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

Alzheimer Disease Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04971733
• Other study ID #: E2814-G000-103
• Secondary ID: 2020-005728-12
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: June 28, 2021
• Est. completion date: July 14, 2025

Study information

• Verified date: November 2023
• Source: Eisai Inc.
• Contact: Eisai Medical Information
• Phone: +1-888-274-2378
• Email: esi_medinfo[@]eisai.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 13
• Est. completion date: July 14, 2025
• Est. primary completion date: July 14, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Alzheimer Disease
• Cognitive Dysfunction

Intervention

Drug:
• E2814
E2814 intravenous infusion.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Eisai Inc.

Countries where clinical trial is conducted

United States,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cohort A, Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs)		Up to 20 weeks
Primary	Cohort A, Phase 2 and Cohort B: Number of Participants With TEAEs		Up to 108 weeks
Primary	Cohort A, Phase 1b: Number of Participants With Serious Adverse Events (SAEs)		Up to 20 weeks
Primary	Cohort A, Phase 2 and Cohort B: Number of Participants With SAEs		Up to 108 weeks
Primary	Cohort A, Phase 1b: Number of Participants With Markedly Abnormal Laboratory Values		Up to 20 weeks
Primary	Cohort A, Phase 2 and Cohort B: Number of Participants With Markedly Abnormal Laboratory Values		Up to 108 weeks
Primary	Cohort A, Phase 1b: Number of Participants With Clinically Significant Vital Signs Values		Up to 20 weeks
Primary	Cohort A, Phase 2 and Cohort B: Number of Participants With Clinically Significant Vital Signs Values		Up to 108 weeks
Primary	Cohort A, Phase 1b: Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings		Up to 20 weeks
Primary	Cohort A, Phase 2 and Cohort B: Number of Participants With Clinically Significant ECG Findings		Up to 108 weeks
Primary	Cohort A: Change From Baseline in CSF Free and Bound MTBR-tau at 12 Weeks		Baseline up to Week 12
Primary	Cohort A: Change From Baseline in Total MTBR-tau at 12 Weeks		Baseline up to Week 12
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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
Secondary	Change From Baseline in tau Positron Emission Tomography (PET) Signal		Cohort A: Baseline up to 108 weeks; Cohort B: Baseline up to 52 weeks