Eisai Presents New Analyses from Phase 3 Studies of DAYVIGO(TM) (lemborexant) CIV for the Treatment of Insomnia in Adult Patients at Virtual SLEEP 2020

WOODCLIFF LAKE, N.J., Aug. 28, 2020 /PRNewswire/ -- Eisai Inc., the U.S. pharmaceutical subsidiary of Eisai Co., Ltd., today announced findings from several post hoc analyses of DAYVIGO™ from the Phase 3 SUNRISE 1 and 2 clinical studies and top-line results from an open label pilot study. The Phase 3 presentations include analyses of the long-term efficacy and safety of DAYVIGO in adults ages 65 and older and in women of perimenopausal age with insomnia disorder, as well as the impact of DAYVIGO on sleep onset, sleep maintenance and fatigue severity. Results from the pilot study on the next-dose transition from zolpidem to DAYVIGO also were presented. The findings were featured in oral and poster presentations at Virtual SLEEP 2020, the 34th annual meeting of the Associated Professional Sleep Societies LLC, taking place August 27-30, 2020.

The following will be shared in these presentations:

• Long-term results evaluating DAYVIGO efficacy and safety in adults ages 65 and older, in measures of time to sleep onset, sleep efficacy and sleep maintenance with DAYVIGO 5 mg or DAYVIGO 10 mg compared to placebo in SUNRISE 2.
• Efficacy and safety results of DAYVIGO in female subjects of perimenopausal age from SUNRISE 2.
• An open-label pilot study evaluating the ability of patients with insomnia disorder to directly transition from zolpidem to DAYVIGO. This study evaluated patients taking zolpidem, either intermittently or frequently, and transitioning to DAYVIGO 5 mg or DAYVIGO 10 mg after two weeks of taking DAYVIGO, as well as the safety and tolerability of DAYVIGO in this patient population.
• The impact of DAYVIGO on fatigue severity at various time points among patients who participated in SUNRISE 1 or SUNRISE 2, and who reported clinically significant fatigue at baseline.

"These new data analyses from our pivotal Phase 3 studies, as well as findings from a pilot study evaluating the transition of insomnia patients from zolpidem to DAYVIGO, further advance our understanding of DAYVIGO's impact in certain patient populations who are more prone to insomnia disorder,"^1,2 said Ivan Cheung, Chairman, Eisai Inc. and Global President, Neurology Business Group, Eisai Co., Ltd. "We hope these findings prove helpful to health care providers as they seek to determine the appropriate treatment for patients experiencing insomnia."

In analyses of patient subgroups in SUNRISE 2, patient-reported (subjective) sleep endpoints were assessed from sleep diary data, including sleep onset latency (sSOL), defined as the estimated minutes from the time that the patient attempted to sleep until sleep onset; sleep efficiency (sSE), defined as the proportion of time spent asleep per time in bed; and sleep maintenance (sWASO), defined as the minutes of wake from the onset of sleep until wake time.³

Long-Term Efficacy and Safety of Lemborexant in Elderly Adults with Insomnia Disorder: Results from SUNRISE 2 (Abstract #0474) 
As reported in an oral presentation, a post-hoc analysis showed patients ages 65 and older (n=262) who participated in SUNRISE 2 (n=949) reported a reduction in sSOL as early as the first week. At Month Six, a greater change from baseline in median sSOL was reported with DAYVIGO 5 mg or DAYVIGO 10 mg compared to placebo (-21.7 minutes, -26.0 minutes and -10.8 minutes, respectively), which was maintained at 12 months (DAYVIGO 5 mg, -29.3 minutes; DAYVIGO 10 mg, -34.3 minutes).

These patients also noted decreases in sWASO at Week One. At six months, a greater change from baseline in sWASO was reported with DAYVIGO 5 mg and 10 mg compared to placebo (-54.5 minutes,    -48.9 minutes and -29.4 minutes, respectively), which persisted at 12 months (DAYVIGO 5 mg, -58.6 minutes; DAYVIGO 10 mg, -60.9 minutes).

Increases in sleep efficiency were noted at Week One. At six months, sSE was also greater among patients receiving either dose of DAYVIGO compared to placebo (DAYVIGO 5 mg, 16.3%; DAYVIGO 10 mg, 14.4%; placebo, 8.9%), which was maintained at 12 months (DAYVIGO 5 mg, 18.1%; DAYVIGO 10 mg, 18.0%).

During the first six months of the study (Treatment Period 1), the most common (greater than 5% in either group and greater than placebo) treatment-emergent adverse events (TEAEs) with DAYVIGO were somnolence (DAYVIGO 5 mg, 8.1%; DAYVIGO 10 mg, 19.0%; placebo, 0%) and headache (DAYVIGO 5 mg, 9.3%, DAYVIGO 10 mg, 1.2%, placebo 6.7%). During the second six months of the study (Treatment Period 2), the most common (greater than 5%) in either group TEAEs occurred only in DAYVIGO 10 mg group; they were headache (6.3%) and urinary tract infection (6.3%).

"Insomnia disorder, a chronic condition with long-term consequences for health and well-being, is prevalent in older adults,"² said Lynn Kramer, MD, Chief Clinical Officer, Neurology Business Group, Eisai. "This new analysis of the SUNRISE 2 data reflects new learnings on the sustained impact of DAYVIGO on sleep onset and sleep maintenance in an older patient population."

Efficacy and Safety of Lemborexant In Female Subjects of Perimenopausal Age with Insomnia Disorder (Abstract #0480)
In a post-hoc analysis of the 280 women 40-58 years of age who participated in SUNRISE 2, the median change in sSOL following six months of exposure was -20.7 minutes for the DAYVIGO 5 mg group, -30.4 minutes for DAYVIGO 10 mg and -17.9 minutes for placebo. These effects were sustained at 12 months (DAYVIGO 5 mg, -27.7 minutes; DAYVIGO 10 mg, -33.9 minutes).

Similarly, at six months, the decrease in mean sWASO was greater among those receiving either dose of DAYVIGO compared to placebo (DAYVIGO 5 mg, -50.1 minutes; DAYVIGO 10 mg, -54.5 minutes; placebo, -37.0 minutes).  These effects were sustained at 12 months (DAYVIGO 5 mg, -59.1 minutes; DAYVIGO 10 mg, -66.2 minutes).

Patients receiving either DAYVIGO 5 mg or DAYVIGO 10 mg reported a greater increase from baseline in mean sSE at six months compared to those received placebo (15.9%, 17.2% and 12.5%, respectively). These effects were sustained at 12 months (DAYVIGO 5 mg, 17.6%; DAYVIGO 10 mg, 19.1%).

The majority of TEAEs were rated by investigators as mild or moderate. The most commonly reported TEAEs were nasopharyngitis (DAYVIGO 5 mg, 9.8%; DAYVIGO 10 mg, 9.3%; placebo, 14.4%), headache (DAVVIGO 5 mg, 13.4%; DAYVIGO 10 mg, 7.5%, placebo, 11.1%), and somnolence (DAYVIGO 5 mg, 9.8%; DAYVIGO 10 mg, 12.1%; placebo, 1.1%).

Sleep Onset and Sleep Maintenance Responder Profiles Over 12 Months of Treatment with Lemborexant: Results from SUNRISE 2 (Abstract #0479)
In a post-hoc analysis of data from the SUNRISE 2 study, at six months, the percentage of patients with a decrease from baseline of at least 20 minutes in time to sleep onset was greater with DAYVIGO compared to placebo (DAYVIGO 5 mg, 45.5%; DAYVIGO 10 mg, 44.9%; placebo, 30.4%). The response to treatment persisted at 12 months (DAYVIGO 5 mg, 40.4%; DAYVIGO 10 mg, 43.3%).

Similarly, a higher percentage of patients receiving either dose of DAYVIGO reported a decrease from baseline in sleep maintenance of at least 60 minutes compared to those who received placebo (DAYVIGO 5 mg, 27.8%; DAYVIGO 10 mg, 30.2%; placebo, 24.2%). This response to treatment was maintained at 12 months (DAYVIGO 5 mg, 27.8%; DAYVIGO 10 mg, 27.7%).

In both treatment periods, the majority of TEAEs were rated by investigators as mild or moderate. During Treatment Period 1, the first 6 months of the study, the most common (greater than 5% in either group and greater than placebo) TEAEs with DAYVIGO were somnolence (DAYVIGO 5 mg, 8.6%; DAYVIGO 10 mg, 13.1%; placebo, 1.6%), headache (DAYVIGO 5 mg, 8.9%; DAYVIGO 10 mg, 6.7%; placebo, 6.6%) and influenza (DAYVIGO 5 mg, 4.8%; DAYVIGO 10 mg, 5.1%; placebo, 4.7%). During Treatment Period 2, the second six months of the study, the most common (greater than 5% in either group) TEAE was nasopharyngitis (DAYVIGO 5 mg, 7.2%; DAYVIGO 10 mg, 6.8%).

A Multicenter Open-Label Pilot Study to Evaluate Next-Dose Transition from Zolpidem to Lemborexant for the Treatment of Insomnia (Abstract #0478)
An open-label pilot study was designed to assess dosing approaches for transitioning from the immediate or extended-release formulation of zolpidem tartrate to DAYVIGO 5 mg or 10 mg. The primary objective was to evaluate the proportion of adults ages 18 or older with insomnia disorder taking immediate or extended-release zolpidem either frequently or intermittently who transitioned to the 5 mg or 10 mg dose of DAYVIGO after two weeks of taking DAYVIGO (n=53). Secondary objectives were to evaluate the proportion of patients who increased from the 5 mg to the 10 mg dose of DAYVIGO or decreased from the 10 mg to the 5 mg dose of DAYVIGO during the two week titration period, and to evaluate the safety and tolerability of DAYVIGO in patients previously taking zolpidem.

Following two weeks of DAYVIGO treatment, 81% of patients transitioned from zolpidem to DAYVIGO, regardless of whether they had previously used zolpidem intermittently or frequently, and 100% of patients who transitioned to DAYVIGO chose to continue taking DAYVIGO in the extension phase of the study. The safety profile for patients transitioning from zolpidem to DAYVIGO was consistent with the known safety profile of DAYVIGO. All TEAEs were rated by investigators as mild to moderate; the most common TEAEs (greater than 5%) for either dose of DAYVIGO were abnormal dreams (DAYVIGO 5 mg, 0%; DAYVIGO 10 mg, 10.8%) and somnolence (DAYVIGO 5 mg, 2.8%; DAYVIGO 10 mg, 8.1%).

This study is subject to the limitations of an open-label pilot study that was not designed or powered for efficacy or safety statistical comparisons between DAYVIGO or zolpidem or between the treatment arms, and assessed only a specified approach to dosing transition.

Impact of Lemborexant on Fatigue Severity in Subjects With Clinically Significant Levels of Fatigue at Baseline (Abstract #0481)
Data from patients who participated in SUNRISE 1 and SUNRISE 2, a one-month trial and a six-month trial in adult patients, respectively, and who at baseline reported clinically significant fatigue, defined as a Fatigue Severity Scale total score (FSSts) of at least 36, was evaluated in a post-hoc analysis. As assessed at one month in SUNRISE 1, mean changes from baseline in FSSts was not significantly different versus placebo for either dose of DAYVIGO. In SUNRISE 2, DAYVIGO 10 mg resulted in a greater decrease in mean FSSts from baseline versus placebo (−11.2 and −8.7, respectively) at this time point.

In SUNRISE 2, as assessed at six months of treatment with DAYVIGO 5 mg or DAYVIGO 10 mg, there was a greater decrease from baseline in mean FSSts versus placebo (−15.4, −15.0 and −11.0, respectively). At 12 months, mean reductions in FSSts were sustained for both DAYVIGO groups (DAYVIGO 5 mg, −20.4; DAYVIGO 10 mg, -17.7).

The majority of TEAEs were rated by investigators as mild or moderate in subjects with clinically significant fatigue at baseline. The most commonly reported TEAEs (greater than 5% across all treatment groups and greater than placebo) for these patients at one month (SUNRISE 1) were headache (DAYVIGO 5 mg, 6.4%; DAYVIGO 10 mg, 4.6%; placebo, 6.0%) and somnolence (DAYVIGO 5 mg, 4.5%; DAYVIGO 10 mg, 8.5%; placebo, 1.7%). In SUNRISE 2, TEAEs greater than 5% only occurred in the first six month treatment period and were headache (DAYVIGO 5 mg, 7.7%; DAYVIGO 10 mg, 7.4%; placebo, 6.5%) and somnolence (DAYVIGO 5 mg, 9.4%; DAYVIGO 10 mg, 14.9%; placebo, 1.2%). The most common TEAE (>5%) during the second six months of the study was nasopharyngitis (DAYVIGO 5 mg, 9.3%; DAYVIGO 10 mg, 8.7%).

Full DAYVIGO Prescribing is available here: https://www.dayvigohcp.com/-/media/Files/DAYVIGOHCP/PDF/prescribing-information.pdf.

[Notes to editors]

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.⁴ In individuals with insomnia, it is possible that orexin signaling regulating 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 (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression, which can cause daytime impairment. 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, an inability to move or speak for up to several minutes during sleep-wake transitions, hypnagogic/hypnopompic hallucinations, including vivid and disturbing perceptions can occur with DAYVIGO. Prescribers should explain these events to patients.
   
  Symptoms similar to mild cataplexy can occur with DAYVIGO and can include periods of leg weakness lasting from seconds to a few minutes, can occur either at night or during the day, and may not be associated with identified triggering event (e.g., laughter or surprise).
   
• Complex Sleep Behaviors:
  Complex sleep behaviors, including sleep-walking, sleep-driving, and engaging in other activities while not fully awake (e.g., preparing and eating food, making phone calls, having sex), 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 higher in patients receiving DAYVIGO than placebo (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 Comorbid Diagnoses:
  Treatment of insomnia should be initiated only after careful evaluation of the patient. Reevaluate for comorbid conditions if insomnia persists or worsens after 7 to 10 days of treatment. Worsening of insomnia or the emergence of new cognitive or behavioral abnormalities may be the result of an unrecognized underlying psychiatric or medical disorder and can emerge during the course of treatment with sleep-promoting drugs such as DAYVIGO.

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

• DAYVIGO is a Schedule IV-controlled substance.
• 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.⁵ Insomnia symptoms affect approximately 30% of the adult population worldwide.⁶ Insomnia disorder is characterized by difficulty falling asleep, staying asleep or both, despite an adequate opportunity to sleep.⁷

Diagnostic criteria for insomnia disorder include if the sleep disturbance causes clinically significant distress or impairment in social, occupational, educational, academic, behavioral or other important areas of functioning, occurs at least three night per week and is present for at least three months.⁸

Sleeping well is essential for good health. Studies suggest an optimal sleep duration between seven and eight hours.⁹

Women are 1.4 times more likely than men to suffer from insomnia.¹ 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.²

3.  About SUNRISE 2 (Study 1)
SUNRISE 2 is a six-month placebo-controlled treatment trial with a 6-month parallel-group extension period including 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 subjective sleep onset latency (sSOL; the estimated minutes from the time that the patient attempted to sleep until sleep onset). Secondary efficacy endpoints were mean change from baseline to end of treatment at six months subjective 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). These endpoints were measured by sleep diary.³

4.  About SUNRISE 1 (Study 2)
SUNRISE 1 is a one-month 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 from baseline to end of treatment at Days 29/30 in latency to persistent sleep (LPS; the number of minutes from lights off to the first 10 consecutive minutes of non-wakefulness). Secondary efficacy endpoints were the mean change from baseline to end of treatment at Days 29/30 in sleep efficiency (SEF) and wake after sleep onset (WASO). These endpoints were measured by overnight polysomnography monitoring.³

5.  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 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.
² Crowley K. Sleep and sleep disorders in older adults. Neuropsychol Rev. 2011;21(1):41-53.
³ Eisai Inc. DAYVIGO Full Prescribing Information. 2020.
⁴ Scammell TE, Winrow CJ. Orexin receptors: pharmacology and therapeutic opportunities. Annu Rev Pharmacol Toxicol. 2011;51:243–266.
⁵Ferrie JE, et al. Sleep epidemiology – a rapidly growing field. Int J Epidemiol. 2011;40(6):1431–1437.
⁶ Roth T. Insomnia: definition, prevalence, etiology and consequences. J Clin Sleep Med. 2007;3(5 Suppl):S7–S10.
⁷ Institute of Medicine. Sleep disorders and sleep deprivation: An unmet public health problem. Washington, DC: National Academies Press. 2006.
⁸ American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-5. Arlington, VA: American Psychiatric Publishing, 2013.
⁹ 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.

Contact:
Eisai Inc.
Libby Holman
201-753-1945 
libby_holman@eisai.com  

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