Long-term Evaluation of Safety, Tolerability, and Efficacy of AL002 and Florquinitau (18F) in Patients with Alzheimer's Disease

The primary objective of this multicenter, long-term extension study is to evaluate the **safety** and **tolerability** of AL002 in participants with **Alzheimer's Disease**. Additionally, the study aims to assess the effect of **immunogenicity** to AL002 on safety, pharmacokinetics (PK), and pharmacodynamics (PD) biomarkers in these participants. Understanding the long-term safety and tolerability of AL002 is clinically relevant as it may provide insights into the potential for sustained use of this therapeutic agent in managing Alzheimer's Disease, a condition characterized by progressive neurodegeneration and cognitive decline. The evaluation of immunogenicity effects is crucial for determining any adverse immune responses that could impact the therapeutic efficacy and safety profile of AL002.

The clinical trial involves a total of **188 participants** diagnosed with **Alzheimer's Disease**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on their completion of the planned treatment period in the AL002-2 study, ensuring they did not prematurely discontinue the study drug. The trial includes individuals who are willing and able to provide informed consent, or have a legally authorized representative do so on their behalf, and who have a study partner available to assist with assessments. Participants are required to have a body mass index (BMI) between 18.5 and 34.9 kg/m² and weigh no more than 120 kg. Lifestyle considerations include the requirement for female participants to be nonpregnant and nonlactating, with specific contraceptive measures in place for both male and female participants. The trial population is characterized by a vulnerable group, necessitating careful ethical considerations. Participants must have adequate visual and auditory acuity to perform neuropsychological testing, and they should be fluent in the language of the tests used at the study site. The study aims to evaluate the long-term safety and tolerability of AL002, as well as the effect of immunogenicity on safety, pharmacokinetics (PK), and pharmacodynamics (PD) biomarkers in this population.

The clinical trial is designed to evaluate the long-term safety, tolerability, and efficacy of **AL002** in participants with **Alzheimer's Disease**. This is a Phase 4, multicenter, randomized, double-blind, placebo-controlled study. The trial involves the administration of **Human ICG1 Monoclonal Antibody Against Trem2** and a placebo, both delivered as a **solution for injection**. The trial is expected to run from June 2023 to October 2025, with recruitment having commenced in April 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on predefined criteria. The inclusion criteria require participants to have completed the planned treatment period in a previous study, among other conditions. The trial includes regular follow-up visits to monitor safety and efficacy endpoints, such as the incidence of adverse events, vital signs, and laboratory results. Participants will also undergo optional imaging assessments using **[18F]MK-6240** for Tau PET imaging, provided they meet specific criteria regarding radiation exposure and availability of the radiotracer.

The end-of-study visit will conclude the participant's involvement, which is expected to last up to 48 weeks, depending on individual treatment periods. Conditions that may lead to early termination from the study include the occurrence of severe adverse events or the participant's inability to comply with study procedures. The trial aims to gather comprehensive data on the safety profile of AL002, including the incidence and severity of ARIA in participants undergoing titration, and to assess the impact of immunogenicity on pharmacokinetic and pharmacodynamic biomarkers.

The clinical trial involves the administration of **florquinitau F18**, an experimental medication formulated as a **solution for injection**. The active substance, **florquinitau (18F)**, is chemically derived and is administered intravenously. The maximum daily dose is 6 mCi, with a total maximum dose of 12 mCi over a treatment period of up to 57 days. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

In addition to the experimental medication, a **placebo** is utilized in the study. The placebo is a sterile solution intended for intravenous infusion, serving as a control to evaluate the efficacy and safety of the experimental treatment. The placebo does not contain any active pharmaceutical ingredients and is used to maintain the study's blinding and integrity.

The trial also includes the administration of **Human ICG1 Monoclonal Antibody Against Trem2**, known by the sponsor product code **AL002**. This investigational product is a **solution for injection** and is a protein-based therapeutic agent. It is administered via intravenous infusion, with a maximum daily dose of 60 mg/kg and a total maximum dose of 780 mg/kg over a treatment period of up to 48 days. The dosing schedule is carefully monitored to ensure participant safety and compliance with the study protocol.

The efficacy of AL002 in participants with **Alzheimer's Disease** will be assessed through a series of primary endpoints. These endpoints include the incidence of adverse events (AEs), including adverse events of special interest (AESIs) and serious adverse events (SAEs). Additionally, vital signs, clinical laboratory results, and findings from physical, neurological, ophthalmological examinations, and electrocardiograms (ECG) will be evaluated. The Columbia-Suicide Severity Rating Scale (C-SSRS) will be utilized to assess any potential suicidal ideation or behavior. Magnetic Resonance Imaging (MRI) will be used to identify any abnormalities, and the incidence and severity of Amyloid-Related Imaging Abnormalities (ARIA) in participants undergoing titration will also be monitored.