- Accession Number
- Small Molecule
- Approved, Investigational
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 .
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 .
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.
- Product Ingredients
Ingredient UNII CAS InChI Key Migalastat hydrochloride CLY7M0XD20 75172-81-5 ZJIHMALTJRDNQI-OLALXQGDSA-N
- Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Galafold Capsule 123 mg/1 Oral Amicus Therapeutics U.S., Inc. 2018-08-10 Not applicable Galafold Capsule 123 mg Oral Amicus Therapeutics 2018-01-15 Not applicable
- International/Other Brands
- CAS number
- Average: 163.1717
- Chemical Formula
- InChI Key
- IUPAC Name
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
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].
Target Actions Organism UAlpha-galactosidase A Not Available Humans
With absorption occurring largely in the gut , 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].
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].
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].
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
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
- Drug Interactions
Drug Interaction Abacavir Abacavir may decrease the excretion rate of Migalastat which could result in a higher serum level. Acarbose Acarbose 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.
- Food Interactions
- Not Available
- 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. [PubMed:26252393]
- 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
- AHFS Codes
- 92:92.00 — Other Miscellaneous Therapeutic Agents
- PDB Entries
- 3s5y / 3thd / 3tv8 / 4cu8 / 4d1j / 4do5 / 4fns / 4ufm / 6euh
- FDA label
- Download (1.3 MB)
- Download (72.5 KB)
- Clinical Trials
Phase Status Purpose Conditions Count 1 Completed Treatment Fabry's Disease 3 2 Completed Treatment Fabry's Disease 5 2 Terminated Treatment Fabry's Disease 1 3 Active Not Recruiting Treatment Fabry's Disease 1 3 Completed Treatment Fabry's Disease 2 3 Recruiting Treatment Fabry's Disease 1 3 Terminated Treatment Fabry's Disease 1 Not Available Available Not Available Fabry's Disease 1
- Not Available
- Not Available
- Dosage forms
Form Route Strength Capsule Oral 123 mg/1 Capsule Oral 123 mg
- Not Available
Patent Number Pediatric Extension Approved Expires (estimated) US9987263 No 2007-05-16 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 2008-04-28 2028-04-28
- 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
- Mass Spec (NIST)
- Not Available
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
- 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.
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Sub Class
- Not Available
- Direct Parent
- Alternative Parents
- Secondary alcohols / 1,2-aminoalcohols / Polyols / Dialkylamines / Azacyclic compounds / Primary alcohols / Organopnictogen compounds / Hydrocarbon derivatives
- 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
- Pharmacological action
- 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
- Uniprot ID
- Uniprot Name
- UDP-glucuronosyltransferase 1-1
- Molecular Weight
- 59590.91 Da
Drug created on October 21, 2007 16:23 / Updated on January 18, 2019 21:51