U.S. FDA Approves Eisai's DAYVIGO™ (lemborexant) for the Treatment of Insomnia in Adult Patients

Approval Based on Robust Clinical Development Program That Included Two Pivotal Trials of Nearly 2,000 Patients

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Dec 23, 2019, 08:05 ET

WOODCLIFF LAKE, N.J., Dec. 23, 2019 /PRNewswire/ -- Eisai Inc., the U.S. pharmaceutical subsidiary of Eisai Co., Ltd., today 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.¹ 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,"²said 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%).¹

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.¹
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.¹
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.¹ 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.¹ There was no evidence of withdrawal effects following DAYVIGO discontinuation at either dose.¹

In addition to these pivotal trials, Eisai conducted a number of studies to further evaluate the safety of DAYVIGO, including a driving study and a study that assessed the effect of DAYVIGO on postural stability and memory performance.

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.¹
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.¹
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.¹

"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."

"DAYVIGO is an important addition to Eisai's rapidly growing neurology portfolio and underscores our leadership in neuroscience," said Ivan Cheung, Chairman and CEO, Eisai Inc. and Global President, Neurology Business Group, Eisai Co., Ltd. "Our commitment to patients and their families drives our relentless pursuit of innovative healthcare solutions."

The Full Prescribing Information is available here.

1. About Lemborexant
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.

INDICATION

DAYVIGO (lemborexant) is an orexin receptor antagonist indicated for the treatment of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

DAYVIGO is contraindicated in patients with narcolepsy.

WARNINGS AND PRECAUTIONS

Central Nervous System (CNS) Depressant Effects and Daytime Impairment:
DAYVIGO can impair daytime wakefulness. CNS depressant effects may persist in some patients up to several days after discontinuing DAYVIGO. Prescribers should advise patients about the potential for next-day somnolence.

Driving ability was impaired in some subjects taking DAYVIGO 10 mg. Risk of daytime impairment is increased if DAYVIGO is taken with less than a full night of sleep remaining or at a higher than recommended dose. If taken in these circumstances, patients should not drive or engage in activities requiring mental alertness.

Use with other classes of CNS depressants increases the risk of CNS depression. Dosage adjustments of DAYVIGO and concomitant CNS depressants may be necessary when administered together. Use of DAYVIGO with other insomnia drugs is not recommended. Patients should be advised not to consume alcohol in combination with DAYVIGO.

Because DAYVIGO can cause drowsiness, patients, particularly the elderly, are at a higher risk of falls.
Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-Like Symptoms:
Sleep paralysis, hypnagogic/hypnopompic hallucinations, and symptoms similar to mild cataplexy can occur with the use of DAYVIGO. Prescribers should explain these events to patients.
Complex Sleep Behaviors:
Complex sleep behaviors have been reported to occur with the use of hypnotics such as DAYVIGO. Events can occur in hypnotic-naïve and hypnotic-experienced persons. Patients usually do not remember these events. Complex sleep behaviors may occur following the first or any subsequent use of DAYVIGO, with or without the concomitant use of alcohol and other CNS depressants. Discontinue DAYVIGO immediately if a patient experiences a complex sleep behavior.
Patients with Compromised Respiratory Function:
The effect of DAYVIGO on respiratory function should be considered for patients with compromised respiratory function. DAYVIGO has not been studied in patients with moderate to severe obstructive sleep apnea (OSA) or chronic obstructive pulmonary disease (COPD).
Worsening of Depression/Suicidal Ideation:
Incidence of suicidal ideation or suicidal behavior, as assessed by questionnaire, was 0.3% for DAYVIGO 10 mg, 0.4% for DAYVIGO 5 mg, and 0.2% for placebo. In primarily depressed patients treated with hypnotics, worsening of depression and suicidal thoughts and actions (including completed suicides) have been reported. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdose is more common in this group of patients; therefore, the lowest number of tablets that is feasible should be prescribed at any one time. The emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
Need to Evaluate for Co-Morbid Diagnoses:
Treatment of insomnia should be initiated only after careful evaluation of the patient. Re-evaluate for comorbid conditions if insomnia persists or worsens after 7 to 10 days of treatment.

ADVERSE REACTIONS

The most common adverse reaction (reported in 5% of patients treated with DAYVIGO and at least twice the rate of placebo) with DAYVIGO was somnolence (10% for DAYVIGO 10 mg, 7% for DAYVIGO 5 mg, 1% for placebo).

DRUG INTERACTIONS

CYP3A inhibitors: The maximum recommended dose of DAYVIGO is 5 mg no more than once per night when co-administered with weak CYP3A inhibitors. Avoid concomitant use of DAYVIGO with strong or moderate CYP3A inhibitors.

CYP3A inducers: Avoid concomitant use of DAYVIGO with moderate or strong CYP3A inducers.

USE IN SPECIFIC POPULATIONS

Pregnancy and Lactation: There is a pregnancy exposure registry that monitors pregnancy outcomes in women who are exposed to DAYVIGO during pregnancy. Healthcare providers are encouraged to register patients in the DAYVIGO pregnancy registry by calling 1-888-274-2378. There are no available data on DAYVIGO use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

There are no data on the presence of lemborexant in human milk, the effects on the breastfed infant, or the effects on milk production. Infants exposed to DAYVIGO through breastmilk should be monitored for excess sedation.
Geriatric Use: Exercise caution when using doses higher than 5 mg in patients ≥65 years old.

Renal impairment: Patients with severe renal impairment may experience an increased risk of somnolence.

Hepatic impairment: The maximum recommended dose of DAYVIGO is 5 mg in patients with moderate hepatic impairment. DAYVIGO is not recommended in patients with severe hepatic impairment. Patients with mild hepatic impairment may experience an increased risk of somnolence.

DRUG ABUSE AND DEPENDENCE

Controlled substance scheduling of DAYVIGO is pending review by the U.S. Drug Enforcement Administration (DEA).
Because individuals with a history of abuse or addiction to alcohol or other drugs may be at increased risk for abuse and addiction to DAYVIGO, follow such patients carefully.

For more information about DAYVIGO, see full Prescribing Information.

2. About Sleep Disorders
Population studies show that sleep disorders affect many more people worldwide than previously thought.³ Insomnia symptoms affect approximately 30% of the adult population worldwide.⁴ Insomnia disorder is characterized by difficulty falling asleep, staying asleep or both, despite an adequate opportunity to sleep, which can lead to daytime consequences, such as fatigue, difficulty concentrating and irritability.^2,5

Sleeping well is essential for good health, including brain health. Poor sleep is associated with a wide range of health consequences.²

Experimental studies in animals and humans provide evidence of associations between sleep and disease risk factors, diseases and mortality.⁶ Studies suggest an optimal sleep duration between seven and eight hours.⁷

Women are 1.4 times more likely than men to suffer from insomnia.⁸ Older adults also have a higher prevalence of insomnia; aging is often accompanied by changes in sleep patterns, including disrupted sleep, frequent waking, and early waking, that can lead to less sleep time.⁹

3. About Eisai Inc.
At Eisai Inc., human health care (hhc) is our goal. We give our first thoughts to patients and their families, and helping to increase the benefits health care provides. As the U.S. pharmaceutical subsidiary of Tokyo-based Eisai Co., Ltd., we have a passionate commitment to patient care that is the driving force behind our efforts to discover and develop innovative therapies to help address unmet medical needs.

Eisai is a fully integrated pharmaceutical business that operates in two global business groups: oncology and neurology (dementia-related diseases and neurodegenerative diseases). Our U.S. headquarters, commercial and clinical development organizations are located in New Jersey; our discovery labs are in Massachusetts and Pennsylvania; and our global demand chain organization resides in Maryland and North Carolina. To learn more about Eisai Inc., please visit us at www.eisai.com/US and follow us on Twitter and LinkedIn.

References
¹ Eisai Inc. DAYVIGO Full Prescribing Information. 2019.
² Institute of Medicine. Sleep disorders and sleep deprivation: An unmet public health problem. Washington, DC: National Academies Press. 2006.
³ Ferrie JE, et al. Sleep epidemiology – a rapidly growing field. Int J Epidemiol. 2011;40(6):1431–1437.
⁴ Roth T. Insomnia: definition, prevalence, etiology and consequences. J Clin Sleep Med. 2007;3(5 Suppl):S7–S10.
⁵ Ohayon MM, et al. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev. 2002;6(2):97-111.
⁶Cappuccio FP, et al. Sleep and cardio-metabolic disease. Curr Cardiol Rep. 2017;19:110.
⁷ Cappuccio FP, et al. Sleep duration and all-cause mortality: a systematic review and meta-analysis of prospective studies. Sleep. 2010;33(5):585-592.
⁸ Roth T, et al. Prevalence and perceived health associated with insomnia based on DSM-IV-TR; International Statistical Classification of Diseases and Related Health Problems, tenth revision; and Research Diagnostic Criteria/International Classification of Sleep Disorders, second edition criteria: results from the America Insomnia Survey. Biol Psychiatry. 2011;69:592– 600.
⁹ Crowley K. Sleep and sleep disorders in older adults. Neuropsychol Rev. 2011;21(1):41-53.