Efficacy of Pegipanermin (XPro1595) in Early Alzheimer's Disease with Inflammatory Biomarkers: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to assess the **efficacy** of XPro1595 compared with placebo on cognitive performance in patients with early Alzheimer's Disease with biomarkers of inflammation. This is clinically relevant as cognitive decline is a hallmark of Alzheimer's Disease, and improving cognitive performance could significantly impact patient quality of life and disease progression.

Secondary objectives include:

• Assessing the effect of XPro1595 compared with placebo on cognition and global function in patients with early Alzheimer's Disease.
• Evaluating the effect of XPro1595 compared with placebo on the Everyday Cognition (E-Cog) scale in patients with early Alzheimer's Disease.
• Assessing the effect of XPro1595 compared with placebo on noncognitive behavioral symptoms in patients with early Alzheimer's Disease.

The clinical trial involves a total of **62 participants** diagnosed with **Early Alzheimer’s Disease with Biomarkers of Inflammation**. The study population comprises both male and female subjects, aged between **50 to 85 years**. Participants were selected based on specific inclusion criteria, including a diagnosis of mild cognitive impairment (MCI) of probable Alzheimer’s disease or mild dementia, with a Clinical Dementia Rating (CDR) global rating at screening of 0.5 or 1, and a Mini-Mental State Examination (MMSE) score greater than 22. Additionally, participants exhibit at least one inflammatory biomarker, such as high-sensitivity C-reactive protein (hsCRP) greater than 1.5 mg/L, erythrocyte sedimentation rate (ESR) greater than 10 mm/h, hemoglobin A1c (HbA1C) greater than 6 DCCT %, or at least one APOE4 allele. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity were not specified by the sponsor. The study aims to assess the efficacy of XPro1595 compared with placebo on cognitive performance in these patients.

The clinical trial is designed to evaluate the efficacy of **XPro1595** compared to a placebo in patients with early Alzheimer's disease characterized by biomarkers of inflammation. This study is structured as a randomized, placebo-controlled, double-blind trial, ensuring that neither the participants nor the researchers know who is receiving the active treatment or the placebo, thus minimizing bias. The trial is expected to last until July 31, 2025, with recruitment starting on October 16, 2023. Participants will be involved in the study for a maximum treatment period of 33 weeks.

The trial will include several key visits: an initial screening visit, regular follow-up visits, and an end-of-study visit. During the **screening visit**, potential participants will be assessed for eligibility based on criteria such as age (50 to 85 years), diagnosis of mild cognitive impairment or mild dementia due to Alzheimer's disease, and the presence of at least one inflammatory biomarker. Follow-up visits will occur at regular intervals to monitor the participants' cognitive performance and overall health, with primary endpoints including changes in the Early and Mild Alzheimer's Cognitive Composite (EMACC) from baseline to week 24. Secondary endpoints will assess changes in the Clinical Dementia Rating Scale, Everyday Cognition, and the Neuropsychiatric Inventory caregiver items over the same period.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions may include adverse reactions to the treatment, withdrawal of consent, or any significant protocol deviations. The study aims to provide valuable insights into the potential benefits of XPro1595 in improving cognitive function in patients with early Alzheimer's disease, contributing to the broader understanding of therapeutic options for this condition.

The clinical trial involves the administration of **XPro1595**, a recombinant PEGylated protein, as the experimental medication. **XPro1595** is formulated as a **solution for injection** and is administered at a dosage of 1.0 mg/kg. The route of administration is via injection, and the treatment is given once daily. The maximum treatment period for **XPro1595** is 33 days. The active substance in **XPro1595** is **pegipanermin**, which is a protein of other origin. The product is manufactured by INMUNE BIO, INC. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

The study also includes a **placebo** treatment to match **XPro1595**. The placebo is designed to mimic the **XPro1595** drug product in all aspects except for the absence of the active ingredient, **pegipanermin**. The placebo is also provided as a **solution for injection** and is administered at the same dosage and frequency as the experimental medication, 1.0 mg/kg once daily, for a maximum of 33 days. The placebo serves as a comparator to evaluate the efficacy of **XPro1595** in patients with early Alzheimer's disease with biomarkers of inflammation. Participant compliance with the placebo administration is similarly monitored to maintain the integrity of the study results.

The efficacy of XPro1595 in patients with early Alzheimer's disease will be assessed through a randomized, placebo-controlled, double-blind study. The primary endpoint for evaluating efficacy is the change in the Early and Mild Alzheimer’s Cognitive Composite (EMACC) from baseline to week 24. This will include assessments such as the International Shopping List Test-Immediate Recall, Digit Span Forward and Backward, Category Fluency Test (DKEFS), Letter Fluency Test (DKEFS), Trail Making Test Parts A and B, and Digit Symbol Coding Test.

Secondary endpoints will include changes from baseline to week 24 in the Clinical Dementia Rating Scale (CDR), Everyday Cognition (E-Cog), and the Neuropsychiatric Inventory (NPI-12) caregiver items. These assessments will be conducted at specified intervals to monitor cognitive performance and other relevant clinical parameters. The study aims to provide comprehensive data on the efficacy of XPro1595 in improving cognitive function in patients with early Alzheimer's disease, characterized by the presence of at least one inflammatory biomarker.