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 Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
8
E2814 intravenous infusion.
UC San Diego Altman Clinical and Translational Research Insititute Clinic
La Jolla, California, United States
Indiana University School of Medicine, Health Partners, Adult Neurology Clinic
Indianapolis, Indiana, United States
National Hospital for Neurology and Neurosurgery (NHNN) University College London(UCL) Hospitals NHS Foundation Trust
London, United Kingdom
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
A TEAE was defined as adverse event (AE) that started at or after the time of administration of study drug or a worsening of severity from Baseline on or after 1st dose up to last assessment. An AE was any untoward medical occurrence in a participant or clinical investigation participant administered an investigational product. An AE did not necessarily have a causal relationship with the medicinal product. SAE was any untoward medical occurrence that at any dose: resulted in death; was life-threatening (that is, the participant was at immediate risk of death from the AE as it occurred; this did not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug).
Time frame: From first dose of study drug up to 120 weeks
Number of Participants With Markedly Abnormal Laboratory Values
Clinical laboratory tests included hematology, clinical chemistry, and urinalysis assessments. Markedly abnormal value was defined as a post-baseline value with an increase from baseline to a grade of 2 or higher on Common Terminology Criteria for Adverse events (CTCAE) Version 5.0 scale.
Time frame: From first dose of study drug up to 120 weeks
Number of Participants With Clinically Significant Change in Vital Signs Values
Vital sign measurements included systolic and diastolic blood pressure, pulse, respiratory rate, body temperature, height and weight assessment. The clinically significant assessment was based on investigator judgement.
Time frame: From first dose of study drug up to 120 weeks
Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Findings
The clinically significant assessment was based on investigator judgement.
Time frame: From first dose of study drug up to 120 weeks
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Cohort A: Change From Baseline in Cerebrospinal Fluid (CSF) Free, CSF Bound and Total Microtubule Binding Region of Tau (MTBR-tau; Starting at Amino Acid 354 and 299) at 12 Weeks
Total MTBR-Tau was the total of bound MTBR-Tau + free MTBR-Tau. CSF samples were collected for the assessment.
Time frame: Pre-dose at Week 12
Cohort A, Cmax: Maximum Observed Plasma Concentration for E2814
The concentration of E2814 were measured by validated electrochemiluminescence assay methods and/or by a validated immunoprecipitation/purification followed by liquid chromatography with tandem mass spectrometry methods.
Time frame: Cohort A, E2814 750 mg: Day 1 pre-dose up to 25 hours post-dose; Cohort A, E2814 1500 mg: Day 85 pre-dose up to 25 hours post-dose
Cohort A, Tmax: Time to Reach the Maximum Plasma Concentration for E2814
The concentration of E2814 was measured by validated electrochemiluminescence assay methods and/or by a validated immunoprecipitation/purification followed by liquid chromatography with tandem mass spectrometry methods.
Time frame: Cohort A, E2814 750 mg: Day 1 pre-dose up to 25 hours post-dose; Cohort A, E2814 1500 mg: Day 85 pre-dose up to 25 hours post-dose
Cohort A, AUC(0-672h): Area Under the Plasma Concentration-time Curve From Zero Time to 672 Hours for E2814
The concentration of E2814 was measured by validated electrochemiluminescence assay methods and/or by a validated immunoprecipitation/purification followed by liquid chromatography with tandem mass spectrometry methods.
Time frame: Cohort A, E2814 750 mg: Day 1 pre-dose up to 672 hours post-dose; Cohort A, E2814 1500 mg: Day 85 pre-dose up to 672 hours post-dose
Cohort A, Cmax: Maximum Observed Serum Concentration for E2814
The concentration of E2814 was measured by validated electrochemiluminescence assay methods and/or by a validated immunoprecipitation/purification followed by liquid chromatography with tandem mass spectrometry methods.
Time frame: Cohort A, E2814 750 mg: Day 1 pre-dose up to 25 hours post-dose; Cohort A, E2814 1500 mg: Day 85 pre-dose up to 25 hours post-dose
Cohort A, Tmax: Time to Reach the Maximum Serum Concentration for E2814
The concentration of E2814 was measured by validated electrochemiluminescence assay methods and/or by a validated immunoprecipitation/purification followed by liquid chromatography with tandem mass spectrometry methods.
Time frame: Cohort A, E2814 750 mg: Day 1 pre-dose up to 25 hours post-dose; Cohort A, E2814 1500 mg: Day 85 pre-dose up to 25 hours post-dose
Cohort A, AUC(0-672h): Area Under the Serum Concentration-time Curve From Zero Time to 672 Hours for E2814
The concentration of E2814 was measured by validated electrochemiluminescence assay methods and/or by a validated immunoprecipitation/purification followed by liquid chromatography with tandem mass spectrometry methods.
Time frame: Cohort A, E2814 750 mg: Day 1 pre-dose up to 672 hours post-dose; Cohort A, E2814 1500 mg: Day 85 pre-dose up to 672 hours post-dose
Cohort A: CSF Concentrations of E2814
The concentration of E2814 was measured by validated electrochemiluminescence assay methods and/or by a validated immunoprecipitation/purification followed by liquid chromatography with tandem mass spectrometry methods.
Time frame: Pre-dose at Days 1, 84, 85, 169, 253, 421, and 757
Number of Participants With Treatment-emergent Positive Serum Anti-E2814 Antibody
Anti-E2814 antibodies were measured by validated electrochemiluminescence assay.
Time frame: From first dose of study drug up to 120 weeks
Number of Participants With Treatment-emergent Positive Plasma Anti-E2814 Antibody
Anti-E2814 antibodies were measured by validated electrochemiluminescence assay.
Time frame: From first dose of study drug up to 120 weeks
Cohort A: Change From Baseline in CSF Concentrations of Total MTBR-tau243
CSF samples were collected for the assessment.
Time frame: Baseline, and pre-dose at Days 84, 169, 253, 421, 505, 589, and 757
Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217
CSF samples were collected for the assessment.
Time frame: Baseline, and pre-dose at Days 84, 169, 253, 421, 505, 589, and 757
Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205
CSF samples were collected for the assessment.
Time frame: Baseline, and pre-dose at Days 84, 169, 253, 421, 505, 589, and 757
Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region
Tau-PET imaging uses radiotracers to visualize tau protein deposits in the brain for regional assessment of tau pathology. SUVR is ratio of tracer uptake in each of the cingulate, frontal, medial, occipital, parietal, whole cortical, meta temporal, and temporal cortices relative to tracer uptake in the cerebellum.
Time frame: Baseline, at Weeks 60 and 108