One of the pivotal trials underpinning the FDA’s approval of lemborexant (Dayvigo) earlier this week for adult insomnia has now been published, confirming its benefits over both placebo and extended-release zolpidem (Ambien CR).
The new drug, a dual orexin receptor antagonist, met its primary endpoint in the short-term SUNRISE 1 trial in adults over age 55 by besting placebo in latency to persistent sleep, reported Margaret Moline, PhD, executive director of drugmaker Eisai’s neurology business group in Woodcliff Lake, New Jersey, and colleagues in JAMA Network Open.
Sleep latency was also cut markedly relative to zolpidem in the phase III study, and the new drug was moderately more effective in reducing wake times after sleep onset.
“Most patients in this study who took lemborexant fell asleep in under 20 minutes, which is the amount of time it typically takes people without insomnia to fall asleep,” Moline said. “Importantly, lemborexant was effective both at the start of treatment and after one month of treatment.”
The reduction in time spent awake among patients using lemborexant was mostly in the second half of the night, “a common time when people with sleep maintenance complaints experience difficulty staying asleep,” she told MedPage Today.
Lemborexant inhibits orexin signaling by binding to orexin receptors 1 and 2, dampening orexin activity and affecting sleep/wake function. The drug was approved by the FDA based on research that included two pivotal trials: SUNRISE 1, which tested 5- and 10-mg doses against zolpidem and placebo for 1 month in older adults, and SUNRISE 2, which studied the drug against placebo for 6 months.
Nearly all other drugs indicated for insomnia disorder are γ-aminobutyric acid agonists and most are associated with significant risks in older adults, observed Michael Grandner, PhD, MTR, of the University of Arizona in Tucson, and Michael Perlis, PhD, of the University of Pennsylvania in Philadelphia, in an accompanying editorial. Because of this, other medications tend to be prescribed for older adults who have insomnia, including “on-label approaches (e.g., melatonin agonists, such as ramelteon) and off-label approaches (e.g., sedating antidepressants, such as trazodone),” they noted.
Dual orexin receptor antagonists hold “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,” Grandner and Perlis wrote. Given their potential, it’s especially important the new agents be studied in older adults and compared with standard treatments, especially with benzodiazepine receptor agonists, they added.
SUNRISE 1 evaluated lemborexant against extended-release zolpidem and placebo in 1,006 adults 55 and older who had insomnia disorder with sleep maintenance difficulties confirmed by sleep history, sleep diary, and polysomnography. For 1 month at bedtime, 208 participants received placebo, 263 received zolpidem tartrate extended release 6.25 mg, 266 received lemborexant 5 mg, and 269 received lemborexant 10 mg. Most patients (86.4%) were women and the median age was 63.
Polysomnograms were collected at baseline, and on the first two nights and last two nights of treatment. The primary end point was the change from baseline in latency to persistent sleep for lemborexant compared with placebo. Secondary end points included wake-after-sleep onset compared with placebo, and wake-after-sleep onset in the second half of the night compared with zolpidem.
On nights 1 and 2, patients in the placebo group had a decrease in sleep latency of 6.5 minutes from baseline; patients treated with zolpidem had a decrease of 12.6 minutes, while patients treated with lemborexant had decreases of 16.6 minutes for the 5-mg dose and 19.5 minutes for the 10-mg dose. On nights 29 and 30, decreases from baseline were 7.9 minutes for placebo, 7.5 minutes for zolpidem, 19.5 minutes for lemborexant 5 mg, and 21.5 minutes for lemborexant 10 mg.
Overall wake-after-sleep-onset on nights 1 and 2 was reduced from baseline by 15.1 minutes for placebo, 44.4 minutes for zolpidem, 50.0 minutes for lemborexant 5 mg, and 59.6 minutes for lemborexant 10 mg. On nights 29 and 30, reductions from baseline were 18.6 minutes for placebo, 36.5 minutes for zolpidem, 43.9 minutes for lemborexant 5 mg, and 46.4 minutes for lemborexant 10 mg.
Wake-after-sleep-onset in the second half of the night was reduced on nights 1 and 2 from baseline by 7.1 minutes for placebo, 24.6 minutes for zolpidem, 30.3 minutes for lemborexant 5 mg, and 37.1 minutes for lemborexant 10 mg. On nights 29 and 30, reductions from baseline were 8.9 minutes for placebo, 21.4 minutes for zolpidem, 27.2 minutes for lemborexant 5 mg, and 28.8 minutes for lemborexant 10 mg.
Subjective data using the Insomnia Severity Index showed the three treatment groups differed significantly from placebo, but not from each other. “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,” the editorialists noted. “Absent these data, one cannot know how the variables that represent the patients’ presenting concerns were affected.”
The incidence of treatment-emergent adverse events was similar among groups, and non-serious events were mostly mild or moderate. A total of six participants (four in the zolpidem group and two in the lemborexant 5 mg group) reported eight serious events, but none were considered to be treatment related. All adverse events were transient and resolved completely, the researchers reported.
The study has several limitations, they added: the study looked only at people 55 and older and only for 1 month, and participants were required to have sleep maintenance insomnia.