With IC50 and Ki values of 0.04 μM, migalastat inhibits human lysosomal a-Gal A [1].

α-galactosidase A activity defects are the cause of Fabry disease, an X-linked recessive genetic illness [2]. In transgenic mice expressing human mutant α-Gal A (TgM), migalastat (oral gavage, 3 mg/kg daily for 4 weeks) enhances α-Gal A activity in the heart, kidney, spleen, and liver and demonstrates dose- and time-dependent effects. )[2]. During the first two weeks of treatment, Migasalstat demonstrated half-lives of less than one day for all key issues in TgM [2]. In transgenic mice, migastat (oral gavage, 100 mg/kg daily for 28 days) decreased the levels of lyso-Gb3 in the kidney, heart, and skin by as much as 64%, 59%, and 81%, in that order [3].

Cell Viability Assay [4]
Cell Types: EHK Cell Mutated α-Gal A
Tested Concentrations: 10 μM
Incubation Duration: 9 days
Experimental Results: Gb3 accumulation and lysosomal volume reduction.

Animal/Disease Models: Male non-transgenic (Non-Tg) C57BL/6 mice; transgenic mice expressing human mutant R301Q α-Gal A (TgM), α-Gal A knockout mice (KO), in null background Mice expressing human R301Q α-Gal A (TgM/KO) [2]
Doses: 3 mg/kg
Route of Administration: po (oral gavage); one time/day for 4 weeks
Experimental Results: Triacylceramide (Gb3) in mouse kidneys Storage is Dramatically diminished.

Absorption, Distribution and Excretion
Since absorption primarily occurs in the intestine, the absolute bioavailability (AUC) of a single oral dose of 150 mg miglustat hydrochloride or a single intravenous infusion of 150 mg over 2 hours is approximately 75%, with a time to peak (Tmax) of approximately 3 hours. Plasma miglustat exposure (AUC0-∞) and Cmax increase dose-proportionately with oral doses of miglustat hydrochloride from 50 mg to 1250 mg (equivalent to 0.5 to 8.3 times the approved recommended dose). Concomitant administration with a high-fat meal (850 calories; 56% from fat), or 1 hour before or after a high-fat or light meal (507 calories; 30% from fat), significantly reduces mean total miglustat exposure (AUC0-∞) by 37% to 42% and mean peak miglustat exposure (Cmax) by 15% to 39% (compared to fasting). In a quality balance study of healthy male subjects, approximately 77% of the total radiolabeled dose was recovered in urine and 20% in feces after oral administration of 123 mg [14C]-miglustat, with a total recovery rate of 98% within 96 hours post-administration. In urine, unmetabolized miglustat accounted for 80% of the radioactivity, equivalent to 62% of the administered dose. In feces, unmetabolized miglustat was the only drug-related component. In plasma, unmetabolized miglustat accounted for approximately 77% of plasma radioactivity, and the three dehydro-O-glucuronide conjugates M1 through M3 accounted for approximately 13% of plasma radioactivity, with each metabolite accounting for no more than 6% of the radiolabeled dose. Approximately 9% of the total radioactivity in plasma remained unallocated. In healthy volunteers, the volume of distribution (Vz/F) of miglustat ranged from 77 to 133 L following a single oral escalation dose (25–675 mg miglustat hydrochloride), indicating good tissue distribution and distribution greater than the total body fluid volume (42 L). No trend in clearance (CL/F) was observed following a single oral escalation dose (25–675 mg miglustat hydrochloride). At a 150 mg dose, the CL/F was approximately 11–14 L/hr, while at a 123 mg dose, the apparent clearance was calculated to be 12.5 L/hr. Metabolites/Metabolites: Based on in vivo data, miglustat is a substrate of uridine diphosphate glucuronyl transferase (also known as UGT or UDPGT) and is eliminated via a minor elimination pathway.

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Biological Half-Life
The mean elimination half-life (t1/2) of a single oral dose of 150 mg miglustat is approximately 3 to 5 hours. For a 123 mg dose, the mean elimination half-life is estimated to be 4 hours.

Hepatotoxicity
In placebo-controlled trials, liver function abnormalities were rare, and the incidence was not significantly different between the migalastat and placebo groups. The abnormalities were mild and resolved spontaneously without discontinuation of treatment. No cases of acute liver injury with jaundice due to migalastat have been reported during these premarketing clinical trials or after the wider clinical use of migalastat. However, overall clinical experience with it is limited. Probability score: E (unlikely a clinically significant cause of liver injury). Use during Pregnancy and Lactation ◉ Overview of Use During Lactation There is currently no information on the use of migalastat during lactation. Because there is currently no information on the use of migalastat during lactation, caution should be exercised, especially in breastfed newborns or preterm infants. ◉ Effects on Breastfed Infants As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding
No plasma protein binding was detected after administration of [14C]-miglustat hydrochloride at concentrations ranging from 1 to 100 µM.

[1]. Asano N, et al. In vitro inhibition and intracellular enhancement of lysosomal alpha-galactosidase A activity in Fabry lymphoblasts by 1-deoxygalactonojirimycin and its derivatives. Eur J Biochem. 2000 Jul;267(13):4179-86.
[2]. Ishii S, et al. Preclinical efficacy and safety of 1-deoxygalactonojirimycin in mice for Fabry disease. J Pharmacol Exp Ther. 2009 Mar;328(3):723-31.
[3]. Young-Gqamana B, et al. Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients. PLoS One. 2013;8(3):e57631.
[4]. Welford RWD, et al. Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types. Hum Mol Genet. 2018 Oct. 27(19):3392-3403.

Miglustat belongs to the piperidine class of drugs. Fabry disease is a rare, progressive, inherited disorder characterized by a deficiency in the GLA gene leading to a lack of α-galactosidase A (α-Gal A). This enzyme is responsible for breaking down glycosphingolipid substrates, and in Fabry disease patients, insufficient α-Gal A causes glycosphingolipids to accumulate in blood vessels, kidneys, nerves, heart, and other organs. It is estimated that more than 3,000 people in the United States have Fabry disease, and more than 50% of those diagnosed are currently untreated. Miglustat (approved and marketed under the brand name Galafold by Amicus Therapeutics) is an oral α-Gal A pharmacological companion for the treatment of adults with Fabry disease who carry an adaptive GLA variant. In these patients, miglustat works by stabilizing the dysfunctional α-galactosidase A (α-Gal A) in the body, enabling it to clear the accumulation of glycosphingolipid disease substrates. It is estimated that approximately 35% to 50% of Fabry disease patients worldwide may carry a tolerable GLA variant gene that can be treated with miglustat. Given the rarity of Fabry disease and the high proportion of Fabry disease patients who can benefit from miglustat treatment, Amicus Therapeutics' brand name Galafold has been approved through the accelerated approval pathway. Under this pathway, the FDA can approve drugs for the treatment of serious diseases with unmet medical needs, provided that the drug has been shown to have some efficacy that is likely to predict clinical benefit for patients. Further research is needed to validate and characterize the clinical benefit of Galafold, and the sponsor will conduct confirmatory clinical trials of Galafold in adult patients with Fabry disease. In addition, Galafold has also received Priority Review designation. Under this designation, the FDA aims to act on an application within six months of submission, provided that the FDA determines that, if approved, the drug would be a significant improvement over existing therapies in the treatment, diagnosis, or prevention of serious disease. Galafold has also received Orphan Drug designation, which aims to incentivize and encourage the development of drugs for rare diseases. As of August 2018, migalastat, marketed by Amicus Therapeutics under the brand name Galafold, is approved in Australia, Canada, the European Union, Israel, Japan, South Korea, Switzerland, and the United States. Migalastat is a pharmacological accompaniment to α-galactosidase, an enzyme deficient in the liver of patients with Fabry disease. Clinical experience with migalastat is limited, but it has not been found to be associated with elevated serum enzyme levels or clinically significant acute liver injury during treatment. See also: migalastat hydrochloride (salt form). Laprazole peptide acetate (note moved to).

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Drug Indications
Based on in vitro data, migalastat has been approved by the FDA for the treatment of adult patients diagnosed with Fabry disease who carry a treatable variant of the α-galactosidase gene (GLA). This indication received accelerated approval based on the reduction of the substrate of trihexosylceramide (KIC GL-3) in renal interstitial capillary cells. Continued approval for this indication may depend on validation and description of clinical benefit in confirmatory trials. Migalatal has also been approved by the European Medicines Agency (EMA) and Health Canada for the treatment of the same disease, although it is approved in Europe for adults and adolescents aged 16 years and older.
FDA Label
Galafold is indicated for the long-term treatment of adults and adolescents aged 16 years and older diagnosed with Fabry disease (α-galactosidase A deficiency) and carrying a treatable mutation.

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Mechanism of Action
Fabry disease is a progressive X-linked lysosomal storage disorder that can affect both men and women. The pathogenic mutation in Fabry disease occurs in the galactosidase α (GLA) gene, resulting in a deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A), which is essential for the metabolism of glycosphingolipid substrates (GL-3 and lyso-Gb3). Therefore, decreased α-galactosidase A activity is associated with the gradual accumulation of glycosphingolipid substrates in susceptible organs and tissues, ultimately leading to morbidity and mortality associated with Fabry disease. Miglustat is a pharmacological chaperone that reversibly binds to the active site of the α-galactosidase A (α-Gal A) protein (encoded by the galactosidase α gene GLA), in which α-Gal A protein activity is insufficient in patients with Fabry disease. This binding stabilizes α-Gal A, allowing it to be transported from the endoplasmic reticulum to lysosomes, where it functions. In lysosomes, at lower pH and in the presence of higher concentrations of the relevant substrate, miglustat dissociates from α-Gal A, thereby enabling the breakdown of glycosphingolipids such as trihexysylceramide (GL-3) and trihexysphingosine (lyso-Gb3). Certain GLA gene variants (mutations) that cause Fabry disease produce abnormally folded and less stable α-galactosidase A proteins, but these proteins still retain enzymatic activity. These GLA gene mutations, known as "treatable variants," produce α-galactosidase A protein that can be stabilized by miglucostat, thereby restoring its transport to and activity within the lysosome. Information on treatable and untreatable GLA gene mutations is regularly updated on a website easily accessible to healthcare providers.

C6H13NO4

199.63266

163.084

108147-54-2

Migalastat hydrochloride;75172-81-5

176077

Typically exists as solid at room temperature

1.456g/cm3

361.1ºC at 760 mmHg

197.3ºC

1.13E-06mmHg at 25°C

1.582

-2.3

5

5

1

11

132

4

C1[C@@H]([C@H]([C@H]([C@@H](CO)N1)O)O)O

LXBIFEVIBLOUGU-DPYQTVNSSA-N

1S/C6H13NO4/c8-2-3-5(10)6(11)4(9)1-7-3/h3-11H,1-2H2/t3-,4+,5+,6-/m1/s1

D-Galactitol, 1,5-dideoxy-1,5-imino-

Amigal, DDIG, Migalastat 1-Deoxygalactonojirimycin 1-Deoxygalactostatin AT1001 AT 1001 AT-1001 GR181413A GR 181413A GR-181413A Galafold

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)