Pharmacodynamics

Mechanism of Action

Lemborexant is a competitive antagonist of both orexin receptors, OX1R and OX2R, with a higher affinity for OX2R. It belongs to the pharmacologic class of orexin receptor antagonists. The orexin neuropeptide signaling system is a central promoter of wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive.

Cardiac Electrophysiology

The effect of lemborexant on the QTc interval using a high precision analysis was measured in multiple dose studies in human patients administered daily doses up to 75 mg. The concentration-response relationship was analyzed using a linear mixed-effects model. The model-predicted QTc effect at the highest observed concentration was 1.1 msec (90% CI: –3.49 to 5.78), indicating that a QTc prolongation effect >10 msec could be excluded at a dose 7.5-times the maximum recommended dose. Thus, lemborexant does not prolong the QTc interval at clinically relevant doses.


Clinical Studies

Lemborexant was evaluated for efficacy and safety in 2 clinical trials (each with >900 patients) in patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance.

The efficacy and safety of Lemborexant was evaluated in Study E2006-G000-303 (Study303), a randomized, double-blind and placebo-controlled 6 month sleep diary study, followed by an additional 6 months of blinded active treatment period where all patients received lemborexant. Study E2006-G000-304 (Study 304) was a 1-month, randomized, double-blind, placebo- and active-controlled, parallel-group polysomnography (PSG) and sleep diary study. In both studies, adult patients (mean age 51.8 years; 714 females, 213 males) were treated with lemborexant 5 mg (n=467) or 10 mg (n=460). Elderly patients (≥65 years; mean age 70.4 years, 342 females, 149 males) were treated with lemborexant 5 mg (n=246) or 10 mg (n=245).

In Study 303 and Study 304, as measured by subjective and/or objective methods, lemborexant led to significantly larger decreases (improvements) in both the time needed to fall asleep and the amount of time spent awake during the night after sleep onset compared to placebo, and significantly larger increases in sleep efficiency (time spent asleep/time spent in bed) compared to placebo, all of which were sustained through 6 months (Tables 2, 3, & 4).

In Study 304, lemborexant 5 mg and 10 mg led to significantly larger decreases in sleep onset (latency to persistent sleep [LPS]) and wake after sleep onset (WASO) during the full sleep period and during the second half of the sleep period) compared to placebo as assessed objectively by PSG. Lemborexant led to significantly larger increases in sleep efficiency (SE) compared to placebo (Table 2). As measured by PSG, lemborexant 5mg and 10mg led to significantly larger decreases in sleep onset (LPS),WASO across the entire night, and WASO in the second half of the night compared with active comparator .

The statistically significant effects of lemborexant on patient-reported (subjective) sleep onset and sleep maintenance (sWASO and sSE) after the first 7 nights of treatment remained statistically significant compared with placebo through 6 months (Study 303).

The efficacy of lemborexant was similar between women and men, adult and elderly, and between Caucasians and non-Caucasians.

Table 2: Sleep Diary Assessments of Sleep Parameters in Study 303 and 304
Placebo
n=527
Lemborexant
5 mg
n=582
Lemborexant
10 mg
n=584
Difference between Lemborexant and
Placebo
Lemborexant
5 mg
Lemborexant
10 mg
Sleep Onset (sSOL), minutes
Baseline (median) 54 56 55
First 7 Days
Median Change from Baseline
-3 -13 -14 -10 -11
LSGM Ratio 0.871 0.692 0.653 0.794*** 0.750***
Month 1
Median Change from Baseline
-5 -16 -18 -11 -13
LSGM Ratio 0.776 0.611 0.571 0.788*** 0.736***
Sleep Maintenance (sSE),%
Baseline (mean) 59 60 59
First 7 Days
LSM Change from Baseline
5 9 11 4*** 6***
Month 1
LSM Change from Baseline
8 11 12 3*** 5***
Sleep Maintenance (sWASO),minutes
Baseline (mean) 147 148 155
First 7 Days
LSM Change from Baseline
-17 -30 -38 -13*** -21***
Month 1
LSM Change from Baseline
-28 -36 -38 -8* -13***

LSGM: Least squares geometric mean; LSM: Least squares mean; * P <0.05, ** P <0.01, *** P <0.001

 

Table 3: Sleep Diary Assessments of Sleep Parameters Through Month 6 in Study 303
Placebo
n=318
Lemborexant
5 mg
n=316
Lemborexant
10 mg
n=315
Difference between Lemborexant and
Placebo
Lemborexant
5 mg
Lemborexant
10 mg
Sleep Onset (sSOL), minutes
Baseline (median) 56 54 56
Week 1
Median Change from Baseline
-3 -11 -12 -8 -9
LSGM Ratio 0.931 0.728 0.701 0.781*** 0.752***
Month 1
Median Change from Baseline
-7 -14 -20 -7 -13
LSGM Ratio 0.786 0.637 0.605 0.810*** 0.770***
Month 3
Median Change from Baseline
-11 -21 -26 -10 -15
LSGM Ratio 0.673 0.524 0.518 0.778*** 0.770**
Month 6
Median Change from Baseline
-11 -22 -28 -11 -17
LSGM Ratio 0.618 0.453 0.433 0.723*** 0.701***
Sleep Maintenance (sSE),%
Baseline (mean) 61 63 62
Week 1
Median Change from Baseline
2 6 8 4*** 6***
Month 1
LSM Change from Baseline
6 8 9 2*** 4***
Month 3
LSM Change from Baseline
9 13 13 4*** 4***
Month 6
LSM Change from Baseline
10 14 14 5** 5***
Sleep Maintenance (sWASO),minutes
Baseline (mean) 133 133 137
Week 1
LSM Change from Baseline
-5 -19 -21 -14*** -17***
Month 1
LSM Change from Baseline
-17 -23 -24 -6 -7
Month 3
LSM Change from Baseline
-27 -40 -37 -13** -10*
Month 6
LSM Change from Baseline
-29 -47 -42 -17*** -13*

LSGM: Least squares geometric mean; LSM: Least squares mean; * P <0.05, ** P <0.01, *** P <0.001

 

Table 4: Polysomnographic Assessments of Sleep Parameters in Study 304
Placebo
n=208
Lemborexant
5 mg
n=266
Lemborexant
10 mg
n=269
Difference between Lemborexant and
Placebo
Active Comparator n=262 Difference between Lemborexant and
Active Comparator
Lemborexant
5 mg
Lemborexant
10 mg
Lemborexant
5 mg
Lemborexant
10 mg
Sleep Onset (sSOL), minutes
Baseline (median) 44 45 45 45
Days 1/2
Median Change from Baseline
-6 -17 -19 -11 -13 -13 -4 -6
LSGM Ratio 0.763 0.649 0.607 0.850** 0.795*** 0.742 0.874* 0.818***
Month 1
Median Change from Baseline
-8 -20 -21 -12 -13 -8 -12 -13
LSGM Ratio 0.699 0.541 0.506 0.773*** 0.723*** 0.852 0.634*** 0.594***
Sleep Maintenance (SE),%
Baseline (median) 69 68 68 68
Days 1/2
LSM Change from Baseline
5 14 17 9*** 12*** 12 2** 5***
Month 1
LSM Change from Baseline
6 13 14 7*** 8*** 10 4*** 5***
Sleep Maintenance (WASO),minutes
Baseline (median) 112 113 115 114
Days 1/2
LSM Change from Baseline
-18 -51 -60 -33*** -42*** -45 -6* -15***
Month 1
LSM Change from Baseline
-21 -45 -47 -24*** -25*** -38 -8** -9**
Sleep Maintenance (WASO2H),minutes
Baseline (median) 74 77 77 7
Days 1/2
LSM Change from Baseline
-9 -30 -37 -22*** -28*** -24 -6** -13***
Month 1
LSM Change from Baseline
-11 -27 -29 -16*** -18*** -21 -7** -8***

LSGM: Least squares geometric mean; LSM: Least squares mean; ZOL ER: zolpidem extended-release * P <0.05, ** P <0.01, *** P <0.001

 

Special Safety Studies

Effects on Driving

A randomized, double-blind, placebo- and active-controlled, four-period crossover study evaluated the effects of nighttime administration of lemborexant on next-morning driving performance approximately 9 hours after dosing in 24 healthy elderly patients (≥65 years old, median age 67 years; 14 men, 10 women) and 24 adult patients (median age 49 years; 12 men, 12 women).The primary driving performance outcome measure was change in Standard Deviation of Lateral Position (SDLP). Testing was conducted after one night (a single dose) and after eight consecutive nights of treatment with lemborexant. Although lemborexant at doses of 5 mg and 10 mg did not cause statistically significant impairment in next-morning driving performance in adult or elderly subjects (compared with placebo), driving ability was impaired in some subjects taking 10 mg lemborexant. Patients using the 10 mg dose should be cautioned about the potential for next-morning driving impairment because there is individual variation in sensitivity to lemborexant. The results of a symmetry analysis support the findings from the primary outcome.

Effects on Next-day Postural Stability and Cognitive Performance

The effect of lemborexant on next-day postural stability and cognitive performance (tests of attention and memory) compared to placebo was evaluated in 2 randomized, placebo-and active-controlled trials in healthy subjects and insomnia patients age 55 and older. There were no meaningful differences between lemborexant (5 mg or 10 mg) and placebo on next-day postural stability or memory.

Middle of the Night Safety in Older Patients (age 55 years and older)

The effect of lemborexant was evaluated in a randomized, placebo- and active-controlled trial with a scheduled awakening 4 hours after the start of the 8-hour time in bed. Postural stability, the ability to awaken in response to a sound stimulus, and attention and memory were tested following the awakening. The active comparator in the study, showed a statistically significant decrease in postural stability (increased body sway) compared to both lemborexant and placebo. There were no statistical differences between lemborexant and placebo on the ability to awaken in response to sound. There were no statistically significant differences between lemborexant 5 mg and placebo on measures of attention and memory.

 Rebound Insomnia

Rebound insomnia was assessed by comparing sleep diary-recorded sSOL and sWASO from the screening period to the two weeks following treatment discontinuation in both Study 303 (12 months) and Study 304 (1 month). Analyses of group means and the proportion of patients with rebound insomnia suggest that lemborexant was not associated with rebound insomnia following treatment discontinuation.

Withdrawal Effects

In a 12-month and 1-month controlled safety and efficacy trials (Study 303, Study 304, respectively), withdrawal effects were assessed by the Tyrer Benzodiazepine Withdrawal Symptom Questionnaire following discontinuation from study drug in patients who received lemborexant 5 mg or 10 mg. There was no evidence of withdrawal effects following lemborexant discontinuation at either dose.

Respiratory Safety

In a study of healthy adult and elderly patients, there were no differences between placebo and lemborexant 10 mg and 25 mg with respect to mean peripheral capillary oxygen saturation during sleep. In a study of patients with mild sleep apnea, overall, lemborexant did not increase the frequency of apneic events or decrease mean peripheral capillary oxygen saturation when compared with placebo following single and multiple doses of 10 mg.

In a study of patients with moderate or severe obstructive sleep apnea (apnea-hypopnea index ≥15 events per hour of sleep), overall, lemborexant did not increase the frequency of apneic events or decrease mean peripheral capillary oxygen saturation following single or multiple doses of 10 mg.

In a study of patients with moderate or severe chronic obstructive pulmonary disease (COPD), overall, lemborexant did not increase the frequency of apneic events or decrease mean peripheral capillary oxygen saturation following single or multiple doses of 10 mg.

Daily Functioning

In Study 303 and Study 304, the effect of lemborexant on daily functioning was assessed by scores on the Insomnia Severity Index (ISI). For patients treated with lemborexant, the ISI score decreased significantly compared to placebo, indicating that patients treated with lemborexant had improvement of functional impairment.

Sleep Stages

In Study 304, sleep stages for patients treated with lemborexant were assessed by polysomnography. Lemborexant demonstrated a significant increase in rapid eye movement (REM) sleep compared to placebo and to zolpidem tartrate ER.