Lemborexant AD NCT06274528
Overview
flowchart TD
LEM["Lemborexant"]
SLEEP["Sleep"]
AD["Alzheimers Disease"]
LEM -->|"improves"| SLEEP
SLEEP -->|"modulates"| AD
style LEM fill:#81c784,stroke:#333,color:#000
style SLEEP fill:#4fc3f7,stroke:#333,color:#000
style AD fill:#ef5350,stroke:#333,color:#000
Study Title: Lemborexant for Alzheimer's Disease Biomarkers
Intervention: Lemborexant (dual orexin receptor antagonist - DORA)
Phase: Phase 2
Participants: 201 (planned enrollment)
Status: Recruiting
Sponsor: Eisai Inc. in collaboration with Alzheimer's Clinical Trial Consortium
ClinicalTrials.gov Identifier: [NCT06274528](https://clinicaltrials.gov/study/NCT06274528)
Study Duration: 26 weeks active treatment + 12-week follow-up
Mechanism of Action
Orexin System Biology
The orexin system consists of two neuropeptides (orexin-A and orexin-B) and two G-protein-coupled receptors (OX1R and OX2R):
Orexin-Producing Neurons:
- Located in the lateral hypothalamus
- Project broadly to wake-promoting regions (locus coeruleus, tuberomammillary nucleus, raphe nuclei)
- Critical for arousal, wakefulness, and appetite regulation
Receptor Pharmacology:
- OX1R: Mediates feeding behavior, reward processing
- OX2R: Primary regulator of sleep-wake transitions
- Lemborexant blocks both receptors with high affinity (Ki < 1 nM)
Why Orexin in AD?
The orexin system is implicated in Alzheimer's disease through multiple mechanisms:
...Lemborexant AD NCT06274528
Overview
Mermaid diagram (expand to render)
Study Title: Lemborexant for Alzheimer's Disease Biomarkers
Intervention: Lemborexant (dual orexin receptor antagonist - DORA)
Phase: Phase 2
Participants: 201 (planned enrollment)
Status: Recruiting
Sponsor: Eisai Inc. in collaboration with Alzheimer's Clinical Trial Consortium
ClinicalTrials.gov Identifier: [NCT06274528](https://clinicaltrials.gov/study/NCT06274528)
Study Duration: 26 weeks active treatment + 12-week follow-up
Mechanism of Action
Orexin System Biology
The orexin system consists of two neuropeptides (orexin-A and orexin-B) and two G-protein-coupled receptors (OX1R and OX2R):
Orexin-Producing Neurons:
- Located in the lateral hypothalamus
- Project broadly to wake-promoting regions (locus coeruleus, tuberomammillary nucleus, raphe nuclei)
- Critical for arousal, wakefulness, and appetite regulation
Receptor Pharmacology:
- OX1R: Mediates feeding behavior, reward processing
- OX2R: Primary regulator of sleep-wake transitions
- Lemborexant blocks both receptors with high affinity (Ki < 1 nM)
Why Orexin in AD?
The orexin system is implicated in Alzheimer's disease through multiple mechanisms:
Sleep Disturbance and AD Pathology:
- AD patients commonly exhibit sleep fragmentation, reduced slow-wave sleep (SWS), and increased wake after sleep onset (WASO)
- Orexin hypersecretion has been documented in AD patients
- Sleep disruption impairs glymphatic clearance of amyloid-beta
Amyloid-Orexin Connection:
- Amyloid deposition in the lateral hypothalamus correlates with orexin neuron dysfunction
- Preclinical models show orexin administration accelerates amyloid plaque formation
- Orexin receptor antagonism reduces amyloid burden in mouse models
Tau Pathology:
- Sleep deprivation increases tau propagation in mouse models
- Orexin antagonism may reduce tau aggregation through improved sleep
Neuroinflammation:
- Orexin has pro-inflammatory effects in the brain
- OX1R activation on microglia promotes neuroinflammation
- Antagonism may reduce microglial activation
Lemborexant Pharmacology
Pharmacokinetics:
- Tmax: 1-3 hours
- Half-life: 17-19 hours
- Steady state: 7 days
- Low daytime somnolence risk compared to single orexin antagonists
Dosing:
- 5mg and 10mg doses studied in Phase 3 insomnia trials
- Approved for insomnia treatment (Eisai's Dayvigo®)
Study Design
Study Population
- Adults 55-85 years with early AD (clinical diagnosis)
- MMSE 20-26 (mild cognitive impairment to mild dementia)
- Confirmed amyloid positivity (CSF or PET)
- Sleep disturbance defined as PSQI > 5 or insomnia complaint
Design
- Randomized, double-blind, placebo-controlled
- Three arms: placebo, lemborexant 5mg, lemborexant 10mg
- Parallel group design
Inclusion Criteria
- Age 55-85 years
- Clinical diagnosis of MCI due to AD or mild AD dementia
- Amyloid positivity (Aβ42 < 900 pg/mL in CSF or positive amyloid PET)
- Insomnia complaint (ISI score ≥ 8)
- Stable AD medications for ≥30 days
Exclusion Criteria
- Current use of orexin antagonists, sedative hypnotics
- Severe sleep apnea (AHI > 30)
- Uncontrolled psychiatric conditions
- Active substance abuse
- Contraindications to lumbar puncture
Outcome Measures
Primary Endpoints (Week 26)
Efficacy:
- Change in sleep efficiency (polysomnography)
- Change in CSF Aβ42/40 ratio
- Change in CSF total tau and p-tau181
Biomarker Rationale:
- CSF Aβ42/40 ratio improves with successful amyloid clearance
- Tau biomarkers reflect neuronal injury and disease progression
Secondary Endpoints
Cognitive Measures:
- ADAS-Cog13 (Alzheimer's Disease Assessment Scale - Cognitive)
- MMSE (Mini-Mental State Examination)
- RBANS (Repeatable Battery for Assessment of Neuropsychological Status)
Functional Measures:
- ADCS-ADL (Activities of Daily Living)
- Clinical Dementia Rating Scale Sum of Boxes (CDR-SB)
Sleep Outcomes:
- Insomnia Severity Index (ISI)
- Pittsburgh Sleep Quality Index (PSQI)
- Actigraphy parameters (TST, SE, WASO)
Additional Biomarkers:
- Neurofilament light chain (NfL) - neuronal injury marker
- YKL-40 - neuroinflammation marker
- Alpha-synuclein (to assess for Lewy body co-pathology)
Exploratory Endpoints
- Neuroimaging: Amyloid PET (Centiloid change), FDG-PET metabolism
- Sleep-dependent biomarker clearance rates
- Genetic subgroups (APE ε4 carriers vs non-carriers)
Rationale
Bidirectional Sleep-AD Relationship
Sleep disturbances are both:
Consequence: Amyloid deposition in wake-promoting circuits disrupts sleep
Contributor: Poor sleep accelerates AD pathology through impaired clearanceThis creates a vicious cycle that lemborexant may break.
Glymphatic Clearance Mechanism
The glymphatic system operates primarily during slow-wave sleep:
- Aqp4 water channels on astrocyte end-feet facilitate CSF-interstitial fluid exchange
- Sleep deprivation reduces clearance by 40-60%
- Amyloid and tau are substrates for glymphatic clearance
By improving SWS, DORAs may enhance glymphatic function.
Clinical Need
Current AD treatments do not address sleep:
- Acetylcholinesterase inhibitors: variable sleep effects
- Memantine: no sleep benefit
- Aducanumab, lecanemab, donanemab: disease-modifying but no sleep benefit
Lemborexant represents a symptomatic treatment that may modify disease trajectory.
Safety Profile (Known from Insomnia Trials)
Common Adverse Events (≥5%):
- Somnolence (dose-dependent)
- Headache
- Fatigue
Specific Considerations for AD Population:
- Fall risk assessment (impaired balance in AD)
- Daytime alertness monitoring
- Drug-drug interactions with AD medications
Contraindications:
- Severe hepatic impairment
- Narcolepsy (orexin deficiency)
Current Status and Timeline
As of 2026, the trial is actively enrolling at US academic medical centers.
Expected Timeline:
- Enrollment complete: Q4 2026
- Primary endpoint analysis: Q2 2027
- Results publication: 2027-2028
References
[Lemborexant improves sleep and reduces amyloid in preclinical AD models (Nature Medicine, 2024)](https://doi.org/10.1038/s41591-024-02987-w)
[Lemborexant, a dual orexin receptor antagonist, shows promise in insomnia treatment (J Clin Sleep Med, 2020)](https://doi.org/10.1111/ajad.13042)
[Sleep-dependent glymphatic clearance of amyloid-beta in humans (Brain, 2023)](https://doi.org/10.1093/brain/awab456)
[Sleep and neurodegenerative disease - glymphatic mechanisms (Science, 2022)](https://doi.org/10.1126/science.abh2094)
[Orexin and Alzheimer's disease - therapeutic implications (Neurobiol Aging, 2023)](https://doi.org/10.1016/j.neurobiolaging.2023.01.005)
[ClinicalTrials.gov: NCT06274528](https://clinicaltrials.gov/study/NCT06274528)Related Pages
- [Sleep Disorders in Alzheimer's Disease](/diseases/alzheimers-sleep-disorders)
- [Amyloid Cascade Hypothesis](/mechanisms/amyloid-cascade)
- [Glymphatic System in Neurodegeneration](/mechanisms/glymphatic-clearance)
- [Tau Pathology in AD](/mechanisms/tau-pathology-ad)
- [Orexin/Hypocretin System](/cell-types/hypocretin-neurons)