Highlights

Dayvigo (lemborexant) is a new drug indicated for the treatment of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance.

Dayvigo, developed by Japan’s Eisai, was approved by the U.S. Food and Drug Administration (FDA) in late December 2019.

Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) granted marketing authorization for Dayvigo in late January 2020.

In early February 2021, Dayvigo was approved in Canada.

Dayvigo (lemborexant).

 

Insomnia: Some Essential Points

According to the International Classification of Sleep Disorders (ICSD), sleep disorders include sleep-related breathing disorders, central disorders of hypersomnolence, circadian rhythm sleep-wake disorders, parasomnias, sleep-related movement disorders, and others. Among such disorders insomnia (sleeplessness) is the most common: approximately one third of the adult population suffers from its intermittent form.

Insomnia is accompanied by difficulty falling asleep, sleep maintenance problems, and poor sleep quality, leading to daytime consequences in the form of fatigue or malaise, poor attention, mood disturbance or irritability. Proper sleep quality sleep is critical to maintaining a healthy body. Otherwise the risks of hypertension, accidental injury, diabetes, obesity, depression, heart attack, stroke, dementia, and adverse changes in mood and behavior increase.

Insomnia therapy involves a multicomponent approach including sleep hygiene, lifestyle changes, avoidance of stimulants like caffeine and alcohol, regular physical activity, cognitive behavioral interventions, and additional and sometimes controversial techniques like bright light therapy, acupuncture and acupressure, moxibustion, musical relaxation, and aromatherapy.

When it comes to pharmacotherapy for insomnia, there are many medications suggested: benzodiazepine sleeping pills of the short and intermediate duration of action (nitrazepam, temazepam, lorazepam, estazolam, triazolam, flurazepam, quazepam), non-benzodiazepine sedative-hypnotics (zolpidem, zaleplon, eszopiclone, zopiclone), melatonin receptor agonists (ramelteon), sedative antidepressants (doxepin, trazodone, paroxetine, amitriptyline, mirtazapine). Nevertheless, there remains a medical need for new sleeping pills that are effective and have minimal adverse reactions.

 

Dayvigo: Efficacy of Lemborexant in Treating Insomnia

The regulatory verdict was guided by the results of a clinical program that included SUNRISE 2 (NCT02952820) and SUNRISE 1 (NCT02783729) phase 3 pivotal clinical trials (randomized, double-blind, multicenter, international) which evaluated the safety and efficacy of lemborexant in the therapy of insomnia compared with placebo among persons 18 years and older (n=900) and zolpidem among persons 55 years and older (n=1006), respectively.

Subjects were administered an experimental lemborexant at a dose of 5 or 10 mg immediately before they intended to fall asleep.

Among the trials inclusion criteria: dissatisfaction with nighttime sleep due to difficulty getting to sleep, staying asleep, and/or waking up, with such problems lasting at least three months, and participants had to experience such problems at least three times a week.

The clinical outcomes of SUNRISE 2 after 6 months of therapy are as follows:

  • The mean change in logarithmically transformed subjective sleep onset latency (sSOL), reported by the patient and defined as estimated minutes from the time that the participant attempted to sleep until sleep onset. The groups receiving 5 or 10 mg of lemborexant demonstrated a more than halving of sSOL, from baseline 43.0 and 45.0 minutes to 20.0 and 19.2 minutes — versus a decrease from 45.0 to 27.3 minutes in the placebo group.
  • The mean change in subjective sleep efficiency (sSEF), reported by the patient and defined as the proportion of time spent asleep per time in bed. Lamborexant provided an increase from baseline 63.1% and 62.0% to 75.9% and 75.9% — vs. an increase from 61.3% to 71.4% in the control group.
  • The mean change in the subjective wake after sleep onset (sWASO), reported by the patient and defined as sum of estimated minutes of wake during the night after initial sleep onset until the time the participant stopped trying to sleep for the night, operationalized as the time the participant got out of bed for the day. This score representing the fragmentation of sleep is relevant to the facts of sudden awakening at night in insomnia. Use of the lemborexant changed sWASO from baseline 132.8 and 136.8 minutes to 87.9 and 92.7 minutes — vs. a change from 132.5 to 105.3 minutes in the placebo group.
dayvigo efficacy 01 - Dayvigo: New Japanese Drug for Insomnia

The clinical outcomes of SUNRISE 1 after 1 month of therapy are as follows:

  • The mean change in logarithmically transformed latency to persistent sleep (LPS) as assessed by overnight polysomnography (PSG) monitoring and defined by the number of minutes from lights off to the first 10 consecutive minutes of non-wakefulness. The groups receiving 5 or 10 mg of lemborexant demonstrated a more than halving of LPS, from baseline 33.0 and 33.3 minutes to 15.5 and 14.5 minutes — versus a reduction in LPS from 33.6 to 20.0 minutes in the zolpidem group.
  • The SEF score assessed by PSG increased from baseline 68.4% and 67.8% to 80.7% and 82.7% — vs. an increase from 68.9% to 74.6% in the control group.
  • The WASO score assessed by PSG changed from baseline 113.4 and 114.8 minutes to 68.3 and 66.9 minutes — vs. a change from 111.7 to 92.2 minutes in the zolpidem group.
dayvigo efficacy 02 - Dayvigo: New Japanese Drug for Insomnia

 

Dayvigo: Safety of Lemborexant in Treating Insomnia

Insomnia therapy with Dayvigo was accompanied by the following most common adverse effects noted in the first 30 days of the first and second clinical trials: somnolence, lethargy, fatigue, or sluggishness (6.9% and 9.6% of patients in the 5- and 10-mg groups of the drug), headache (5.9% and 4.5%), nightmare or abnormal dreams (0.9% and 2.2%).

Several specialized tests were performed to clarify the safety profile of the lemborexant:

  • Dayvigo resulted in postural instability (impaired balance) and impaired attention and memory, assessed in the middle of the night, but did not affect the ability to wake up to a loud sound.
  • Dayvigo showed no adverse effects with respect to postural stability (balance retention) and memory scores the day after administration.
  • And although the use of Dayvigo did not affect driving ability the morning after the drug, some patients who received the 10-mg dose experienced the above.
  • Discontinuation of Dayvigo did not result in either rebound insomnia or withdrawal syndrome.
Dayvigo (lemborexant).

 

Dayvigo: Mechanism of Action of Lemborexant

Lemborexant (E2006) is an oral low-molecular-weight competitive dual orexin receptor antagonist (DORA), OX1R and OX2R.

The orexin neuropeptide signaling system is the main mechanism providing the waking state. Orexin-producing nerve cells are located in the hypothalamus and affect the brain neurons responsible for the wakefulness process. Lemborexant triggers the physiological process of brain transition from wakefulness to sleep by reversibly blocking the binding of wake-promoting neuropeptides, orexin A and orexin B, to OX1R and OX2R receptors thereby suppressing the maintenance of wakefulness.

 

Dayvigo: Competitive Landscape

Eisai, according to agreements of August 2015, was developing lemborexant together with Purdue Pharma but in April 2019 the Japanese pharma manufacturer bought all rights to the drug from the latter.

Dayvigo will have to compete directly with Belsomra (suvorexant) for which Merck & Co. received regulatory approval in August 2014 and which was the first DORA.

Dayvigo and Belsomra are lacking the negative side effects that accompany traditional insomnia medications. Thus, benzodiazepine and non-benzodiazepine sleeping pills increase the inhibitory effect of GABA, the main inhibitory neurotransmitter of the brain, especially in the limbic system and cortex, which is reflected in motor coordination disorders, drowsiness and lethargy, slurred speech, dizziness, sudden mood swings, fatigue. Prolonged use, leading to adaptation of GABA receptors, causes addiction and withdrawal syndrome. Lemborexant and suvorexant, which target orexin signaling rather than the entire population of GABAergic neurons in the brain, are much more targeted, resulting in a significantly better safety profile.

Again, in April 2019, the FDA required the inclusion of a boxed warning about the risks of complex sleep behaviors that are traumatic and even fatal when a still not fully awake person begins walking, driving, and engaging in other activities, with no memory of it after waking up, in the medical instructions for non-benzodiazepine sedative-hypnotic drugs (zolpidem, zaleplon, eszopiclone).

It is believed that DORAs promote not only non-rapid eye movement (NREM) but also rapid eye movement (REM), which GABA-mediated molecules do not do.

In general, targeting orexin signaling comes from the concept that insomnia should be perceived as a reflection of hyperactivity and wakefulness inappropriately timed for natural bedtime rather than as a failure of the brain to fall asleep. In other words, instead of drug stimulation of sleep-promoting signaling pathways, it is better to suppress the signaling pathways responsible for wakefulness.

The commercial future of Dayvigo and Belsomra looks promising but we cannot expect rapid growth in sales yet because the common sleeping pills have long since moved into the generic category and therefore are prescribed by the entire population due to their low cost. Thus, Belsomra earned $210 million, $260 million, $306 million, and $327 million in 2017, 2018, 2019, and 2020.

Lamborexant is also being studied in the therapy of irregular sleep-wake rhythm disorder (ISWRD) in mild-to-moderate dementia due to Alzheimer’s disease. Lamborexant has successfully passed the NCT03001557 phase 2 clinical trial and is being prepared for further clinical validation.

Meanwhile, another DORA for the treatment of adult patients with insomnia, daridorexant by Idorsia Pharmaceuticals, is awaiting regulatory approval. Should approval be received, daridorexant anticipates launch in the US in the first half of 2022.

In phase 3 clinical development is seltorexant, selective OX2R antagonist by Minerva Neurosciences and Johnson & Johnson’s Janssen, for the adjunctive treatment of major depressive disorder (MDD) with insomnia symptoms. In January 2021, Minerva sells royalty interest in seltorexant to Royalty Pharma for an upfront payment of $60 million and up to $95 million in additional milestone payments.

 

Extras

Dayvigo (lemborexant). Prescribing information. US. [PDF]

Dayvigo (lemborexant). FDA CDER. Multi-disciplinary review and evaluation. [PDF]

Dayvigo (lemborexant). Prescribing information. Canada. [PDF]

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 Sep 14;43(9):zsaa123. [source]

Efficacy and safety of lemborexant in adults with insomnia: comparing Japanese and non-Japanese subgroups from the global, phase 3, randomized, double-blind, placebo-controlled SUNRISE 2 study. J Clin Sleep Med. 2021 Feb 12. [source]

Long-term effectiveness and safety of lemborexant in adults with insomnia disorder: results from a phase 3 randomized clinical trial. Sleep Med. 2021 Apr;80:333-342. [source]

Comparison of the effect of lemborexant with placebo and zolpidem tartrate extended release on sleep architecture in older adults with insomnia disorder. J Clin Sleep Med. 2021 Feb 16. [source]

Comparison of lemborexant with placebo and zolpidem tartrate extended release for the treatment of older adults with insomnia disorder: a phase 3 randomized clinical trial. JAMA Netw Open. 2019 Dec 2;2(12):e1918254. [source]

Lemborexant and suvorexant for treating insomnia: an indirect comparison using number needed to treat, number needed to harm, and likelihood to be helped or harmed. [PDF]

Effect of lemborexant treatment across 12 months on fatigue severity and sleep outcomes in subjects with clinically significant fatigue at baseline. [PDF]

Long-term efficacy and safety of lemborexant in adults with insomnia disorder over 12 months: results from a phase 3 clinical trial. [PDF]

Impact of lemborexant on patient-reported insomnia-related worry/distress and interference with daily functioning over 6 months: results from SUNRISE-2. [PDF]

Post hoc analysis of the efficacy and safety of lemborexant in adults with insomnia disorder and depression history. [PDF]

Effectiveness and safety of lemborexant in subjects previously treated with placebo for 6 months in SUNRISE-2. [PDF]

Response to treatment with lemborexant: subjects with irregular sleep-wake rhythm disorder and Alzheimer’s disease dementia. [PDF]

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Mark Gubar

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