Evaluation of RO7269162 on Amyloid Biomarkers in Prodromal Alzheimer's Disease: A Phase IIa Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to investigate the **safety** and tolerability of daily oral dosing of RO7269162 and to assess its effect on brain **amyloid** accumulation in participants at risk for or at the prodromal stage of **Alzheimer's Disease**. This is clinically relevant as it aims to determine the potential of RO7269162 in modifying disease progression by targeting amyloid pathology, a hallmark of Alzheimer's Disease.

Secondary objectives include: - To assess the effect of daily oral dosing of RO7269162 on pharmacodynamic biomarkers related to Aβ metabolism in cerebrospinal fluid (CSF) and plasma. - To investigate the pharmacokinetics of daily oral dosing of RO7269162 (and its metabolite[s] as appropriate) in plasma and CSF. These objectives are crucial for understanding the drug's mechanism of action and its distribution and metabolism in the body, which are essential for optimizing therapeutic strategies.

The clinical trial involves a total of **45 participants** diagnosed with or at risk for **Alzheimer's Disease**. The study population includes both male and female subjects, with an age range that encompasses middle-aged to older adults. Participants were selected based on specific criteria, including a **Body Mass Index (BMI)** between 18 to 35 kg/m² and either being cognitively unimpaired or having a diagnosis of mild cognitive impairment due to Alzheimer's Disease. The trial also requires a Clinical Dementia Rating-Global Score of 0 or 0.5 and a positive amyloid PET scan. Participants must have a study partner who meets certain criteria to ensure accurate reporting of cognitive and functional abilities. The trial population includes individuals who may be considered vulnerable, and those on symptomatic Alzheimer's medications must have a stable dosing regimen for at least eight weeks prior to the study. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase IIa**, randomized, double-blind, placebo-controlled, multiple-dose, multicenter, parallel-group study designed to evaluate the safety, tolerability, and effects of RO7269162 on amyloid and non-amyloid disease-related biomarkers in participants at risk for or at the prodromal stage of **Alzheimer's Disease**. The trial involves daily oral administration of RO7269162, a gamma-secretase modulator, and includes a placebo group for comparison. The study is expected to commence recruitment on March 28, 2024, and conclude by July 21, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as a **Body Mass Index (BMI)** between 18 to 35 kg/m², a Clinical Dementia Rating-Global Score (CDR-GS) of 0 or 0.5, and a positive amyloid PET scan. The trial will include follow-up visits to monitor safety and efficacy endpoints, such as changes in brain amyloid load and biomarker levels in cerebrospinal fluid (CSF) and plasma. The end-of-study visit will evaluate the overall outcomes and any adverse events experienced during the trial.

The expected duration of participant involvement is up to 72 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. Primary endpoints focus on the nature, incidence, severity, and outcome of adverse events, as well as changes in vital signs, ECG parameters, and brain amyloid load. Secondary endpoints include changes in specific amyloid peptides in CSF and plasma, and the concentrations of RO7269162 and its metabolites. The trial is not classified as low intervention and is part of an ongoing development program for the investigational product.

The clinical trial involves the administration of several treatments, including the experimental medication **RO7269162**, a gamma-secretase modulator. This compound is provided in the form of a hard capsule and is administered orally. The maximum treatment period for RO7269162 is 72 days. The dosing schedule is designed to assess the safety, tolerability, and effect on brain amyloid accumulation in participants at risk for or at the prodromal stage of Alzheimer's disease. The specific dosage in milligrams is not provided, indicating that the dosing may be adjusted based on individual participant response or study protocol requirements.

In addition to the experimental medication, a **Placebo** is utilized in the study to serve as a comparator treatment. The placebo is identified as Placebo RO7269162, although specific details regarding its pharmaceutical form, active substance, and route of administration are not available. The use of a placebo is critical in maintaining the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby reducing bias.

Auxiliary treatments include **FLORBETABEN (18F)** and **FLUTEMETAMOL (18F)**, both of which are solutions for injection. These compounds are administered via intravenous slow bolus injection. FLORBETABEN (18F) has a maximum daily dose of 300 MBq and a total dose limit of 900 MBq over a maximum treatment period of 3 days. Similarly, FLUTEMETAMOL (18F) has a maximum daily dose of 185 MBq and a total dose limit of 555 MBq, also over a 3-day period. These radiopharmaceuticals are likely used for imaging purposes to assess amyloid deposition in the brain, providing critical data on the disease state and the effect of the experimental treatment.

The efficacy of the investigational product RO7269162 in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint involves the change from baseline in brain **amyloid** load, which will be measured using amyloid PET scans. This imaging technique is crucial for evaluating the effect of RO7269162 on amyloid accumulation in the brain, a key factor in Alzheimer's disease progression.

Secondary efficacy endpoints include changes from baseline in specific biomarkers such as Aβ37, Aβ38, Aβ40, and Aβ42 in cerebrospinal fluid (CSF), as well as Aβ40 and Aβ42 in plasma. Additionally, the plasma and CSF concentrations of RO7269162 and its metabolites will be measured to further understand the pharmacokinetic profile of the drug. These measurements will provide insights into the drug's impact on amyloid and non-amyloid disease-related biomarkers.

The collection and analysis of these efficacy parameters will be conducted at specified timepoints throughout the trial, ensuring a comprehensive evaluation of the drug's therapeutic potential. The use of validated laboratory tests and imaging techniques will ensure the reliability and accuracy of the data collected. The trial is designed to provide robust evidence on the efficacy of RO7269162 in participants at risk for or at the prodromal stage of Alzheimer's disease.