Migalastat

Identification

Summary

Migalastat is an alpha-galactosidase A chaperone used for the treatment of Fabry disease in patients with an amenable galactosidase alpha gene (GLA) variant.

Brand Names

Galafold

Generic Name

Migalastat

DrugBank Accession Number

DB05018

Background

Fabry disease is a rare, progressive genetic disorder characterized by a defective GLA gene that causes a deficiency in the enzyme alpha-Galactosidase A (alpha-Gal A) ^Label,6,3,2. This enzyme is responsible for breaking down glycosphingolipid substrate that, when deficient in patients with Fabry disease, builds up in the blood vessels, the kidneys, the nerves, the heart, and other organs ^Label,6,3,4. In the U.S., it is estimated that more than 3,000 people are living with Fabry disease, and an estimated more than 50 percent of these diagnosed patients are currently untreated ³.

Migalastat (approved and sold under Amicus Therapeutics' brand name Galafold) is subsequently an oral pharmacological chaperone of alpha-Gal A for the treatment of Fabry disease in adults who have amenable GLA variants ^Label,6,3,4. In these patients, migalastat works by stabilizing the body’s own dysfunctional alpha-Gal A enzyme so that it can clear the accumulation of glycosphingolipid disease substrate ^Label,6,3,4. Globally, it is estimated that approximately 35 to 50 percent of Fabry patients may have amenable GLA variants that are treatable with migalastat ³.

Given the rarity of Fabry disease and the proportion of Fabry disease patients that could benefit from migalastat therapy, Amicus Therapeutics' brand name Galafold was approved using the Accelerated Approval pathway, under which the FDA may approve drugs for serious conditions where there is an unmet medical need and where a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients ^Label,6,3,4. A further study is required to verify and describe the clinical benefits of Galafold, and the sponsor will be conducting a confirmatory clinical trial of Galafold in adults with Fabry disease ^Label,6,3,4.

Additionally, Galafold was alzo granted Priority Review designation, under which the FDA’s goal is to take action on an application within six months of application filing where the agency determines that the drug, if approved, would provide a significant improvement in treating, diagnosing or preventing a serious condition over available therapies ^Label,6. Galafold also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases ^Label,6.

As of August 2018, migalastat under Amicus Therapeutics' brand name Galafold is currently approved in Australia, Canada, European Union, Israel, Japan, South Korea, Switzerland, and the United States.

Type

Small Molecule

Groups

Approved, Investigational

Structure

Similar Structures

Weight: Average: 163.1717
Monoisotopic: 163.084457909
Chemical Formula: C₆H₁₃NO₄

Synonyms

1-Deoxygalactonojirimycin
1-Deoxygalactostatin
Migalastat

Pharmacology

Indication

Migalastat is an alpha-galactosidase A (alpha-Gal A) pharmacological chaperone indicated for the long-term treatment of adults and adolescents aged 16 years and older with a confirmed diagnosis of Fabry disease (alpha-galactosidase A deficiency) and an amenable galactosidase alpha gene (GLA) mutation/variant based upon in vitro assay data ^Label,6.

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

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Associated Conditions

Fabry's Disease

Contraindications & Blackbox Warnings

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Pharmacodynamics

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 ^Label,6. 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 ^Label,6.

Mechanism of action

Fabry disease is a progressive X-linked lysosomal storage disorder which affects males and females ^Label,6. 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 ^Label,6. 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 ^Label,6.

Certain GLA mutations can result in the production of abnormally folded and unstable mutant forms of alpha-Gal A ^Label,6. Migalastat is subsequently a pharmacological chaperone that is designed to selectively and reversibly bind with high affinity to the active sites of certain mutant forms of alpha-Gal A, the genotypes of which are referred to as amenable mutations ^Label,6. Such migalastat binding stabilizes these mutant forms of alpha-Gal A in the endoplasmic reticulum and facilitates their proper trafficking to lysosomes ^Label,6. Once in the lysosomes and surrounded by an environment defined by lower pH and higher concentrations of relevant glycosphingolipid substrates, migalastat dissociates from alpha-Gal A, thereby restoring the alpha-Gal A activity, leading to the catabolism of glycosphingolipids like globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3) since the alpha-Gal A variants still retain enzymatic activity ^Label,6.

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 ^Label,6.

Target	Actions	Organism
UAlpha-galactosidase A	Not Available	Humans

Absorption

With absorption occurring largely in the gut ², the absolute bioavailability (AUC) for a single oral 150 mg migalastat hydrochloride dose or a single 2-hour 150 mg intravenous infusion was approximately 75% ^Label,6. Following a single oral dose of 150 mg migalastat hydrochloride solution, the time to peak plasma concentration was approximately 3 hours ^Label,6. Plasma migalastat exposure (AUC0-∞) and Cmax demonstrated dose-proportional increases at migalastat hydrochloride oral doses from 50 mg to 1,250 mg ^Label,6.

Migalastat administered with a high-fat meal, or 1 hour before a high-fat or light meal, or 1 hour after a light meal, resulted in significant reductions of 37% to 42% in mean total migalastat exposure (AUC0-∞) and reductions of 15% to 40% in mean peak migalastat exposure (Cmax) compared with the fasting state ^Label,6.

Volume of distribution

In healthy volunteers, the volume of distribution (Vz/F) of migalastat following ascending single oral doses (25-675 mg migalastat HCl) ranged from 77 to 133 L, indicating it is well distributed into tissues and greater than total body water (42 liters) ^Label,6.

Protein binding

There was no detectable plasma protein binding following administration of [14C]-migalastat hydrochloride in the concentration range between 1 and 100 uM ^Label,6.

Metabolism

Based upon in vivo data, migalastat is a substrate for uridine diphosphate glucuronosyltransferase (otherwise known as UGT or UDPGT), being a minor elimination pathway ^Label,6. Migalastat is not a substrate for P-glycoprotein (P-gP) in vitro and it is considered unlikely that migalastat would be subject to drug-drug interactions with cytochrome P450s ^Label,6. A pharmacokinetic trial in healthy male volunteers with 150 mg [14C]-migalastat HCl revealed that 99% of the radiolabeled dose recovered in plasma was comprised of unchanged migalastat (77%) and 3 dehydrogenated O-glucuronide conjugated metabolites, M1, M2, and M3 (13%) ^Label,6. Approximately 9% of the total radioactivity was unassigned ^Label,6.

Route of elimination

A pharmacokinetic trial in healthy male volunteers with 150 mg [14C]-migalastat hydrochloride revealed that approximately 77% and 20% of the radiolabeled dose was recovered in urine and excreted in the feces, respectively ^Label,6.

Half-life

The mean elimination half-life (t1/2) of migalastat ranges from approximately 3 to 5 hours ^Label,6.

Clearance

Following ascending single oral doses (25-675 mg migalastat hydrochloride), no trends were found for clearance, CL/F). At the 150 mg dose, CL/F was approximately 11 to 14 L/hr ^Label,6.

Adverse Effects

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Toxicity

The most common adverse reactions reported with migalastat (≥ 10%) during the 6-month placebo-controlled, double-blind phase of its Study 1 clinical studies were headache, nasopharyngitis, urinary tract infection, nausea, and pyrexia ^Label,6.

In case of overdose, general medical care is recommended ^Label,6. Headache and dizziness were the most common adverse reactions reported at doses of migalastat of up to 1250 mg and 2000 mg, respectively ^Label,6.

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Abacavir	Abacavir may decrease the excretion rate of Migalastat which could result in a higher serum level.
Aceclofenac	Aceclofenac may decrease the excretion rate of Migalastat which could result in a higher serum level.
Acemetacin	Acemetacin may decrease the excretion rate of Migalastat which could result in a higher serum level.
Acetaminophen	Acetaminophen may decrease the excretion rate of Migalastat which could result in a higher serum level.
Acetazolamide	Acetazolamide may increase the excretion rate of Migalastat which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acid	Acetylsalicylic acid may decrease the excretion rate of Migalastat which could result in a higher serum level.
Aclidinium	Migalastat may decrease the excretion rate of Aclidinium which could result in a higher serum level.
Acrivastine	Migalastat may decrease the excretion rate of Acrivastine which could result in a higher serum level.
Acyclovir	Acyclovir may decrease the excretion rate of Migalastat which could result in a higher serum level.
Adefovir dipivoxil	Adefovir dipivoxil may decrease the excretion rate of Migalastat which could result in a higher serum level.

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Food Interactions

Take at the same time every day.
Take on an empty stomach. Avoid eating for at least two hours before and after taking migalastat.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Migalastat hydrochloride	CLY7M0XD20	75172-81-5	ZJIHMALTJRDNQI-OLALXQGDSA-N

International/Other Brands

Amigal

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Galafold	Capsule	123 mg	Oral	Amicus Therapeutics	2018-01-15	Not applicable
Galafold	Capsule	123 mg/1	Oral	Amicus Therapeutics US, LLC	2018-08-10	Not applicable
Galafold	Capsule	123 mg	Oral	Amicus Therapeutics Europe Limited	2020-12-22	Not applicable

Chemical Identifiers

UNII: C4XNY919FW
CAS number: 108147-54-2
InChI Key: LXBIFEVIBLOUGU-DPYQTVNSSA-N
InChI: InChI=1S/C6H13NO4/c8-2-3-5(10)6(11)4(9)1-7-3/h3-11H,1-2H2/t3-,4+,5+,6-/m1/s1
IUPAC Name: (2R,3S,4R,5S)-2-(hydroxymethyl)piperidine-3,4,5-triol
SMILES: OC[C@H]1NC[C@H](O)[C@@H](O)[C@H]1O

References

Synthesis Reference

Patent US20180208955A1: Process for the microbial synthesis of migalastat (https://patents.google.com/patent/US20180208955A1/en)

General References

Warnock DG, Bichet DG, Holida M, Goker-Alpan O, Nicholls K, Thomas M, Eyskens F, Shankar S, Adera M, Sitaraman S, Khanna R, Flanagan JJ, Wustman BA, Barth J, Barlow C, Valenzano KJ, Lockhart DJ, Boudes P, Johnson FK: Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active alpha-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase. PLoS One. 2015 Aug 7;10(8):e0134341. doi: 10.1371/journal.pone.0134341. eCollection 2015. [Article]
Migalastat for the treatment of Fabry Disease: Sunder-Plassmann G., Schiffmann R., and Nicholls K. [Link]
Amicus Therapeutics News Release: FDA Approves Galafold™ (migalastat) for the Treatment of Certain Adult Patients with Fabry Disease [Link]
Drugs.com: FDA Approves Galafold (migalastat) for the Treatment of Fabry Disease [Link]
Patent US20180208955A1: Process for the microbial synthesis of migalastat [File]
Migalastat EMA Label [File]

External Links

PubChem Compound: 176077
PubChem Substance: 347827704
ChemSpider: 153388
BindingDB: 50163440
RxNav: 2054252
ChEBI: 135923
ChEMBL: CHEMBL110458
ZINC: ZINC000001636704
PDBe Ligand: DGJ
Wikipedia: Migalastat

PDB Entries

3s5y / 3thd / 3tv8 / 4cu8 / 4d1j / 4do5 / 4fns / 4ufm / 6euh / 6tsh …

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FDA label

Download (1.3 MB)

MSDS

Download (72.5 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Fabry's Disease	1
3	Completed	Treatment	Fabry's Disease	4
3	Recruiting	Treatment	Fabry's Disease	2
3	Terminated	Treatment	Fabry's Disease	1
2	Completed	Treatment	Fabry's Disease	5
2	Terminated	Treatment	Fabry's Disease	1
1	Completed	Treatment	Fabry's Disease	3
Not Available	Active Not Recruiting	Not Available	Fabry's Disease	1
Not Available	Approved for Marketing	Not Available	Fabry's Disease	1
Not Available	Recruiting	Not Available	Fabry's Disease	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral	123 mg
Capsule	Oral	123 mg/1
Capsule, coated	Oral	150 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US9987263	No	2018-06-05	2027-05-16
US9000011	No	2015-04-07	2027-05-16
US8592362	No	2013-11-26	2029-02-12
US9095584	No	2015-08-04	2029-02-12
US9480682	No	2016-11-01	2027-05-16
US9999618	No	2018-06-19	2028-04-28
US10076514	No	2018-09-18	2037-03-15
US10251873	No	2019-04-09	2038-05-30
US10383864	No	2019-08-20	2027-05-16
US10471053	No	2019-11-12	2038-05-30
US10406143	No	2019-09-10	2027-05-16
US10525045	No	2020-01-07	2028-04-28
US10792278	No	2020-10-06	2038-05-30
US10792279	No	2020-10-06	2038-05-30
US10813921	No	2020-10-27	2029-02-12
US10857141	No	2020-12-08	2038-05-30
US10849890	No	2020-12-01	2038-05-30
US10849889	No	2020-12-01	2038-05-30
US10857142	No	2020-12-08	2038-05-30
US10874657	No	2020-12-29	2038-05-30
US10874655	No	2020-12-29	2038-05-30
US10874656	No	2020-12-29	2038-05-30
US10799491	No	2020-10-13	2038-05-30
US10806727	No	2020-10-20	2038-05-30
US10925866	No	2021-02-23	2028-04-28
US11033538	No	2021-06-15	2028-04-28
USRE48608	No	2021-06-29	2029-02-12
US11241422	No	2007-05-16	2027-05-16
US11234972	No	2017-03-15	2037-03-15
US11278538	No	2018-05-30	2038-05-30
US11278537	No	2018-05-30	2038-05-30
US11278536	No	2018-05-30	2038-05-30
US11278539	No	2018-05-30	2038-05-30
US11278540	No	2018-05-30	2038-05-30
US11304940	No	2018-05-30	2038-05-30
US11357761	No	2008-05-30	2028-05-30
US11357762	No	2018-05-30	2038-05-30
US11357763	No	2018-05-30	2038-05-30
US11357784	No	2019-02-06	2039-02-06
US11389437	No	2018-05-30	2038-05-30
US11389436	No	2018-05-30	2038-05-30
US11357764	No	2018-05-30	2038-05-30
US11376244	No	2018-05-30	2038-05-30
US11357765	No	2018-05-30	2038-05-30
US11426396	No	2018-05-30	2038-05-30
US11458128	No	2018-05-30	2038-05-30

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	244-246	MSDS

Predicted Properties

Property	Value	Source
Water Solubility	511.0 mg/mL	ALOGPS
logP	-2.2	ALOGPS
logP	-2.9	Chemaxon
logS	0.5	ALOGPS
pKa (Strongest Acidic)	12.91	Chemaxon
pKa (Strongest Basic)	8.06	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	5	Chemaxon
Hydrogen Donor Count	5	Chemaxon
Polar Surface Area	92.95 Å²	Chemaxon
Rotatable Bond Count	1	Chemaxon
Refractivity	36.57 m³·mol^-1	Chemaxon
Polarizability	15.86 Å³	Chemaxon
Number of Rings	1	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	Not Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Targets

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Details1. Alpha-galactosidase A

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Receptor binding
Specific Function: Not Available
Gene Name: GLA
Uniprot ID: P06280
Uniprot Name: Alpha-galactosidase A
Molecular Weight: 48766.34 Da

Enzymes

Details1. UDP-glucuronosyltransferase 1-1

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: Steroid binding
Specific Function: UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name: UGT1A1
Uniprot ID: P22309
Uniprot Name: UDP-glucuronosyltransferase 1-1
Molecular Weight: 59590.91 Da

Drug created at October 21, 2007 22:23 / Updated at June 03, 2023 08:16

Migalastat

Identification

Structure for Migalastat (DB05018)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Targets

Enzymes