Lemborexant Shows Positive Results in Pair of Phase I Studies

Marcelo Bigal, MD, PhD, the Chief Medical Officer at Purdue

Marcelo Bigal, MD, PhD

The results of a duo of key phase I studies that assessed lemborexant revealed results that support the phase III findings of the investigational sleep-wake regulation’s safety and efficacy.

Presented at the 32^nd Annual Meeting of the Associated Professional Sleep Societies (SLEEP 2018), in Baltimore, Maryland, the data have been anticipated by the therapy’s manufacturers, Purdue Pharma and Eisai, since the beginning of the collaboration in 2015, Marcelo Bigal, MD, PhD, the Chief Medical Officer at Purdue, said in May.¹

The drug acts on the orexin neurotransmitter system and is assumed by its manufacturers to regulate sleep and wake by diminishing any excessive arousal or wakefulness without obstructing the ability to awaken to external stimuli. Study 108 and Study 106 assessed safety endpoints related to the risk for falls and the residual next-morning effects, respectively, both of which demonstrated positive results.

In Study 108, the primary endpoint was an assessment of a difference in postural stability—thought to be the best predictor of falls.² The trial compared lemborexant in 2 doses to placebo and an active comparator, 6.25-mg zolpidem ER, in the middle of the night in a group of 56 healthy volunteers. The participants were administered the therapies at bedtime, with investigators assessing body sway after roughly 4 hours in bed.

The mean changes in body sway were -1.1 units for the placebo group, compared to 5.8 units and 8.1 units for the 5-mg and 10-mg lemborexant groups, respectively. Meanwhile, the zolpidem ER group reported a change in body sway of 20.4 units, statistically significant when compared to both lemborexant doses (P <.0001 for both).

“[A] significant unmet need exists for a treatment that can help people awaken in the night or the next morning without this type of impairment,” said Lynn Kramer, MD, the Chief Clinical Officer and Chief Medical Officer of the Neurology Business Group, Eisai, in a statement.³ “If approved, lemborexant, our investigational sleep/wake regulation agent, may have the potential to reduce the risk of postural instability.”

The zolpidem ER group experienced a body sway equivalent to almost 3 times that associated with a 0.05 blood alcohol content (BAC). The 10-mg lemborexant group observed an increase just above the 7-unit clinically meaningful threshold, while the 5-mg group remaining below the limit.

Shortly after approximately 8 hours in bed, neither dose of lemborexant results in statistically significant residual effects compared to placebo. Mean baseline changes at this point were 0.4 units and -0.4 units for the 5-mg and 10-mg doses, respectively (P not significant for both vs. placebo), compared to -2.2 units for placebo and 5.0 units for zolpidem ER (P = .01 for zolpidem vs. placebo).

Study 108’s secondary objective, a measurement of the effects on the auditory awakening threshold (AAT), revealed that neither dose of lemborexant resulted in a significant difference relative to placebo or the active comparator. The treatment differences compared to placebo were 1.7 decibels (dB) for the 5-mg dose, -0.9 dB for the 10-mg dose, and 7.2 dB for zolpidem ER. In total, 8 patients administered the active comparator did not awaken to the 105-dB maximum tone, compared with 4 patients in each of the other groups.

“As the largest study conducted to date evaluating postural stability and auditory awakening threshold in the middle of the night, these data about the effects of lemborexant on measures of balance and responsiveness to external stimuli are encouraging with respect to addressing current unmet needs in the treatment of sleep disorders,” Russell Rosenberg, PhD, DABSM, a principal investigator and former Chairman of the Board of the National Sleep Foundation, noted in a statement.

Additionally, the therapy showed mean treatment differences in sleep latency compared to placebo of -22.5 minutes for the 5-mg dose, -28.7 minutes for the 10-mg dose, and -21.0 minutes for zolpidem ER (P <.0001 for all). The 10-mg lemborexant group experienced a quicker return to sleep compared to zolpidem ER as well (P = .02).

In Study 106, the therapy’s next-morning effects were examined in comparison with placebo, including zopiclone as a positive control. The effects were measured by examining 48 adult and elderly patients’ performances in an on-road driving test, with a primary endpoint of the difference from placebo of the standard deviation of lateral position (SDLP), an index of weaving, the mornings following the first and last doses of therapy in each treatment period.

The 3 doses of lemborexant—2.5 mg, 5 mg, and 10 mg&mdash;showed no significant impairment of driving performance measured by SDLP after single dose administration on day 2 nor after multiple dose administration on day 9, in comparison with placebo. The active comparator, zopiclone 7.5 mg, significantly increased the mean SDLP.

“Sleep medications should not only improve the ability to sleep through the night, but also allow patients to awaken in the middle of the night, if needed, and to function upon awakening,” said Bigal in a statement. “We are pleased to share these study results and are committed to exploring the value of lemborexant in specific unmet needs of patients with sleep disorders.”

Mean SDLP changes in contrast with placebo on day 2 was 0.02 cm for 2.5-mg lemborexant, 0.23 cm for 5-mg lemborexant, 0.73 cm for 10-mg lemborexant, and 2.04 cm for 7.5-mg zopiclone. On day 9, the mean drug-placebo changes in SDLP were 0.48 cm, 0.36 cm, and 0.74 cm for lemborexant 2.5 mg, 5 mg, and 10 mg, respectively. The mean changes for 7.5-mg zopiclone were 1.88 cm. The upper bound of the 95% CI for all 3 lemborexant doses were below 2.4 cm on both days, indicating no clinically meaningful impairment—however, with 7.5-mg zopiclone, the upper bound of the 95% CI exceed 2.4 cm, demonstrating assay sensitivity.

None of the drive were halted prior to completion in the lemborexant treatment groups. Of the 384 total drives, only 0.8% (n = 3) were stopped, all after zopiclone exposure.

Neither study resulted in serious or severe adverse events (AEs) in any group, nor any treatment-related AEs resulting in study withdrawal in Study 106. In Study 108, 2 patients discontinued due to an AE, but lemborexant was only associated with headache in ≥2 subjects. Lemborexant was most commonly associated with somnolence, headache, and dry mouth—most often occurring with the 10-mg dose&mdash;in Study 106.

REFERENCES

1. Eisai and Purdue Pharma to present latest phase I clinical data on lemborexant at 32^nd Annual SLEEP Meeting [press release]. Tokoyo, Japan: Eisai Co., Ltd.; Stamford, Connecticut: Purdue Pharma, LP; May 23, 2018. eisai.com/news/2018/news201838.html. Accessed June 6, 2018.

2. Blaszczyk JW, Michalski A. Ageing and postural stability. Stud Phys Cult Tourism. 2006;13(S):11-14.

3. Positive New Data on Investigational Lemborexant Presented at 32nd Annual SLEEP Meeting [press release]. Tokoyo, Japan: Eisai Co., Ltd.; Stamford, Connecticut: Purdue Pharma, LP; June 6, 2018. eisai.com/news/2018/news201845.html. Accessed June 6, 2018.