FDA Approves DAYVIGO for Insomnia

Eisai announced the U.S. Food and Drug Administration (FDA) approved DAYVIGO™ (lemborexant) 5 mg and 10 mg for the treatment of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. The approval was based on a robust clinical development program that included two pivotal Phase 3 studies, which evaluated DAYVIGO versus placebo for up to one month and DAYVIGO versus placebo for six months. The FDA has recommended that DAYVIGO be classified as a controlled substance, and this recommendation has been submitted to the U.S. Drug Enforcement Administration (DEA). DAYVIGO will be commercially available following scheduling by the DEA, which is expected to occur within 90 days.

"Insomnia disorder is a chronic condition that has a variety of potential negative impacts and long-term consequences for health and well-being," said Russell Rosenberg, PhD, D.ABSM, a principal investigator in the DAYVIGO clinical studies and former Chairman of the Board of the National Sleep Foundation. "The clinical trials provide evidence that DAYVIGO may improve patients' ability to fall asleep and stay asleep."

The most common adverse reaction (reported in 5% or more of patients treated with DAYVIGO and at least twice the rate of placebo) in Study 1 (the first 30 days) and Study 2 was somnolence (DAYVIGO 10 mg, 10%; DAYVIGO 5 mg, 7%; placebo, 1.0%). The most common adverse reactions leading to discontinuation of DAYVIGO were somnolence (DAYVIGO 10 mg, 1.0%; DAYVIGO 5 mg, 0.7%; placebo, 0.4%) and nightmares (DAYVIGO 10 mg, 0.3%; DAYVIGO 5 mg, 0.3%; and placebo, 0%).

The FDA approval was based on findings from the lemborexant clinical development program, including two pivotal Phase 3 studies – Study 1 and Study 2.

Study 1 was a six-month, randomized, double-blind, placebo-controlled, multi-center trial in adult patients age 18 or older who met DSM-5 criteria for insomnia disorder. Patients were randomized to placebo (n=325), DAYVIGO 5 mg (n=323), or DAYVIGO 10 mg (n=323) once nightly. The primary efficacy endpoint was the mean change from baseline to end of treatment at six months for log-transformed, patient-reported (subjective) sleep onset latency (sSOL; the estimated minutes from the time that the patient attempted to sleep until sleep onset). Pre-specified secondary efficacy endpoints for sleep maintenance were change from baseline to end of treatment at six months for patient-reported sleep efficiency (sSEF; the proportion of time spent asleep per time in bed) and wake after sleep onset (sWASO; the minutes of wake from the onset of sleep until wake time). The primary and pre-specified secondary efficacy endpoints were measured by sleep diary. In Study 1, DAYVIGO 5 mg and 10 mg demonstrated statistically significant superiority on the primary efficacy measure, sSOL, compared to placebo. DAYVIGO 5 mg and 10 mg also showed statistically significant superiority in sSEF and sWASO.

Study 2 was a one-month randomized, double-blind, placebo- and active-controlled, multi-center, parallel-group clinical trial in adult female patients age 55 and older and male patients 65 years and older who met DSM-5 criteria for insomnia disorder. Patients were randomized to placebo (n=208), DAYVIGO 5 mg (n=266) or 10 mg (n=269), or active comparator (n=263) once nightly. The primary efficacy endpoint was the mean change in log-transformed latency to persistent sleep (LPS; the number of minutes from lights off to the first 10 consecutive minutes of non-wakefulness) from baseline to end of treatment (Days 29/30), as measured by overnight polysomnography (PSG) monitoring. The pre-specified secondary efficacy endpoints in Study 2 were the mean change from baseline to end of treatment (Days 29/30) in sleep efficiency (SEF) and wake after sleep onset (WASO) measured by PSG. In Study 2, DAYVIGO 5 mg and 10 mg demonstrated statistically significant superiority on the primary efficacy measure, LPS, compared to placebo. DAYVIGO 5 mg and 10 mg demonstrated statistically significant improvement in SEF and WASO compared to placebo.

The effects of DAYVIGO at the beginning of treatment were generally consistent with later timepoints.

In 12-month and one-month controlled safety and efficacy trials (Studies 1 and 2, respectively), DAYVIGO was not associated with rebound insomnia following treatment discontinuation. Withdrawal effects were also assessed by the Tyrer Benzodiazepine Withdrawal Symptom Questionnaire following discontinuation from study drug in patients who received DAYVIGO 5 mg or 10 mg. There was no evidence of withdrawal effects following DAYVIGO discontinuation at either dose.

Middle-of-the-Night Safety: The effect of DAYVIGO on middle-of-the-night safety was evaluated in a randomized, placebo- and active-controlled trial in healthy female subjects ≥ 55 years or male subjects ≥ 65 years. Postural stability, the ability to awaken in response to a sound stimulus, and attention and memory were assessed following a scheduled awakening four hours after the start of the eight-hour time in bed. Nighttime dosing of DAYVIGO 5 mg and 10 mg resulted in impairment of balance (measured by body sway area) at four hours as compared to placebo. There were no meaningful differences between DAYVIGO (5 mg or 10 mg) and placebo on ability to awaken to sound. DAYVIGO was associated with dose-dependent worsening on measures of attention and memory as compared to placebo. Patients should be cautioned about the potential for middle-of-the-night postural instability, as well as attention and memory impairment.

Effects on Next-Day Postural Stability and Memory: The effects of DAYVIGO on next-day postural stability and memory were evaluated in two randomized, placebo- and active-controlled trials in healthy subjects and insomnia patients age 55 and older. There were no meaningful differences between DAYVIGO (5 mg or 10 mg) and placebo on next-day postural stability or memory compared to placebo.

Effects on Driving: A randomized, double-blind, placebo- and active-controlled, four-period crossover study evaluated the effects of nighttime administration of DAYVIGO on next-morning driving performance approximately nine hours after dosing in 24 healthy elderly subjects (≥65 years, median age 67 years; 14 men, 10 women) and 24 adult subjects (median age 49 years; 12 men, 12 women). The primary driving performance outcome measure was change in Standard Deviation of Lane Position (SDLP). Testing was conducted after one night (a single dose) and after eight consecutive nights of treatment with DAYVIGO. Although DAYVIGO 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 DAYVIGO. 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 DAYVIGO.

"We believe the approval of DAYVIGO is particularly exciting because it is the first FDA-approved medication to report safety data over a 12-month period along with sleep onset and sleep maintenance efficacy data over a six-month period in a pivotal clinical study," said Lynn Kramer, MD, Chief Clinical Officer, Neurology Business Group, Eisai. "We look forward to making this new therapeutic option available to the millions of patients who suffer with insomnia."

Lemborexant is a small-molecule compound, discovered and developed by Eisai in-house scientists, that inhibits orexin signaling by binding competitively to both orexin receptor subtypes (orexin receptor 1 and 2). In individuals with normal daily sleep-wake rhythms, orexin signaling is believed to promote periods of wakefulness. In individuals with sleep-wake disorders, it is possible that orexin signaling that regulates wakefulness is not functioning normally.

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