3 results
Post Hoc Analysis of the Impact of Lemborexant on Patient-Reported Sleep and Insomnia Severity in Adults with Insomnia and Depression Histories
- Larry Culpepper, Andrew D. Krystal, Kate Pinner, Margaret Moline
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- Journal:
- CNS Spectrums / Volume 27 / Issue 2 / April 2022
- Published online by Cambridge University Press:
- 28 April 2022, p. 243
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Introduction
The dual orexin receptor antagonist lemborexant (LEM) is approved in multiple countries including the United States, Japan, Canada, and Australia for insomnia treatment in adults. In phase 3 study E2006-G000-303 (Study 303; SUNRISE-2; NCT02952820), LEM provided significant benefit vs placebo (PBO) on subjective sleep outcomes over 6 months and was well tolerated. This post hoc analysis evaluated the effect of LEM on sleep outcome measures and insomnia severity as assessed by the Insomnia Severity Index (ISI) over 6 months in subjects with a lifetime history of depression (DepHx subgroup). We performed this analysis as insomnia in DepHx subjects could be a residual symptom of unresolved depression, and therefore, these subjects may respond differently to insomnia treatment.
MethodsStudy 303 was a randomized, double-blind, 12 months global study in adults (≥18 years) with DSM-5 insomnia disorder. For 6 months (Treatment Period 1), subjects were randomized to PBO or LEM (5 mg [LEM5]; 10 mg [LEM10]). For the next 6 months (Treatment Period 2; not reported), PBO subjects were rerandomized to LEM and LEM subjects continued their original dose. The inclusion criteria allowed for participation of subjects with a lifetime DepHx, concomitant antidepressant medication use and/or mild depression (maximum Beck Depression Inventory II score of 19). Subjects had a baseline ISI total score (ISI-ts) ≥15.
ResultsThe Full Analysis Set comprised 949 subjects, including 112 subjects in the DepHx subgroup (PBO, n = 34; LEM5, n = 39; LEM10, n = 39). Baseline median subjective sleep onset latency (sSOL; minutes) was 52.9, 57.1, and 70.7 for PBO, LEM5, and LEM10, respectively. At 6 months, greater median decreases from baseline in sSOL were observed with LEM5 (−21.7) and LEM10 (−40.1) vs PBO (−12.9). Baseline mean subjective sleep efficiency (sSE; %) was 62.2, 59.2, and 62.4 for PBO, LEM5, and LEM10, respectively. At 6 months, greater mean (SD) increases from baseline in sSE were observed with LEM5 (17.2 [18.3]) and LEM10 (20.9 [19.0]) vs PBO (14.9 [15.4]). Baseline mean subjective wake after sleep onset (sWASO; minutes) was 123.7, 151.0, and 132.6 for PBO, LEM5, and LEM10, respectively. At 6 months, greater mean (SD) decreases from baseline in sWASO were observed with LEM5 (−52.7 [69.2]) and LEM10 (−68.8 [81.9]) vs PBO (−46.7 [69.4]). Mean baseline ISI-ts were 18.6, 19.9, and 19.0 PBO, LEM5, and LEM10, respectively. At 6 months, greater mean (SD) decreases from baseline in ISI-ts were observed with LEM5 (−9.1 [6.8]) and LEM10 (−10.0 [5.9]) vs PBO (−7.9 [5.6]). Treatment-emergent adverse event rates in the DepHx subgroup were similar to those in the overall study population.
DiscussionAt 6 months, LEM improved patient-reported sleep outcomes and reduced patient-reported insomnia severity in subjects with DepHx. These results suggest that LEM may be a therapeutic option for patients with insomnia and DepHx.
FundingEisai, Inc.
165 Impact of Lemborexant on Insomnia Disease Severity and Fatigue: Results from the 6-Month Placebo-Controlled Period of the Phase 3 SUNRISE-2 Study
- Margaret Moline, Mikko Kärppä, Jane Yardley, Dinesh Kumar, Kate Pinner, Carlos Perdomo, Gleb Filippov, Norman Atkins, Jr
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- Journal:
- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, pp. 305-306
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Study Objective(s):
This study examined the effects of lemborexant (LEM) compared with placebo (PBO) on subject-reported insomnia disease severity, assessed by the Insomnia Severity Index (ISI), and fatigue, assessed by the Fatigue Severity Score (FSS), from the 6-month PBO-controlled period of SUNRISE-2.
Method:SUNRISE-2 (NCT02952820; E2006-G000-303) was a 12-month randomized, double-blind, PBO-controlled (first 6-months) Phase 3 study. After an ~2-week PBO run-in, subjects were randomized to PBO, LEM 5mg (LEM5) or LEM 10mg (LEM10) for 6 months. The ISI and the FSS were administered at baseline [BL] and at the end of Months 1, 3, and 6. The ISI daytime functioning score (DFS), based on the ISI items that assess the impact of insomnia symptoms specific to daily functioning (items 4-7), was also evaluated. Mean changes from BL in ISI total score (ISI TS), ISI DFS, and FSS total score (FSS TS) were analyzed using a mixed-effect model repeated measurement analysis, adjusted for relevant factors and BL score (ISI TS, ISI DFS, or FSS TS) as a covariate.
Results:949 subjects (PBO, n=318; LEM5, n=316; LEM10, n=315) were included in the full analysis set. Median age was 55y (range 18-88y). Mean ISI TS at BL for PBO, LEM5, and LEM10 was 19.0, 19.6 and 19.1, respectively. While mean ISI TS decreased (improved) from BL for all groups, decreases were significantly larger for both LEM5 and LEM10 vs PBO at Month 1 (least squares mean treatment difference [LSM TD]: LEM5, −1.5 [P=0.001]; LEM10, −1.9 [P<0.0001]), Month 3 (LSM TD: LEM5, −2.0; LEM10, −2.6 [both P<0.0001]), and Month 6 (LSM TD: LEM5, −2.1; LEM10, −2.4 [both P<0.0001]). Decreases from BL in mean ISI DFS were also significantly larger for LEM5 and LEM10 vs PBO at Month 1 (LSM TD: LEM5, −0.7 [P=0.014]; LEM10, −0.9 [P=0.001]), Month 3 (LSM TD: LEM5, −1.2 [P=0.0001]; LEM10, −1.4 [P<0.0001]), and Month 6 (LSM TD: LEM5, −1.3; LEM10, −1.3 [both P<0.0001]).
Mean FSS TS at BL was 35.2, 37.4, and 36.0 for PBO, LEM5, and LEM10, respectively. Mean FSS TS decreased (improved) from BL in all groups at the end of Month 1 (decreases were larger and significant for LEM10 vs PBO [LSM TD: –2.0 (P=0.026)]), and Month 3 (decreases were larger and significant for LEM5 [LSM TD: –2.2 (P=0.021)] and LEM10 [LSM TD: –3.0; (P=0.001)] vs PBO). At Month 6, mean FSS TS remained improved from BL in all treatment groups (PBO, –6.3; LEM5, –10.1; and LEM10, –8.9). These decreases were larger and significant for LEM5 (LSM TD: –2.5 [P=0.013]) and LEM10 (LSM TD: –2.6 [P=0.013]) vs PBO. LEM was well tolerated with most adverse events mild to moderate in severity.
Conclusions:In SUNRISE-2, LEM5 and LEM10 significantly reduced subject-reported disease severity and fatigue vs PBO after 6 months of treatment. Reduced severity in insomnia symptoms with LEM5 and LEM10 also translated to improved daytime functioning.
Funding Acknowledgements:Supported by Eisai Inc.
164 Pooled Analyses of Patient-Reported Sleep Onset and Maintenance from Two Phase 3 Studies of Lemborexant
- Russell Rosenberg, Gary Zammit, Jane Yardley, Kate Pinner, Carlos Perdomo, Margaret Moline, Norman Atkins
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- Journal:
- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, pp. 304-305
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Study Objective(s):
The dual orexin receptor antagonist, lemborexant (LEM), is being investigated for the treatment of insomnia disorder. Drugs targeting the orexin system, like LEM, may decrease wakefulness and promote sleep with fewer potential adverse effects (AEs) than some currently available pharmacological insomnia therapies. LEM has been studied in 2 pivotal phase 3 trials for insomnia disorder, SUNRISE-1 (NCT02783729; E2006-G000-304) and SUNRISE-2 (NCT02952820; E2006-G000-303). Analyses presented here are derived from patient-reported (subjective) efficacy data pooled from SUNRISE-1 and SUNRISE-2 during 1-month of treatment in adult and elderly (age ≥65y) subjects with DSM-5 insomnia disorder.
Method:SUNRISE-1 was a 1-month, double-blind, randomized, placebo (PBO)- and active-controlled (zolpidem tartrate extended-release 6.25mg [ZOL; not reported), parallel-group study in 1006 subjects (age ≥55y). SUNRISE-2 was a 12-month (6-month PBO-controlled, 6-month active treatment), double-blind study in 949 subjects (age ≥18y). In both studies, subjects were randomized to PBO, LEM5, or LEM10 (SUNRISE-1 subjects could also be randomized to ZOL; not included in pooled analysis) following a 2-week PBO run-in. Changes from baseline (BL) in subjective sleep onset latency (sSOL), subjective sleep efficiency (sSE), and subjective wake after sleep onset (sWASO) were analyzed using mixed effect model repeated measurement analysis. Sleep onset and sleep maintenance responders were analyzed via Cochran–Mantel–Haenszel test stratified by study, region and age group.
Results:The pooled analysis set comprised 1693 subjects (PBO, n=527; LEM5, n=582; LEM10, n=584). Reductions from BL in sSOL were significantly greater for LEM5 and LEM10 vs PBO during the first 7 days of treatment and at the end of Month 1 (all comparisons P<0.0001). Both doses of LEM significantly increased sSE from BL (P<0.001 both time points) more than PBO and reduced sWASO from BL (P<0.0001 first 7 days [both doses]; P<0.05 [LEM5] and P<0.001 [LEM10] at Month 1) more than PBO. After the first 7 days and at the end of Month 1, the proportion of sSOL responders (≤20 min if BL >30 min) was statistically significantly larger for LEM5 and LEM10 vs PBO (first 7 days: both P<0.0001; last 7 days of Month 1: both P<0.001) and the proportion of sWASO responders (≤60 minutes and a reduction from BL by >10 min, if BL >60 min) was statistically significantly larger for LEM5 and LEM10 vs PBO (first 7 days: both P<0.01; last 7 days of Month 1: both P<0.05). LEM was well tolerated. Most AEs were mild to moderate in severity, and rates of severe or serious AEs were low.
Conclusions:LEM improved sleep onset and sleep maintenance in adult and elderly subjects with insomnia disorder, and was well tolerated. Average values on sleep maintenance endpoints showed that subjects treated with LEM obtained >1 hour of additional sleep per night vs subjects who received PBO.
Funding Acknowledgements:Supported by Eisai Inc.