New Insomnia Drug Appears Safe, Effective in Older Patients

Pauline Anderson

March 07, 2019

ATLANTA — Clinicians may soon have a new option for treating insomnia in older patients, new research suggests.

Subanalyses from the phase 3 SUNRISE-1 trial showed that lemborexant (Eisai Inc), an investigational dual orexin receptor antagonist being developed for the treatment of insomnia and irregular sleep-wake rhythm disorder, was both safe and effective in an older population — and was not different from placebo on postural stability.

The results suggest that this new agent may be a suitable treatment for patients aged 65 years and older with insomnia disorder, the investigators note.

"We showed that the drug was effective on the objective endpoints of the study, which included efficacy in helping patients with sleep onset and with sleep maintenance, and the drug was well tolerated," study author Margaret Moline, PhD, executive director of clinical development of Eisai’s Neurological Business Group, told Medscape Medical News.

The findings were presented here at the American Association for Geriatric Psychiatry (AAGP) 2019 Annual Meeting.

Facilitates Sleep

Lemborexant inhibits orexin signaling by binding competitively to both orexin receptor subtypes (orexin receptor 1 and 2). In individuals with normal daily sleep-wake rhythms, orexin signaling is believed to promote periods of wakefulness; but in those with sleep-wake disorders, orexin signaling may not be functioning normally.

"Blocking the orexin signaling at bedtime is thought to dampen wakefulness so sleep can happen at the appropriate time," said Moline.

Two pivotal phase 3 studies (SUNRISE-1 and SUNRISE-2) investigated lemborexant in patients with a history of subjective wake after sleep onset (WASO) of 60 or more minutes at least three times a week in the previous 4 weeks.

SUNSHINE-1 was a 1-month, multicenter randomized double-blind, placebo-controlled study. It incorporated both objective outcomes using polysomnography sleep studies and subjective outcomes using sleep diaries. It included over 1000 participants with insomnia disorder, defined as an Insomnia Severity Index score of 13 or more.

SUNRISE-2 was a 12-month study that subjectively assessed the ability to fall asleep and stay asleep based on patient self-reports — again using sleep diaries.

Both studies compared lemborexant with a placebo. SUNSHINE-1 also had an active comparator arm (6.25 mg of zolpidem tartrate extended release [ER]). Zolpidem targets a different neurotransmitter system than lemborexant and is a type-A GABA receptor agonist.

"These two drugs are from totally different classes of drugs," said Moline.

The SUNRISE studies showed that sleep onset and sleep maintenance were significantly improved in patients with insomnia disorder treated with lemborexant vs placebo. In both studies, lemborexant was well tolerated.

Focus on Older Adults

The current analysis looked at the efficacy of lemborexant 5 mg and 10 mg in 453 participants from the SUNRISE-1 study, all of whom were 65 years or older.

"It's important to understand how the drug works in different populations, including the elderly," Moline said.

The prevalence of insomnia is higher in older adults, but many sleep medications are not indicated for sleep maintenance insomnia in the elderly. Insomnia is also more common in women, who are 1.4 times more likely than men to have the condition.

The mean age of the 453 participants in this current analysis was 70.2 years and 69.8% were women. About 74.6% were white and the mean body mass index was 26.8.

Sleep onset was based on the polysomnographic parameter latency to persistent sleep (LPS). This is a measure of the time to sleep, defined as the start of the first 10 minutes of sleep that is not interrupted by wakefulness.

Sleep maintenance was assessed using several measures, including overall WASO and WASO in the second half of the night (WASO2H), which is the time when elderly individuals tend to have the most difficulty maintaining sleep.

It was also assessed with sleep efficiency, defined as the total amount of sleep divided by time spent in bed.

Among the subanalysis participants, 93 received a placebo, 120 received zolpidem ER 6.25 mg, 118 received lemborexant 5 mg, and 122 received lemborexant 10 mg.

Researchers collected data for sleep efficiency, LPS, WASO, and WASO2H at baseline and calculated these measures as a mean for nights 1 and 2 (1-2) and for nights 29 and 30 (29-30). A total of 95.6% (433/453) of the participants completed the study.

Less Time to Sleep

Lemborexant appeared to be better at reducing the time to sleep onset. The changes for LPS at the end of the study were:

  • –10.4 minutes for the placebo group,

  • –5.3 minutes for the zolpidem ER group,

  • –17.5 minutes for the lemborexant 5 mg group, and

  • –17.9 minutes for the lemborexant 10 mg group.

For WASO, reductions at the end of the study were: –18.7 minutes for placebo, –31.1 minutes for zolpidem ER, –47.0 minutes for lemborexant 5 mg, and –42.8 minutes for lemborexant 10 mg.

For WASO2H and sleep efficiency, outcomes for both lemborexant doses appeared to be superior to placebo and zolpidem.

The researchers plotted results on a graph that corrected for placebo results, showing changes beyond those seen in placebo.

For sleep onset, reductions in LPS were significantly greater than placebo for both lemborexant doses at nights 1-2 (P < .01 for 5 mg, P < .05 for 10 mg), for lemborexant 10 mg at nights 29-30 (P < .05), and compared with zolpidem at both time points.

As for sleep maintenance, both doses of lemborexant significantly reduced WASO2H compared with zolpidem.

These results in older participants were similar to those observed in the full population of SUNRISE-1.

In addition, both doses of lemborexant were well tolerated. The most common adverse events (AEs) were somnolence and headache. Most AEs were mild or moderate in severity, and no falls were reported.

Postural Stability

A more detailed safety analysis in this subgroup of patients, also presented at the AAGP meeting, showed that zolpidem ER led to significantly more "body sway" in the morning after the first doses compared with lemborexant and placebo, whereas lemborexant was not different from placebo.

"Postural stability is important when you're thinking about the risk of fall," said Moline. "Elderly people are more at risk for falling in general, so we were looking at how well they were able to maintain their balance in the morning."

In the study, postural stability was assessed with a 1-minute test upon waking. The test involves closing one's eyes and trying to keep still.

Body sway was detected through a cable around the patient's waist, with information transmitted to a laptop, Moline noted.

Another drug that targets orexin receptors (suvorexant, Merck & Co) is approved by the US Food and Drug Administration (FDA), but is distinct from lemborexant.

"These two drugs are structurally different, have different affinities for the receptors, and they have different receptor kinetics," said Moline.

Lemborexant is being jointly developed by Eisai Co Ltd and Imbrium Therapeutics. These companies have submitted a new drug application for lemborexant to the FDA.

Not a "Blanket Over The Brain"

Commenting on the study for Medscape Medical News, Robert Breen, MD, geriatric psychiatrist in the Department of Neuropsychiatry and Behavioral Science, University of South Carolina, Columbia, said he's keen to have access to a sleep agent that is safe in the elderly.

The older drug that targets GABA "just throws a blanket over the brain. It doesn't touch a switch," noted Breen, who was not involved with the research. This new agent also appears to not affect stability in older adults.

"If you're practicing geriatric psychiatry, it would be wonderful to have a sleeping pill that is not going to cause people to have difficulty walking or to break their hip," he said.

The research was supported by Eisai Inc and Imbrium Therapeutics LP. However, the investigators report that they retained full independence in the conduct of the research.

American Association for Geriatric Psychiatry (AAGP) 2019: Abstract NR-20, Abstract NR-21. Presented March 3, 2019.

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