Long-term Safety and Efficacy of Avalglucosidase Alfa in French Patients with Glycogen Storage Disease Type II: A Phase 4 Open-label Extension Study

The primary objective of this study is to assess the long-term **safety** of avalglucosidase alfa in patients with Glycogen storage disease type II, also known as Pompe disease, in France. This evaluation is crucial as it provides insights into the sustained safety profile of the treatment from the time of market authorization until the reimbursement of the drug in France, or until December 2025, whichever occurs first. Understanding the long-term safety is essential for ensuring that the therapeutic benefits of avalglucosidase alfa outweigh any potential risks over an extended period.

Secondary objectives include assessing long-term efficacy outcomes in the same patient population. This involves evaluating the effectiveness of avalglucosidase alfa in maintaining or improving clinical outcomes over the same timeframe. These assessments are vital for determining the overall therapeutic value of the treatment in real-world settings, ensuring that patients continue to derive clinical benefits from the therapy.

The clinical trial involves participants diagnosed with **Glycogen storage disease type II**, also known as Pompe disease. The study population includes both male and female subjects, encompassing a broad age range from children to adults. Participants are those who have previously completed specific studies in France, namely EFC14028, LTS13769, or ACT14132. The trial population was selected based on their completion of these studies and the current status of reimbursement for avalglucosidase alfa in France. The sponsor has not provided the total number of participants. The study includes individuals who are part of a vulnerable population, and lifestyle considerations such as the use of effective contraception methods are required for sexually active participants of childbearing potential. The trial does not specify any particular dietary or physical activity requirements. Key inclusion criteria include the ability to comply with the clinical protocol and, for females of childbearing potential, a negative pregnancy test at enrollment. The sponsor has not disclosed additional information regarding the general health status of the participants.

The clinical trial is designed to evaluate the long-term safety and efficacy of **avalglucosidase alfa** in patients with **Glycogen storage disease type II**, also known as Pompe disease. This is a Phase 4 open-label extension study conducted in France, targeting patients who have previously participated in specific avalglucosidase development studies. The trial will continue until the market authorization of avalglucosidase alfa is reimbursed in France or until December 2025, whichever occurs first. The study employs an open-label design, meaning both the researchers and participants are aware of the treatment being administered. The primary endpoint focuses on the number of adverse events, including treatment-emergent adverse events and infusion-associated reactions. Secondary endpoints include assessments of motor function, pulmonary function, and quality of life metrics.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as previous completion of specific studies and the ability to comply with the protocol. Follow-up visits will be scheduled to monitor safety and efficacy outcomes, with assessments including the six-minute walk test, quick motor function test, and various quality of life evaluations. The end-of-study visit will conclude the participant's involvement, summarizing the outcomes and any adverse events experienced. The expected length of participant involvement is up to 16 weeks, with conditions for early termination including non-compliance with the protocol or the occurrence of significant adverse events. The study aims to provide comprehensive data on the long-term use of avalglucosidase alfa, contributing to the understanding of its safety profile and therapeutic benefits in managing Pompe disease.

The clinical trial involves the administration of **Nexviadyme**, a pharmaceutical product containing the active substance **avalglucosidase alfa**. Nexviadyme is provided as a 100 mg powder for concentrate, intended for the preparation of a solution for infusion. The pharmaceutical form is a solution for infusion, and the route of administration is intravenous. The dosing regimen specifies a maximum daily dose of 40 mg/kg, with a total maximum dose of 1280 mg/kg over a treatment period of up to 16 weeks. The product is not formulated for pediatric use and is not classified as an orphan drug. Avalglucosidase alfa is a recombinant human alpha-glucosidase conjugated with synthetic bis-mannose-6-phosphate glycans, and it is categorized under the ATC code A16AB22.

Throughout the study, participant compliance with the dosing schedule will be monitored to ensure adherence to the prescribed regimen. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The study aims to assess the long-term safety and efficacy of Nexviadyme in patients with Pompe disease who have previously participated in avalglucosidase development studies. The trial will continue until the market authorization of avalglucosidase alfa is reimbursed in France or until December 2025, whichever occurs first.

The efficacy of the clinical trial will be assessed through a series of predefined primary and secondary endpoints. The primary endpoint focuses on the number of adverse events (AEs), treatment-emergent adverse events (TEAEs), including infusion-associated reactions (IARs), and death. These parameters will provide a comprehensive overview of the safety profile of the treatment.

Secondary endpoints will include a variety of assessments to evaluate the efficacy of the treatment in patients with **Pompe disease**. These assessments will involve the six-minute walk test, measuring distance in meters and percentage of predicted value, applicable to both late-onset Pompe disease (LOPD) and infantile-onset Pompe disease (IOPD) participants. Additionally, the quick motor function test (QMFT) will be used for LOPD participants. Pulmonary function tests, including forced vital capacity (FVC) and maximum expiratory pressure/maximum inspiratory pressure, will be conducted in both upright and supine positions for LOPD and IOPD participants.

Quality of life evaluations will be conducted using the 12-item short form health survey (SF-12), Pompe Disease Symptom Scale (PDSS), and Pompe Disease Impact Scale (PDIS) for LOPD participants. For IOPD participants, the Pompe Pediatric Evaluation of Disability Inventory (Pompe-PEDI) score and PedsQL score will be utilized. Additionally, the Left Ventricular Mass Index (LVMI) Z-score will be assessed in IOPD participants. These assessments will be conducted at various time points throughout the trial to monitor changes and improvements in patient conditions.