Efficacy, Safety, and Tolerability of Bepranemab in Prodromal to Mild Alzheimer's Disease: A Placebo-Controlled Study with Open-Label Extension

The primary objective of this study is to investigate the effect of **bepranemab** versus placebo on the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) up to Week 80 in participants with prodromal or mild **Alzheimer's Disease** (AD). This objective is clinically relevant as it aims to assess the potential of bepranemab in slowing cognitive decline, which is a critical aspect of managing Alzheimer's Disease.

Secondary objectives include:

• Evaluation of the safety and tolerability of bepranemab versus placebo over 80 weeks in participants with prodromal or mild AD.
• Investigation of the effect of bepranemab on tau burden in the brain, as measured by [18F]Genentech tau probe 1 (GTP1) positron emission tomography (PET) imaging in participants with prodromal or mild AD.
• Investigation of the effect of bepranemab versus placebo on cognitive and functional measures over time in participants with prodromal or mild AD.
• Characterization of the pharmacokinetics (PK) of bepranemab following repeated intravenous administration in participants with prodromal or mild AD.

The clinical trial involves a total of **184 participants** diagnosed with **Alzheimer's Disease**, specifically in the prodromal or mild stages. The study population includes both male and female subjects, aged between **50 to 80 years**. Participants were selected based on specific criteria, including a diagnosis of prodromal or mild cognitive impairment due to Alzheimer's Disease, as defined by the National Institute of Aging-Alzheimer's Association. The trial population is characterized by a global Clinical Dementia Rating score of 0.5 to 1.0 and a CDR-Memory Box score of at least 0.5 at screening and baseline. Additionally, participants must have a Mini-Mental State Examination score of 20 or higher at screening and evidence of cerebral Aβ accumulation. The study also requires participants to have an identified informant who maintains sufficient contact to provide accurate information on the participant's cognitive, functional, and emotional states. The trial includes individuals with at least six years of formal education after the age of five or equivalent work experience to exclude mental deficits other than those related to prodromal or mild Alzheimer's dementia. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study population is considered vulnerable, given the nature of the disease being investigated.

The clinical trial is designed to evaluate the **efficacy**, safety, and tolerability of **Bepranemab** in participants with prodromal to mild **Alzheimer's Disease**. This study is a randomized, double-blind, placebo-controlled trial followed by an open-label extension period. The trial is expected to last until July 2025, with participant recruitment having commenced in October 2021. The primary objective is to assess the change from baseline to Week 80 in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) total score. Secondary endpoints include the incidence of treatment-emergent adverse events, changes in tau burden in the brain, and cognitive assessments.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, cognitive impairment level, and evidence of cerebral amyloid-beta accumulation. The double-blind treatment period will involve regular follow-up visits to monitor safety and efficacy, with assessments conducted at baseline, Week 56, and Week 80. The end-of-study visit will conclude the double-blind phase, after which participants may enter the open-label extension period.

The expected duration of participant involvement in the double-blind phase is approximately 80 weeks. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, significant protocol deviations, or withdrawal of consent by the participant. The trial will utilize **Bepranemab** administered as a solution for infusion, with a placebo group receiving a matching solution without active substance. Auxiliary products such as **(18F) GTP1** and **Neuraceq** will be used for imaging purposes to assess tau burden and amyloid-beta accumulation, respectively.

The clinical trial involves the administration of **Bepranemab**, an investigational medication, which is provided in the form of a **solution for infusion**. Bepranemab is administered intravenously, with the dosing regimen based on a milligram per kilogram (mg/kg) body weight calculation. The maximum treatment period for Bepranemab is 144 weeks. The active substance, Bepranemab, is a protein of other origin, developed by UCB Biopharma SRL. Participant compliance with the dosing schedule will be monitored throughout the study.

A **placebo** is also utilized in this study, designed to match the Bepranemab solution but without any active substance. The placebo serves as a control to evaluate the efficacy and safety of Bepranemab. The placebo is administered in a manner consistent with the experimental treatment to maintain the study's blind design.

Additionally, the study employs **(18F) GTP1**, a solution for injection, used as an auxiliary substance. This chemical compound is administered intravenously, with a maximum dose of 259 megabecquerels (MBq) over a treatment period of up to 4 weeks. The compound is developed by UCB Biopharma SRL and is used to support the study's objectives.

Another auxiliary substance used in the trial is **Neuraceq**, a 300 MBq/mL solution for injection containing the active substance **Florbetaben (18F)**. This chemical is also administered intravenously, with a maximum dose of 300 MBq. The treatment period for Neuraceq is limited to 1 week. Neuraceq is produced by Life Molecular Imaging GmbH and is utilized to assist in the evaluation of the study's primary endpoints.

The efficacy of Bepranemab in the clinical trial will be assessed primarily through the change from baseline to Week 80 in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) total score. This endpoint is designed to evaluate the effect of Bepranemab compared to placebo in participants with prodromal or mild **Alzheimer's Disease**. The CDR-SB is a validated scale used to quantify the severity of symptoms of dementia, providing a comprehensive measure of cognitive and functional performance.

Secondary efficacy endpoints include changes from baseline to Week 56 and Week 80 in several cognitive and functional assessments. These include the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14), the Amsterdam-Instrumental Activities of Daily Living (AiADL), and the Mini-Mental State Examination (MMSE) total score. Additionally, changes in tau burden in the brain will be measured using [18F]Genentech tau probe 1 (GTP1) positron emission tomography (PET) at the same time points. Serum concentrations of Bepranemab will also be monitored over the 80-week double-blind treatment period to assess pharmacokinetics.

The schedule for measuring these efficacy parameters involves assessments at baseline, Week 56, and Week 80. The use of validated scales and imaging techniques ensures the reliability and accuracy of the data collected. The trial is designed to provide a comprehensive evaluation of Bepranemab's potential as a therapeutic option for Alzheimer's Disease, with a focus on both cognitive and functional outcomes.