Identification

Name
Migalastat
Accession Number
DB05018
Type
Small Molecule
Groups
Approved, Investigational
Description

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]. 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]. 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]. 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]. 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]. 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].

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]. Galafold also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases [Label].

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.

Structure
Thumb
Synonyms
  • 1-Deoxygalactonojirimycin
  • 1-Deoxygalactostatin
Product Ingredients
IngredientUNIICASInChI Key
Migalastat hydrochlorideCLY7M0XD2075172-81-5ZJIHMALTJRDNQI-OLALXQGDSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
GalafoldCapsule123 mgOralAmicus Therapeutics2018-01-15Not applicableCanada
GalafoldCapsule123 mg/1OralAmicus Therapeutics U.S., Inc.2018-08-10Not applicableUs
International/Other Brands
Amigal
Categories
UNII
C4XNY919FW
CAS number
108147-54-2
Weight
Average: 163.1717
Monoisotopic: 163.084457909
Chemical Formula
C6H13NO4
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

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].

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].

Associated Conditions
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]. 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].

Mechanism of action

Fabry disease is a progressive X-linked lysosomal storage disorder which affects males and females [Label]. 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]. 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].

Certain GLA mutations can result in the production of abnormally folded and unstable mutant forms of alpha-Gal A [Label]. 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]. Such migalastat binding stabilizes these mutant forms of alpha-Gal A in the endoplasmic reticulum and facilitates their proper trafficking to lysosomes [Label]. 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].

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].

TargetActionsOrganism
UAlpha-galactosidase ANot AvailableHuman
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]. Following a single oral dose of 150 mg migalastat hydrochloride solution, the time to peak plasma concentration was approximately 3 hours [Label]. Plasma migalastat exposure (AUC0-∞) and Cmax demonstrated dose-proportional increases at migalastat hydrochloride oral doses from 50 mg to 1,250 mg [Label].

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].

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].

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].

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]. 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]. 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]. Approximately 9% of the total radioactivity was unassigned [Label].

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].

Half life

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

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].

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].

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

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcetaminophenAcetaminophen may decrease the excretion rate of Migalastat which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Migalastat which could result in a higher serum level.
AlprazolamAlprazolam may decrease the excretion rate of Migalastat which could result in a higher serum level.
AmilorideAmiloride may increase the excretion rate of Migalastat which could result in a lower serum level and potentially a reduction in efficacy.
AmitriptylineMigalastat may decrease the excretion rate of Amitriptyline which could result in a higher serum level.
AmlodipineAmlodipine may decrease the excretion rate of Migalastat which could result in a higher serum level.
AmoxicillinAmoxicillin may decrease the excretion rate of Migalastat which could result in a higher serum level.
AmphetamineAmphetamine may decrease the excretion rate of Migalastat which could result in a higher serum level.
AmpicillinAmpicillin may decrease the excretion rate of Migalastat which could result in a higher serum level.
AuranofinAuranofin may decrease the excretion rate of Migalastat which could result in a higher serum level.
Food Interactions
Not Available

References

Synthesis Reference

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

General References
  1. 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. [PubMed:26252393]
  2. Migalastat for the treatment of Fabry Disease: Sunder-Plassmann G., Schiffmann R., and Nicholls K. [Link]
  3. Amicus Therapeutics News Release: FDA Approves Galafold™ (migalastat) for the Treatment of Certain Adult Patients with Fabry Disease [Link]
  4. Drugs.com: FDA Approves Galafold (migalastat) for the Treatment of Fabry Disease [Link]
  5. Patent US20180208955A1: Process for the microbial synthesis of migalastat [File]
  6. Migalastat EMA Label [File]
External Links
PubChem Compound
176077
PubChem Substance
347827704
ChemSpider
153388
BindingDB
50163440
ChEBI
135923
ChEMBL
CHEMBL110458
HET
DGJ
Wikipedia
Migalastat
AHFS Codes
  • 92:92.00 — Other Miscellaneous Therapeutic Agents
PDB Entries
3s5y / 3thd / 3tv8 / 4cu8 / 4d1j / 4do5 / 4fns / 4ufm
FDA label
Download (1.3 MB)
MSDS
Download (72.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentFabry's Disease3
2CompletedTreatmentFabry's Disease5
3Active Not RecruitingTreatmentFabry's Disease1
3CompletedTreatmentFabry's Disease3
3Not Yet RecruitingTreatmentFabry's Disease1
Not AvailableAvailableNot AvailableFabry's Disease1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral123 mg
CapsuleOral123 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)244-246MSDS
Predicted Properties
PropertyValueSource
Water Solubility511.0 mg/mLALOGPS
logP-2.2ALOGPS
logP-2.9ChemAxon
logS0.5ALOGPS
pKa (Strongest Acidic)12.91ChemAxon
pKa (Strongest Basic)8.06ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area92.95 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity36.57 m3·mol-1ChemAxon
Polarizability15.86 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as piperidines. These are compounds containing a piperidine ring, which is a saturated aliphatic six-member ring with one nitrogen atom and five carbon atoms.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Piperidines
Sub Class
Not Available
Direct Parent
Piperidines
Alternative Parents
Secondary alcohols / 1,2-aminoalcohols / Polyols / Dialkylamines / Azacyclic compounds / Primary alcohols / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Piperidine / 1,2-aminoalcohol / Secondary alcohol / Secondary aliphatic amine / Polyol / Secondary amine / Azacycle / Primary alcohol / Alcohol / Organic oxygen compound
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
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

Kind
Protein
Organism
Human
Pharmacological action
Yes
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 on October 21, 2007 16:23 / Updated on September 22, 2018 22:34