Efficacy, Safety, and Immunogenicity of JNJ-64042056 in Preclinical Alzheimer's Disease: A Randomized, Placebo-Controlled, Double-Blind Study

The primary objective of this multicenter, randomized, placebo-controlled, double-blind, parallel-group study is to investigate the effect of **JNJ-64042056** versus placebo on cognitive decline in participants with preclinical Alzheimer's disease. This is assessed by the Preclinical AD Cognitive Composite 5 (PACC-5) total scores. The clinical relevance of this objective lies in its potential to provide insights into the efficacy of JNJ-64042056 as a phosphorylated tau-targeted active immunotherapy, which could contribute to the development of therapeutic strategies aimed at slowing or preventing cognitive decline in the early stages of Alzheimer's disease.

The clinical trial involves a total of **342 participants** diagnosed with **Preclinical Alzheimer’s Disease**. The study population includes both male and female subjects, aged between **55 to 75 years**. Participants were selected based on specific criteria, including elevated brain tau pathology and a Clinical Dementia Rating (CDR) global score of 0 at screening and baseline. All participants have a Mini-Mental State Examination (MMSE) score of 27 or higher, adjusted for education, and possess the ability to read and write with at least five years of formal education. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection process.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, parallel-group study to evaluate the efficacy, safety, and immunogenicity of JNJ-64042056, a phosphorylated tau-targeted active immunotherapy, in participants with preclinical **Alzheimer's disease**. The primary objective is to assess the effect of JNJ-64042056 versus placebo on cognitive decline, measured by changes in the Preclinical AD Cognitive Composite 5 (PACC-5) total scores. The trial is expected to span approximately seven years, with an estimated end date in April 2031.

Participants will be involved in the study for a maximum treatment period of 48 weeks. The study will commence with an inclusion (screening) visit, where eligibility criteria such as age (55 to 75 years), elevated brain tau pathology, and cognitive assessments will be evaluated. Following successful screening, participants will be randomized to receive either the investigational product or placebo. The investigational product, JNJ-64042056, is administered as a dispersion for injection via intramuscular use, while florquinitau F18, used for imaging purposes, is administered as a solution for injection via intravenous use.

Study visits will be scheduled at regular intervals to monitor safety, efficacy, and immunogenicity. These visits will include cognitive assessments, imaging studies, and safety evaluations. The primary endpoint is the change from baseline in PACC-5 total scores at Week 206. Participants will continue in the study until the end-of-study visit, which will include final assessments and evaluations. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures.

The clinical trial involves the administration of **JNJ-64042056**, a phosphorylated tau-targeted active immunotherapy, in participants with preclinical Alzheimer's disease. **JNJ-64042056** is provided in the form of a **dispersion for injection** and is administered via **intramuscular use**. The dosing schedule is structured over a maximum treatment period of 48 weeks. The specific dosage in micrograms is not detailed, and the maximum daily and total dose amounts are indicated as zero, suggesting a flexible dosing regimen within the trial parameters. Participant compliance with the dosing schedule is monitored throughout the study period.

Another investigational product used in the trial is **florquinitau F18**, also known by its sponsor product code **[18F]MK-6240**. This compound is a **solution for injection** and is administered through **intravenous use**. The active substance in **florquinitau F18** is **6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)-5-isoquinolinamine**, a chemical substance. The dosing unit is measured in megabecquerels (MBq), with the maximum daily and total dose amounts also recorded as zero, indicating a tailored dosing approach. The treatment period for this product is similarly capped at 48 weeks, with adherence to the administration protocol being closely monitored.

The study design includes a **placebo** group to serve as a comparator for evaluating the efficacy and safety of **JNJ-64042056**. The placebo is administered in a manner consistent with the active treatment to maintain the double-blind nature of the trial. The placebo is used to assess the cognitive decline in participants, as measured by the Preclinical AD Cognitive Composite 5 (PACC-5) total scores, ensuring a robust evaluation of the investigational product's impact.

Efficacy in this clinical trial will be assessed by evaluating the effect of JNJ-64042056 on cognitive decline in participants with preclinical Alzheimer's Disease. The primary endpoint for efficacy evaluation is the change from baseline on the Preclinical AD Cognitive Composite 5 (PACC-5) total scores at Week 206. The PACC-5 is a validated scale used to measure cognitive performance, and it will be employed to determine the impact of the treatment over the specified period. The trial is designed as a multicenter, randomized, placebo-controlled, double-blind, parallel-group study, ensuring rigorous assessment of the treatment's efficacy. The schedule for measuring and collecting efficacy data involves baseline assessments followed by evaluations at Week 206, allowing for a comprehensive analysis of the treatment's long-term effects on cognitive decline.