Evaluation of Avalglucosidase Alfa Efficacy and Safety in Non-Classic Pompe Disease Patients Aged ≥5 Years with Deterioration on Alglucosidase Alfa Therapy

The primary objective of this study is to explore the **safety**, tolerability, and efficacy of **avalglucosidase alfa** in patients aged 5 years and older with non-classic **Pompe disease** whose clinical condition deteriorates while on standard treatment with alglucosidase alfa. This is clinically relevant as it aims to address the unmet medical needs of patients who do not respond adequately to existing therapies, potentially offering an alternative treatment option that could improve patient outcomes.

The clinical trial involves participants diagnosed with **Pompe disease**, specifically those with nonclassic forms of the condition. The study population includes both male and female subjects aged between 5 and 55 years. Participants are required to have been on enzyme-replacement therapy with alglucosidase alfa for at least two years, with a dosage regimen of 20 or 40 mg/kg bi-weekly. The trial targets individuals whose clinical condition is deteriorating despite standard treatment. Participants must reside in the Netherlands and have a confirmed diagnosis through enzyme deficiency or genetic testing. The study does not focus on a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed as an **open-label**, single-center, exploratory study to evaluate the safety, tolerability, and efficacy of **avalglucosidase alfa** in patients with non-classic **Pompe disease** aged 5 years and older. The trial will involve participants whose clinical condition deteriorates while on standard treatment with alglucosidase alfa. The study is expected to run from May 2022 to November 2027, with a maximum treatment period of 60 weeks for each participant. Participants will be administered the investigational product, Nexviadyme, via **intravenous infusion**. The trial will assess primary endpoints such as safety and tolerability, including the number of adverse events and the occurrence of antibodies against avalglucosidase alfa, as well as efficacy measures like changes in muscle strength and function, pulmonary function, and patient-reported outcomes.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, current enzyme-replacement therapy, and measurable deterioration in pulmonary function or muscle strength. Follow-up visits will be scheduled to monitor the participants' response to treatment and to collect data on the primary endpoints. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted. The expected length of participant involvement is up to 60 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. Participants must be willing and able to adhere to study procedures, and informed consent must be obtained from the patient or their parent/guardian. The trial aims to provide valuable insights into the management of non-classic Pompe disease, particularly in patients who do not respond adequately to existing therapies.

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 specifically formulated for intravenous infusion. Each vial contains 100 mg of the active substance, **avalglucosidase alfa**, a recombinant human alpha-glucosidase conjugated with synthetic bis-mannose-6-phosphate glycans. The maximum daily and total dose is set at 20 mg/kg, with a treatment period not exceeding 60 days. The administration is conducted under controlled conditions to ensure precise dosing and monitoring of patient compliance.

In this study, the experimental treatment is compared against the standard-of-care therapy, which involves the use of **alglucosidase alfa**. Participants are selected based on their clinical condition, which must show deterioration while on the standard treatment. The trial is designed to explore the safety, tolerability, and efficacy of **avalglucosidase alfa** in patients aged 5 years and older with non-classic Pompe disease. The study does not include a placebo group, focusing instead on direct comparison with the existing standard treatment.

Efficacy in this clinical trial will be assessed through a comprehensive evaluation of various parameters in patients with non-classic **Pompe disease**. The primary efficacy endpoints include changes in muscle strength and function, pulmonary function, and patient-reported outcomes. Muscle strength will be measured using Manual Muscle Testing (MMT) and Hand-Held Dynamometry (HHD). Muscle function will be evaluated through the Quick Motor Function Test (QMFT), the 6-Minute Walk Test (6-MWT), and other timed tests. Pulmonary function will be assessed by measuring forced vital capacity in both sitting and supine positions, as well as Maximum Inspiratory Pressure (MIP) and Maximum Expiratory Pressure (MEP). Changes in patient-reported outcomes will be captured using the Rasch-built Pompe Activity Scale (R-PaCT), quality of life assessments, and the modified Borg scale.

The collection and analysis of these efficacy parameters will be conducted at specified intervals throughout the trial. The tools and instruments used for these assessments are validated and widely recognized in clinical settings. The trial aims to provide a detailed understanding of the efficacy of **avalglucosidase alfa** in improving the clinical condition of patients whose disease has deteriorated despite standard treatment with alglucosidase alfa. The data collected will be analyzed to determine the impact of the treatment on the specified endpoints, contributing to the overall evaluation of the drug's efficacy in this patient population.