The Burden of Insomnia
Insomnia is a highly prevalent and debilitating disorder associated with significant functional impairment. A Singapore study conducted by Yeo et al in 1996 places sleep disorder estimates among Singaporeans at 15.3%, a number matched globally across industrialised countries with prevalence rates ranging between 10-50%.
The diagnosis of insomnia is broadly defined by sleep disturbances for at least three nights per week, with consequent daytime impairment arising from sleep difficulty. Chronic insomnia in particular has been shown to be associated with substantial societal costs that result from reduced work productivity, daytime dysfunction and poor health-related quality of life (HR QoL).
Insomnia is both a symptom and a disorder in itself, and warrants a detailed evaluation to ensure the right treatment strategy. Pharmacotherapy can be considered if first-line cognitive behaviour therapy remains ineffectual and must be individualised based on factors such as age, comorbidity, symptom pattern, adverse events, cost and patient preference.
A New Chemical Entity: Dual Orexin Receptor Antagonist
Medications with regulatory approval for insomnia treatment span multiple classes, tapping on a broad range of neurotransmitter and hormonal targets that regulate the sleep-wake cycle. Notwithstanding, the pharmacotherapy landscape for chronic insomnia remains relatively devoid of safe and effective long-term drug therapies.
The newest local entrant, oral lemborexant (Dayvigo), received approval by the Health Sciences Authority (HSA) of Singapore, in September 2021 for the treatment of adult patients with insomnia characterised by difficulties with sleep onset and/or sleep maintenance.
Lemborexant is a dual orexin receptor antagonist that inhibits orexin signalling by selectively binding to orexin receptor 1 (hypothesised to suppress rapid eye movement (REM) sleep) and orexin receptor 2 (thought to suppress non-REM and REM sleep). Orexin, which is produced in the hypothalamus, is a neuropeptide that plays a pivotal role in maintaining wakefulness. Unlike most hypnotics, which have widespread central nervous system (CNS) depressant effects, lemborexant has a more targeted action in promoting sleep by suppressing the wake drive.
Evidence of use
HSA’s approval was based on findings from the SUNRISE clinical development program that comprised two key Phase III studies. Notably, the studies evaluated outcomes using different monitoring and measurement modality settings. Significant subjective and objective improvements in the primary outcome of sleep onset latency was observed in both trials throughout the respective study periods.
- SUNRISE 1 utilised gold-standard polysomnograms to quantify sleep time in the laboratory setting over a 1-month period. Lemborexant was able to demonstrate significant improvements in sleep onset and sleep maintenance compared to placebo and zolpidem tartrate extended release (ER).
- SUNRISE 2 assessed subjective efficacy outcomes via patient-reported sleep diaries, subsequently providing long-term evidence for lemborexant’s sustained subjective efficacy over a 12-month period in the home environment.
- Treatment related adverse events were generally mild across both studies with somnolence being the most prominent adverse effect. Encouragingly, the drug was associated with reduced postural instability compared to Zolpidem suggesting comparatively minor CNS impairment.
Clinical Applications
There is encouraging support for lemborexant’s utility as a potential long-term treatment option for insomnia disorder, conferring improvements in sleep onset and sleep maintenance. The drug also appears to be well tolerated and circumvents adverse effects associated with traditional hypnotics like benzodiazepines.
Its benefit however, must be contextualised to the patient populations included in the SUNRISE development program. Notably, the SUNRISE trials recruited generally older adults of predominantly White ethnicity.
In addition, while the Phase III trials allowed for psychiatric diagnoses, they excluded people with higher scores on anxiety and depression scales. Individuals with evidence of clinically significant disease such as renal impairment, cardiac disease or respiratory disorders etc., that were deemed by the investigator to be unsafe for drug use were also excluded from the trials.
With knowledge that the prevalence of insomnia is considerably higher in patients with chronic medical disorders and co-morbid psychiatric disorders (approximately 40% of all insomnia cases), caution must be exercised with extrapolating lemborexant’s utility as a sleep aid for people with co-morbid psychiatric or severe chronic disorders.
A summary of the SUNRISE clinical trial program is detailed below.
| Study (Population) | Inclusion/ Exclusion Criteria | Study Design | Outcomes |
| SUNRISE 1
Randomised, double-blind, parallel-group, placebo-controlled Conducted at 67 sites in North America and Europe between 2016 – 2018 N=1,006 participants 869 (86.4%) female with a median age of 63y, predominantly white (72.3%) with only 0.2% Chinese and 1.0% of other Asian descent representation. Baseline demographics across all 4 treatment arms were balanced and insomnia severity was considered moderate based on the baseline Insomnia Severity Index (ISI) score (mean 19.1 S.D. 3.5) |
Inclusion
Women >55yo and Men >65yo with insomnia as defined by DSM-5 and an ISI score of 13 or greater. Exclusion Current diagnosis of sleep-related breathing disorder e.g. OSA, restless leg syndrome, narcolepsy. Patients with high depression (Beck Depression Inventory – II >19) or anxiety (Beck Anxiety Index >15) scores at screening were also excluded. Please refer to the study protocol for the full list. |
Patients were randomised in a 5:5:5:4 ratio to receive placebo (n=208), zolpidem tartrate ER 6.25mg (n=263) or lemborexant 5mg (n=266) / 10mg (n=269) for 1 month at bedtime
Paired polysomnograms were collected at baseline, the first 2 nights and the last 2 nights of treatment To Note: At the end of 1 month ISI scores significantly improved in all active arms compared to placebo. Comparisons with Zolpidem therapy were also not significantly different for either dose of lemborexant. There was no evidence of rebound insomnia in the 2 weeks after the study period with either lemborexant or zolpidem therapy. |
Efficacy
Primary endpoint – change from baseline in log-transformed latency to persistent sleep (LPS): Both doses of lemborexant demonstrated statistically significant changes from baseline compared with placebo. Treatment ratio at 1 month:
Secondary endpoints
Safety AEs were mostly mild or moderate in severity. 6 participants (4 in zolpidem group and 2 in the lemborexant 5mg group) reported serious AEs and none were treatment-related. Sleep paralysis was reported by 1 participant receiving lemborexant 5mg and 3 participants receiving lemborexant 10mg. |
| SUNRISE 2
Randomised, double-blind, parallel group with a 6-month placebo-controlled period followed by a 6-month active-treatment only period. Conducted at 119 sites globally, including America, Europe, Asia and Oceania between Nov 2016 – Jan 2019. N=949, mean age 54.5yo (72.4% were aged less than 65), 68.2% female, predominantly white (71.5%) and 17% Japanese. Mean ISI score was 19.2 (S.D. 3.2) |
Inclusion
Adults >/= 18y of age with insomnia disorder meeting the DSM-5 criteria and an ISI score of at least 15. Exclusion Co-morbid sleep disorders e.g. sleep apnea, restless legs syndrome or narcolepsy. Individuals with a diagnosis of major medical or psychiatric disorder that was not adequately treated (investigator opinion), BDI-II > 19, BAI > 15, excessive caffeine consumption and drug or alcohol dependency Please refer to the study protocol for the full list. |
Patients were randomised in a 1:1:1 manner to receive placebo (n=318), 5mg lemborexant (n=316) or 10mg lemborexant (n=315). For the first 6-months. In the second 6-months, participants in the placebo group were randomised 1:1 to 5mg lemborexant or 10mg lemborexant. Participants on active drug in the first 6-months continued on their originally assigned doses.
Within 1h of waking, participants were instructed to complete the electronic sleep diary. Sleep onset and maintenance endpoints were analysed using data from these sleep diaries. |
Efficacy
Primary endpoint – Subjective sleep onset latency (sSOL) i.e. estimated time (mins) from attempt to sleep until sleep onset: Both doses of lemborexant (5mg, -21.8min; 10mg, -28.2min vs placebo, 11.4min) demonstrated statistically significant decreases from baseline compared with placebo (p<0.0001 for both comparisons). Significant reductions were observed from the 1st week through to the 6 and 12 month mark. Secondary endpoints
Safety 24.8% and 29% of participants receiving lemborexant 5mg and 10mg respectively experienced at least 1 treatment emergent adverse event (TEAE) with 4.1% and 8.3% discontinuing the drug as a result. The most common TEAE leading to discontinuation was somnolence. The most common TEAE was headache and influenza (>5%). |
