Lemborexant (Dayvigo, Eisai) emerged superior to placebo and to a commonly prescribed medication, zolpidem tartrate extended release (Ambien CR, sanofi-aventis), in a phase 3 randomized clinical trial of older adults with insomnia.
Four days before release of these results, the US Food and Drug Administration approved lemborexant for treatment of insomnia characterized by difficulties with sleep onset or sleep maintenance, as previously reported by Medscape Medical News.
People randomly assigned to one of two doses of lemborexant, for example, fell asleep faster — and maintained sleep longer — compared with others assigned to placebo or zolpidem.
"Older adults tend to have more difficulty maintaining sleep, so Dayvigo could be considered as a possible treatment in this population," lead study author Russell Rosenberg, PhD, of NeuroTrials Research in Atlanta, Georgia, told Medscape Medical News.
The study was published online December 27 in JAMA Network Open.
Asleep in Under 20 Minutes
Lemborexant is an orexin/hypocretin receptor antagonist. The drug promotes sleep by inhibiting signaling from orexin, a neuropeptide in the brain that promotes wakefulness.
The Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older with Insomnia Disorder (SUNRISE I) is the first phase 3 trial to compare a dual orexin receptor antagonist with an active comparator sedative-hypnotic using both subjective sleep diary and objective polysomnography measures.
Decreases in sleep-onset latency with lemborexant "were notable, as most participants fell asleep in less than 20 minutes, which is typical for those without insomnia," the researchers note. "Participants receiving lemborexant therapy also gained more than 60 minutes of sleep per night than they had before treatment."
When first-line cognitive behavioral therapy does not adequately address insomnia in older adults, pharmacologic treatment is often considered next. The authors note, however, that "many treatment options do not adequately address both sleep initiation and maintenance symptoms…[and] adverse effects from these medications may be associated with falls, hip fractures, and risk of unintentional injury."
Rosenberg and colleagues studied 1006 adults age 55 years or older. They randomly assigned 266 people to lemborexant 5 mg, 269 to lemborexant 10 mg, 263 to 6.25 mg zolpidem extended release, and another 208 to placebo. They enrolled participants at 67 sites in the United States and Europe from May 2016 to January 2018.
Median age was 63 years (range, 55 to 88 years). The study population was 86% women, 72% white, and 25% black.
Participants reported a history of subjective wake-after-sleep onset (WASO) of at least 60 minutes, at least 3 nights per week in the previous 4 weeks, and evidence of issues with sleep maintenance. They also had a score of 13 or more on the Insomnia Severity Index, where 0 represents no insomnia and 28 reflects severe clinical insomnia.
Snoozing Sooner
Rosenberg and colleagues showed that lemborexant 5 mg or 10 mg was superior to placebo for sleep onset measured on nights 29 and 30 using polysomnography. Compared to baseline, the primary outcome of time to fall asleep, also known as the mean "log-transformed latency to persistent sleep (LPS)," was statistically shorter in the lemborexant 5 mg group compared with placebo (0.85; 95% confidence interval [CI], 0.75 - 0.96; P = .009).
The LPS likewise was shorter for the lemborexant 10 mg group vs placebo (0.80; 95% CI, 0.70 - 0.90; P < .001).
Participants in the two lemborexant groups also compared favorably with those treated with zolpidem on this outcome, including a significant difference with the 10 mg lemborexant group (P < .001).
The efficacy of lemborexant for decreasing LPS was maintained at the follow-up assessment.
The secondary endpoint of sleep efficiency was defined as proportion of time spent asleep compared with total time in bed with lights off. Again, both doses of lemborexant emerged superior to placebo or zolpidem compared with baseline on nights 1, 2, 29, and 30 of the study.
Other secondary outcomes, including minutes of wake from LPS until lights on and WASO in the second half of the night, also favored lemborexant.
The subjective reports of sleep onset time and maintenance of sleep using the sleep diaries further supported the efficacy of lemborexant compared with placebo and the active comparator.
Furthermore, total and daily functioning scores on the Insomnia Severity Index significantly improved in both lemborexant groups after 1 month of treatment vs placebo. Differences on these scores, however, were not statistically significant between lemborexant and zolpidem groups.
The investigators also assessed safety over 12 months. "The findings indicated somnolence and nightmares were the only adverse events that occurred in 5% or more of subjects and at a rate twice that of placebo," Rosenberg said.
He described insomnia as a highly prevalent disorder, especially in older adults. "It can have a profound, long-term impact on health and quality of life, so all healthcare providers should inquire about sleep difficulties in their patients."
"Many questions remain with regards to insomnia disorder and optimal treatments," Rosenberg said. "This is obviously good news for those of us sleep scientists that want answers to improve outcomes."
SUNRISE I and other trials of lemborexant did not focus on special populations, such as people with comorbid cardiovascular disease, psychiatric illness, or neurocognitive disorders. "It would be extremely useful to demonstrate that Dayvigo is safe and effective in these populations."
A separate study, SUNRISE II, was a 12-month, phase 3 trial that compared lemborexant with placebo using sleep diaries.
Future research could assess if orexin antagonism could treat insomnia related to circadian rhythm sleep disorders. For example, this agent is already being investigated in Alzheimer's disease. A phase 2 study showed lemborexant was beneficial in Alzheimer's patients with irregular sleep-wake rhythm disorder.
"Promise and Potential"
"This new class of dual orexin receptor antagonists holds the promise of greater efficacy, as the target mechanism may more directly address the issue of the failure to inhibit wakefulness, and the potential for reduced adverse effects, especially in the domain of cognition, memory, and psychomotor behavior," Michael A. Grandner, PhD, MTR, and Michael L. Perlis, PhD, note in an accompanying editorial.
"Given the promise and potential of dual orexin receptor antagonists," they write, "it is especially important that these compounds be specifically evaluated in older adults in a manner that allows for the assessment of the efficacy and safety of this new therapeutic modality compared with standard treatments, especially with benzodiazepine receptor agonists. The study by Rosenberg and colleagues does precisely this."
"Of note, if not concern, is that sleep diary values for sleep latency and wake-after-sleep onset were assessed and reported to be statistically improved, but the specific values were not reported," they add. "Absent these data, one cannot know how the variables that represent the patients’ presenting concerns were affected."
The study showed that improvements in objective sleep continuity "were larger with lemborexant, particularly for the second half of the night, and both medications positively affected daytime function," Grandner and Perlis write. However, "neither medication was superior with respect to safety or subjective outcomes as measured with the Insomnia Severity Index."
Grandner is affiliated with the Sleep and Health Research Program, Department of Psychiatry, University of Arizona College of Medicine in Tucson. Perlis is with the Behavioral Sleep Medicine Program, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania in Philadelphia.
