Extensive Analyses of Phase 3 Data for Investigational Lemborexant Assess Efficacy and Safety Profile for the Potential Treatment of Insomnia in Adults

WOODCLIFF LAKE, N.J., June 11, 2019 /PRNewswire/ -- Eisai Inc. today announced new long-term safety and pooled analyses from the Phase 3 clinical development program for lemborexant, an investigational agent for sleep-wake regulation, currently being studied for the treatment of insomnia, a sleep-wake disorder, and irregular sleep-wake rhythm disorder (ISWRD). These analyses of lemborexant assessed its efficacy on key insomnia measures, improvement in patient daytime function and long-term safety. Additionally, sleep architecture data were presented from the Phase 3 SUNRISE 1 study. The findings were presented at the 33rd annual meeting of the Associated Professional Sleep Societies (SLEEP 2019) in San Antonio.

"The Phase 3 pooled analyses provide new insights into lemborexant's impact on insomnia severity and several other important sleep measures, including sleep onset, sleep maintenance, and next-day functioning. As insomnia is a chronic condition, the long-term safety data are important for both potential patients and health care professionals," said Russell Rosenberg, PhD, D.ABSM, a principal investigator in the lemborexant studies and former Chairman of the Board of the National Sleep Foundation. "Many patients battle sleepless nights and can struggle to function the next day. These new findings presented at SLEEP 2019 provide further support for the potential role of lemborexant as a treatment option for the millions of people in the U.S. suffering from insomnia."

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.

"Treatment of insomnia can be challenging as it should address not only sleep onset and maintenance, but also the patient's ability to wake ready the next day," said Lynn Kramer, MD, Chief Clinical Officer and Chief Medical Officer, Neurology Business Group, Eisai. "Patients who participated in our pivotal Phase 3 studies and were treated with lemborexant experienced a reduction in Insomnia Severity Index scores, which include measures of daytime functioning."

Key safety and efficacy data presented at SLEEP 2019 are from SUNRISE 1 (Study 304), a one-month study in adults 55 and over, SUNRISE 2 (Study 303), a long-term study in adults 18 and over, and pooled analyses from the two Phase 3 clinical studies. Some of these data were derived from post hoc and exploratory analyses. Multiplicity adjustments were not applied, and these results should be interpreted appropriately.

Lemborexant Treatment for Insomnia: Six-month Safety (Poster 102/Abstract 0367)
This analysis presents safety results from the first six-month placebo-controlled period of the 12-month Phase 3 study, SUNRISE 2, which included 947 patients (lemborexant 5 mg, n=314, lemborexant 10 mg, n=314, placebo, n=319).

The majority of treatment-emergent adverse events (TEAEs) reported were mild or moderate. Serious TEAEs were observed in a small proportion of patients (2.2% with lemborexant 5 mg, 2.9% with lemborexant 10 mg, 1.6% with placebo). Treatment-related TEAEs were reported in a higher proportion of lemborexant 5 mg and 10 mg subjects compared to placebo (24.8%, 29.0%, 13.8%), with the most common treatment-related TEAE being somnolence. Overall, the incidence of TEAEs leading to discontinuation of the study drug was higher in the lemborexant 10 mg (8.3%) group vs. the lemborexant 5 mg (4.1%) and placebo (3.8%).

Lemborexant Treatment for Insomnia in Phase 3: Impact on Disease Severity (Poster 108/Abstract 0371)
In this post hoc pooled analysis of the Phase 3 SUNRISE 1 (Study 304) and SUNRISE 2 (Study 303) studies, which included a total of 1,693 patients (lemborexant 5 mg, n=582; lemborexant 10 mg, n=584; placebo, n=527), Insomnia Severity Index (ISI) total scores decreased compared to baseline after one month of nightly use as measured by least squares mean (LSM) (-7.2 for lemborexant 5 mg, -7.5 for lemborexant 10 mg, – 5.5 for placebo). Approximately one-third of those taking lemborexant experienced declines in the ISI total score < 10, the clinical threshold for insomnia, at the end of one month (33.0% for lemborexant 5 mg, 33.4% for lemborexant 10 mg, 20.3% for placebo). The proportion of patients with a decrease in ISI total score of ≥ 7 at the end of one month of treatment was greater with both doses of lemborexant compared with placebo (47.3% for lemborexant 5 mg, 47.8% for lemborexant 10 mg, 33.6% for placebo).

Decrease from baseline in ISI items 4-7 (ISI daytime functioning score) was evaluated to assess the change in insomnia symptoms of daytime functioning.

Efficacy and Tolerability of Lemborexant in Female and Male Subjects With Insomnia (Poster 105/Abstract 0368)
To determine the response of males and females to lemborexant treatment, post hoc analysis of pooled Phase 3 data was performed to assess change from baseline in patient-reported sleep diary parameters. Efficacy analyses included 402 (23.7%) male and 1,291 (76.3%) female patients, and safety analyses included 404 (25.0%) male and 1,286 (75.0%) female patients.

Patient-Reported Sleep Onset and Sleep Maintenance: Pooled Analyses of Lemborexant Phase 3 Studies (Poster 107/Abstract 0370)
In this post hoc pooled analysis of one-month data from the Phase 3 SUNRISE 1 and SUNRISE 2 studies, changes from baseline with lemborexant treatment were larger than those with placebo on subjective measures of sleep onset and sleep maintenance in adults and elderly patients with insomnia disorder. Average values on sleep maintenance endpoints showed that patients taking lemborexant obtained more than one hour of additional sleep per night.

A total of 1,693 patients were included in the efficacy analysis (lemborexant 5 mg, n=582, lemborexant 10 mg, n=584, placebo, n=527), and 1,690 patients in the safety analysis (lemborexant 5 mg, n=580, lemborexant 10 mg, n=582, placebo, n=528).

Median reductions from baseline in subjective sleep onset latency (sSOL) were larger for lemborexant 5 mg and 10 mg compared to placebo during the first seven days of treatment (-12.9 for lemborexant 5 mg, -13.6 for lemborexant 10 mg, -2.9 for placebo) and at the end of month one of treatment (-16.1 for lemborexant 5 mg, -17.9 for lemborexant 10 mg, -5.2 for placebo).

Median reductions from baseline in subjective wake after sleep onset (sWASO) were larger for lemborexant 5 mg and 10 mg compared to placebo during the first seven days of treatment (-29 for lemborexant 5 mg, -37.9 for lemborexant 10 mg, -14.7 for placebo) and at the end of month one of treatment (-33.1 for lemborexant 5 mg, -41.3 for lemborexant 10 mg, -25.8 for placebo).

Mean increases from baseline in subjective sleep efficiency (sSE) were greater for lemborexant 5 mg and 10 mg compared to placebo after the first seven days of treatment (8.4 for lemborexant 5 mg, 10.9 for lemborexant 10 mg, 4.3 for placebo) and at the end of month one of treatment (10.2 for lemborexant 5 mg, 12.8 for lemborexant 10 mg, 7.0 for placebo).

The majority of TEAEs were mild or moderate in severity. The overall incidence of TEAEs was 8.4% for lemborexant 5 mg, 10.9% for lemborexant 10 mg and 4.3% for placebo. The incidence of serious TEAEs was 10.2% for lemborexant 5 mg, 12.8% for lemborexant 10 mg and 7.0% for placebo. The most frequent TEAEs across treatment groups were somnolence and headache.

Effect of Lemborexant on Sleep Architecture in Older Adults With Insomnia Disorder (Poster 106/Abstract 0369)
In this exploratory analysis of adults age 55 and older with insomnia disorder from the Phase 3 SUNRISE 1 study, treatment with both doses of lemborexant assessed change from baseline in total sleep time compared to placebo and zolpidem ER after one month of treatment. SUNRISE 1 included the first ever Phase 3 head-to-head comparison versus zolpidem ER. 

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 SUNRISE 1 (Study 304)¹ 
   SUNRISE 1 was a multicenter, randomized, double-blind, placebo-controlled, active comparator, parallel-group study evaluating the efficacy and safety of lemborexant in 1,006 male or female adult patients 55 years and older (45% of patients were 65 years and older) with insomnia disorder conducted in North America and Europe. SUNRISE 1 included a pre-randomization phase of up to 35 days (including a two-week placebo run-in period) and a randomization phase comprised of a 30-day treatment period and a minimum two-week period without treatment prior to the end-of-study visit. In this study, patients were randomized to receive placebo or one of three treatment regimens (lemborexant 5 mg, lemborexant 10 mg, zolpidem ER 6.25 mg). The primary objective for SUNRISE 1 was to demonstrate using polysomnography that lemborexant at either the 5 mg or 10 mg dose is superior to placebo on objective sleep onset, as measured by latency to persistent sleep after the last two nights of one month of treatment. Key secondary objectives included change from baseline in sleep efficiency and wake after sleep onset (WASO) for both lemborexant doses compared to placebo, and WASO in the second half of the night (WASO2H) for both lemborexant doses compared to zolpidem ER, each after the last two nights of one month of treatment.
   
3. About SUNRISE 2 (Study 303)² 
   SUNRISE 2 was a 12-month multicenter, global, randomized, controlled, double-blind, parallel-group study of the efficacy and safety of lemborexant in 949 male or female adult participants 18 to 88 years of age with insomnia disorder. SUNRISE 2 included a pre-randomization phase of up to 35 days (including a two-week placebo run-in period) and a randomization phase comprised of a six-month placebo-controlled treatment period, a six-month period of only active treatment and a two-week period without treatment prior to the end-of-study-visit. In this study, during the placebo-controlled treatment period, patients were randomized to receive placebo or one of two treatment regimens (lemborexant 5 mg or 10 mg). During the active-only treatment period, patients who received placebo during the first period were re-randomized to receive lemborexant 5 mg or 10 mg. Patients who received active treatment during the first period continued on the treatment to which they were originally randomized. The primary objective was to determine the efficacy of lemborexant 5 mg and 10 mg compared to placebo on patient-reported (subjective) sleep onset latency after six months of treatment. Key secondary endpoints were mean change from baseline in subjective sleep efficiency and subjective wake after sleep onset (sWASO) for lemborexant 5 mg and 10 mg compared to placebo after six months of treatment.
   
4. 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.^5,6
   
   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.^5,7
   
   Experimental studies in animals and humans provide evidence of associations between sleep and disease risk factors, diseases, and mortality.⁸ 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.¹⁰ 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.¹¹
   
5. 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 Eisai Inc. A multicenter, randomized, double-blind, placebo-conrolled, active comparator, parallel-group study of the efficacy and safety of lemborexant in subjects 55 years and older with insomnia disorder. (E2006-G000-304). (Clinicaltrials.gov Identifier NCT02783729). 2018. Unpublished data on file.
² Eisai Inc. A long-term multicenter, randomized, double-blind, controlled, parallel-group study of the safety and efficacy of lemborexant in subjects with insomnia disorder (E2006-G000-303). (Clinicaltrials.gov Identifier NCT02952820). 2018. Unpublished data on file.
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 Institute of Medicine. Sleep disorders and sleep deprivation: An unmet public health problem. Washington, DC: National Academies Press. 2006.
⁶ 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.
⁷ 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.
⁸ Cappuccio FP, et al. Sleep and cardio-metabolic disease. Curr Cardiol Rep. 2017;19:110.
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.
¹⁰ 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.
¹¹ Crowley K. Sleep and sleep disorders in older adults. Neuropsychol Rev. 2011;21(1):41-53.

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