Dr Lynn KramerLynn Kramer, MD
The results of a phase 1 safety study (Study 106) recently published in SLEEP determined when evaluating the impact of bedtime administration of lemborexant (Eisai, Purdue Pharma), a therapy under investigation for treatment of insomnia, there were no statistically significant or clinically relevant effects on next-morning driving performance in adult and elderly healthy volunteers compared to placebo (primary endpoint).

Study 106 which evaluated the next-morning effects of lemborexant 2.5 mg, 5 mg, and 10 mg doses compared to placebo, was designed to evaluate the effect of lemborexant on driving performance after single and repeated bedtime use in healthy adult and elderly volunteers 23 to 78 years of age (n=48).

“Our aspiration is to address unmet needs for patients suffering from insomnia so that they can fall asleep, stay asleep and wake without impairment,” Lynn Kramer, MD, chief clinical officer and chief medical officer, Neurology Business Group, Eisai, said in a statement.1 “Results from our phase 1 safety study suggest no significant driving impairment with lemborexant, bolstering our confidence in this investigational agent being studied for the treatment of insomnia.”

The randomized, double-blind, placebo-and active-controlled, 4-period incomplete crossover design study, selected zopiclone 7.5 mg as the active control to demonstrate assay sensitivity versus placebo. Each treatment period lasted for 8 days, and residual effects were assessed in the morning of days 2 and 9. Participants age 65 and older (n=24) and 23 to 64 years of age (n=24) were treated at bedtime for 8 consecutive nights with 2 out of 3 dose levels of lemborexant, zopiclone 7.5 mg as an active control on the first and last night only with placebo given on intervening nights, or placebo. Randomized to 1 of 12 treatment sequences was arranged by age in a 1:1 ratio and balanced for sex so that there were no fewer than 10 males or females per age group. Washout intervals were at least 14 days between treatment periods.  

Investigators assessed driving performance by standard deviation of lateral position (SDLP) during 1-hour on-road driving tests conducted in mornings on Day 2 and Day 9—approximately 9 hours post-dose of lemborexant. During the on-road test, participants drove a specifically instrumented vehicle for approximately 61 miles over a primary highway circuit accompanied by a licensed driving instructor. Participants were tasked with driving a steady lateral position between the delineated boundaries of the slower traffic lane, all while maintaining a constant speed of 58 mph. During the drive, the vehicle’s speed and lateral position to the left lane line are constantly recorded via a camera positioned on top of the car.

Lemborexant showed no clinically meaningful or statistically significant impairment of driving performance after single (the morning of Day 2) or multiple (the morning of Day 9) dose administration at all doses compared to placebo while zopiclone 7.5 significantly increased the mean SDLP compared to placebo.

The mean drug-placebo differences in the SDLP following Day 2 and Day 9 were 0.74 cm or less. The 95% Confidence Interval of these changes all included 0, and the upper limits were below the threshold of 2.4 cm for impairment, which indicated that none of the changes were statistically significant or clinically meaningful.

The plasma concentrations of lemborexant after driving were roughly dose-proportional across the dose range, following single and repeated administrations. After a single dose, there was no relationship between plasma concentrations and drug-placebo changes in driving performance, however, after repeated dosing, a weak but statistically significant relationship was observed and higher concentrations of lemborexant were associated with small increases in SDLP that were not clinically relevant. The results align with previous studies.

Researchers reported that no drives were stopped before completion because of drowsiness after use of lemborexant or placebo, however, 3.1% of drives (3 out of 96) after use of zopiclone were stopped early. All study participants completed all treatments.

Adverse effects were mild to moderate in severity; the most commonly reported adverse effects for lemborexant across all doses were somnolence, headache, and dry mouth. After zopiclone, somnolence, dysgeusia, and dizziness. Overall, females reported adverse effects more frequently than males (37 vs. 28), and adults reported adverse effects more frequently than elderly (36 vs. 29).

Investigators concluded that about 9 hours after lemborexant administration at bedtime the previous night, there was no statistically significant or clinically meaningful effect on driving performance in healthy adults and elderly.

Eisai has recently submitted a new drug application (NDA) to the FDA for lemborexant for the treatment of insomnia. The NDA is backed by results of 2 phase 3 clinical trials, SUNRISE 1 (Study 304) and SUNRISE 2 (Study 303), in addition to important safety studies like the assessment of postural stability after awakening in the middle of the night and the next-morning driving study.
REFERENCE
1. On-Road Driving Safety Study of Investigational Lemborexant Published in SLEEP® [news release]. Tokyo and Stamford, Conn.: Eisai Co., Ltd, and Purdue Pharma; Jan. 22, 2019. https://www.purduepharma.com/news-media/2019/01/on-road-driving-safety-study-ofinvestigational-lemborexant-published-in-sleep/?rel=0" ?rel=0" . Accessed Jan. 22, 2019.

2. Vermeern A, Jongen S, Murphy P, et al. On-the-road driving performance the morning after bedtime administration of lemborexant in healthy adult and elderly volunteers. SLEEP. 2018;1–9. doi: 10.1093/sleep/zsy260.