An Open-label Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of 12-month Treatment with Migalastat in Pediatric Subjects (aged 2 to < 12 years) with Fabry Disease and Amenable GLA Variants

The primary objective of this study is to characterize the pharmacokinetics of migalastat and to confirm pediatric dose regimens predicted to provide plasma migalastat exposure levels similar to adolescents and adults in pediatric subjects aged 6 to < 12 years old and 2 to < 6 years old with Fabry disease and who have GLA variants amenable to treatment with migalastat. Additionally, the primary objective includes the evaluation of the safety of migalastat treatment in pediatric subjects diagnosed with Fabry disease and who have GLA variants amenable to treatment with migalastat. The clinical relevance lies in establishing appropriate dosing regimens for younger pediatric populations to achieve therapeutic exposure levels comparable to those observed in older age groups, while ensuring treatment safety in this vulnerable population with a lysosomal storage disorder caused by deficient α-galactosidase A enzyme activity.

This clinical trial enrolled a total of **5 participants** diagnosed with **Fabry disease**, a genetic lysosomal storage disorder. The study population consisted of **pediatric subjects** aged **2 to less than 12 years**, with both **male and female** participants included. Eligible subjects were required to have a documented **GLA variant** (gene encoding **α-galactosidase A**) amenable to treatment with **migalastat**. All participants had at least one documented complication of Fabry disease, which could include **corneal whorls**, **neuropathic pain**, **acroparesthesia**, gastrointestinal symptoms such as **diarrhea** or **abdominal pain**, **hypohidrosis**, elevated **left ventricular mass index**, cardiac rhythm or conduction disturbances, reduced **estimated glomerular filtration rate** or **hyperfiltration**, **proteinuria**, **albuminuria**, elevated plasma **globotriaosylsphingosine** (lyso-Gb3), **hearing impairment**, **tinnitus**, or history of **transient ischemic attack** or **stroke**. Subjects were required to have discontinued **enzyme replacement therapy** (ERT) for at least 14 days prior to baseline. Participants of reproductive potential were required to use medically accepted contraception methods throughout the study duration and for up to 30 days following the last dose of study medication.

This is an open-label, Phase III clinical trial evaluating the safety, pharmacokinetics, pharmacodynamics, and efficacy of migalastat in pediatric subjects aged 2 to less than 12 years diagnosed with Fabry disease and who have amenable GLA variants. The primary objectives are to characterize the pharmacokinetics and confirm pediatric dose regimens predicted to provide plasma migalastat exposure levels similar to adolescents and adults, as well as to evaluate the safety of migalastat treatment in this pediatric population. The investigational medicinal product is migalastat hydrochloride formulated as a dispersible tablet for oral use, with a maximum daily dose of 140 mg and a maximum total dose of 25.62 g administered over the treatment period. The study employs an open-label design without randomization or blinding procedures.

The trial duration is estimated to span from November 2025 to December 2027. Individual participant involvement extends for 12 months of treatment with migalastat. The maximum treatment period is 12 months. Subjects must discontinue any enzyme replacement therapy at least 14 days prior to the baseline visit. The study medication is designated as an orphan drug with designation number EU/3/06/368.

Eligible participants include male or female subjects diagnosed with Fabry disease who are between 2 and less than 12 years of age at randomization, with subjects aged 11 years required to have birthdays more than 30 days after randomization. Subjects must have a documented GLA variant that is amenable to migalastat treatment prior to Visit 2. For subjects without a known GLA variant, an amenable GLA genotyping result from the local laboratory must be received prior to Visit 2. Subjects must not have received enzyme replacement therapy for at least 14 days prior to the baseline visit. Additionally, subjects must have at least one documented complication of Fabry disease, which may include corneal whorls, neuropathic pain, acroparesthesia, gastrointestinal symptoms, hypohidrosis, abnormal left ventricular mass index, cardiac rhythm or conduction disturbances, reduced estimated glomerular filtration rate or hyperfiltration, proteinuria, albuminuria, elevated plasma globotriaosylsphingosine (lyso-Gb3), hearing impairment, tinnitus, or history of transient ischemic attack or stroke. Subjects of reproductive potential must agree to use medically accepted contraception throughout the study duration and for up to 30 days after the last dose of migalastat.

The primary endpoints encompass pharmacokinetic parameters derived from plasma concentrations of migalastat and comprehensive safety assessments. Safety evaluations include the incidence of treatment-emergent adverse events, serious adverse events, and adverse events leading to discontinuation of study drug. Additional safety measures involve changes from baseline over time in clinical laboratory test results, vital signs, physical examination findings, body weight and height, electrocardiogram results, echocardiogram parameters at Month 12 or early termination, and Tanner stage assessment for female subjects aged 8 years or older and male subjects aged 9 years or older at Month 12 or early termination. The study protocol includes provisions for early termination from the study under specified conditions, though the specific circumstances are determined according to protocol-defined criteria.

The experimental treatment in this clinical trial is **Migalastat Hydrochloride Dispersible Tablet**, a **paediatric formulation** containing the active substance **migalastat hydrochloride**, which is of chemical origin. The product is designated as an **orphan drug** with the designation number EU/3/06/368 and carries the sponsor product code AT1001. The **pharmaceutical form** is a **dispersible tablet** administered via the **oral route**. The **maximum daily dose** is 140 mg, with a **maximum total dose** of 25.62 g over a **treatment period** of 12 months. The dosing regimen is designed to achieve plasma migalastat exposure levels comparable to those observed in adolescents and adults, with specific dose adjustments predicted for paediatric subjects aged 2 to less than 12 years with **Fabry disease** who have **GLA variants amenable** to treatment with migalastat.

The study is an **open-label trial** evaluating the safety, **pharmacokinetics**, **pharmacodynamics**, and efficacy of migalastat treatment in the paediatric population. The trial design focuses on characterizing the pharmacokinetic profile and confirming the appropriateness of the paediatric dosing regimens in two age cohorts: subjects aged 6 to less than 12 years and subjects aged 2 to less than 6 years. Participant compliance monitoring is an integral component of the study to ensure adherence to the prescribed dosing schedule throughout the 12-month treatment period.

Efficacy will be assessed through pharmacodynamic parameters in pediatric subjects with Fabry disease treated with migalastat over a 12-month period. The primary focus of efficacy evaluation includes characterization of pharmacokinetics, with derived pharmacokinetic parameters estimated based on plasma concentrations of migalastat to confirm pediatric dose regimens. Safety assessments will be conducted as part of the primary endpoints, including monitoring the incidence of treatment-emergent adverse events, serious adverse events, and adverse events leading to discontinuation of study drug. Changes from baseline over time will be evaluated for clinical laboratory test results, vital signs, physical examination findings, body weight, height, and electrocardiogram results. Additional efficacy parameters include change from baseline to Month 12 or early termination in echocardiogram parameters and Tanner stage for female subjects aged 8 years or older and male subjects aged 9 years or older. The study aims to evaluate migalastat treatment in pediatric subjects aged 2 to less than 12 years who have GLA variants amenable to migalastat, with plasma migalastat exposure levels targeted to be similar to those observed in adolescents and adults.