Regulatory Decision Summary for Galafold

The purpose of this Supplement to a New Drug Submission (SNDS) for Galafold (migalastat) was threefold, as follows:

1) to expand the indication to include adolescents aged 12 years and older with a confirmed diagnosis of Fabry disease (deficiency of α galactosidase [α-Gal A]) and who have an α-Gal A mutation determined to be amenable by an in vitro assay;

2) to provide long-term safety and efficacy data; and

3) to update the list of mutations amenable and non-amenable to treatment with Galafold.

The revised indication to include adolescents ages 12 to < 18 years old was approved with a weight specification (≥ 45 kg). The updated Product Monograph (PM) includes new safety and efficacy data reflecting the pediatric indication, the long-term extension data, and the updated list of mutations amenable to treatment with Galafold.

Fabry disease is an inherited, rare, progressive, multi-system disease with symptom onset beginning in childhood. This Supplement to a New Drug Submission (SNDS) provided data to expand the indication for Galafold (migalastat) in the treatment of Fabry disease to include adolescents aged 12 to < 18 years old who weigh ≥ 45 kg, as well as to provide long-term safety and efficacy results from an extension study in adult patients. New data also supported an update to include 21 new mutations amenable to treatment with Galafold in the Product Monograph (PM) as well as 16 new non-amenable mutations to the listing of non-amenable mutations on the product Website. The updated listing of mutations provides pertinent information refining patient suitability for treatment.

Trial AT1001-020 was an open-label, uncontrolled, 1-year study in 21 Fabry disease patients aged 12-17 years who weighed ≥ 45 kg and were naïve to/stopped enzyme replacement therapy (ERT) at the time of screening. The primary objective characterized the pharmacokinetics (PK) of migalastat where the adult population PK (popPK) model dataset was appended with data from 20 adolescent patients to validate extrapolation of exposure in adults receiving migalastat 123 mg once every other day to adolescents receiving the same dosage regimen. Model derived exposure (C_max and AUC_tau) in adolescent patients was determined to be similar to adult exposures. Given relevant similarities of the disease process and response to treatment, extrapolation based on the population PK data extend what is known about the adult population to the target pediatric population.

Safety was also assessed as a primary objective in Trial AT1001-020 with no deaths, 1 serious adverse event (unrelated) and no discontinuations due to treatment emergent adverse events (TEAEs). Twenty patients (95.2%) experienced ≥ 1 TEAE with 11 TEAEs (in 5 patients) considered related to treatment. The TEAEs aligned with the known safety profile for Galafold with all related TEAEs listed in the PM. The vital signs, hematology and chemistry laboratory parameters showed subtle mean changes over the study fluctuating within normal limits. Efficacy was assessed as a secondary objective with no clinically meaningful decline in the renal, cardiac, pharmacodynamic (biomarker plasma lyso-Gb3), or patient-reported outcomes (PROs) observed at 1 year, compared to baseline. The mean (SD) change from baseline to 1 year in estimated glomerular filtration rate (eGFR) was -1.6 (15.4) mL/min/1.73 m² and in left ventricular mass index (LVMi) was -3.9 (13.5) g/m² with all patients remaining within normal limits. The overall mean (SD) change from baseline to 1 year in plasma lyso-Gb3 was -0.06 (32.9) and there were no notable changes in PROs over the 1-year study.

The basis for approval of the expanded indication to include pediatric patients included consideration of the rare, serious nature of Fabry disease as well as the underlying pathophysiology of the disease and corresponding mechanism of action of the drug. Moreover, the safety and efficacy data from Trial AT1001-020 supported a favourable benefit-risk profile for pediatric patients 12 to < 18 years old within the current clinical context. The Product Monograph directs to monitor individual patient response to treatment through continual assessment for clinical deterioration. Additionally, the risk management plan (RMP) was updated to characterize use in pediatric patients through the addition of data from Trial AT1001-020 as well as continual monitoring through an expansion of the on-going registry study to capture pediatric age-specific data.

Trial AT1001-042, an open-label, non-comparative, long-term extension study investigated safety and efficacy of Galafold treatment for a mean duration of 32.32 months in 84 adult patients (mean age 51.9 years). The results showed the mean annualized rate of change in eGFR from baseline was -1.78 mL/min/1.73 m² and -1.71 mL/min/1.73 m² for ERT-experienced patients and ERT-naïve patients, respectively, treated for an average of 4.3 and 5.2 years in total (original trial plus extension). The mean change in LVMi from baseline was 1.2 g/m² and -5.6 g/m² for ERT-experienced and ERT-naïve patients, respectively, treated with Galafold for an average of 2.4 and 2.9 years (extension study). There were no deaths, 1 discontinuation due to an AE (unrelated) and 26 patients (31.0%) who reported 59 SAEs with 1 considered to be possibly related (captured in PM). All of the observed most common (≥ 2 patients) drug-related TEAEs are listed in the PM. There were no new or clinically meaningful trends in laboratory findings. Trial AT1001-042 extends existing information regarding safe and effective use of Galafold longer-term. Long-term safety and effectiveness continue to be assessed through the Galafold Registry study, as detailed in the RMP.

Based on the data provided in this SNDS, the overall benefit-risk profile of migalastat remains favourable.

The revised Product Monograph and updated Canadian Risk Management Plan were considered acceptable.

For more details on Galafold, please consult the product monograph, approved by Health Canada and available in the Drug Product Database.