Phase IIIb/IV Open-Label Study of Lecanemab in the Prevention and Progression of Dominantly Inherited Alzheimer's Disease

The primary objective of this study is to evaluate the effects of **amyloid** removal on the age of onset and clinical progression of Dominantly Inherited Alzheimer Disease (DIAD) compared to external controls. This is clinically relevant as it aims to assess whether the intervention can delay or alter the course of this genetically driven form of Alzheimer's disease, potentially offering insights into therapeutic strategies for managing the condition.

Secondary objectives include:

• Determining if amyloid plaque, as measured by amyloid PET, can be fully removed in DIAD.
• Assessing the effects of amyloid removal on biomarkers of disease progression.

These secondary objectives are crucial for understanding the broader impact of amyloid removal on disease pathology and progression, which may inform future therapeutic approaches and biomarker development in Alzheimer's disease research.

The clinical trial involves a total of **61 participants** diagnosed with **Dominantly Inherited Alzheimer Disease (DIAD)**. The study population includes both male and female subjects, with an age range that corresponds to categories 3 and 4, indicating adult participants. The trial population was selected based on specific criteria, including previous participation in the DIAN-TU-001 gantenerumab OLE period and willingness to engage in ongoing anti-amyloid therapy. Participants are required to have a **Body Mass Index (BMI)** between 17 and 35 and must have adequate vascular access for study drug administration. The study also considers lifestyle factors, requiring participants to have an identified study partner who can provide support and follow-up information. The trial includes a vulnerable population, emphasizing the need for informed consent and adherence to contraceptive measures for people of childbearing potential. The selection process ensures that participants can undergo necessary safety MRI scans and are co-enrolled in the DIAN Observational Study, demonstrating a commitment to comprehensive monitoring and assessment throughout the study duration.

The clinical trial is designed to evaluate the effects of **lecanemab**, a **biological** product, on the prevention and progression of **Dominantly Inherited Alzheimer Disease (DIAD)**. This is a Phase IIIb/IV open-label study, with a primary objective to assess the impact of amyloid removal on the age of onset and clinical progression compared to external controls. The trial is expected to commence recruitment on November 27, 2024, and conclude by May 9, 2030. Participants will be involved in the study for a maximum treatment period of 60 months, receiving **lecanemab** as a concentrate for solution for infusion, with a maximum daily dose of 10 mg/kg and a total dose not exceeding 1300 mg.

The trial follows a structured sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as previous participation in the DIAN-TU-001 gantenerumab OLE period, willingness to continue anti-amyloid therapy, and adequate vascular access for drug administration. Participants must also have a Body Mass Index (BMI) between 17 and 35 and an identified study partner. Follow-up visits will be conducted to monitor the primary and secondary endpoints, including changes in amyloid PET and tau PET imaging, clinical assessments, and biomarkers of disease progression. The primary endpoint for interim analysis is the change in amyloid Pittsburgh compound B (PiB) PET standardized uptake value ratio (SUVR) from baseline to year 1 or 2, while the final analysis focuses on the time to recurrent progression of Clinical Dementia Rating – Sum of Boxes (CDR-SB).

The end-of-study visit will mark the completion of the trial, where final assessments will be conducted. Participants may be terminated early from the study if they fail to meet ongoing eligibility criteria, experience adverse effects, or withdraw consent. The trial is not categorized as low intervention, and it is crucial for participants to adhere to the study protocol to ensure the integrity of the data collected. The study is conducted under the sponsorship of EISAI LTD, with **lecanemab** being the investigational product under evaluation.

The clinical trial involves the administration of **Lecanemab**, a **biological** product developed by EISAI LTD. Lecanemab is provided in the form of a **concentrate for solution for infusion**. The active substance, **lecanemab**, is a protein of other origin. The pharmaceutical form is specifically designed for **solution for injection**. The dosing regimen for Lecanemab is set at a maximum daily dose of 10 mg/kg, with a total maximum dose of 1300 mg over the course of the treatment period. The maximum treatment duration is 60 weeks. The administration route is intravenous, and the frequency of administration is determined by the study protocol. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen.

In this study, Lecanemab is the primary investigational product, and no additional non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial aims to evaluate the effects of amyloid removal on the age of onset and clinical progression of Dominantly Inherited Alzheimer's Disease. The study does not include a pediatric formulation, and the product is not classified as an orphan drug. The trial is conducted as an open-label study, allowing for direct observation of the treatment effects without the use of blinding.

Efficacy in the clinical trial titled "The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) Amyloid Removal Trial (ART): A Phase IIIb/IV Open-Label Study of Lecanemab to Evaluate Prevention and Progression of Dominantly Inherited Alzheimer's Disease" will be assessed using specific primary and secondary endpoints. The primary endpoint for the interim analysis is the change from ART baseline to year 1 or year 2 in amyloid Pittsburgh compound B (PiB) PET standardized uptake value ratio (SUVR). The primary endpoint for the final analysis is the time to recurrent progression of **Clinical Dementia Rating – Sum of Boxes (CDR-SB)**.

The secondary endpoint analysis will focus on the change from ART baseline to year 5 in various assessments, including imaging (amyloid PET, tau PET), clinical evaluations using the Functional Assessment Scale, and plasma and cerebrospinal fluid (CSF) biomarkers of disease progression. These biomarkers include Aβ42/40, tau species (%phosphorylated tau217, 205, 231), total tau, and microtubule-binding region (MTBR) species, such as MTBR-243. These assessments are collected at the initial DIAN Obs Visit, which coincides with DIAN-TU-003 Visit 2.