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Goodman & Gilman's: Annual FDA Approvals


Brand Name


Pharmacological Class

Alpha-galactosidase A chaperone25

FDA Indication

Fabry disease


Migalastat is a first-in-class “pharmacological chaperone” of alpha-galactosidase A (α-Gal A) protein. Two other chaperones, lumacaftor and tezacaftor (Table P1-2), both specifically intended to shepherd amenable cystic fibrosis transmembrane conductance regulator (CFTR) protein variants, are approved for use in the United States.108 Migalastat is indicated for the treatment of adults with Fabry disease and an “amenable” α-Gal A gene (GLA) mutation.50 For eligible patients in the United States, migalastat offers an oral alternative to twice-monthly IV enzyme replacement therapy with agalsidase beta. Fabry disease is a rare X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-Gal A activity. The disease results in the abnormal accumulation of globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), globotriaosylceramide (GL-3), and related glycosphingolipids inside intracellular lysosomes distributed throughout the body. The disease causes progressive multiorgan damage.109-111 Some GLA mutations causing Fabry disease result in the production of abnormally folded α-Gal A proteins that are catalytically active but unstable. Migalastat (1-deoxygalactonojirimycin)112 is a structural analogue of the terminal galactose group of GL-3.109,111,113 The chemical structure of migalastat is shown in Figure P1-6.

At low doses, migalastat enters the cell and selectively and reversibly binds to the active site on “amenable” α-Gal A variants, thereby stabilizing the enzyme within the endoplasmic reticulum to enable its normal routing through the Golgi apparatus and into the lysosome.109,112 Once safely inside the lysosome, the pH change causes migalastat to dissociate from mutated α-Gal A allowing normal clearance of accumulated GL-3 and lyso-Gb3.50,109,111 Notably, at high doses, and in the presence of non-amenable variants, migalastat acts as a competitive inhibitor of α-Gal A and may cause disease progression.112 Dysfunctional α-Gal A variants are categorized as amenable if after in vitro incubation with migalastat they increase cell lysate α-Gal A activity by ≥20% over pretreatment levels and also increase wild-type activity by at least 3%.50 Over 300 amenable variants are listed in the prescribing information for migalastat. In all, at least 841 known mutations of the GLA gene are associated with Fabry disease, of which 348 are known to be amenable.110 However, because some variants may not be disease-causing, and because migalastat may act as a competitive inhibitor of α-Gal A activity to advance disease progression in non-amenable genotypes,112,113 consultation with a genetics professional is recommended to assist in determining appropriate candidates for treatment.50 The drug sponsor (Amicus Therapeutics U.S., Inc.) has developed a pharmacogenetics website (intended for use by licensed prescribers outside the United States) to assist in the accurate identification of amenable variants (

As a means to balance chaperone efficacy and safety (i.e., minimize the risk of competitive inhibition),112 migalastat is administered orally on an every-other-day schedule at a dose of 123 mg. Food must be withheld for at least 2 hours before and after each dose.50,112 Migalastat is excreted mainly by the kidneys as unchanged drug with a mean half-life of ~4 hours. Due to safety concerns, migalastat is not recommended for patients with severe renal impairment.50,112 Migalastat has been designated as an orphan drug for the treatment of Fabry disease since 2004.21 For FDA approval, it was studied in two multi-phase clinical trials that exposed 139 patients with Fabry disease (79 females and 60 males, 16–72 years of age).50 Patients were exposed to migalastat for ≥6 months (n = 127) and 123 patients were exposed for >1 year. The most common adverse reactions were headache, nasopharyngitis, nausea, pyrexia, and urinary tract infection. No adverse developmental effects in the offspring were observed among three pregnant women exposed to migalastat.50

Approval of migalastat for Fabry disease was based on a surrogate endpoint (the reduction in the number of interstitial capillary cell GL-3 inclusions (KIC GL-3) obtained from kidney biopsy samples) before and after 6 months of treatment with migalastat vs. placebo in patients with amenable GLA variants.50 In the subset of patients with baseline plasma lyso-Gb3 ≥0.3 nmol/L, seven of nine (78%) receiving migalastat achieved a ≥50% reduction in average number of GL-3 inclusions per KIC versus only 2 of 8 patients (25%) given placebo.50,113 Among this subset, the change in average number of GL-3 inclusions for patients receiving migalastat was –0.91 versus –0.02 for patients receiving placebo.50,113 As a condition of accelerated approval, migalastat will continue to be studied in a phase 4 program.114 The impact of migalastat on plasma lyso-Gb3 concentrations was also evaluated with mixed results obtained.111,113-117 Other pharmacodynamic results associated with migalastat administration have been reported, and a thorough systematic review of potential patient benefits and harms has been published.116-118 The annual cost of therapy is expected to be in excess of $300,000.110,119-121

Note: Take care to avoid confusing migALAstat (for Fabry disease) and migLUstat (for Gaucher disease). Miglustat is an inhibitor of glucosylceramide synthase, a glucosyltransferase enzyme responsible for the first step in the synthesis of most glycosphingolipids. Both drugs are used to treat a liposomal storage disease. They also share similar sounding names and chemical structures. Both are synthetic imino sugar analogs of D-glucose in which nitrogen has replaced the oxygen in the 6-member ring. This substitution allows both to avoid metabolism as normal dietary carbohydrates, allowing their respective pharmacological actions to inhibit glycosidases (migalastat) and glycosyltransferases (miglustat).

Table P1-2Pharmacological Similars Licensed in 2018
Figure P1-6

Chemical structure of migalastat122 (PubChem CID: 176077; IUPAC Name: (2R,3S,4R,5S)-2-(hydroxymethyl)piperidine-3,4,5-triol).

Further Reading in Goodman & Gilman’s