A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study with a Long-Term Extension Treatment Period to Assess the Efficacy and Safety of JNJ-63733657, an Anti-tau Monoclonal Antibody, in Participants with Early Alzheimer's Disease

The primary objective of this study is to evaluate the effect of **JNJ-63733657** versus placebo on clinical decline in participants with early Alzheimer's disease, as measured by the Integrated Alzheimer's Disease Rating Scale (iADRS), which is a composite measure of cognition and function. This is clinically relevant as it aims to assess the potential of JNJ-63733657, an anti-tau monoclonal antibody, to slow the progression of Alzheimer's disease, thereby potentially improving patient outcomes.

Secondary objectives include:

• Evaluating the effect of JNJ-63733657 versus placebo on cognitive decline as measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog13).
• Assessing changes in functional status between participants treated with JNJ-63733657 versus placebo, as measured by the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory for Mild Cognitive Impairment (ADCS-ADL-MCI).
• Evaluating the effect of JNJ-63733657 compared with placebo on cognitive decline, as measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Scale Index Score.
• Assessing the effect of JNJ-63733657 on clinical progression compared with placebo, as measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB).
• Evaluating the effect of JNJ-63733657 on the accumulation and/or propagation of tau pathology compared with placebo, as measured by tau positron emission tomography (PET).

The clinical trial involves a total of **523 participants** diagnosed with **Early Alzheimer's Disease**. The study population includes both male and female subjects, aged between **55 to 80 years**, who exhibit a gradual and progressive decline in cognition over at least the past six months. Participants were selected based on specific criteria, including evidence of pathologic tau on a screening tau PET scan. The trial does not involve a vulnerable population. Participants are required to have a designated study partner with adequate literacy to ensure the likelihood of study completion. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled, parallel-group** study to evaluate the efficacy and safety of JNJ-63733657, an anti-tau monoclonal antibody, in participants with early **Alzheimer's disease**. The trial includes a long-term extension treatment period and is conducted across multiple centers. The primary objective is to assess the effect of JNJ-63733657 versus placebo on clinical decline, measured by the integrated Alzheimer's Disease Rating Scale (iADRS), a composite of cognition and function. The trial is expected to run until December 31, 2032, with recruitment having started on April 15, 2021.

Participants will be involved in the study for a maximum treatment period of 140 weeks. The study visits are structured as follows: an initial **screening visit** to confirm eligibility, followed by regular **follow-up visits** to monitor safety and efficacy, and an **end-of-study visit** to conclude participation. The inclusion criteria require participants to be between 55 and 80 years of age, with evidence of pathologic tau on a screening tau PET scan, and a gradual and progressive decline in cognition over at least the past six months. Participants must also have a designated study partner capable of participating throughout the study.

Early termination from the study may occur if participants experience adverse events that compromise safety, fail to adhere to the study protocol, or withdraw consent. The primary endpoint is the change from baseline on the iADRS total score at week 104. The trial is categorized as a Phase 4 study, focusing on the proof-of-concept for slowing clinical decline in early Alzheimer's disease. The investigational product, JNJ-63733657, is administered as a **solution for infusion** via intravenous use, while the placebo is also administered intravenously. The study is not classified as a low-intervention trial.

The clinical trial involves the administration of **florquinitau F18**, a radiopharmaceutical agent formulated as a **solution for injection**. The active substance, **6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)-5-isoquinolinamine**, is of chemical origin. The solution is administered via **intravenous use**. The dosing schedule is determined by the study protocol, with a maximum treatment period of 140 days. The administration of florquinitau F18 is monitored to ensure participant compliance and safety throughout the trial.

Another investigational product in the study is **JNJ-63733657**, an anti-tau monoclonal antibody, presented as a **solution for infusion**. The active substance, **posdinemab**, is a protein of other origin. This biological product is also administered through **intravenous use**. The trial aims to assess the efficacy and safety of JNJ-63733657 in participants with early Alzheimer's disease, with a focus on clinical decline as measured by the iADRS. The treatment period for JNJ-63733657 is also set at a maximum of 140 days, with careful monitoring of dosing and participant adherence to the protocol.

The study includes a **placebo** group, referred to as **PL1**, which serves as a comparator to evaluate the effects of the investigational treatments. The placebo is utilized to maintain the double-blind nature of the trial, ensuring unbiased assessment of the investigational products' efficacy and safety. The administration details for the placebo are aligned with those of the active treatments to maintain consistency in the study design.

The efficacy of JNJ-63733657, an anti-tau monoclonal antibody, will be assessed in a randomized, double-blind, placebo-controlled, parallel-group, multicenter study involving participants with early Alzheimer's Disease. The primary endpoint for evaluating efficacy is the change from baseline on the Integrated Alzheimer's Disease Rating Scale (iADRS) total score at week 104. The iADRS is a composite measure that assesses both cognition and function, providing a comprehensive evaluation of clinical decline in participants.

Participants will undergo a screening process to confirm the presence of pathologic tau using a tau PET scan, which will be reviewed centrally by a qualified reader. The study will include individuals aged 55 to 80 years who exhibit a gradual and progressive subjective decline in cognition over at least the past six months, as reported by both the participant and an informant. The study will also require a Clinical Dementia Rating-Global Score (CDR-GS) of 0.5 and a memory box score of ≥0.5 at screening.

The trial is designed to assess the long-term effects of JNJ-63733657 over a treatment period of up to 140 weeks. Efficacy assessments will be conducted at specified intervals, with the primary analysis focusing on the change in iADRS scores from baseline to week 104. This study is part of a Phase 2 clinical development program aimed at demonstrating the potential of JNJ-63733657 to slow clinical decline in early Alzheimer's Disease.