Efficacy and Safety Evaluation of VHB937 in Early Alzheimer's Disease: A Randomized, Placebo-Controlled, Parallel Group, 72-Week Study

The primary objective of this study is to evaluate the effect of **VHB937** compared to placebo on cognition and function in participants with early **Alzheimer's disease**. This is clinically relevant as it aims to determine the potential therapeutic benefits of VHB937 in improving cognitive and functional outcomes in this patient population, which could lead to advancements in treatment options for Alzheimer's disease.

Secondary objectives include:

• To evaluate the safety and tolerability of VHB937 compared to placebo.
• To evaluate the effect of VHB937 compared to placebo on cognition.
• To evaluate the effect of VHB937 compared to placebo on activities of daily living.
• To assess pharmacokinetics (PK) and immunogenicity (IG) of VHB937 in serum.

The clinical trial involves a total of **240 participants** diagnosed with **Alzheimer’s disease**. The study population includes both male and female subjects aged between **50 to 85 years**. Participants are required to have a maximum body weight of 180 kg at the time of signing the informed consent. The trial specifically targets individuals with a diagnosis of Mild Cognitive Impairment (MCI) due to Alzheimer's disease or mild Alzheimer's disease, as per the NIA-AA criteria. Participants must have a Clinical Dementia Rating (CDR) Global score of 0.5 or 1.0 at Screening and Baseline, and an ADAS-Cog14 total score between CCI at Screening. Biomarker-based confirmation of Alzheimer's disease is necessary, either through cerebral spinal fluid biomarkers or amyloid PET imaging, with historical confirmation of amyloid positivity being acceptable. A reliable study partner is required to accompany participants during study visits where informant scales are administered. Participants receiving an acetylcholinesterase inhibitor (AChEI) or memantine, or both, must be on a stable dose for at least 12 weeks before randomization. Those who discontinued these medications before screening should have a stop date at least 12 weeks prior to randomization. Treatment-naïve participants are also eligible for enrollment. The trial population was selected based on these criteria to ensure a focused study on the effects of VHB937 compared to placebo on cognition and function in individuals with Alzheimer's disease.

The clinical trial is designed to evaluate the efficacy and safety of **VHB937** in participants with early **Alzheimer's disease**. This study is a randomized, placebo-controlled, parallel-group trial with a duration of 72 weeks. The trial will assess the effect of VHB937 compared to placebo on cognition and function. Participants will be randomly assigned to receive either VHB937 or a placebo, with both the participants and investigators blinded to the treatment allocation to ensure unbiased results.

The trial will commence with an inclusion (screening) visit, where potential participants will be evaluated against the inclusion criteria, which include being between 50 to 85 years of age, having a diagnosis of mild cognitive impairment due to Alzheimer's disease, and a Clinical Dementia Rating (CDR) Global score of 0.5 or 1.0. Biomarker-based confirmation of Alzheimer's disease is required, and participants must have a reliable study partner for visits. Following successful screening, eligible participants will be enrolled and randomized.

Throughout the study, participants will attend regular follow-up visits to monitor their health and the effects of the treatment. These visits will include assessments of cognitive function, safety evaluations, and pharmacokinetic measurements. The primary endpoint is the change from baseline to week 72 in the Clinical Dementia Rating scale – Sum of Boxes (CDR-SB). Secondary endpoints include the incidence and severity of adverse events, changes in cognitive and daily living activities, and the determination of VHB937 concentrations and immunogenicity in serum.

The expected length of participant involvement is 72 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. The trial is not categorized as low intervention and is classified as a phase 2 trial. The study aims to provide valuable insights into the potential benefits and risks of VHB937 for individuals with early Alzheimer's disease.

The clinical trial involves the administration of **VHB937**, a **monoclonal antibody** developed by Novartis Pharma AG. VHB937 is provided as a **concentrate for solution for infusion**. The pharmaceutical form is specifically designed for **intravenous use**. The dosing regimen is based on a weight-adjusted protocol, with the dosage expressed in **milligrams per kilogram (mg/kg)**. The maximum treatment period for VHB937 is set at 72 weeks. The trial aims to evaluate the efficacy and safety of VHB937 in participants with early **Alzheimer's Disease**. The administration schedule and participant compliance are closely monitored to ensure adherence to the protocol.

The study also includes a **placebo** group to serve as a comparator. The placebo is formulated to match the appearance and administration route of VHB937, ensuring blinding of both participants and investigators. The placebo is administered intravenously, following the same schedule as the experimental treatment. This design allows for a rigorous assessment of VHB937's effects on cognition and function in the target population. Compliance with the dosing schedule is monitored throughout the study to maintain the integrity of the trial data.

The efficacy of VHB937 in participants with early **Alzheimer's Disease** will be assessed through a randomized, placebo-controlled, parallel group study over a 72-week period. The primary endpoint for evaluating efficacy is the change from baseline to week 72 in the Clinical Dementia Rating scale – Sum of Boxes (CDR-SB). Secondary endpoints include changes from baseline in CDR-SB and ADAS-Cog14 over time until week 72, as well as changes in instrumental activities of daily living (iADL) on the ADCS-ADL scale over the same period. Additionally, pharmacokinetics will be assessed by determining VHB937 concentrations in serum at selected timepoints, and immunogenicity will be evaluated by measuring anti-VHB937 antibodies in serum at selected timepoints.

Data collection will involve the use of validated scales and laboratory tests. The CDR-SB and ADAS-Cog14 scales will be used to measure cognitive and functional changes, while the ADCS-ADL scale will assess daily living activities. Pharmacokinetic and immunogenicity assessments will be conducted through serum analysis. The schedule for these assessments includes baseline measurements and follow-up evaluations at specified intervals up to week 72. The study will also monitor the incidence and severity of adverse events, safety findings from brain MRI, laboratory tests, vital signs, ECG findings, and suicidality assessments using the Columbia Suicide Severity Rating Scale (C-SSRS).