An Open-label Study of the Safety, Pharmacokinetics, Efficacy, Pharmacodynamics, and Immunogenicity of Cipaglucosidase Alfa/Miglustat in Pediatric Subjects Aged 0 to < 18 Years with Late-onset Pompe Disease

The primary objective of this study is to evaluate the **safety** and tolerability of the co-administration of cipaglucosidase alfa and miglustat in pediatric subjects with late-onset Pompe disease. This is clinically relevant as it aims to ensure that the treatment regimen is safe for use in a vulnerable population, potentially leading to improved management of the disease.

Secondary objectives include:

• Characterizing the pharmacokinetics (PK) of cipaglucosidase alfa/miglustat for different cohorts.
• Comparing plasma cipaglucosidase alfa and miglustat exposure in pediatric age groups to adult exposure to confirm or adjust starting dose regimens.
• Evaluating the effect of cipaglucosidase alfa/miglustat on efficacy.
• Assessing the effect on pharmacodynamics (PD).
• Evaluating the effect of cipaglucosidase alfa exposure on efficacy and PD endpoints, focusing on exposure-response relationships.
• Investigating the impact of anti-rhGAA antibodies and immunogenicity on cipaglucosidase alfa exposure.

The clinical trial involves a total of **16 participants** diagnosed with **Late-onset Pompe disease** (LOPD). The study population includes both male and female subjects, with an age range from 0 months to less than 18 years. Participants are divided into two cohorts: Cohort 1 consists of subjects aged 12 to less than 18 years, while Cohort 2 includes those from 0 months to less than 12 years. The trial includes both enzyme replacement therapy (ERT)-naïve individuals and those with prior ERT experience. Participants were selected based on specific criteria, including a diagnosis of LOPD confirmed by GAA enzyme deficiency or genotyping. The study population is characterized by a vulnerable group, as it includes minors. Lifestyle considerations such as diet and physical activity are not specified, but participants must meet certain health benchmarks, such as a minimum sitting forced vital capacity and the ability to perform a 6-Minute Walk Test. The trial aims to evaluate the safety and tolerability of cipaglucosidase alfa/miglustat co-administration.

The clinical trial is designed to evaluate the **safety** and tolerability of the co-administration of **cipaglucosidase alfa** and **miglustat** in pediatric subjects with late-onset Pompe disease. This is an open-label, Phase 3 study, which will involve participants aged 0 to less than 18 years. The trial is structured as a controlled study, with a focus on assessing pharmacokinetics, efficacy, pharmacodynamics, and immunogenicity. The trial is expected to last for a total duration of 52 weeks, with the estimated end date set for June 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on specific criteria, such as age, weight, and previous enzyme replacement therapy (ERT) experience. The inclusion criteria require subjects to have a confirmed diagnosis of late-onset Pompe disease, with documentation of GAA enzyme deficiency or relevant genotyping. Following the screening, participants will attend regular follow-up visits to monitor treatment-emergent adverse events (AEs), serious adverse events (SAEs), and changes in clinical laboratory test results, vital signs, and electrocardiogram (ECG) values. The primary endpoints include the incidence of treatment-emergent AEs and changes in anti-rhGAA antibody titers over time.

The study will conclude with an end-of-study visit, where final assessments will be conducted to evaluate the overall impact of the treatment on the participants. The expected length of participant involvement is approximately 52 weeks, with conditions for early termination including the occurrence of significant adverse events or withdrawal of consent. Secondary endpoints will assess changes in ambulatory and motor function, muscle strength, pulmonary function, and patient-reported outcomes over the course of the study. The trial aims to provide comprehensive data on the therapeutic potential of cipaglucosidase alfa and miglustat in managing late-onset Pompe disease in a pediatric population.

The clinical trial involves the administration of **cipaglucosidase alfa**, marketed under the name ATB200, which is provided as a **lyophilized powder for preparation for injection**. This experimental medication is administered via the **intravenous route**. The dosing regimen for cipaglucosidase alfa is set at a maximum daily dose of 30 mg/kg, with a total maximum dose of 780 mg/kg over the course of the treatment period. The treatment duration is capped at 52 weeks. Cipaglucosidase alfa is a protein-based therapeutic agent developed by Amicus Therapeutics, designated as an orphan drug under the number EU/3/18/2000.

In conjunction with cipaglucosidase alfa, the trial also includes the administration of **miglustat**, known commercially as AT2221. Miglustat is formulated as a **hard gelatin capsule** and is administered **orally**. The maximum daily dose for miglustat is 260 mg, with a cumulative maximum dose of 6760 mg over the 52-week treatment period. Miglustat is a chemical-based compound, also developed by Amicus Therapeutics, and holds an orphan drug designation with the number EU/3/18/2129.

Both medications are administered concurrently to evaluate their combined safety, pharmacokinetics, efficacy, pharmacodynamics, and immunogenicity in pediatric subjects with late-onset Pompe disease. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. No non-experimental treatments, such as standard-of-care therapy or placebo, are utilized in this study.

The efficacy of the clinical trial evaluating **Cipaglucosidase Alfa** and Miglustat in pediatric subjects with late-onset Pompe Disease will be assessed using a range of primary and secondary endpoints. Primary endpoints include the incidence of treatment-emergent adverse events (AEs), serious adverse events (SAEs), infusion-associated reactions (IARs), and AEs leading to discontinuation of the study drug. Additionally, changes in anti-rhGAA antibody titers, clinical laboratory test results, vital signs, and 12-lead ECG values from baseline over time will be monitored.

Secondary endpoints focus on pharmacokinetic parameters such as the area under the plasma drug concentration-time curve (AUC) and maximum observed concentration (Cmax). For Cohort 1, changes from baseline to Week 52 in ambulatory function, motor function, muscle strength, and pulmonary function will be evaluated. This includes assessments like the 6-Minute Walk Test (6MWT), Gait, Stairs, Gowers’ maneuver, and Chair (GSGC) test, and maximal inspiratory and expiratory pressures. Patient-reported outcomes (PRO) measures, such as the NeuroQOL Pediatric Lower Extremity Function, will also be considered.

For Cohort 2, similar assessments will be conducted, with additional focus on the Alberta Infant Motor Scale (AIMS) for younger subjects. Changes in serum creatine kinase (CK) levels and urinary Hex4 levels will be measured as pharmacodynamic variables. Immunogenicity endpoints will include total and neutralizing anti-rhGAA antibodies for both cohorts. These efficacy parameters will be collected and analyzed at specified timepoints, including baseline and Week 52, to determine the impact of the treatment on the subjects' health outcomes.