Evaluation of Lecanemab, E2814, and Florquinitau (18F) in Dominantly Inherited Alzheimer's Disease: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the **safety**, tolerability, biomarker, cognitive, and clinical efficacy of investigational products in participants with a mutation causing Dominantly Inherited Alzheimer's Disease (DIAD). This is clinically relevant as it aims to determine whether treatment with the study drug can slow the progression of cognitive and clinical impairment or improve disease-related biomarkers, potentially offering a therapeutic strategy for individuals with this genetic form of Alzheimer's disease.

Secondary objectives include:

• Assessing the safety and tolerability of each study drug in individuals with mutations causing dominantly inherited Alzheimer's disease.
• Utilizing data collected during the CRI period for analysis in the respective drug arm under which participants are randomized and treated.

The clinical trial involves a total of **151 participants** diagnosed with **Dominantly Inherited Alzheimer Disease (DIAD)**. The study population includes both male and female subjects, encompassing a broad age range, specifically adults and older adults. Participants were selected based on their genetic predisposition to Alzheimer's disease, with a focus on those carrying a known mutation or having a 50% risk due to family history. The trial includes individuals within -10 to +10 years of the estimated age at symptom onset, as well as those 11 to 25 years younger than their estimated age at symptom onset. The study population is characterized by a mix of primary and secondary prevention groups, with participants required to be willing to complete all study-related testing and procedures. The trial also considers vulnerable populations, ensuring comprehensive representation in the study. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate potential disease-modifying therapies for **Dominantly Inherited Alzheimer Disease (DIAD)**. The trial aims to assess the safety, tolerability, and efficacy of investigational products, including **Lecanemab**, **E2814**, and **MK-6240**, in participants with a genetic mutation causing Alzheimer's disease. The study will utilize biomarker, cognitive, and clinical endpoints to determine if treatment with the study drugs can slow the progression of cognitive and clinical impairment or improve disease-related biomarkers.

The trial is expected to run until December 31, 2027, with participant recruitment having commenced on July 13, 2014. Participants will be involved in the study for a maximum treatment period of 208 weeks. The trial includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits every 26 weeks to monitor progress and collect data, and an end-of-study visit to assess final outcomes. The primary outcome measures will include biomarker, cognitive, and clinical outcomes, with comparisons made between active drug groups, mutation-positive placebos, and control groups.

Participants will be required to meet specific inclusion criteria, such as being within a certain age range relative to the estimated age of symptom onset and having a known eligible mutation carrier status. Conditions that may lead to early termination from the study include the discovery that an at-risk parent is a non-carrier, which would result in the withdrawal of the participant. The study will also assess secondary endpoints, including the safety and tolerability of each study drug, biomarker engagement, and changes in cognitive and clinical measures. Imaging and fluid biomarker measures will be used to evaluate the effects of the investigational products on Alzheimer's disease pathology.

The clinical trial involves the administration of several investigational products, including **MK-6240**, **Lecanemab**, **PiB**, and **E2814**, as well as a placebo. **MK-6240** is a **solution for injection** containing the active substance **Florquinitau (18F)**. It is administered via **intravenous bolus use**. The maximum daily dose is 6 mCi, with a total maximum dose of 42 mCi over a treatment period of 208 weeks. This compound is chemically synthesized and is provided by Alnylam Pharmaceuticals Inc.

**Lecanemab** is a **concentrate for solution for infusion** and is classified as a biological product. The active substance is **Lecanemab**, a protein-based compound. It is administered through **intravenous use**. The maximum daily dose is 10 mg/kg, with a total maximum dose of 1820 mg/kg over the same treatment period. This product is developed by Eisai Ltd.

**PiB**, also known as **Pittsburgh compound B**, is an **injection** containing the active substance **N-Methyl-2-(4'-methylaminophenyl)-6-hydroxybenzothiazole**. It is administered via **intravenous bolus use**. The maximum daily dose is 18 mCi, with a total maximum dose of 90 mCi over 208 weeks. This chemical compound is provided by Washington University School of Medicine.

**E2814** is a **solution for infusion** and is also classified as a biological product. The active substance is **E2814**, a protein-based compound. It is administered through **intravenous use**. The maximum daily dose is 3000 mg, with a total maximum dose of 234000 mg over the treatment period. This product is developed by Eisai Ltd.

The trial also includes an **E2814 Placebo**, which serves as a comparator treatment. The placebo is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators know which treatment is being administered. The placebo is administered in a manner consistent with the active treatments to ensure blinding is maintained.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The trial aims to assess the safety, tolerability, and efficacy of these investigational products in participants with dominantly inherited Alzheimer's disease, focusing on slowing cognitive and clinical impairment or improving disease-related biomarkers.

The efficacy of investigational products in the clinical trial will be assessed using a combination of **biomarker**, cognitive, and clinical endpoints. The primary outcome measures will include biomarker, cognitive, or clinical outcomes, with comparisons made between active drug groups, mutation-positive placebos, and control groups. Secondary endpoints will focus on assessing the safety and tolerability of each study drug in individuals with mutations causing dominantly inherited Alzheimer's disease. Biomarker endpoints will be used at interim analysis to assess target engagement, including soluble biochemical measures such as amyloid-beta and tau, imaging measures of pathology like amyloid and tau PET, and changes in Alzheimer's disease biomarkers such as atrophy measured by MRI and hypometabolism by FDG PET.

Cognitive measures will be obtained at baseline and every 26 weeks, administered at the DIAN-TU site or via a home health nurse trial-certified cognitive rater. These measures include the DIAN Memory Complaint Questionnaire, Buschke and Grober Free and Cued Selective Reminding Test Immediate Recall, and Wechsler Memory Scale-Revised. Imaging measures in randomized drug arms will include glucose metabolism PET imaging with FDG-PET, amyloid PET imaging with [11C]PiB-PET, tau PET imaging with [18F]MK-6240, and structural brain measures with volumetric MRI. Fluid biomarker measures may include CSF and plasma amyloid species analyses, CSF and plasma tau species analyses, and CSF and plasma neurofilament light chain analyses.

For the E2814 arm, the symptomatic population (Cohort 1) will be assessed to determine whether E2814 is superior to placebo when concurrently administered with lecanemab, focusing on changes from Week 24 to Week 208 in the Clinical Dementia Rating Scale Sum of Boxes. The asymptomatic population (Cohort 2) will be evaluated to determine whether E2814 is superior to placebo when administered alone and then concurrently with lecanemab, focusing on changes from Week 0 to Week 104 (interim analysis) and Week 208 (final analysis) in CSF phosphorylated tau.