NCT04971733已完成1 期
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
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Eisai Inc.
- 入组人数
- 8
- 试验地点
- 3
- 主要终点
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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
排除标准
- •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
- •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
研究组 & 干预措施
Cohort A, Phase 1b and 2: E2814
Experimental
Participants will receive E2814 as an intravenous infusion at set intervals over 12 weeks in Phase 1b and over 96 weeks in Phase 2.
干预措施: E2814 (Drug)
Cohort B: E2814
Experimental
Participants will receive E2814 as an intravenous infusion at set intervals over 52 weeks.
干预措施: E2814 (Drug)
结局指标
主要结局
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- Cohort A: CSF Concentrations of E2814(Pre-dose at Days 1, 84, 85, 169, 253, 421, and 757)
- Number of Participants With Treatment-emergent Positive Serum Anti-E2814 Antibody(From first dose of study drug up to 120 weeks)
- Number of Participants With Treatment-emergent Positive Plasma Anti-E2814 Antibody(From first dose of study drug up to 120 weeks)
- 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)
- 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)
- 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)
- Cohort A: Change From Baseline in Tau Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) by Region(Baseline, at Weeks 60 and 108)
研究者
研究点 (3)
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相关资讯
Eisai's Tau Antibody Etalanetug Receives FDA Fast Track Designation for Alzheimer's Disease- Eisai's investigational anti-MTBR tau antibody etalanetug (E2814) has been granted FDA Fast Track designation to expedite development for Alzheimer's disease treatment.
- Phase I/II clinical trial results showed target engagement with MTBR-tau species in cerebrospinal fluid and reduction in CSF MTBR-tau243 biomarker in patients with Dominantly Inherited Alzheimer's Disease.
- The antibody is currently being evaluated in combination with lecanemab in two ongoing clinical trials targeting both inherited and sporadic early Alzheimer's disease.
- Fast Track designation enables more frequent FDA interactions and potential eligibility for accelerated approval pathways if clinical data supports efficacy.12 months agoKey Neurology Advances of 2024: From Novel Therapies to Trial Innovations• Donanemab's enhanced titration method significantly reduces ARIA-E frequency and severity while maintaining amyloid reduction in Alzheimer's patients.
• Liraglutide demonstrates neuroprotective effects against Alzheimer's disease dementia, highlighting the potential of GLP-1 analogues in AD treatment.
• Tolebrutinib shows promise in slowing disability progression in non-relapsing secondary progressive multiple sclerosis patients in the HERCULES trial.last yearAlzheimer's Disease Therapeutics: Donanemab Dosing, Anti-Tau Antibody E2814, and Combination Intranasal Insulin/Empagliflozin Show Promise• Enhanced titration dosing of donanemab in the TRAILBLAZER-ALZ-6 trial significantly reduced the frequency and severity of ARIA-E in early symptomatic Alzheimer's disease patients.
• Phase 1b/2 study data of E2814, an anti-tau therapeutic antibody, demonstrated a significant impact on early and late tau biomarkers in patients with dominantly inherited Alzheimer's disease.
• A phase 2 trial showed that combination treatment with intranasal insulin and empagliflozin improved cognition and modulated immune/inflammatory biomarkers in mild cognitive impairment or early Alzheimer's disease.last yearEisai's Anti-MTBR Tau Antibody E2814 Shows Promise in Early Alzheimer's Disease• Eisai's E2814, an anti-MTBR tau antibody, demonstrated significant reductions in CSF MTBR-tau243 and p-tau217 levels in patients with Dominantly Inherited Alzheimer's Disease (DIAD).
• Tau PET imaging suggested that E2814 stabilized or reduced brain tau accumulation in DIAD subjects, indicating potential inhibition of tau propagation.
• Eisai has initiated a Phase II clinical study (Study 202) to evaluate the safety and biomarker efficacy of E2814 in early Alzheimer's disease patients receiving lecanemab.
• The Phase II study will assess E2814's impact on early AD patients already on lecanemab therapy, with plans to expand the study to Japan.last yearEisai's Anti-MTBR Tau Antibody E2814 Shows Promise in Alzheimer's Disease• Eisai's E2814, an anti-MTBR tau antibody, demonstrated significant reductions in CSF MTBR-tau243 and p-tau217 levels in patients with Dominantly Inherited Alzheimer's Disease (DIAD).
• Brain tau accumulation, as observed by tau PET, stabilized or trended towards decrease in DIAD subjects administered E2814, suggesting inhibition of tau propagation.
• Eisai has initiated a Phase II clinical study (Study 202) to evaluate the safety, tolerability, and biomarker efficacy of E2814 in early Alzheimer's disease patients receiving lecanemab.
• The Phase II study will be a placebo-controlled, double-blind, parallel-group, dose exploration study, evaluating the safety, tolerability, and biomarker efficacy of E2814.last year