Objective:

To discuss interpreting treatment-emergent adverse events of somnolence (TEAE‑S) from 2 large phase 3 studies of lemborexant (LEM), a dual orexin-receptor antagonist approved to treat adults with insomnia.

Background:

Assessment of TEAE-S is important since residual sleepiness can lead to functional impairment. In assessing the effect of TEAE-S, incidence, severity, timing relative to treatment initiation, and impact on morning/daytime function should be considered.

Design/Methods:

Studies E2006-G000-304 (NCT02783729) and E2006-G000-303 (NCT02952820) evaluated efficacy and safety across 1 and 12 months, respectively, of LEM 5mg (LEM5), LEM 10mg (LEM10), and placebo (PBO) in adults with insomnia disorder. In addition to assessing the incidence/severity of TEAE-S, a Kaplan-Meier analysis was conducted using pooled safety data. To assess the potential for morning residual sleepiness, a highway-driving study (Study E2006-E044-106; NCT02583451) tested healthy adult and elderly participants following single and multiple doses of approved doses, LEM5 and LEM10, versus PBO and active control, zopiclone (7.5mg).

Results:

In the pooled dataset, TEAE-S was the most common TEAE, and while the overall incidence of TEAE-S was low, there was a dose-related increase in incidence. LEM5 and LEM10 consistently showed approximately 5%–6% and 7%–8% higher incidence, respectively, than PBO. Few participants discontinued due to somnolence (PBO: 0.6%; LEM5: 1.1%; LEM10: 2.3%); most TEAE-S were mild and transient. Kaplan-Meier analysis revealed that the greatest probability of a first incidence of TEAE‑S occurred during the first 2 weeks, with lower probability later in the treatment period. In Study E2006-E044-106, there were no statistical differences in the standard deviation of lateral position between LEM5, LEM10, and PBO, supporting lack of driving impairment.

Conclusions:

Incidence of somnolence was dose-dependent, but patients are advised to start on LEM5. The probability of reporting somnolence diminished after the first 2 weeks. LEM10 was not associated with driving impairment, suggesting TEAE-S do not equate with impairment.