General Information

Galafold (migalastat) is an alpha-galactosidase A (alpha-Gal A) pharmacological chaperone. Galafold works by stabilizing the body’s own dysfunctional enzyme so that it can clear the accumulation of disease substrate.

Galafold is specifically indicated for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene (GLA) variant based on in vitro assay data.

Galafold is supplied as a capsule for oral administration. Treatment is indicated for patients with an amenable GLA variant that is interpreted by a clinical genetics professional as causing Fabry disease (pathogenic, likely pathogenic) in the clinical context of the patient. Consultation with a clinical genetics professional is strongly recommended in cases where the amenable GLA variant is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease). The recommended dosage regimen of Galafold is 123 mg orally once every other day at the same time of day. Galafold should be taken on an empty stomach. Do not consume food at least 2 hours before and 2 hours after taking Galafold to give a minimum 4 hours fast. Clear liquids can be consumed during this 4-hour period. Do not take Galafold on 2 consecutive days. If a dose is missed entirely for the day, take the missed dose of Galafold only if it is within 12 hours of the normal time that the dose should have been taken. If more than 12 hours have passed, resume taking Galafold at the next planned dosing day and time, according to the every-other-day dosing schedule. Swallow capsules whole. Do not cut, crush, or chew.

Clinical Results

FDA Approval

This indication is approved under accelerated approval based on reduction in kidney interstitial capillary cell globotriaosylceramide (KIC GL-3) substrate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

The FDA Approval of Galafold was based on a phase III, double-blind, randomized, placebo-controlled study - FACETS. A total of 67 patients with Fabry disease who were naïve to Galafold and enzyme replacement therapy (ERT) or were previously treated with ERT (agalsidase beta or non-U.S. approved agalsidase alfa) and had been off ERT for at least 6 months were randomized in a 1:1 ratio to receive either Galafold 123 mg every other day or placebo for the first 6 months. In the second 6 months, all patients were treated with Galafold. Of the 67 enrolled patients, 50 patients (32 females, 18 males) had amenable GLA variants. The major efficacy outcome measure of the average number of GL-3 inclusions per kidney interstitial capillary (KIC) in renal biopsy samples was assessed by light microscopy before and after treatment. Efficacy was evaluated after 6 months of treatment in 45 of 50 patients with available histology data both at baseline and month 6. Of the 45 evaluable patients, 25 received Galafold and 20 received placebo. In the Galafold treatment arm, 52% had a ≥ 50% reduction from baseline in Average Number of GL-3 Inclusions per KIC versus 45% in the placebo arm.

Mechanism of Action

Galafold (Migalastat) is a pharmacological chaperone that reversibly binds to the active site of the alpha-galactosidase A (alpha-Gal A) protein (encoded by the galactosidase alpha gene, GLA), which is deficient in Fabry disease. This binding stabilizes alpha-Gal A allowing its trafficking from the endoplasmic reticulum into the lysosome where it exerts its action. In the lysosome, at a lower pH and at a higher concentration of relevant substrates, migalastat dissociates from alpha-Gal A allowing it to break down the glycosphingolipids globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3). Certain GLA variants (mutations) causing Fabry disease result in the production of abnormally folded and less stable forms of the alpha-Gal A protein which, however, retain enzymatic activity. Those GLA variants, referred to as amenable variants, produce alpha-Gal A proteins that may be stabilized by migalastat thereby restoring their trafficking to lysosomes and their intralysosomal activity.