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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: E2814

• Study Type: Interventional
• Enrollment (Estimated): 13
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Eisai Medical Information; Phone Number: +1-888-274-2378; Email: esi_medinfo@eisai.com

Study Locations

• United Kingdom
  • London, United Kingdom, WC1N 3BG
    • Recruiting
    • National Hospital for Neurology and Neurosurgery (NHNN) University College London(UCL) Hospitals NHS Foundation Trust
• United States
  • California
    • La Jolla, California, United States, 92037
      • Recruiting
      • UC San Diego Altman Clinical and Translational Research Insititute Clinic
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Indiana University School of Medicine, Health Partners, Adult Neurology Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 1st dose or a clinically significant infection that required medical treatment within 4 weeks before 1st 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 milligram [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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A, Phase 1b and 2: E2814; Participants will receive E2814 as an intravenous infusion at set intervals over 12 weeks in Phase 1b and over 96 weeks in Phase 2.	Drug: E2814; E2814 intravenous infusion.
Experimental: Cohort B: E2814; Participants will receive E2814 as an intravenous infusion at set intervals over 52 weeks.	Drug: E2814; E2814 intravenous infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Cohort A, Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs)	Up to 20 weeks
Cohort A, Phase 2 and Cohort B: Number of Participants With TEAEs	Up to 108 weeks
Cohort A, Phase 1b: Number of Participants With Serious Adverse Events (SAEs)	Up to 20 weeks
Cohort A, Phase 2 and Cohort B: Number of Participants With SAEs	Up to 108 weeks
Cohort A, Phase 1b: Number of Participants With Markedly Abnormal Laboratory Values	Up to 20 weeks
Cohort A, Phase 2 and Cohort B: Number of Participants With Markedly Abnormal Laboratory Values	Up to 108 weeks
Cohort A, Phase 1b: Number of Participants With Clinically Significant Vital Signs Values	Up to 20 weeks
Cohort A, Phase 2 and Cohort B: Number of Participants With Clinically Significant Vital Signs Values	Up to 108 weeks
Cohort A, Phase 1b: Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings	Up to 20 weeks
Cohort A, Phase 2 and Cohort B: Number of Participants With Clinically Significant ECG Findings	Up to 108 weeks
Cohort A: Change From Baseline in CSF Free and Bound MTBR-tau at 12 Weeks	Baseline up to Week 12
Cohort A: Change From Baseline in Total MTBR-tau at 12 Weeks	Baseline up to Week 12

Secondary Outcome Measures

Outcome Measure	Time Frame
Cohort A and Cohort B, Cmax: Maximum Observed Plasma Concentration for E2814	Cohort A, Days 1 and 85: 0-24 hours post-infusion; Cohort B: Pre-dose and immediately at the end of the infusion on Day 1 up to Day 449
Cohort A and Cohort B, Tmax: Time to Reach the Maximum Plasma Concentration for E2814	Cohort A, Days 1 and 85: 0-24 hours post-infusion; Cohort B: Pre-dose and immediately at the end of the infusion on Day 1 up to Day 449
Cohort A and Cohort B, AUC(0-672h): Area Under the Plasma Concentration-time Curve From Zero Time to 672 Hours for E2814	Cohort A, Days 1 and 85: 0-672 hours post-infusion; Cohort B, Day 1 up to Day 449: 0-672 hours post-infusion
Cohort A and Cohort B, Cmax Serum: Maximum Observed Serum Concentration for E2814	Cohort A, Days 1 and 85: 0-24 hours post-infusion; Cohort B: Pre-dose and immediately at the end of the infusion on Day 1 up to Day 449
Cohort A and Cohort B, Tmax Serum: Time to Reach the Maximum Serum Concentration for E2814	Cohort A, Days 1 and 85: 0-24 hours post-infusion; Cohort B: Pre-dose and immediately at the end of the infusion on Day 1 up to Day 449
Cohort A and Cohort B, AUC(0-672h) Serum: Area Under the Serum Concentration-time Curve From Zero Time to 672 Hours for E2814	Cohort A, Days 1 and 85: 0-672 hours post-infusion; Cohort B, Day 1 up to Day 449: 0-672 hours post-infusion
CSF Concentrations of E2814	Cohort A: From first dose the study drug up to 12 weeks after last dose (up to 120 weeks); Cohort B: From first dose the study drug up to 52 weeks
Serum anti-E2814 Antibody Concentration	Cohort A: From first dose the study drug up to 12 weeks after last dose (up to 120 weeks); Cohort B: From first dose the study drug up to 12 weeks after last dose (up to 64 weeks)
Plasma anti-E2814 Antibody Concentration	Cohort A: From first dose the study drug up to 12 weeks after last dose (up to 120 weeks); Cohort B: From first dose the study drug up to 12 weeks after last dose (up to 64 weeks)
Change From Baseline in CSF Concentrations of Total tau (t-tau) and Phosphorylated tau (p-tau)	Cohort A: From first dose the study drug up to 12 weeks after last dose (up to 120 weeks); Cohort B: From first dose the study drug up to 52 weeks
Change From Baseline in tau Positron Emission Tomography (PET) Signal	Cohort A: Baseline up to 108 weeks; Cohort B: Baseline up to 52 weeks

Collaborators and Investigators

• Sponsor: Eisai Inc.

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2021
• Primary Completion (Estimated): July 14, 2025
• Study Completion (Estimated): July 14, 2025

Study Registration Dates

• First Submitted: July 20, 2021
• First Submitted That Met QC Criteria: July 20, 2021
• First Posted (Actual): July 21, 2021

Study Record Updates

• Last Update Posted (Actual): November 30, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Alzheimer disease; E2814; Central nervous system disease; Dominantly inherited Alzheimer disease; Mild and moderate cognitive impairment
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Cognition Disorders; Alzheimer Disease; Cognitive Dysfunction
• Other Study ID Numbers: E2814-G000-103; 2020-005728-12 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Eisai's data sharing commitment and further information on how to request data can be found on our website http://eisaiclinicaltrials.com/.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No