A Study to Assess Safety and Target Engagement of E2814 in Participants With Mild to Moderate Cognitive Impairment Due to Dominantly Inherited Alzheimer’s Disease

Overview

The primary objective of the study is to assess the safety and tolerability of intravenous (IV) infusions of E2814 in participants with dominantly inherited Alzheimer's disease (DIAD), and to evaluate target engagement (TE) of E2814 on microtubule binding region (MTBR)-tau species in cerebrospinal fluid (CSF) in participants with DIAD.

Full Title of Study: “An Open-Label Phase 1b/2 Study to Assess Safety and Target Engagement of E2814 in Subjects With Mild to Moderate Cognitive Impairment Due to Dominantly Inherited Alzheimer’s Disease”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: April 15, 2024

Interventions

  • Drug: E2814
    • E2814 intravenous infusion.

Arms, Groups and Cohorts

  • Experimental: Phase 1b: E2814
    • Participants will receive E2814 as an intravenous infusion at set intervals over 12 weeks in Phase 1b
  • Experimental: Phase 2: E2814
    • Participants will receive E2814 as an intravenous infusion at set intervals over 96 weeks in Phase 2.

Clinical Trial Outcome Measures

Primary Measures

  • Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    • Time Frame: Screening up to 100 days after the last dose of study drug (approximately 122 Weeks)
  • Number of Participants With Markedly Abnormal Laboratory Values
    • Time Frame: Up to Week 120
  • Number of Participants With Clinically Significant Vital Signs Values
    • Time Frame: Up to Week 120
  • Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings
    • Time Frame: Baseline up to Week 120
  • Change From Baseline in CSF Free and Bound MTBR-tau at 12 Weeks
    • Time Frame: Baseline up to Week 12
  • Change From Baseline in Total MTBR-tau at 12 Weeks
    • Time Frame: Baseline up to Week 12

Secondary Measures

  • Cmax: Maximum Observed Plasma Concentration for E2814 on Days 1 and 85
    • Time Frame: Days 1 and 85: 0-24 hours post-infusion
  • Tmax: Time to Reach the Maximum Plasma Concentration for E2814 on Days 1 and 85
    • Time Frame: Days 1 and 85: 0-24 hours post-infusion
  • AUC(0-672h): Area Under the Plasma Concentration-time Curve From Zero Time to 672 Hours for E2814 on Days 1 and 85
    • Time Frame: Days 1 and 85: 0-672 hours post-infusion
  • Cmax Serum: Maximum Observed Serum Concentration for E2814 on Days 1 and 85
    • Time Frame: Days 1 and 85: 0-24 hours post-infusion
  • Tmax Serum: Time to Reach the Maximum Serum Concentration for E2814 on Days 1 and 85
    • Time Frame: Days 1 and 85: 0-24 hours post-infusion
  • AUC(0-672h) Serum: Area Under the Serum Concentration-time Curve From Zero Time to 672 Hours for E2814 on Days 1 and 85
    • Time Frame: Days 1 and 85: 0-672 hours post-infusion
  • CSF Concentrations of E2814
    • Time Frame: Up to Week 108
  • Serum anti-E2814 Antibody Concentration
    • Time Frame: Up to Week 120
  • Plasma anti-E2814 Antibody Concentration
    • Time Frame: Up to Week 120
  • Change From Baseline in CSF Concentrations of Total tau (t-tau) and Phosphorylated tau (p-tau)
    • Time Frame: Baseline up to Week 108
  • Change From Baseline in tau Positron Emission Tomography (PET) Signal
    • Time Frame: Baseline up to Week 108

Participating in This Clinical Trial

Inclusion Criteria

1. Male or female, age 18 to 80 years at the time of informed consent 2. Individuals who are confirmed to be mutation positive for presenilin 1 (PSEN1), amyloid precursor protein (APP), or presenilin 2 (PSEN2) gene that is associated with DIAD 3. Clinical Dementia Rating – Sum of Boxes (CDR-SB) score 5 to 12 at Screening 4. Evidence of positive amyloid status based on historical or screening amyloid PET 5. Able to undergo magnetic resonance imaging (MRI), lumbar puncture (LP), PET, and complete all study-related testing and evaluations 6. Has a study partner who in the investigator's judgment is able to provide accurate information as to the participant's cognitive and functional abilities, who agrees to provide information at the study visits which require informant input for scale completion Exclusion Criteria:

1. Clinically significant illness that required medical treatment within 8 weeks before the first dose or a clinically significant infection that required medical treatment within 4 weeks before first dose 2. Females who are breastfeeding or pregnant at Screening or Baseline. 3. Females of childbearing potential who: Within 3 months before screening, did not use a highly effective method of contraception 4. Any neurological condition that may be contributing to cognitive impairment above and beyond that caused by the participant's Alzheimer's disease (AD) 5. History of transient ischemic attacks, stroke, or seizures within 12 months of Screening 6. History of clinically important carotid or vertebrobasilar stenosis, plaque, or other prominent risk factor for stroke or cerebral haemorrhage (including atrial fibrillation and anticoagulation). Low dose aspirin (less than or equal to [<=] 325 mg daily) is not exclusionary 7. Any current psychiatric diagnosis or symptoms, (example, hallucinations, major depression, or delusions) that could interfere with study procedures in the participant 8. Geriatric Depression Scale (GDS) score greater than or equal to 8 at Screening 9. Contraindications to MRI scanning, including but not limited to pacemaker/cardiac defibrillator, neurostimulators, ferromagnetic metal implants (example, in skull and cardiac devices other than those approved as safe for use in MRI scanners) 10. Evidence of other clinically significant lesions on brain MRI at Screening that could indicate a dementia diagnosis other than AD 11. Other significant pathological findings on brain MRI at Screening. 12. Hypersensitivity to E2814 or any of the excipients, or to any monoclonal antibody (mAb) treatment 13. Any immunological disease which is not adequately controlled, or which requires treatment with immunoglobulins, systemic monoclonal antibodies (or derivatives of monoclonal antibodies), systemic immunosuppressants, or plasmapheresis during the study 14. With a bleeding disorder of current chronic use of anticoagulants (example, warfarin, dabigatran, rivaroxaban or apixaban) or of clopidogrel is exclusionary. Limited (occasional or isolated) use of anticoagulants/antiplatelet compounds in cases such as surgical procedures. 15. Have thyroid stimulating hormone outside of normal range. Other tests of thyroid function with results outside the normal range should only be exclusionary if they are considered clinically significant by the investigator. 16. Hemoglobin A1c (HgbA1c) greater than (>) 8 percent (%) (retesting is permitted if slightly elevated) or poorly controlled insulin-dependent diabetes (including hypoglycemic episodes). Participants may be rescreened after 3 months to allow optimization of diabetic control. 17. Abnormally low serum vitamin B12 levels for the testing laboratory. 18. History of human immunodeficiency virus (HIV) infection, history of hepatitis B infection within the past year, history of hepatitis C infection which has not been adequately treated, or history of spirochete infection of the central nervous system (example, syphilis, Lyme, or borreliosis) 19. Any other clinically significant abnormalities in physical examination, vital signs, laboratory tests, or ECG at Screening or Baseline which in the opinion of the investigator require further investigation or treatment or which may interfere with study procedures or safety 20. Malignant neoplasms within 3 years of Screening (except for basal or squamous cell carcinoma in situ of the skin, or localized prostate cancer in male participant, or localized breast cancer in female participants). 21. Answers "yes" to Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation Type 4 or 5, or any suicidal behavior assessment within 6 months before Screening, at Screening, or at the Baseline Visit, or has been hospitalized or treated for any suicidal behavior in lifetime. 22. Known or suspected history of drug or alcohol abuse or dependence within 2 years before Screening or a positive urine drug test at Screening. 23. Any other medical conditions (example, cardiac, respiratory, gastrointestinal, renal disease) which are not stably and adequately controlled, or which in the opinion of the investigator could affect the participant's safety or interfere with the study assessments 24. Concurrent participation in a clinical study involving any anti-amyloid therapies (including any mAb therapies) within 6 months before Screening 25. Concurrent participation in a clinical study involving any anti-tau therapies. 26. Participated in any other investigational medication or device study in the 3 months or 5 half-lives (whichever is longer) of the medication before Screening 27. Planned surgery which requires general anesthesia that would take place during the study. 28. Visual or hearing impairment that would prevent the participant from performing psychometric tests accurately.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 80 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Eisai Inc.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Contact(s)
    • Eisai Medical Information, +1-888-274-2378, esi_medinfo@eisai.com

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