Alzheimer Disease
Conditions
Keywords
E2814, Alzheimer disease, Dominantly inherited Alzheimer disease, Mild and moderate cognitive impairment, Central nervous system disease
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.
Interventions
DRUGE2814
E2814 intravenous infusion.
Sponsors
Eisai Inc.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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. Able to undergo magnetic resonance imaging (MRI), lumbar puncture (LP), PET, and complete all study-related testing and evaluations 5. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | From first dose of study drug up to 120 weeks | 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). |
| Number of Participants With Markedly Abnormal Laboratory Values | From first dose of study drug up to 120 weeks | 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. |
| Number of Participants With Clinically Significant Change in Vital Signs Values | From first dose of study drug up to 120 weeks | 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. |
| Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Findings | From first dose of study drug up to 120 weeks | The clinically significant assessment was based on investigator judgement. |
| 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 | Pre-dose at Week 12 | Total MTBR-Tau was the total of bound MTBR-Tau + free MTBR-Tau. CSF samples were collected for the assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohort A, AUC(0-672h): Area Under the Serum Concentration-time Curve From Zero Time to 672 Hours for E2814 | 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 | 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. |
| Cohort A: CSF Concentrations of E2814 | Pre-dose at Days 1, 84, 85, 169, 253, 421, and 757 | 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. |
| Number of Participants With Treatment-emergent Positive Serum Anti-E2814 Antibody | From first dose of study drug up to 120 weeks | Anti-E2814 antibodies were measured by validated electrochemiluminescence assay. |
| Number of Participants With Treatment-emergent Positive Plasma Anti-E2814 Antibody | From first dose of study drug up to 120 weeks | Anti-E2814 antibodies were measured by validated electrochemiluminescence assay. |
| Cohort A, Cmax: Maximum Observed Plasma Concentration for E2814 | 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 | 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. |
| Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Baseline, and pre-dose at Days 84, 169, 253, 421, 505, 589, and 757 | CSF samples were collected for the assessment. |
| Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Baseline, and pre-dose at Days 84, 169, 253, 421, 505, 589, and 757 | CSF samples were collected for the assessment. |
| Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region | Baseline, at Weeks 60 and 108 | 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. |
| Cohort A: Change From Baseline in CSF Concentrations of Total MTBR-tau243 | Baseline, and pre-dose at Days 84, 169, 253, 421, 505, 589, and 757 | CSF samples were collected for the assessment. |
| Cohort A, Tmax: Time to Reach the Maximum Plasma Concentration for E2814 | 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 | 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. |
| Cohort A, AUC(0-672h): Area Under the Plasma Concentration-time Curve From Zero Time to 672 Hours for E2814 | 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 | 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. |
| Cohort A, Cmax: Maximum Observed Serum Concentration for E2814 | 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 | 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. |
| Cohort A, Tmax: Time to Reach the Maximum Serum Concentration for E2814 | 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 | 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. |
Countries
United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 3 investigative sites in the United States and United Kingdom from 28 June 2021 and 24 May 2024.
Pre-assignment details
The study was conducted in two cohorts (Cohort A \[Phase 1b and 2\] and Cohort B). A total of 11 participants were screened, of which 3 were screen failures and 8 were enrolled to receive study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: E2814 Participants received E2814 IV infusion, Q4W at dose of 750 mg for 12 weeks, followed by 1500 mg for 12 weeks, further followed by 3000 mg for 12 weeks and then 4500 mg for up to 72 weeks. | 7 |
| Cohort B: E2814 Participants received E2814 3000 mg, IV infusion, Q4W for 52 weeks. | 1 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Subject choice | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort A: E2814 | Cohort B: E2814 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 0 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 1 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 1 Participants | 8 Participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 4 Participants | 0 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 7 | 0 / 8 | 0 / 4 |
| other Total, other adverse events | 4 / 7 | 1 / 7 | 7 / 8 | 4 / 4 |
| serious Total, serious adverse events | 0 / 7 | 0 / 7 | 2 / 8 | 1 / 4 |
Outcome results
Primary
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
Population: The Pharmacodynamic (PD) Analysis Set was the group of participants who received at least 1 dose of study drug and had sufficient PD data to derive at least 1 PD parameter. As planned, this outcome measure was assessed for E2814 750 mg only in Cohort A.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: E2814 750 mg | 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 | Change in CSF Free MTBR-tau354 | -0.0534 nanogram per milliliter (ng/mL) | Standard Deviation 0.069 |
| Cohort A: E2814 750 mg | 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 | Change in CSF Free MTBR-tau299 | -0.0147 nanogram per milliliter (ng/mL) | Standard Deviation 0.0267 |
| Cohort A: E2814 750 mg | 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 | Change in CSF Bound MTBR-tau354 | 0.178 nanogram per milliliter (ng/mL) | Standard Deviation 0.0886 |
| Cohort A: E2814 750 mg | 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 | Change in CSF Bound MTBR-tau299 | 0.0420 nanogram per milliliter (ng/mL) | Standard Deviation 0.0194 |
| Cohort A: E2814 750 mg | 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 | Change in CSF Total MTBR-tau354 | 0.125 nanogram per milliliter (ng/mL) | Standard Deviation 0.0899 |
| Cohort A: E2814 750 mg | 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 | Change in CSF Total MTBR-tau299 | 0.0273 nanogram per milliliter (ng/mL) | Standard Deviation 0.0191 |
Primary
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
Population: The Safety Analysis Set was the group of participants who received at least 1 dose of study drug and had at least 1 post-dose safety assessment. As pre-specified in SAP, the data of Cohort B was combined with Cohort A for E2814 3000 mg group due to same dosing in both cohorts.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: E2814 750 mg | Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Findings | 0 Participants |
| Cohort A: E2814 1500 mg | Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Findings | 0 Participants |
| Cohort A+B: E2814 3000 mg | Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Findings | 0 Participants |
| Cohort A: E2814 4500 mg | Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Findings | 0 Participants |
Primary
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
Population: The Safety Analysis Set was the group of participants who received at least 1 dose of study drug and had at least 1 post-dose safety assessment. As pre-specified in SAP, the data of Cohort B was combined with Cohort A for E2814 3000 mg group due to same dosing in both cohorts.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: E2814 750 mg | Number of Participants With Clinically Significant Change in Vital Signs Values | 0 Participants |
| Cohort A: E2814 1500 mg | Number of Participants With Clinically Significant Change in Vital Signs Values | 0 Participants |
| Cohort A+B: E2814 3000 mg | Number of Participants With Clinically Significant Change in Vital Signs Values | 0 Participants |
| Cohort A: E2814 4500 mg | Number of Participants With Clinically Significant Change in Vital Signs Values | 0 Participants |
Primary
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
Population: The Safety Analysis Set was the group of participants who received at least 1 dose of study drug and had at least 1 post-dose safety assessment. As pre-specified in SAP, the data of Cohort B was combined with Cohort A for E2814 3000 mg group due to same dosing in both cohorts.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: E2814 750 mg | Number of Participants With Markedly Abnormal Laboratory Values | 0 Participants |
| Cohort A: E2814 1500 mg | Number of Participants With Markedly Abnormal Laboratory Values | 1 Participants |
| Cohort A+B: E2814 3000 mg | Number of Participants With Markedly Abnormal Laboratory Values | 1 Participants |
| Cohort A: E2814 4500 mg | Number of Participants With Markedly Abnormal Laboratory Values | 2 Participants |
Primary
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
Population: The Safety Analysis Set was the group of participants who received at least 1 dose of study drug and had at least 1 post-dose safety assessment. As pre-specified in statistical analysis plan (SAP), the data of Cohort B was combined with Cohort A for E2814 3000 mg group due to same dosing in both cohorts.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A: E2814 750 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 4 Participants |
| Cohort A: E2814 750 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 0 Participants |
| Cohort A: E2814 1500 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 0 Participants |
| Cohort A: E2814 1500 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 1 Participants |
| Cohort A+B: E2814 3000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 8 Participants |
| Cohort A+B: E2814 3000 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 2 Participants |
| Cohort A: E2814 4500 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 4 Participants |
| Cohort A: E2814 4500 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 1 Participants |
Secondary
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
Population: PK Analysis Set was group of participants who received at least 1 dose of test drug and had sufficient PK data to derive at least 1 PK parameter. As planned, this PK parameter was assessed for E2814 750 mg and 1500 mg only in Cohort A. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure (sampling for first dose of 1500 mg was less intense versus the first dose of 750 mg; thus, no participants were evaluable for 1500 mg group for AUC\[0-672h\]).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: E2814 750 mg | Cohort A, AUC(0-672h): Area Under the Plasma Concentration-time Curve From Zero Time to 672 Hours for E2814 | 66500 hour*microgram per milliliter (h*mcg/mL) | Geometric Coefficient of Variation 23.2 |
Secondary
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
Population: PK Analysis Set was group of participants who received at least 1 dose of test drug and had sufficient PK data to derive at least 1 PK parameter. As planned, this PK parameter was assessed for E2814 750 mg and 1500 mg only in Cohort A. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure (sampling for first dose of 1500 mg was less intense versus the first dose of 750 mg; thus, no participants were evaluable for 1500 mg group for AUC\[0-672h\]).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: E2814 750 mg | Cohort A, AUC(0-672h): Area Under the Serum Concentration-time Curve From Zero Time to 672 Hours for E2814 | 8030 h*mcg/mL | Geometric Coefficient of Variation 54.8 |
Secondary
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
Population: The PD Analysis Set was the group of participants who received at least 1 dose of study drug and had sufficient PD data to derive at least 1 PD parameter. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and Number Analyzed signifies participants evaluable at given time points for specified dosing group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 217 at Day 84: Predose | -190.56 pg/mL | Standard Deviation 120.537 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 205 at Day 84: Predose | -38.37 pg/mL | Standard Deviation 26.736 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 181 at Day 84: Predose | -166.50 pg/mL | Standard Deviation 33.177 |
| Cohort A: E2814 1500 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 205 at Day 84: Predose | -14.70 pg/mL | Standard Deviation 101.226 |
| Cohort A: E2814 1500 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 217 at Day 84: Predose | -216.52 pg/mL | Standard Deviation 258.741 |
| Cohort A: E2814 1500 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 181 at Day 84: Predose | 2.41 pg/mL | Standard Deviation 204.061 |
| Cohort A: E2814 1500 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 181 at Day 169: Predose | -10.32 pg/mL | Standard Deviation 131.136 |
| Cohort A: E2814 1500 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 205 at Day 169: Predose | -67.43 pg/mL | Standard Deviation 126.128 |
| Cohort A: E2814 1500 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 217 at Day 169: Predose | -294.28 pg/mL | Standard Deviation 350.271 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 205 at Day 253: Predose | -84.42 pg/mL | Standard Deviation 71.648 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 181 at Day 169: Predose | -249.82 pg/mL | Standard Deviation 351.972 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 181 at Day 253: Predose | -308.74 pg/mL | Standard Deviation 443.284 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 181 at Day 421: Predose | -84.85 pg/mL | Standard Deviation 106.021 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 205 at Day 169: Predose | -34.19 pg/mL | Standard Deviation 86.949 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 205 at Day 421: Predose | -25.26 pg/mL | Standard Deviation 4.975 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 217 at Day 169: Predose | -188.49 pg/mL | Standard Deviation 47.791 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 217 at Day 253: Predose | -375.74 pg/mL | Standard Deviation 246.487 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 217 at Day 421: Predose | -217.44 pg/mL | Standard Deviation 134.88 |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 205 at Day 505: Predose | -24.12 pg/mL | — |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 205 at Day 589: Predose | 4.48 pg/mL | — |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 205 at Day 757: Predose | -73.59 pg/mL | Standard Deviation 58.215 |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 181 at Day 505: Predose | -50.49 pg/mL | — |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 181 at Day 421: Predose | -1032.26 pg/mL | — |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 217 at Day 505: Predose | -368.02 pg/mL | — |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 217 at Day 589: Predose | -135.13 pg/mL | — |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 181 at Day 757: Predose | -606.64 pg/mL | Standard Deviation 561.342 |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 217 at Day 757: Predose | -422.60 pg/mL | Standard Deviation 335.717 |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 181 at Day 589: Predose | -106.21 pg/mL | — |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 217 at Day 421: Predose | -680.92 pg/mL | — |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in CSF Concentrations of Phosphorylated Tau (P-tau) 181, 205, and 217 | Change in P-tau 205 at Day 421: Predose | -113.91 pg/mL | — |
Secondary
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
Population: The PD Analysis Set was the group of participants who received at least 1 dose of study drug and had sufficient PD data to derive at least 1 PD parameter. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and Number Analyzed signifies participants evaluable at given time points for specified dosing group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in CSF Concentrations of Total MTBR-tau243 | Change at Day 84: Pre-dose | -210 picogram per milliliter (pg/mL) | Standard Deviation 156 |
| Cohort A: E2814 1500 mg | Cohort A: Change From Baseline in CSF Concentrations of Total MTBR-tau243 | Change at Day 84: Pre-dose | -139 picogram per milliliter (pg/mL) | Standard Deviation 53.5 |
| Cohort A: E2814 1500 mg | Cohort A: Change From Baseline in CSF Concentrations of Total MTBR-tau243 | Change at Day 169: Pre-dose | -151 picogram per milliliter (pg/mL) | — |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in CSF Concentrations of Total MTBR-tau243 | Change at Day 169: Pre-dose | -236 picogram per milliliter (pg/mL) | Standard Deviation 88.3 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in CSF Concentrations of Total MTBR-tau243 | Change at Day 253: Pre-dose | -296 picogram per milliliter (pg/mL) | Standard Deviation 232 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in CSF Concentrations of Total MTBR-tau243 | Change at Day 421: Pre-dose | -216 picogram per milliliter (pg/mL) | Standard Deviation 127 |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in CSF Concentrations of Total MTBR-tau243 | Change at Day 505: Pre-dose | -315 picogram per milliliter (pg/mL) | — |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in CSF Concentrations of Total MTBR-tau243 | Change at Day 589: Pre-dose | -147 picogram per milliliter (pg/mL) | — |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in CSF Concentrations of Total MTBR-tau243 | Change at Day 757: Pre-dose | -381 picogram per milliliter (pg/mL) | Standard Deviation 377 |
Secondary
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
Population: The PD Analysis Set was the group of participants who received at least 1 dose of study drug and had sufficient PD data to derive at least 1 PD parameter. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and Number Analyzed signifies participants evaluable at given time points for specified dosing group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau181/np-tau181 ratio at Day 84: Predose | 0.95 ratio | Standard Deviation 2.463 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau205/np-tau205 ratio at Day 84: Predose | 0.42 ratio | Standard Deviation 0.95 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau217/np-tau217 ratio at Day 84: Predose | -3.03 ratio | Standard Deviation 4.624 |
| Cohort A: E2814 1500 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau205/np-tau205 ratio at Day 169: Predose | 2.08 ratio | Standard Deviation 0.525 |
| Cohort A: E2814 1500 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau181/np-tau181 ratio at Day 169: Predose | 17.54 ratio | Standard Deviation 16.734 |
| Cohort A: E2814 1500 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau181/np-tau181 ratio at Day 84: Predose | 10.21 ratio | Standard Deviation 12.187 |
| Cohort A: E2814 1500 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau217/np-tau217 ratio at Day 169: Predose | -8.13 ratio | Standard Deviation 5.564 |
| Cohort A: E2814 1500 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau217/np-tau217 ratio at Day 84: Predose | -5.49 ratio | Standard Deviation 4.24 |
| Cohort A: E2814 1500 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau205/np-tau205 ratio at Day 84: Predose | 3.51 ratio | Standard Deviation 2.221 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau205/np-tau205 ratio at Day 421: Predose | 1.16 ratio | Standard Deviation 0.915 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau181/np-tau181 ratio at Day 169: Predose | -8.88 ratio | Standard Deviation 15.713 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau181/np-tau181 ratio at Day 253: Predose | 2.96 ratio | Standard Deviation 12.693 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau181/np-tau181 ratio at Day 421: Predose | 3.23 ratio | Standard Deviation 4.146 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau205/np-tau205 ratio at Day 169: Predose | 0.86 ratio | Standard Deviation 4.695 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau205/np-tau205 ratio at Day 253: Predose | 2.53 ratio | Standard Deviation 1.647 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau217/np-tau217 ratio at Day 169: Predose | -8.48 ratio | Standard Deviation 6.258 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau217/np-tau217 ratio at Day 253: Predose | -10.74 ratio | Standard Deviation 5.265 |
| Cohort A+B: E2814 3000 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau217/np-tau217 ratio at Day 421: Predose | -10.16 ratio | Standard Deviation 4.143 |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau205/np-tau205 ratio at Day 589: Predose | 2.02 ratio | — |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau205/np-tau205 ratio at Day 757: Predose | 1.80 ratio | Standard Deviation 0.035 |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau181/np-tau181 ratio at Day 589: Predose | 0.40 ratio | — |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau181/np-tau181 ratio at Day 505: Predose | 11.64 ratio | — |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau181/np-tau181 ratio at Day 421: Predose | -8.78 ratio | — |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau217/np-tau217 ratio at Day 505: Predose | -16.05 ratio | — |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau217/np-tau217 ratio at Day 589: Predose | -8.52 ratio | — |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau217/np-tau217 ratio at Day 757: Predose | -14.56 ratio | Standard Deviation 5.138 |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau217/np-tau217 ratio at Day 421: Predose | -15.35 ratio | — |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau181/np-tau181 ratio at Day 757: Predose | -6.87 ratio | Standard Deviation 7.47 |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau205/np-tau205 ratio at Day 421: Predose | 4.53 ratio | — |
| Cohort A: E2814 4500 mg | Cohort A: Change From Baseline in Ratio of CSF Concentrations of p-Tau/Non-phosphorylated (np) Tau for 181, 217, and 205 | Change in P-tau205/np-tau205 ratio at Day 505: Predose | 2.32 ratio | — |
Secondary
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
Population: The PD Analysis Set was the group of participants who received at least 1 dose of study drug and had sufficient PD data to derive at least 1 PD parameter. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure. As planned, this outcome measure was assessed for 4500 mg only in Cohort A.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region | Change in PET tau SUVR in Cingulate Region at Week 60 | 0.135 SUVR | Standard Deviation 0.3756 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region | Change in PET tau SUVR in Cingulate Region at Week 108 | 0.296 SUVR | Standard Deviation 0.4628 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region | Change in PET tau SUVR in Frontal Region at Week 60 | 0.138 SUVR | Standard Deviation 1.0103 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region | Change in PET tau SUVR in Frontal Region at Week 108 | 0.159 SUVR | Standard Deviation 0.9609 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region | Change in PET tau SUVR in Medial Temporal Region at Week 60 | 0.165 SUVR | Standard Deviation 0.5615 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region | Change in PET tau SUVR in Medial Temporal Region at Week 108 | 0.071 SUVR | Standard Deviation 0.5421 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region | Change in PET tau SUVR in Occipital Region at Week 60 | 0.258 SUVR | Standard Deviation 0.9359 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region | Change in PET tau SUVR in Occipital Region at Week 108 | 0.320 SUVR | Standard Deviation 0.8409 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region | Change in PET tau SUVR in Parietal Region at Week 60 | 0.124 SUVR | Standard Deviation 0.9826 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region | Change in PET tau SUVR in Parietal Region at Week 108 | 0.017 SUVR | Standard Deviation 0.8415 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region | Change in PET tau SUVR in Temporal Region at Week 60 | 0.218 SUVR | Standard Deviation 0.9283 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region | Change in PET tau SUVR in Temporal Region at Week 108 | 0.093 SUVR | Standard Deviation 0.7699 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region | Change in PET tau SUVR in Meta-Temporal Region at Week 60 | 0.179 SUVR | Standard Deviation 0.9515 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region | Change in PET tau SUVR in Meta-Temporal Region at Week 108 | 0.014 SUVR | Standard Deviation 0.7942 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region | Change in PET tau SUVR in Whole Cortical Gray Matter (GM) Region at Week 60 | 0.172 SUVR | Standard Deviation 0.9461 |
| Cohort A: E2814 750 mg | Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region | Change in PET tau SUVR in Whole Cortical GM Region at Week 108 | 0.133 SUVR | Standard Deviation 0.8421 |
Secondary
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
Population: The Pharmacokinetic (PK) Analysis Set was the group of participants who received at least 1 dose of test drug and had sufficient PK data to derive at least 1 PK parameter. As planned, this PK parameter was assessed for E2814 750 mg and 1500 mg only in Cohort A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: E2814 750 mg | Cohort A, Cmax: Maximum Observed Plasma Concentration for E2814 | 218 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 25.9 |
| Cohort A: E2814 1500 mg | Cohort A, Cmax: Maximum Observed Plasma Concentration for E2814 | 499 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 24.3 |
Secondary
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
Population: The PK Analysis Set was the group of participants who received at least 1 dose of test drug and had sufficient PK data to derive at least 1 PK parameter. As planned, this PK parameter was assessed for E2814 750 mg and 1500 mg only in Cohort A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: E2814 750 mg | Cohort A, Cmax: Maximum Observed Serum Concentration for E2814 | 41.7 mcg/mL | Geometric Coefficient of Variation 64.1 |
| Cohort A: E2814 1500 mg | Cohort A, Cmax: Maximum Observed Serum Concentration for E2814 | 101 mcg/mL | Geometric Coefficient of Variation 47.1 |
Secondary
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
Population: The PK Analysis Set was the group of participants who received at least 1 dose of test drug and had sufficient PK data to derive at least 1 PK parameter. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and Number Analyzed signifies participants evaluable at given time points for specified dosing group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: E2814 750 mg | Cohort A: CSF Concentrations of E2814 | Day 1: Pre-dose | 0 ng/mL | Standard Deviation 0 |
| Cohort A: E2814 750 mg | Cohort A: CSF Concentrations of E2814 | Day 84: Pre-dose | 172 ng/mL | Standard Deviation 77.8 |
| Cohort A: E2814 750 mg | Cohort A: CSF Concentrations of E2814 | Day 85: Pre-dose | 153 ng/mL | Standard Deviation 32.2 |
| Cohort A: E2814 1500 mg | Cohort A: CSF Concentrations of E2814 | Day 169: Pre-dose | 429 ng/mL | Standard Deviation 212 |
| Cohort A+B: E2814 3000 mg | Cohort A: CSF Concentrations of E2814 | Day 253: Pre-dose | 806 ng/mL | Standard Deviation 426 |
| Cohort A+B: E2814 3000 mg | Cohort A: CSF Concentrations of E2814 | Day 421: Pre-dose | 1035 ng/mL | Standard Deviation 35.4 |
| Cohort A: E2814 4500 mg | Cohort A: CSF Concentrations of E2814 | Day 757: Pre-dose | 1611 ng/mL | Standard Deviation 1567 |
Secondary
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
Population: The PK Analysis Set was the group of participants who received at least 1 dose of test drug and had sufficient PK data to derive at least 1 PK parameter. As planned, this PK parameter was assessed for E2814 750 mg and 1500 mg only in Cohort A.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: E2814 750 mg | Cohort A, Tmax: Time to Reach the Maximum Plasma Concentration for E2814 | 1.00 hours |
| Cohort A: E2814 1500 mg | Cohort A, Tmax: Time to Reach the Maximum Plasma Concentration for E2814 | 1.00 hours |
Secondary
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
Population: The PK Analysis Set was the group of participants who received at least 1 dose of test drug and had sufficient PK data to derive at least 1 PK parameter. As planned, this PK parameter was assessed for E2814 750 mg and 1500 mg only in Cohort A.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: E2814 750 mg | Cohort A, Tmax: Time to Reach the Maximum Serum Concentration for E2814 | 1.00 hours |
| Cohort A: E2814 1500 mg | Cohort A, Tmax: Time to Reach the Maximum Serum Concentration for E2814 | 5.00 hours |
Secondary
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
Population: The Safety Analysis Set was the group of participants who received at least 1 dose of study drug and had at least 1 post-dose safety assessment. As pre-specified in SAP, the data of Cohort B was combined with Cohort A for E2814 3000 mg group due to same dosing in both cohorts. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: E2814 750 mg | Number of Participants With Treatment-emergent Positive Plasma Anti-E2814 Antibody | 1 Participants |
| Cohort A: E2814 1500 mg | Number of Participants With Treatment-emergent Positive Plasma Anti-E2814 Antibody | 1 Participants |
| Cohort A+B: E2814 3000 mg | Number of Participants With Treatment-emergent Positive Plasma Anti-E2814 Antibody | 1 Participants |
| Cohort A: E2814 4500 mg | Number of Participants With Treatment-emergent Positive Plasma Anti-E2814 Antibody | 1 Participants |
Secondary
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
Population: The Safety Analysis Set was the group of participants who received at least 1 dose of study drug and had at least 1 post-dose safety assessment. As pre-specified in SAP, the data of Cohort B was combined with Cohort A for E2814 3000 mg group due to same dosing in both cohorts. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: E2814 750 mg | Number of Participants With Treatment-emergent Positive Serum Anti-E2814 Antibody | 1 Participants |
| Cohort A: E2814 1500 mg | Number of Participants With Treatment-emergent Positive Serum Anti-E2814 Antibody | 1 Participants |
| Cohort A+B: E2814 3000 mg | Number of Participants With Treatment-emergent Positive Serum Anti-E2814 Antibody | 0 Participants |
| Cohort A: E2814 4500 mg | Number of Participants With Treatment-emergent Positive Serum Anti-E2814 Antibody | 0 Participants |