Assessment of morning sleep propensity with lemborexant in adults with insomnia disorder in a randomized, placebo-controlled crossover study

Abstract Objective To evaluate effects of lemborexant (LEM), a dual orexin receptor antagonist, on next-morning sleep propensity assessed by a modified Multiple Sleep Latency Test (M-MSLT) in adults with insomnia disorder. Methods Study 107 (E2006-A001-107) was a phase 1, randomized, double-blind, four-period crossover study. Subjects (n=69) received oral single-dose placebo, LEM 5 mg (LEM5), and LEM 10 mg (LEM10) at bedtime in periods 1–3 in a randomized crossover and open-label flurazepam 30 mg in period 4. After an 8-h overnight sleep opportunity, the M-MSLT measured average sleep onset latency (SOL). Mean change from baseline in average SOL vs. placebo of -6.0 min or more was considered clinically meaningful. Other sleep propensity assessments included the proportion of subjects with average SOL >6 min shorter than placebo. LEM plasma concentrations, safety, and tolerability were also assessed. Results M-MSLT assay sensitivity was confirmed by a clinically meaningful decrease in average SOL with flurazepam vs. placebo (least squares mean [LSM] difference –6.06 min; 1-sided p<0.0001). In contrast, decreases in average SOL with LEM5 (LSM difference vs. placebo –1.15 min; 1-sided p=0.0262) and LEM10 (–3.48 min; p<0.0001) did not meet the pre-defined threshold for a clinically meaningful effect (LEM5, –2.12; LEM10, –4.46). Some individuals did experience higher sleep propensity (average SOL >6.0 min shorter than placebo), particularly with LEM10 (LEM10, 29.4%; LEM5, 13.2%). Conclusions In contrast to flurazepam, LEM5 and LEM10 did not show clinically meaningful mean increases in next-morning sleep propensity vs. placebo. The possibility that some subjects may experience residual morning effects cannot be excluded.

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164 Pooled Analyses of Patient-Reported Sleep Onset and Maintenance from Two Phase 3 Studies of Lemborexant

CNS Spectrums ◽

10.1017/s1092852920000802 ◽

2020 ◽

Vol 25 (2) ◽

pp. 304-305 ◽

Cited By ~ 1

Author(s):

Russell Rosenberg ◽

Gary Zammit ◽

Jane Yardley ◽

Kate Pinner ◽

Carlos Perdomo ◽

...

Keyword(s):

Sleep Onset ◽

Pooled Analysis ◽

Elderly Subjects ◽

Sleep Onset Latency ◽

Phase 3 ◽

Double Blind ◽

Subjective Sleep ◽

Sleep Maintenance ◽

Insomnia Disorder ◽

Patient Reported

Abstract: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.

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0486 Impact of Intrinsic Factors on Efficacy of Lemborexant: Subgroup Analyses of SUNRISE-2

SLEEP ◽

10.1093/sleep/zsaa056.483 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A186-A187

Author(s):

M Moline ◽

Y Inoue ◽

N Kubota ◽

K Pinner ◽

C Perdomo ◽

...

Keyword(s):

Sleep Onset ◽

Sleep Diary ◽

Sleep Onset Latency ◽

Double Blind ◽

Intrinsic Factors ◽

Insomnia Disorder ◽

Patient Reported ◽

Full Analysis ◽

The Impact ◽

Patient Subgroups

Abstract Introduction Lemborexant (LEM), a dual orexin receptor antagonist, demonstrated significant benefits vs placebo on patient-reported sleep outcomes in adults age ≥18y in SUNRISE-2 (NCT02952820; E2006-G000-303). The impact of intrinsic factors (sex, race, and region) on LEM efficacy outcomes was assessed. Methods SUNRISE-2 was a randomized, double-blind, global phase 3 study in adults age ≥18y with insomnia disorder (Full Analysis Set, n=949). Subjects received placebo (n=318) or LEM (5mg [LEM5], n=316; 10mg [LEM10]; n=315) for 6 months. At 6 months, placebo subjects were rerandomized to LEM for another 6 months (not reported here); LEM subjects remained on their assigned dose. Sleep diary-based (subjective) sleep onset latency (sSOL) and wake after sleep onset (sWASO) were assessed for prespecified patient subgroups including: sex (male [n=302], female [n=647]), race (white [n=679], black [n=76], Asian [n=178]), and region (North America [n=302], Europe/New Zealand [n=483], Asia [n=164]). Analyses were not controlled for multiplicity. Results LEM5 and LEM10 provided numerically greater median reductions (improvement) from baseline in sSOL vs placebo at 6 months in across all subgroups examined. Also, LEM5 and LEM10 led to mean reductions (improvement) from baseline at 6 months in sWASO for all subgroups. While several subgroups had small numbers of subjects, changes from baseline in sSOL and sWASO were in the direction of improvement in the majority of subgroups. Pharmacokinetic analyses showed no important differences in exposure by these factors. Conclusion LEM treatment demonstrated efficacy in improving sSOL and sWASO across patient subgroups, supporting common dosing instructions for both sexes and all races. Support Eisai Inc.

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0479 Sleep Onset and Sleep Maintenance Responder Profiles Over 12 Months of Treatment with Lemborexant: Results from SUNRISE-2

SLEEP ◽

10.1093/sleep/zsaa056.476 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A184-A184

Author(s):

G Zammit ◽

J Yardley ◽

K Pinner ◽

M Moline

Keyword(s):

Treatment Success ◽

Sleep Onset ◽

Sleep Diary ◽

Sleep Onset Latency ◽

Double Blind ◽

Subjective Sleep ◽

Sleep Maintenance ◽

Insomnia Disorder ◽

Patient Reported

Abstract Introduction In addition to analyzing treatment response by comparing change from baseline (CFB) between active treatment and placebo (PBO), it is also informative to evaluate the percent of patients with a given magnitude of response. This can help establish the expected degree of improvement for patients, thereby helping to determine treatment success. Methods SUNRISE-2 (NCT02952820; E2006-G000-303) was a randomized, double-blind, global phase 3 study of lemborexant (LEM) in adults (≥18y) with insomnia disorder. Subjects received PBO or LEM (5mg [LEM5]; 10mg [LEM10]) for 6mo. LEM subjects continued their original dose, while PBO subjects were rerandomized to LEM for another 6mo (not reported here). Responder profiles were constructed separately for patient-reported, sleep diary-based subjective sleep onset and sleep maintenance based on the cumulative proportion of subjects with CFBs in 10-minute increments for subjective sleep onset latency (sSOL) or subjective wake after sleep onset (sWASO), respectively. The proportion was based on number of subjects with baseline data (denominator) and data available at time of visit; study dropouts were considered nonresponders. Results Baseline values were similar (median sSOL [min]: PBO, 55.9; LEM5, 53.6; LEM10, 55.7; mean[SD] sWASO [min]: PBO, 132.5[80.2]; LEM5, 132.8[82.5]; LEM10, 136.8[87.4]). At 6mo, a higher percentage of subjects with CFB of ≥20min in sSOL was observed with LEM versus PBO (PBO, 30.4%; LEM5, 45.5%; LEM10, 44.9%). At 12mo, a similar percentage of responders with a ≥20min CFB in sSOL was observed for LEM (LEM5, 40.4%; LEM10, 43.3%). A higher percentage of subjects with a CFB in sWASO of ≥60min was observed for LEM versus PBO at 6mo (PBO, 24.2%; LEM5, 27.8%: LEM10, 30.2%); similar percentages were observed at 12mo with LEM (LEM5, 27.8%; LEM10, 27.7%). The majority of treatment-emergent adverse events were mild/moderate. Conclusion LEM treatment provided important levels of sustained efficacy over the long term. LEM was well tolerated. Support Eisai Inc.

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0473 Effectiveness and Safety of Lemborexant in Subjects Previously Treated with Placebo for 6 Months in SUNRISE-2

SLEEP ◽

10.1093/sleep/zsaa056.470 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A181-A182

Author(s):

J Yardley ◽

Y Inoue ◽

K Pinner ◽

C Perdomo ◽

G Filippov ◽

...

Keyword(s):

Adverse Events ◽

Sleep Onset ◽

Sleep Diary ◽

Sleep Onset Latency ◽

Double Blind ◽

Subjective Sleep ◽

Insomnia Disorder ◽

Previously Treated ◽

Treatment Changes ◽

Additional Improvement

Abstract Introduction In SUNRISE-2 (NCT02952820; E2006-G000-303), while lemborexant (LEM) provided significant benefit versus placebo (PBO) on sleep-diary measurements over 6mo, some improvement was noted in PBO subjects. We report outcomes from PBO subjects rerandomized to LEM during the last 6mo of SUNRISE-2. Methods SUNRISE-2 was a randomized, double-blind, global phase 3 study in adults (≥18y) with insomnia disorder. Subjects received PBO or LEM (5mg [LEM5]; 10mg [LEM10]) for 6mo. PBO subjects were rerandomized to LEM for another 6mo; LEM subjects continued assigned treatment. Changes from 6mo baseline (calculated after PBO completion) in subjective sleep onset latency (sSOL), subjective sleep efficiency (sSE), and subjective wake after sleep onset (sWASO) are reported for rerandomized subjects. Results At study baseline for PBO subjects (n=318), median sSOL (min) was 55.9, mean (SD) sSE (%) and sWASO (min) were 61.3 (17.8) and 132.5 (80.2), respectively. The 6mo baseline values for rerandomized PBO-LEM5 (n=133) and PBO-LEM10 (n=125) subjects, respectively, were: median sSOL, 31.2, 34.3; mean (SD) sSE, 70.5 (20.2), 71.1 (18.0); mean (SD) sWASO, 105.1 (80.6), 100.1 (84.6). Median sSOL decreased from the 6mo baseline after 1mo (PBO-LEM5, −3.2; PBO-LEM10, −2.9) and 6mo (PBO-LEM5, −2.7; PBO-LEM10, −5.0). Mean (SD) sSE increased from the 6mo baseline after 1mo (PBO-LEM5, 3.9 [12.1]; PBO-LEM10, 3.5 [8.1]) and 6mo (PBO-LEM5, 3.9 [13.6]; PBO-LEM10, 4.5 [13.0]). Mean (SD) sWASO decreased after 1mo (PBO-LEM5, −8.5 [49.4]; PBO-LEM10, −5.7 [36.1]) and 6mo (PBO-LEM5, −8.2 [49.0]; PBO-LEM10, −10.0 [58.8]). Treatment-emergent adverse events incidence was similar during PBO (62.7%) and LEM treatment (PBO-LEM5, 54.9%; PBO-LEM10, 57.7%). Adverse events were consistent with those seen in the initial 6mo of treatment for patients originally randomized to LEM. Conclusion Rerandomization to LEM was associated with additional improvement in sleep outcomes following the PBO-related response. LEM benefit was evident after 1mo and was sustained throughout treatment. LEM was well tolerated. Support Eisai Inc.

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Tasimelteon safely and effectively improves sleep in Smith–Magenis syndrome: a double-blind randomized trial followed by an open-label extension

Genetics in Medicine ◽

10.1038/s41436-021-01282-y ◽

2021 ◽

Author(s):

Christos M. Polymeropoulos ◽

Justin Brooks ◽

Emily L. Czeisler ◽

Michaela A. Fisher ◽

Mary M. Gibson ◽

...

Keyword(s):

Sleep Quality ◽

Crossover Study ◽

Total Sleep Time ◽

Sleep Time ◽

Open Label ◽

Double Blind ◽

Open Label Study ◽

Label Study ◽

Sleep Complaints ◽

Open Label Extension

Abstract Purpose To assess the efficacy of tasimelteon to improve sleep in Smith–Magenis syndrome (SMS). Methods A 9-week, double-blind, randomized, two-period crossover study was conducted at four US clinical centers. Genetically confirmed patients with SMS, aged 3 to 39, with sleep complaints participated in the study. Patients were assigned to treatment with tasimelteon or placebo in a 4-week crossover study with a 1-week washout between treatments. Eligible patients participated in an open-label study and were followed for >3 months. Results Improvement of sleep quality (DDSQ50) and total sleep time (DDTST50) on the worst 50% of nights were primary endpoints. Secondary measures included actigraphy and behavioral parameters. Over three years, 52 patients were screened, and 25 patients completed the randomized portion of the study. DDSQ50 significantly improved over placebo (0.4, p = 0.0139), and DDTST50 also improved (18.5 minutes, p = 0.0556). Average sleep quality (0.3, p = 0.0155) and actigraphy-based total sleep time (21.1 minutes, p = 0.0134) improved significantly, consistent with the primary outcomes. Patients treated for ≥90 days in the open-label study showed persistent efficacy. Adverse events were similar between placebo and tasimelteon. Conclusion Tasimelteon safely and effectively improved sleep in SMS.

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O043 “My Fitbit tells me I don’t sleep” – Validation of a consumer-wearable device (Fitbit Charge 3TM) using gold standard in-laboratory polysomnography to assess sleep in adults presenting for medical evaluation in a sleep laboratory

SLEEP Advances ◽

10.1093/sleepadvances/zpab014.042 ◽

2021 ◽

Vol 2 (Supplement_1) ◽

pp. A19-A19

Author(s):

M Munsif ◽

R Jumabhoy ◽

K Rangamuwa ◽

D Mansfield ◽

S Drummond ◽

...

Keyword(s):

Sleep Disorders ◽

Sleep Onset ◽

Sleep Time ◽

Sleep Onset Latency ◽

Medical Evaluation ◽

Insomnia Disorder ◽

Epoch Analysis ◽

A Prospective Study ◽

Screening Device ◽

Wake State

Abstract Background There has been a rapid growth in wearable devices marketed for sleep. Trackers such as the Fitbit collect data through an accelerometer and use heart rate variability to estimate the sleep-wake state. Currently, Fitbit validation studies have only been with “healthy” adults and Insomnia Disorder. Aims The purpose of this study is to evaluate the accuracy of Fitbit Charge3TM compared to in-lab polysomnography (PSG) in patients with sleep disorders. Our hypothesis is that Fitbit Charge 3TM will perform with less sensitivity and specificity relative to PSG in the presence of sleep disorders. Methods A prospective study of patients attending a PSG through Epworth Camberwell Sleep Lab between 2019–2021 will be conducted. Fitbit Charge3TM will be worn on the wrist with concurrent PSG monitoring. Parameters measured with both PSG and Fitbit Charge3TM will include total sleep time, Sleep onset latency, wake after sleep onset and time spent in N1, N2, N3 and REM sleep (min). Standard PSG data will be evaluated to diagnose sleep-disordered breathing. Progress to date:Ethics approval has been obtained, and 110 participants have been recruited. 30-second epoch-by-epoch analysis will now be conducted. Bland-Altman analyses will be performed to assess agreement between the Fitbit and PSG. Intended outcome and impact: Our novel study findings will provide evidence to address queries regarding the accuracy of the Fitbit trackers to evaluate sleep and may support the use of Fitbit Charge3TM as an initial screening device to assess sleep duration and sleep architecture in select patients.

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Serum and Lung Pharmacokinetics of ASN100, a Monoclonal Antibody Combination for the Prevention and Treatment of Staphylococcus aureus Pneumonia

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.722 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S310-S310 ◽

Cited By ~ 4

Author(s):

Zoltan Magyarics ◽

Fraser Leslie ◽

Steven A Luperchio ◽

Johann Bartko ◽

Christian Schörgenhofer ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Bacterial Infections ◽

Phase 1 ◽

Fixed Dose ◽

Open Label ◽

Post Dose ◽

Double Blind ◽

Dose Time ◽

Prevention And Treatment ◽

Acute Bacterial Infections

Abstract Background Monoclonal antibodies (mAbs) are well-suited for the prevention and treatment of acute bacterial infections. ASN100 is a combination of two fully human IgG1 mAbs, ASN-1 and ASN-2 that together neutralize six Staphylococcus aureus cytotoxins, alpha-hemolysin (Hla) and five leukocidins (HlgAB, HlgCB, LukED, LukSF [PVL] and LukGH) that are important in the pathogenesis of S. Aureus pneumonia. We aimed to characterize the pharmacokinetics (PK) of ASN100 in both serum and lung epithelial lining fluid (ELF) in male and female healthy volunteers. Methods The safety, tolerability, and serum and lung PK of single intravenous infusion of ASN100 was evaluated in a Phase 1 study. Eight subjects (3:1 randomization) in two double-blind cohorts received ASN100 (doses of 3600 mg or 8000 mg) or placebo. ASN-1 and ASN-2 were administered in a fixed dose 1:1 ratio. Twelve subjects received ASN100 open-label at doses of 3600 mg or 8000 mg and each underwent two bronchoalveolar lavage (BAL) fluid collections either on days 1 and 30 or on days 2 and 8 post-dosing. ASN-1 and ASN-2 concentrations were determined by ELISA. The ELF concentrations were normalized based on urea concentrations in serum and BAL fluid. Results No dose limiting toxicity was observed. Adverse events (AEs) showed no association of increased incidence with higher dose. All AEs were mild or moderate in severity, with 83.3% of subjects receiving ASN100 reporting at least one AE vs. 100% of placebo subjects. A dose proportional increase in serum peak and exposure (AUC) of ASN-1 and ASN-2 was observed and the serum PK of ASN-1 and ASN-2 were comparable (approximate half-life of each antibody was 3 weeks). Penetration of ASN-1 and ASN-2 into the ELF of the lung was observed at the first post-dose time point of 24 hours, peak concentrations were observed after day 2 and the mAbs remained detectable at day 30. Conclusion ASN100 was safe and well tolerated at doses up to 8000 mg (4000 mg ASN-1 and 4000 mg ASN-2). The PK profiles of ASN-1 and ASN-2 were comparable following simultaneous administration. Significant lung concentrations of each mAb were demonstrated between day 1 and 30 post-dosing. These data support continued clinical development of ASN100 for the prevention and treatment of S. Aureus pneumonia. Disclosures Z. Magyarics, Arsanis Biosciences GmbH: Employee, Salary. Arsanis, Inc.: Shareholder, Share options. F. Leslie, Arsanis., Inc.: Employee and Shareholder, Salary. S. A. Luperchio, Arsanis Inc.: Employee and Shareholder, Salary. B. Jilma, Arsanis Biosciences GmbH: Investigator, Investigator fee. C. Stevens, Arsanis Inc.: Employee and Shareholder, Salary.E. Nagy, Arsanis: Employee and Shareholder, Salary.

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Switching to Tenofovir Alafenamide in Elvitegravir-Based Regimens: Pharmacokinetics and Antiviral Activity in Cerebrospinal Fluid

Clinical Infectious Diseases ◽

10.1093/cid/ciz926 ◽

2019 ◽

Vol 71 (4) ◽

pp. 982-988 ◽

Cited By ~ 1

Author(s):

Qing Ma ◽

Andrew J Ocque ◽

Gene D Morse ◽

Chelsea Sanders ◽

Alina Burgi ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Antiviral Activity ◽

Virologic Failure ◽

Plasma Concentrations ◽

Open Label ◽

Assay Sensitivity ◽

Once Daily ◽

Hiv Rna ◽

The Central Nervous System ◽

Tenofovir Alafenamide

Abstract Background Tenofovir alafenamide fumarate (TAF) co-formulated with elvitegravir (EVG; E), cobicistat (C), and emtricitabine (F), a recommended antiretroviral regimen, was evaluated for distribution and antiviral activity in cerebrospinal fluid (CSF) as well as neurocognitive (NC) performance change in participants switching from E/C/F/tenofovir disoproxil fumarate (TDF) to E/C/F/TAF. Methods This was a 24-week, single-arm, open-label study in treatment-experienced adults living with human immunodeficiency virus (HIV). Nine participants switched from E/C/F/TDF (150/150/200/300 mg once daily) to E/C/F/TAF (150/150/200/10 mg once daily) at week 12. CSF and total plasma concentrations of EVG, TDF, TAF, tenofovir (TFV), and HIV RNA levels were measured at baseline and week 24. NC performance was estimated by the Montreal Cognitive Assessment. Results EVG concentrations in CSF and the CSF:plasma ratio remained stable (P = .203) over time. Following the switch, TFV concentrations in CSF and plasma declined (P = .004), although the TFV CSF:plasma ratio increased (P = .004). At week 24, median TAF plasma concentration was 11.05 ng/mL (range, 2.84–147.1 ng/mL) 2 hours postdose but was below assay sensitivity 6 hours after dosing. TAF was below assay sensitivity in all CSF specimens. HIV RNA was ≤40 copies/mL in all CSF and plasma specimens. Three participants (33%) had NC impairment at baseline and 2 (22%) remained impaired at week 24. Conclusions Switch to E/C/F/TAF was associated with reductions in TFV concentrations in CSF but stable EVG concentrations that exceeded the 50% inhibitory concentration for wild-type HIV, suggesting that EVG achieves therapeutic concentrations in the central nervous system. No virologic failure or significant NC changes were detected following the switch. Clinical Trials Registration NCT02251236.

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