AN OPEN-LABEL STUDY TO EVALUATE THE SAFETY AND PHARMACOKINETICS OF MIGALASTAT HCL IN SUBJECTS WITH FABRY DISEASE AND AMENABLE GLA VARIANTS AND SEVERE RENAL IMPAIRMENT OR END-STAGE RENAL DISEASE TREATED WITH HEMODIALYSIS

The primary objective of this study is to **characterize the pharmacokinetics (PK)** of migalastat and confirm the proposed dosing regimens based on modeling and simulations in subjects with **Fabry disease** who have severe renal impairment (SRI) or end-stage renal disease (ESRD) and are undergoing hemodialysis. Understanding the PK profile is crucial for optimizing dosing strategies, ensuring therapeutic efficacy, and minimizing potential adverse effects in this specific patient population.

Secondary objectives include:

• Assessing the **safety** of migalastat in subjects with Fabry disease and SRI or ESRD on hemodialysis.
• Evaluating the **tolerability** of migalastat in the same patient group.
• Investigating the **pharmacodynamics (PD)** of migalastat to support adjusted dose regimens in these patients.

The clinical trial involves a total of **10 participants** diagnosed with **Fabry disease** and possessing amenable GLA variants, who also exhibit severe renal impairment or are undergoing hemodialysis due to end-stage renal disease. The study population includes both male and female subjects aged 18 years or older. Participants were selected based on their medical history, specifically those with an eGFR value of less than 30 mL/min/1.73 m² or those on a stable hemodialysis regimen. The trial includes individuals who are considered a vulnerable population due to their health status. Participants are required to adhere to specific lifestyle considerations, such as maintaining a stable hemodialysis schedule and, if of reproductive potential, using medically accepted contraception methods during the study and for 30 days post-treatment. The selection criteria ensure that the study focuses on individuals who can provide informed consent and have the necessary medical documentation to confirm their eligibility.

The clinical trial is designed to evaluate the **safety** and pharmacokinetics of **migalastat** in subjects diagnosed with **Fabry disease** and amenable GLA variants, who also have severe renal impairment or end-stage renal disease treated with hemodialysis. This is an open-label study, meaning both the researchers and participants know which treatment is being administered. The trial aims to confirm the proposed dosing regimens based on modeling and simulations. The study is expected to run from November 28, 2022, to December 13, 2026, with a maximum treatment period of 24 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and renal function. This visit will include GLA genotyping to verify the presence of an amenable variant. Following the screening, eligible participants will proceed to the treatment phase, where they will receive **Galafold 123 mg hard capsules** orally. Regular follow-up visits will be scheduled to monitor pharmacokinetic parameters, safety endpoints, and tolerability, including assessments of adverse events, clinical laboratory parameters, and vital signs. The end-of-study visit will conclude the participant's involvement, with final evaluations of pharmacokinetic and safety data.

The expected length of participant involvement is up to 24 weeks, contingent upon adherence to the study protocol. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, non-compliance with the study regimen, or withdrawal of consent. The primary endpoint focuses on estimating pharmacokinetic parameters and dosing confirmation based on **migalastat** concentrations in plasma and urine. Secondary endpoints include safety assessments and changes in plasma lyso-Gb3 levels. The trial is not classified as low intervention and is categorized as a Phase III study.

The clinical trial involves the administration of **Galafold** 123 mg hard capsules, which contain the active substance **migalastat**. This pharmaceutical form is a hard capsule designed for oral administration. The dosage regimen for the trial is set at a maximum daily dose of 123 mg, with the treatment period extending up to 24 weeks. The administration route is oral, and the medication is intended for subjects with **Fabry disease** who have severe renal impairment or end-stage renal disease and are undergoing hemodialysis. The chemical origin of migalastat is confirmed, and it is not a pediatric formulation. The trial aims to evaluate the pharmacokinetics and confirm the proposed dosing regimens based on modeling and simulations.

In addition to the experimental treatment, the study may include standard-of-care therapy for managing Fabry disease and renal conditions, as appropriate. No placebo or comparator treatment is specified in the trial documentation. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen. The trial is conducted under the sponsorship of Amicus Therapeutics Europe Limited, and the product is authorized for use in the European Union under the marketing authorization number EU/1/15/1082/001.

Efficacy in this clinical trial will be assessed through the evaluation of **pharmacokinetic** parameters and dosing confirmation, which will be estimated based on the concentrations of migalastat in plasma and urine. The primary endpoint focuses on these pharmacokinetic parameters to ensure the proposed dosing regimens are appropriate for subjects with Fabry disease who have severe renal impairment or end-stage renal disease and are undergoing hemodialysis.

Secondary endpoints will include safety and tolerability assessments. Safety endpoints will encompass adverse events, clinical laboratory parameters such as serum chemistry, hematology, and urinalysis, as well as eGFRMDRD and eGFRCKD-EPI measurements, vital signs including blood pressure, heart rate, respiratory rate, and body temperature, 12-lead ECGs, and physical examinations. Tolerability will be evaluated by monitoring treatment-emergent adverse events, including the incidence of serious adverse events, discontinuations due to adverse events, and the severity of treatment-emergent adverse events. Additionally, a pharmacodynamic endpoint will assess the change from baseline in plasma lyso-Gb3 levels.