02 Oct SUNRISE 2 Trial: Long-Term Safety and Efficacy of DAYVIGO™ (lemborexant) For Insomnia in Adults

MedicalResearch.com Interview with:

Dr. Moline

Margaret Moline, PhD
Executive Director, Neurology Business Group, Eisai, Inc
Lemborexant International Program Lead and Global Medical Lead

MedicalResearch.com: What is the background for this study? What are the main findings?

• SUNRISE 2 was one of two pivotal Phase 3 studies evaluated in the U.S. Food and Drug Administration’s approval of DAYVIGO (lemborexant) CIV in December 2019.
• SUNRISE 2 was a pivotal six-month placebo-controlled treatment trial with a 6-month active treatment 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 for the first six months of the study (Treatment Period 1).
• 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 (sSE; the proportion of time spent asleep per time in bed) and subjective wake after sleep onset (sWASO; the minutes of wake from the onset of sleep until wake time). These endpoints were measured by sleep diary.
• At Virtual SLEEP 2020, a post-hoc analysis of SUNRISE 2 was shared in an oral presentation, which looked specifically at the long-term efficacy and safety of lemborexant in elderly adults with insomnia disorder.
• Insomnia disorder, a chronic condition with long-term consequences for health and well-being, is prevalent in older adults.
• This 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. 

MedicalResearch.com: What should readers take away from your report?

• This 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 TEAEs were headache (DAYVIGO 5 mg, 1.4%; DAYVIGO 10 mg, 6.3%) and urinary tract infection (DAYVIGO 5 mg, 1.4%; DAYVIGO 10 mg, 6.3%).

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

• Eisai remains committed to studying DAYVIGO and offering additional research that is helpful to health care providers as they seek to determine the appropriate treatment for patients experiencing insomnia.
• For example, additional data presented at Virtual SLEEP 2020 included:
  • 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

MedicalResearch.com: Is there anything else you would like to add?

• The full prescribing information is available at www.dayvigo.com.
• Patients with insomnia symptoms should speak to a health care professional about treatment options.

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.

Citation:

Mikko Kärppä, Jane Yardley, Kate Pinner, Gleb Filippov, Gary Zammit, Margaret Moline, Carlos Perdomo, Yuichi Inoue, Kohei Ishikawa, Naoki Kubota, Long-term efficacy and tolerability of lemborexant compared with placebo in adults with insomnia disorder: results from the phase 3 randomized clinical trial SUNRISE 2, Sleep, Volume 43, Issue 9, 1 September 2020, zsaa123, https://doi.org/10.1093/sleep/zsaa123

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Last Updated on October 2, 2020 by Marie Benz MD FAAD