Long-term Safety and Efficacy Assessment of Intravenous Cipaglucosidase Alfa Co-administered with Oral Miglustat in Adults with Late-onset Pompe Disease

The primary objective of this study is to assess the long-term **safety** and tolerability of the co-administration of ATB200 and AT2221 in adult subjects with late-onset Pompe disease. This is clinically relevant as it aims to ensure that the treatment regimen is safe for prolonged use, which is crucial for managing a chronic condition like Pompe disease.

Secondary objectives include evaluating the long-term efficacy of ATB200/AT2221 co-administration on various clinical parameters:

• ambulatory function, measured by the 6-minute walk test (6MWT)
• pulmonary function, assessed by sitting forced vital capacity (FVC) (% predicted)
• muscle strength
• health-related patient-reported outcomes
• motor function
• overall clinical impression, as assessed by both physician and subject
• other measures of pulmonary function beyond FVC (% predicted)
• biomarkers of muscle injury and disease substrate

The clinical trial involves a total of **85 participants** diagnosed with **Late Onset Pompe Disease (LOPD)**. The study population includes both male and female subjects, with an age range that encompasses both adults and adolescents. Participants were selected based on their completion of a prior study, ATB200-03, with allowances for those who withdrew due to non-drug-related logistical reasons. The trial includes a vulnerable population, indicating careful consideration of ethical standards. Participants are required to adhere to medically accepted methods of contraception during the study and for 90 days following the last dose of the study drug. The trial aims to assess the long-term safety and tolerability of the co-administration of ATB200/AT2221.

The clinical trial is designed to evaluate the long-term safety and efficacy of **cipaglucosidase alfa** (ATB200) co-administered with **miglustat** (AT2221) in adult subjects with late-onset Pompe disease. This is a Phase 3, open-label extension study, which is not categorized as low intervention. The trial employs a controlled design, with participants receiving intravenous ATB200 and oral AT2221. The study is expected to run until December 31, 2027, with recruitment having commenced on December 19, 2019.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as completion of a prior study (ATB200-03) and agreement to use contraception. The primary endpoint focuses on the long-term safety, including the incidence of treatment-emergent adverse events and immunogenicity to ATB200. Secondary endpoints include changes from baseline in various functional and physiological measures, such as the 6-minute walk distance and manual muscle test scores.

The trial involves multiple follow-up visits to monitor the safety and efficacy of the treatment, with assessments including clinical laboratory tests, ECGs, and vital signs. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 96 weeks. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or other safety concerns as determined by the study investigators.

The clinical trial involves the administration of two experimental medications, **ATB200** and **AT2221**, to assess their long-term safety and efficacy in adult subjects with late-onset Pompe disease. **ATB200** is a lyophilized powder for preparation for injection, containing the active substance **cipaglucosidase alfa**, a protein of other origin. It is administered intravenously. The dosage is calculated based on the participant's body weight, with a maximum daily dose of 20 mg/kg and a total maximum dose of 4160 mg/kg over a treatment period of up to 96 weeks. The administration schedule is designed to ensure optimal therapeutic levels while monitoring participant compliance through regular assessments.

**AT2221** is provided in the form of hard gelatin capsules, containing the active substance **miglustat**, a chemical compound. This medication is administered orally, with a maximum daily dose of 260 mg and a total maximum dose of 54080 mg over the same treatment period of 96 weeks. The oral administration of **AT2221** is intended to complement the intravenous administration of **ATB200**, with both medications being co-administered to evaluate their combined effect on the disease. Compliance with the dosing schedule is monitored through participant self-reporting and periodic evaluations by the study team.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized in this study. The trial is designed to focus solely on the investigational products, **ATB200** and **AT2221**, to determine their safety and tolerability when used in combination. The study protocol includes detailed instructions for the preparation and administration of the investigational products, ensuring consistency and accuracy in dosing across all participants.

The efficacy of the clinical trial will be assessed through a series of secondary endpoints designed to evaluate the impact of the treatment on various functional and physiological parameters in adult subjects with Late-onset Pompe Disease. These endpoints include changes from baseline in the 6-minute walk distance (6MWD) and its percentage predicted, as well as changes in sitting forced vital capacity (FVC) percentage predicted. Muscle strength and function will be evaluated using the manual muscle test scores for both upper and lower extremities, and quantitative muscle test values in kilograms. Additionally, patient-reported outcome measures will be utilized, including the PROMIS physical function and fatigue scores, PROMIS-dyspnea, and PROMIS-upper extremity scores, along with the R-PAct Scale and EQ-5D-5L health status scores.

Motor function will be further assessed through the GSGC total score and specific tasks such as the 10-meter walk, 4-stair climb, Gower's maneuver, and time to arise from a chair. The Timed Up and Go (TUG) test will also be used to measure changes in mobility. Pulmonary function will be monitored through changes in sitting slow vital capacity (SVC), maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), and sniff nasal inspiratory pressure (SNIP), all expressed in both absolute values and percentage predicted. Biomarker levels, including serum creatine kinase (CK) and urinary Hex4, will be measured to assess biochemical changes. The subject's functional status, in terms of overall physical well-being, effort of breathing, muscle strength, muscle function, ability to move around, activities of daily living, energy level, and level of muscular pain, will be evaluated using the Subject Global Impression of Change (SGIC) and Patient Global Impression of Change (PGIC) scales.