WOODCLIFF LAKE, N.J., Sept. 27, 2019 /PRNewswire/ -- Eisai Inc., the U.S. pharmaceutical subsidiary of Eisai Co., Ltd., today announced new effectiveness and safety data from the Phase 3 clinical development program for lemborexant, an investigational agent for sleep-wake regulation, which is currently being studied for the treatment of insomnia, a sleep-wake disorder, and for Irregular Sleep-Wake Rhythm Disorder (ISWRD) in patients with Alzheimer's disease (AD) dementia.

The following findings were shared during oral presentations at the 2019 World Sleep Congress, September 20-25, in Vancouver, Canada:

• New 12-month data from the Phase 3 SUNRISE 2 study (Study 303) report the safety/tolerability of lemborexant over a 12-month period and qualitative persistence of lemborexant effectiveness through 12 months. In addition, mean ratings for quality of sleep and morning alertness showed improvement from baseline through 12 months with both doses of lemborexant compared to placebo. Qualitative persistence of improved sleep quality and morning alertness after 12 months of lemborexant was also observed.
• A new analysis of sleep architecture data from SUNRISE 1 (Study 304), the first Phase 3 head-to-head study including pre-specified endpoints vs. zolpidem tartrate extended-release (zolpidem ER), reflected lemborexant's impact on REM and non-REM sleep, and total sleep time compared to placebo and zolpidem ER after one month of treatment.
• Additionally, results of a study of lemborexant in the first mouse model of ISWRD in AD reflected the compound's impact on REM and non-REM sleep during resting and active periods, and on circadian rhythm variability.

"The analysis of long-term data from SUNRISE 2 examines the effectiveness and safety/tolerability of lemborexant, as well as its impact on patient-reported sleep quality and next-morning alertness measures across 12 months of treatment, and further reinforces our confidence in its role as a potential treatment option for insomnia," said Lynn Kramer, MD, Chief Clinical Officer and Chief Medical Officer, Neurology Business Group, Eisai. "Insomnia is often a chronic condition for which patients may require treatment over an extended period of time, underscoring the need for safe and effective treatments.¹ These results are important because lemborexant is the first investigational compound to report both sleep onset and sleep maintenance data over a 12-month period in a pivotal clinical study."   

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.

Long-term Effectiveness and Safety of Lemborexant in Adults with Insomnia Disorder: 12-month Results From SUNRISE 2

In the Phase 3 clinical trial SUNRISE 2, following the six-month placebo-controlled treatment period, patients who received placebo were randomized to lemborexant 5 mg or lemborexant 10 mg for the next six months, while those who received lemborexant in the first six months continued at the same dose. The placebo-controlled treatment period included 942 patients (placebo, n=316; lemborexant 5 mg, n=314; lemborexant 10 mg, n=312) and the active-only treatment period included 881 patients (lemborexant 5 mg, n=444; lemborexant 10 mg, n=437). Mean change from baseline in patient-reported measures of sleep onset and sleep maintenance at 12 months was a secondary endpoint. No multiplicity adjustment was made for the analysis of these data. Active-only treatment period data for patients who received lemborexant in the first six months was presented at 2019 World Sleep Congress.

Treatment with lemborexant 5 mg resulted in mean reductions from baseline in subjective sleep onset latency (sSOL, the time taken between going to bed and falling asleep) of 29.4 minutes at six months and 30.0 minutes at 12 months. Lemborexant 10 mg resulted in mean reductions in sSOL from baseline of 32.5 minutes at six months and 34.5 minutes at 12 months.  Treatment with placebo resulted in mean reductions from baseline in sSOL of 16.6 minutes at six months.

Treatment with lemborexant 5 mg resulted in mean increases from baseline in subjective sleep efficiency (sSE, the percentage of time spent asleep while in bed) of 15.3% at six months and 15.8% at 12 months. Lemborexant 10 mg resulted in mean increases in sSE from baseline of 15.6% at six months and 17.6% at 12 months.  Treatment with placebo resulted in mean increases from baseline in sSE of 10.4% at six months.

In subjective wake after sleep onset (sWASO, a measure of sleep maintenance) lemborexant 5 mg resulted in mean reductions from baseline of 51.5 minutes at six months and 53.4 minutes at 12 months. Lemborexant 10 mg resulted in mean reductions from baseline of 48.1 minutes at six months and 56.8 minutes at 12 months. Treatment with placebo resulted in mean reductions from baseline in sWASO of 32.1 minutes at six months.

In addition to these sleep parameters, patients were asked to rate their quality of sleep and morning sleepiness/alertness on a scale of 1 (extremely poor or sleepy, respectively) to 9 (extremely good or alert, respectively).

In quality of sleep, treatment with lemborexant 5 mg resulted in mean increases from baseline of 1.0 at six months and 1.5 at 12 months. Treatment with lemborexant 10 mg resulted in mean increases from baseline of 1.3 at six months and 1.6 at 12 months. Treatment with placebo resulted in a mean increase from baseline in quality of sleep of 1.0 at six months.

In morning sleepiness/alertness, treatment with lemborexant 5 mg resulted in mean increases in alertness from baseline of 0.78 at six months and 1.11 at 12 months. Treatment with lemborexant 10 mg resulted in mean increases from baseline of 1.1 at six months and 1.31 at 12 months. Treatment with placebo resulted in a mean increase in alertness from baseline of 0.8 at six months.

During the active-only treatment period, the most common treatment-emergent adverse events (TEAEs, greater than 5%) was nasopharyngitis. A small proportion of patients discontinued the study due to a TEAE (lemborexant 5 mg, 1.6%; lemborexant 10 mg, 1.8%).

"These long-term results reinforce our six-month findings on the safety and effectiveness of treatment with lemborexant in adults with insomnia," said Margaret Moline, PhD, Executive Director and International Project Team Lead, Eisai.

Effect of Lemborexant Compared With Placebo and Zolpidem Extended Release on Sleep Architecture in Older Adults With Insomnia Disorder

This exploratory analysis of adults age 55 and older with insomnia disorder using polysomnography (PSG) data from SUNRISE 1 assessed change from baseline in total sleep time in lemborexant 5 mg and lemborexant 10 mg 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. 

PSG was used to assess sleep architecture at baseline during the first two (Nights 1/2) and last two nights of treatment for the month (Nights 29/30). Mean values for each sleep stage were based on two consecutive nights of PSG recordings.

Treatment with either dose of lemborexant led to greater mean increases from baseline compared to placebo in total non-REM sleep on Nights 1/2 (14.4, 45.8, 47.9 minutes for placebo, lemborexant 5 mg, and lemborexant 10 mg respectively).  Greater mean increases in non-REM sleep were reported for both doses of lemborexant compared to placebo and zolpidem ER on Nights 29/30 (21.5, 47.5, 46.0 and 38.3 minutes for placebo, lemborexant 5 mg, lemborexant 10 mg and zolpidem ER respectively).  

Greater mean increases in total REM sleep were also reported for both doses of lemborexant compared to placebo and zolpidem ER on Nights 1/2 (5.0, 19.4, 31.7 and 5.7 minutes for placebo, lemborexant 5 mg, lemborexant 10 mg and zolpidem ER respectively) and Nights 29/30 (4.2, 14.5, 21.9, and 5.0 minutes, respectively).

Treatment with either dose of lemborexant led to greater mean increases in total sleep time (TST) on Nights 1/2 (19.4, 65.2, 79.6 and 55.3 minutes for placebo, lemborexant 5 mg, lemborexant 10 mg and zolpidem ER respectively) and Nights 29/30 (25.7, 62.0, 67.9 and 43.3 minutes respectively).

Additionally, for both doses of lemborexant greater mean decreases from baseline in REM latency compared to placebo and zolpidem were reported for both Nights 1/2 (-6.9, -42.6, -49.6, and -0.2 minutes, for placebo, lemborexant 5 mg, lemborexant 10 mg and zolpidem ER respectively) and Nights 29/30 (-7.7, –30.7, –37.7, and –4.0 minutes, respectively).  

Senescence-Accelerated Mouse Prone-8 SAMP8 Mice as a Preclinical Model For Irregular Sleep- Wake Rhythm Disorder and Efficacy of the Dual Orexin (Hypocretin) Receptor Antagonist Lemborexant

In this preclinical study, senescence-accelerated mouse prone-8 (SAMP8), a mouse strain that has been reported to have memory impairments and AD-like pathophysiological changes, and control mice received placebo, or lemborexant 3 or 30 mg/kg orally at the onset of light (n=8 in each group in a cross-over fashion), with continuous brain wave/neck muscle recordings for three days.

Among SAMP8 mice, lemborexant increased the percentage of time spent in non-REM sleep during the resting period (49.8%, 52.2% and 56.6% for placebo, lemborexant 3 mg/kg and lemborexant 30 mg/kg respectively). Additionally, lemborexant reduced the percentage of time spent in non-REM (37.7%, 35.4% and 32.7% for placebo, lemborexant 3 mg/kg and lemborexant 30 mg/kg respectively) and REM sleep (6.4%, 6.2% and 5.5%, respectively) during the active period.

Both doses of lemborexant also reduced circadian rhythm variability compared to placebo (32.22, 1.32 and 2.11 variability with placebo, lemborexant 3 mg/kg and lemborexant 30 mg/kg respectively) and corrected circadian phase misalignment in SAMP8 mice. With respect to circadian phase misalignment, lemborexant caused a delay of the wakefulness phase in SAMP8 mice (10.31 ± 2.04 ZT, 14.00 ± 0.56 ZT, and 15.41 ± 0.64 ZT with placebo, lemborexant 3 mg/kg and lemborexant 30 mg/kg, respectively).

The results provide support for further clinical evaluation of lemborexant in AD patients suffering from ISWRD.

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 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.

3. About SUNRISE 1 (Study 304)³ 
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.

4. About Sleep Disorders
Population studies show that sleep disorders affect many more people worldwide than previously thought.⁴ Insomnia symptoms affect approximately 30% of the adult population worldwide.⁵ 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.^6,7

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.^6,8

Experimental studies in animals and humans provide evidence of associations between sleep and disease risk factors, diseases, and mortality.⁹ Studies suggest an optimal sleep duration between seven and eight hours.¹⁰

Women are 1.4 times more likely than men to suffer from insomnia.¹¹ 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.¹²

5. About ISWRD (Irregular Sleep-Wake Rhythm Disorder)
ISWRD is a type of circadian rhythm sleep disorder where the pattern of sleep and wakefulness that repeats itself over a 24-hour period in healthy individuals is broken down, and sleeping and waking occur instead at various times during the day and night. This is often observed in patients with dementia.¹³ Although referred to in this press release as ISWRD, the condition is also known as a Circadian Rhythm Sleep Disorder-Irregular Sleep Wake Type.

6. 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 Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307–349.
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 Eisai Inc. A multicenter, randomized, double-blind, placebo-controlled, 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.
⁴ Ferrie JE, et al. Sleep epidemiology – a rapidly growing field. Int J Epidemiol. 2011;40(6):1431–1437.
⁵ Roth T. Insomnia: definition, prevalence, etiology and consequences. J Clin Sleep Med. 2007;3(5 Suppl):S7–S10. 
⁶ Institute of Medicine. Sleep disorders and sleep deprivation: An unmet public health problem. Washington, DC: National Academies Press. 2006.
⁷ 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.
⁸ 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.
⁹ Cappuccio FP, et al. Sleep and cardio-metabolic disease. Curr Cardiol Rep. 2017;19:110.
¹⁰ 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.
¹¹ 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.
¹² Crowley K. Sleep and sleep disorders in older adults. Neuropsychol Rev. 2011;21(1):41-53.
¹³ Zhu L and Zee P. Circadian Rhythm Sleep Disorders. Neurol Clin. 2012 November;30(4):1167–1191.

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