Migalastat

Breast Feeding; Lactation; Alpha-Galactosidase; Enzyme Inhibitors;

EMA approved medicines: Human medicine

In placebo-controlled trials, liver test abnormalities were rare and no more common with migalastat than with placebo treatment. What abnormalities occurred were mild and resolved spontaneously without need for dose interruption. During these premarketing clinical trials and since its more widespread clinical availability, no instances of acute liver injury with jaundice have been reported attributable to migalastat. However, the total clinical experience with its use has been limited.

A - Alimentary tract and metabolism

QA - Alimentary tract and metabolism

In general, treatment in patients with migalastat in Phase 2 pharmacodynamic trials resulted in increases in endogenous alpha-galactosidase (alpha-Gal A) activity in white blood cells, as well as in skin and kidney for the majority of patients. In patients with amenable galactosidase alpha gene (GLA) mutations, globotriaosylceramide (GL-3) levels tended to decrease in the urine and in the kidney interstitial capillaries. In an in vitro assay (HEK-293 assay), Human Embryonic Kidney (HEK-293) cell lines were transfected with specific GLA variants (mutations) which produced mutant alpha-Gal A proteins. In the transfected cells, amenability of the GLA variants was assessed after a 5-day incubation with 10 micromol/L migalastat. A GLA variant was categorized as amenable if the resultant mutant alpha-Gal A activity (measured in the cell lysates) met two criteria: 1) it showed a relative increase of at least 20% compared to the pre-treatment alpha-Gal A activity, and 2) it showed an absolute increase of at least 3% of the wild-type (normal) alpha-Gal activity. The in vitro assay did not evaluate the trafficking of the mutant alpha-Gal A proteins into the lysosome or the dissociation of migalastat from the mutant alpha-Gal A proteins within the lysosome. Also, the in vitro assay did not test whether a GLA variant causes Fabry disease or not.

Fabry disease is a progressive X-linked lysosomal storage disorder that affects males and females. Fabry disease-causing mutations occur in the galactosidase alpha (GLA) gene and result in a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-Gal A) that is required for glycosphingolipid substrate (GL-3 and lyso-Gb3) metabolism. Reduced alpha-Gal A activity is, therefore, associated with the progressive accumulation of glycosphingolipid substrate in vulnerable organs and tissues, which ultimately leads to the morbidity and mortality associated with Fabry disease. 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. The GLA mutations that are amenable and not amenable to treatment with migalastat are regularly maintained and updated on online sites that are readily accessible by healthcare providers.