2R nography (PSG) studies (objective) and Discuss this article at orexin receptors, where it functions as a patient-reported sleep measures (subjec- www.facebook.com/ competitive antagonist. It is hypothesized tive) on selected nights9 MDedgePsychiatry that by modulating orexin activity with a • Sunrise 2, a 6-month trial assessing receptor antagonist, excessive arousal asso- patient-reported sleep characteristics in ciated with insomnia can be reduced, thus adults and older adults.10 improving nighttime sleep. The pharma- Sunrise 1 was performed with older cokinetic properties allow benefits for both adults with insomnia who were randomized Current Psychiatry 44 November 2020 sleep onset and maintenance. to groups with nightly use of lemborexant, Out of the Pipeline Table 2 Sunrise 1 study PSG-measured sleep onset and sleep maintenance efficacy by treatment group in patients with insomnia disorder Measure Treatment group Baseline meana (SD) Night 29/30 LS meana (SE) Latency to Placebo 33.6 (25.9) 20.0 (1.1) persistent sleep Lemborexant, 5 mgb 33.0 (27.2) 15.5 (0.8) (minutes) Lemborexant, 10 mgb 33.3 (27.2) 14.5 (0.7) Sleep efficiency Placebo 68.9 (9.6) 74.6 (0.6) (%) Lemborexant, 5 mgb 68.4 (11.3) 80.7 (0.5) Lemborexant, 10 mgb 67.8 (10.8) 82.7 (0.5) Wake after sleep Placebo 111.7 (37.2) 92.2 (2.5) onset Lemborexant, 5 mgb 113.4 (39.0) 68.3 (2.2) Clinical Point (minutes) Lemborexant, 10 mgb 114.8 (40.0) 66.9 (2.2) Concomitant use of aLatency to persistent sleep mean refers to geometric mean; SD for geometric mean calculated as GM*SD (log transformed LPS); SE least squares geometric mean calculated the same way as SD lemborexant with bDoses statistically significantly superior (P < .05) to placebo after multiplicity adjustment GM: geometric mean; LPS: latency to persistent sleep; LS: least squares; PSG: polysomnography; SD: standard deviation; moderate or strong SE: standard error Source: References 1,9 CYP3A inhibitors or inducers should be avoided 5 mg (n = 266), lemborexant, 10 mg (n = 269), efficiency (percent time asleep during the zolpidem extended-release, 6.25 mg, as an 8-hour laboratory recording period) and active comparator (n = 263), or placebo objective wake after sleep onset (WASO) (n = 208).9 The age range was 55 to 88 compared with placebo, and WASO dur- years with a median age of 63 years. ing the second half of the night (WASO2H) Most patients (86.4%) were women. compared with zolpidem. Patients com- Because this study focused on the assess- pleted Insomnia Severity Index (ISI) ques- ment of efficacy for treating sleep main- tionnaires at baseline and the end of the tenance difficulty, the inclusion criteria treatment to compare disease severity. required a subjective report of experi- Subjective assessments were done daily encing a wake time after sleep onset with electronic diary entries that included (sWASO) of at least 60 minutes for 3 or sleep onset latency (sSOL), sWASO, and more nights per week over the previous subjective sleep efficiency. 4 weeks. The zolpidem extended-release In comparison with placebo, both lem- 6.25 mg comparison was chosen because borexant doses were associated with sig- it has an indication for sleep maintenance nificantly improved PSG measures of LPS, insomnia with this recommended dose for WASO, and sleep efficiency during nights older adults. 1 and 2 that were