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WOODCLIFF LAKE, N.J., June 11, 2019 /PRNewswire/ -- Eisai Inc. today announced data on the respiratory safety of investigational lemborexant with multiple and single dosing in healthy adult and elderly individuals, as well as in those with mild obstructive sleep apnea (OSA). Lemborexant, an investigational agent for sleep-wake regulation, is currently being studied for the treatment of insomnia, a sleep-wake disorder, and irregular sleep-wake rhythm disorder (ISWRD). These studies were presented at the 33^rd annual meeting of the Associated Professional Sleep Societies (SLEEP 2019) in San Antonio.

Insomnia is a chronic condition that leads to significant distress or impairment in daily functioning and often affects the ability of patients to wake ready the next day.¹ Respiratory safety is an important consideration in the treatment of insomnia, particularly in vulnerable individuals, such as the elderly and those with OSA.² Some currently available treatment options, including sedative-hypnotic medications, are associated with central respiratory depression.³

"Given the respiratory concerns regarding the treatment of insomnia and the vital importance of proper breathing during sleep, it is crucial that respiratory patterns are evaluated, particularly when caring for vulnerable populations," said Lynn Kramer, MD, Chief Clinical Officer and Chief Medical Officer, Neurology Business Group, Eisai.

Earlier this year, the U.S. Food and Drug Administration accepted for review the New Drug Application for lemborexant for the treatment of insomnia. A target Prescription Drug User Fee Act date is set for December 27, 2019.

Key respiratory safety data presented at SLEEP 2019 are from Study 102, a two-part study on the respiratory safety of lemborexant.

Respiratory Safety of Lemborexant in Adult and Elderly Subjects With Mild Obstructive Sleep Apnea (Poster 103/Abstract 0429)
This Phase 1, multicenter, multiple-dose, randomized, double-blind, placebo-controlled, two-period crossover study examined pharmacodynamic respiratory safety parameters in subjects with mild OSA following a single dose or multiple doses of lemborexant. Thirty-six adult and elderly subjects (aged 18 to 90 years; mean age=57.2) with mild OSA completed the study and were randomized to receive either lemborexant 10 mg or placebo for two treatment periods of eight nights each, separated by a washout period of at least 14 days. The study met its primary endpoint, finding there was no difference in least squares mean (LSM) apnea-hypopnea index (AHI) for lemborexant 10 mg compared to placebo (9.93 events per hour of sleep with lemborexant 10 mg and 10.00 with placebo) after multiple doses during total sleep time (TST).

The study also met all secondary endpoints, showing there was no difference in:

• LSM AHI after single doses of lemborexant 10 mg versus placebo (10.19 events per hour of sleep with lemborexant 10 mg and 10.22 with placebo).
• Lemborexant 10 mg versus placebo in LSM peripheral capillary oxygen saturation (SpO₂) after single (94.62% with lemborexant 10 mg and 94.54% with placebo) or multiple doses (94.65% and 94.39%).

In addition, the following secondary endpoint was met, assessing if there was a difference in percentage of TST during which SpO₂ dipped below the defined thresholds (less than 90%; less than 85%; less than 80%) after single (1.349% with lemborexant 10 mg and 1.037% with placebo; 0.170% and 0.102%; 0.014% and 0.012%) or multiple doses (1.102% with lemborexant 10 mg and 1.014% with placebo; 0.164% and 0.108%; 0.015% and 0.009%).

In these study populations, treatment-emergent adverse events (TEAEs) were mild to moderate in severity. The incidence of TEAEs reported was 15.8% with lemborexant 10 mg and 13.2% with placebo. The most common reported TEAE was somnolence (5.3%) with lemborexant 10 mg.

Respiratory Safety of Lemborexant in Healthy Adult and Elderly Subjects (Poster 104/Abstract 0430)
This Phase 1, multicenter, single-dose, randomized, double-blind, placebo-controlled, three-period crossover study examined whether a single dose of lemborexant decreased SpO₂ during TST in healthy adult and elderly subjects compared with placebo. Sixteen participants (aged 18 to 90 years; mean age=48.5 years) completed the study and were randomized into one of three treatment sequences to receive either placebo, lemborexant 10 mg, or lemborexant 25 mg, separated by a washout period of at least 14 days. The study met its primary endpoint, finding there was no difference in LSM SpO₂ during TST with a single dose of lemborexant compared with placebo (94.99% with lemborexant 10 mg, 95.06% with lemborexant 25 mg, and 95.35% with placebo).

The study met secondary endpoints, evaluating the difference in LSM AHI during TST for either dose of lemborexant compared to placebo (5.05 events per hour of sleep with lemborexant 10 mg, 3.37 with lemborexant 25 mg and 4.53 with placebo). In addition, the study assessed the differences with either dose of lemborexant compared to placebo in the percentage of TST during which SpO₂ dipped below 90% as measured by LSM (0.218% with lemborexant 10 mg, 0.277% with lemborexant 25 mg, and 0.033% with placebo), below 85% (0.004% with lemborexant 10 mg, 0.043% with lemborexant 25 mg, and -0.001% with placebo) or below 80% (0.002%, 0.001% and 0%).

TEAEs and treatment-related TEAEs were mild in severity. The incidence of TEAEs reported was 6.3% with lemborexant 10 mg, 23.5% with lemborexant 25 mg and 6.3% with placebo. The most common reported TEAE was somnolence, 6.3% with lemborexant 10 mg and 5.9% with lemborexant 25 mg. Lemborexant 10 mg is the maximum dose in Phase 3 clinical trials.

Information about completed and ongoing lemborexant clinical studies is available at clinicaltrials.gov.

This release discusses investigational uses of an agent in development and is not intended to convey conclusions about efficacy or safety. There is no guarantee that such investigational agent will successfully complete clinical development or gain health authority approval.

<Notes to editors> 

1. About Lemborexant
   Lemborexant is a novel investigational 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, suggesting that inhibiting inappropriate orexin signaling may enable initiation and maintenance of sleep. Eisai is investigating lemborexant as a potential treatment option for multiple sleep-wake disorders, such as insomnia. Additionally, a Phase 2 clinical study of lemborexant in patients with irregular sleep-wake rhythm disorder and mild to moderate Alzheimer's dementia is underway.
   
   
2. About Study 102⁴
   This Phase 1 study was conducted to determine if lemborexant as compared to placebo decreases the peripheral oxygen saturation during total sleep time in healthy adult and elderly participants after a single dose of treatment and to determine whether it increases the apnea-hypopnea index after single and multiple doses of treatment in adult and elderly participants with mild obstructive sleep apnea (OSA). The study was conducted in two cohorts, which were evaluated independently and concurrently.
   
   Part one consisted of a randomized, double-blind, placebo-controlled, three-period crossover study that examined the pharmacodynamic respiratory safety parameters in healthy adult and elderly volunteers following a single dose of treatment with lemborexant. Subjects participated in three treatment periods, each of one night's duration, separated by washout intervals of at least 14 days. In each treatment period participants received placebo or a single dose of lemborexant (10 mg or 25 mg). The primary objective for part one was to determine whether lemborexant as compared to placebo decreases mean peripheral oxygen saturation during total sleep time after a single dose of treatment.
   
   Part two consisted of a randomized, double-blind, placebo-controlled, two-period crossover study that examined pharmacodynamic respiratory safety parameters in subjects with mild OSA following a single dose or multiple doses of lemborexant. Subjects participated in two treatment periods, each of eight nights' duration, separated by washout intervals of at least 14 days. In each treatment period participants received placebo or lemborexant 10 mg. The primary objective for part two was to determine whether lemborexant 10 mg compared to placebo increases apnea hypopnea index (AHI) after single or multiple doses of treatment in patients with mild OSA. A secondary outcome for both cohorts was AHI as measured the day after treatment.
   
   
3. 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, which can lead to daytime consequences, such as fatigue, difficulty concentrating and irritability.^7,8
   
   Sleeping well is essential for good health, including brain health. Poor sleep is associated with a wide range of health consequences, including an increased risk of hypertension, accidental injury, diabetes, obesity, depression, heart attack, stroke and dementia, as well as adverse effects on mood and behavior.^7,9
   
   Experimental studies in animals and humans provide evidence of associations between sleep and disease risk factors, diseases and mortality.¹⁰ Studies suggest an optimal sleep duration between seven and eight hours.¹¹
   
   Women are 1.4 times more likely than men to suffer from insomnia.¹² Older adults also have 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.¹³
   
   
4. About Eisai
   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). Each group functions as an end-to-end global business with discovery, development, manufacturing and marketing capabilities. 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 eisai.com/us.

References
¹ American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-5. Arlington, VA: American Psychiatric Publishing, 2013.
² Seda G, Tsai S, Lee-Chiong T. Medication effects on sleep and breathing. Clin Chest Med. 2014;35(3):557–69.
³ Zagaria M. Central sleep apnea: potential impact of benzodiazepines, opioids, and CYP3A4 inhibitors. US Pharm. 2015: 40(7):21-24.
⁴ Eisai Inc. A randomized, double-blind, placebo-controlled, crossover study to evaluate the respiratory safety of lemborexant in adult and elderly healthy subjects and adult and elderly subjects with mild obstructive sleep apnea. (E2006-A001-102). (Clinicaltrials.gov Identifier NCT03471871). 2018. Unpublished data on file.
⁵ Ferrie 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 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.
⁹ Pase MP, Himali JJ, Grima NA, et al. Sleep architecture and the risk of incident dementia in the community. Neurology. 2017;89(12):1244-1250.
¹⁰ Cappuccio FP, et al. Sleep and cardio-metabolic disease. Curr Cardiol Rep. 2017;19:110.
¹¹ 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.
¹² 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.
¹³ Crowley K. Sleep and sleep disorders in older adults. Neuropsychol Rev. 2011;21(1):41-53.

Contacts:

Eisai Inc.
Libby Holman
201-753-1945
Libby_Holman@eisai.com

SOURCE Eisai Inc.