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

Sponsor

Eisai Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT04971733

Collaborator

(none)

Enrollment

Locations

Arms

38.5

Anticipated Duration (Months)

2.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer Disease	Drug: E2814	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

8 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jun 28, 2021

Anticipated Primary Completion Date :

Sep 13, 2024

Anticipated Study Completion Date :

Sep 13, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1b: E2814 Participants will receive E2814 as an intravenous infusion at set intervals over 12 weeks in Phase 1b.	Drug: E2814 E2814 intravenous infusion.
Experimental: Phase 2: E2814 Participants will receive E2814 as an intravenous infusion at set intervals over 96 weeks in Phase 2.	Drug: E2814 E2814 intravenous infusion.

Arm

Intervention/Treatment

Experimental: Phase 1b: E2814

Participants will receive E2814 as an intravenous infusion at set intervals over 12 weeks in Phase 1b.

Drug: E2814

E2814 intravenous infusion.

Experimental: Phase 2: E2814

Participants will receive E2814 as an intravenous infusion at set intervals over 96 weeks in Phase 2.

Drug: E2814

E2814 intravenous infusion.

Outcome Measures

Primary Outcome Measures

Number of Participants With Treatment-emergent Adverse Events (TEAEs) [Screening up to 16 weeks after the last dose of study drug (approximately 124 Weeks)]
Number of Participants With Serious Adverse Events (SAEs) [Screening up to 14 weeks after the last dose of study drug (approximately 122 Weeks)]
Number of Participants With Markedly Abnormal Laboratory Values [Up to Week 120]
Number of Participants With Clinically Significant Vital Signs Values [Up to Week 120]
Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings [Baseline up to Week 120]
Change From Baseline in CSF Free and Bound MTBR-tau at 12 Weeks [Baseline up to Week 12]
Change From Baseline in Total MTBR-tau at 12 Weeks [Baseline up to Week 12]

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male or female, age 18 to 80 years at the time of informed consent
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
Clinical Dementia Rating - Sum of Boxes (CDR-SB) score 5 to 12 at Screening
Evidence of positive amyloid status based on historical or screening amyloid PET
Able to undergo magnetic resonance imaging (MRI), lumbar puncture (LP), PET, and complete all study-related testing and evaluations
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:

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
Females who are breastfeeding or pregnant at Screening or Baseline
Females of childbearing potential who:

Within 3 months before screening, did not use a highly effective method of contraception

Any neurological condition that may be contributing to cognitive impairment above and beyond that caused by the participant's Alzheimer's disease (AD)
History of transient ischemic attacks, stroke, or seizures within 12 months of Screening
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
Any current psychiatric diagnosis or symptoms, (example, hallucinations, major depression, or delusions) that could interfere with study procedures in the participant
Geriatric Depression Scale (GDS) score greater than or equal to 8 at Screening
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)
Evidence of other clinically significant lesions on brain MRI at Screening that could indicate a dementia diagnosis other than AD
Other significant pathological findings on brain MRI at Screening
Hypersensitivity to E2814 or any of the excipients, or to any monoclonal antibody (mAb) treatment
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
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
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
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
Abnormally low serum vitamin B12 levels for the testing laboratory
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)
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
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)
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
Known or suspected history of drug or alcohol abuse or dependence within 2 years before Screening or a positive urine drug test at Screening
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
Concurrent participation in a clinical study involving any anti-amyloid therapies (including any mAb therapies) within 6 months before Screening
Concurrent participation in a clinical study involving any anti-tau therapies
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
Planned surgery which requires general anesthesia that would take place during the study
Visual or hearing impairment that would prevent the participant from performing psychometric tests accurately

Contacts and Locations

Locations

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