Efficacy and Safety Evaluation of Avalglucosidase Alfa in Treatment-Naïve Pediatric Patients with Infantile-Onset Pompe Disease (IOPD)

The primary objective of this study is to evaluate the effect of **avalglucosidase alfa** treatment on survival and invasive ventilator-free survival in pediatric participants with infantile-onset Pompe disease (IOPD) who are ≤ 6 months of age after 52 weeks of treatment. This is clinically relevant as it addresses the critical need for effective therapies in improving survival outcomes in this vulnerable population.

Secondary objectives include:

• Determining the effect of avalglucosidase alfa on survival and invasive ventilator-free survival at 12 and 18 months of age, as well as changes in left ventricular mass Z-score, Alberta Infant Motor Scale (AIMS) score, body length, body weight, head circumference Z scores, and urinary Hex4 at Week 52 in IOPD participants ≤ 6 months of age.
• Assessing the safety, tolerability, and immunogenicity of avalglucosidase alfa.
• Evaluating the pharmacokinetic profile at Week 12 and Week 52.

The clinical trial involves a total of **13 participants** diagnosed with **Glycogen storage disease type II**, commonly known as Pompe disease. The study population consists of both male and female infants, specifically those who are **6 months of age or younger**. Participants were selected based on a confirmed diagnosis of infantile-onset Pompe disease, which includes the presence of specific lysosomal acid α-glucosidase (GAA) pathogenic variants and documented GAA deficiency. Additionally, participants must have established cross-reactive immunological material (CRIM) status and cardiomyopathy at the time of diagnosis. The trial does not focus on a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted. The selection criteria ensure that the study population is homogenous in terms of health status related to the disease, allowing for a focused investigation of the treatment's effects on survival and ventilator-free survival after 52 weeks of treatment with avalglucosidase alfa.

The clinical trial is designed to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of **avalglucosidase alfa** in treatment-naïve pediatric participants with infantile-onset Pompe disease (IOPD). This study is an open-label, multinational, and multicenter trial. The primary objective is to determine the effect of avalglucosidase alfa treatment on survival and invasive ventilator-free survival of participants aged 6 months or younger after 52 weeks of treatment. The trial is expected to last until June 2027, with recruitment having commenced in August 2022.

The trial follows a structured sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as a confirmed diagnosis of IOPD and available cross-reactive immunological material (CRIM) status. Participants must also present with cardiomyopathy at diagnosis. Following the screening, participants will undergo regular follow-up visits to monitor their health status and treatment response. The end-of-study visit will conclude the trial, assessing the primary and secondary endpoints, including survival rates and changes in clinical parameters.

Participant involvement is expected to last up to 104 weeks, with the possibility of early termination if specific conditions arise, such as adverse reactions or withdrawal of consent. The trial's primary endpoint is the proportion of participants who are alive and free of invasive ventilation at Week 52. Secondary endpoints include survival rates at 12 and 18 months, changes in clinical scores, and the incidence of treatment-emergent adverse events. The study employs a rigorous methodology to ensure the collection of reliable and valid data, contributing to the understanding of avalglucosidase alfa's therapeutic potential in managing IOPD.

The clinical trial involves the administration of **avalglucosidase alfa**, marketed under the name Nexviadyme, which is a **powder for concentrate for solution for infusion**. This experimental medication is designed for **intravenous use**. The active substance, **avalglucosidase alfa**, is a recombinant human alpha-glucosidase conjugated with synthetic bis-mannose-6-phosphate glycans. The pharmaceutical form is a solution for infusion, and the medication is provided in a 100 mg dosage. The dosing regimen is calculated based on body weight, with a maximum daily dose of 40 mg/kg and a total maximum dose of 4160 mg/kg over the treatment period. The maximum treatment duration is 104 weeks. The medication is not a pediatric formulation and is not classified as an orphan drug.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial focuses solely on the efficacy, safety, pharmacokinetics, and pharmacodynamics of **avalglucosidase alfa** in treatment-naïve pediatric participants with infantile-onset Pompe disease. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

The efficacy of the clinical trial will be assessed using a range of primary and secondary endpoints. The primary endpoint is the proportion of participants who are alive and free of invasive ventilation at Week 52. Secondary endpoints include the proportion of participants who are alive and free of invasive ventilation at 12 and 18 months of age, the proportion of participants who are alive at Week 52, and the proportion of participants who are free of ventilator use (invasive and non-invasive, separate and combined) at Week 52. Additional secondary endpoints involve changes from baseline to Week 52 in various health metrics, such as left ventricular mass (LVM)-Z score, Alberta Infant Motor Scale (AIMS) score, body length Z-scores, body weight Z-scores, head circumference Z-scores, and urinary Hex4 levels.

Measurements will be collected at specified timepoints, including Week 52, and at 12 and 18 months of age. The tools and instruments used for these assessments include validated scales and laboratory tests. The analysis will focus on the changes in these parameters over the course of the treatment period, which is up to 104 weeks. The trial aims to determine the effect of **avalglucosidase alfa** treatment on survival and invasive ventilator-free survival in pediatric participants with infantile-onset Pompe disease (IOPD) who are 6 months of age or younger after 52 weeks of treatment.