Migalastat

Migalastat
Clinical data
Trade names Galafold
Pregnancy
category
  • Insufficient data
Routes of
administration
By mouth (capsules)
ATC code None
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 75%
Protein binding None
Metabolites O-glucuronides (<15%)
Biological half-life 3–5 hours (single dose)
Excretion Urine (77%), feces (20%)
Identifiers
Synonyms DDIG, AT1001
CAS Number 108147-54-2
75172-81-5 (HCl)
PubChem (CID) 176077
DrugBank DB05018
ChemSpider 153388
UNII C4XNY919FW
KEGG D10359
ChEMBL CHEMBL110458
Chemical and physical data
Formula C6H13NO4
Molar mass 163.17 g·mol−1
3D model (Jmol) Interactive image

Migalastat (INN/USAN), or 1-deoxygalactonojirimycin, trade name Galafold (formerly known as Amigal) is a drug for the treatment of Fabry disease,[1] a rare genetic disorder. It was developed by Amicus Therapeutics. The US Food and Drug Administration (FDA) assigned it orphan drug status in 2004,[2] and the European Committee for Medicinal Products for Human Use (CHMP) followed in 2006. The European Commission approved the drug in May 2016.[3]

Medical uses

Migalastat is used for the long-term treatment of Fabry disease in adults and adolescents aged 16 or older with an amenable mutation of the enzyme alpha-galactosidase A (α-GalA). An "amenable" mutation is one that leads to misfolding of the enzyme, but otherwise would not significantly impair its function.[4][5]

Based on an in vitro test, Amicus Therapeutics has published a list of 269 amenable and nearly 600 non-amenable mutations. About 35 to 50% of Fabry patients have an amenable mutation.[4][5][6]

Adverse effects

No serious adverse effects have been found in small studies over the course of four years.[7] The most common side effect in clinical trials was headache (in about 10% of patients). Less common side effects (between 1 and 10% of patients) included unspecific symptoms such as dizziness, fatigue, and nausea, but also depression. Possible rare side effects could not be assessed because of the low number of patients in studies.[4][5]

Interactions

When combined with intravenous agalsidase alfa or beta, which are recombinant versions of the enzyme α-GalA, migalastat increases tissue concentrations of functional α-GalA compared to agalsidase given alone. This is an expected and desired effect.[1]

Migalastat does not inhibit or induce cytochrome P450 liver enzymes or transporter proteins and is therefore expected to have a low potential for interactions with other drugs.[4]

Pharmacology

Mechanism of action

Fabry disease is a genetic disorder caused by various mutations of the enzyme α-GalA, which is responsible for breaking down the ganglioside globotriaosylceramide (Gb3), among other glycolipids and glycoproteins. Some of these mutations result in misfolding of α-GalA, which subsequently fails protein quality control in the endoplasmic reticulum and is decomposed. Lack of functional α-GalA leads to accumulation of Gb3 in blood vessels and other tissues, with a wide range of symptoms including kidney, heart, and skin problems. Available treatments are substitution therapies with recombinant α-GalA (agalsidase), which has to be applied intravenously.[5][7]

Migalastat is a potent, orally available inhibitor of α-GalA (IC50: 4 μM).[8] When binding to faulty α-GalA, it shifts the folding behaviour towards the proper conformation, resulting in a functional enzyme provided the mutation is amenable.[5][7] Molecules with this type of mechanism are called pharmacological chaperones.[7]

When the enzyme reaches its destination, the lysosome, migalastat dissociates because of the low pH and the relative abundance of Gb3 and other substrates, leaving α-GalA free to fulfill its function.[9] Depending on the mutation, the EC50 is between 0.8 µM and over 1 mM in cellular models.[10]

Pharmacokinetics

Migalastat is almost completely absorbed from the gut, but taking the drug together with food decreases absorption by about 40%. Total bioavailability is about 75% when taken without food. The substance is not bound to blood plasma proteins.[4]

Only a small fraction of a migalastat dose is metabolized, mainly to three dehydrogenated O-glucuronides (4% of the dose) and a number of unspecified metabolites (10%). The drug is mainly eliminated via the urine (77%) and to a smaller extent via the faeces (20%). Practically all of the metabolites are excreted in the urine. Elimination half-life is three to five hours after a single dose.[4]

Chemistry

D-Galactose, for comparison

Migalastat is used in form of the hydrochloride, which is a white crystalline solid and is soluble in water (≥1 mg/mL).[11] The molecule has four asymmetric carbon atoms with the same stereochemistry as the sugar D-galactose,[1] but is missing the first hydroxyl group. It has a nitrogen atom in the ring instead of an oxygen, which makes it an iminosugar.[12]

The structure is formally derived from nojirimycin.

History

Migalastat was isolated as a fermentation product of the bacterium Streptomyces lydicus (strain PA-5726) in 1988 and called 1-deoxygalactonojirimycin.[12][13] In 2004, it was designated orphan drug status by the US FDA for the treatment of Fabry disease,[2] and in 2006 the European CHMP did likewise.[14] The sponsorship for the drug was transferred several times over the following years: from Amicus Therapeutics to Shire Pharmaceuticals in 2008, back to Amicus in 2010, to Glaxo in 2011, and again to Amicus in 2014.[15]

Two phase III clinical trials with a total of about 110 patients were conducted between 2009 and 2015, one double-blind comparing the drug to placebo, and one comparing it to recombinant α-GalA without blinding. Migalastat stabilised heart and kidney function over the 30-months period of these trials.[5][16][17]

In September 2015, the developer announced that they would submit a new drug application for migalastat to the FDA by the end of 2015.[18] The CHMP recommended approval in April 2016, following the results of the two phase III trials,[14] and the drug was approved in the European Union in May 2016.[3] Germany is the first country where migalastat was launched.[3]

See also

References

  1. 1 2 3 4 Warnock, D. G.; Bichet, D. G.; Holida, M; Goker-Alpan, O; Nicholls, K; Thomas, M; Eyskens, F; Shankar, S; Adera, M; Sitaraman, S; Khanna, R; Flanagan, J. J.; Wustman, B. A.; Barth, J; Barlow, C; Valenzano, K. J.; Lockhart, D. J.; Boudes, P; Johnson, F. K. (2015). "Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase a in Fabry Patients when Co-Administered with Infused Agalsidase". PLoS ONE. 10 (8): e0134341. Bibcode:2015PLoSO..1034341W. doi:10.1371/journal.pone.0134341. PMC 4529213Freely accessible. PMID 26252393.
  2. 1 2 "List of Orphan Products Designations". US FDA. 28 April 2009.
  3. 1 2 3 "Amicus Therapeutics Announces European Commission Approval for Galafold (Migalastat) in Patients with Fabry Disease in European Union". GlobeNewswire. 31 May 2016.
  4. 1 2 3 4 5 6 "Summary of Product Characteristics for Galafold" (PDF). European Medicines Agency. June 2016.
  5. 1 2 3 4 5 6 H. Spreitzer (23 April 2016). "Neue Wirkstoffe – Migalastat". Österreichische Apothekerzeitung (in German) (9/2016): 12.
  6. "Galafold Amenability Table". Amicus Therapeutics. Retrieved 7 June 2016.
  7. 1 2 3 4 Germain, Dominique P; Giugliani, Roberto; Hughes, Derralynn A; Mehta, Atul; Nicholls, Kathy; Barisoni, Laura; Jennette, Charles J; Bragat, Alexander; Castelli, Jeff; Sitaraman, Sheela; Lockhart, David J; Boudes, Pol F (2012). "Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies". Orphanet Journal of Rare Diseases. 7: 91. doi:10.1186/1750-1172-7-91. PMC 3527132Freely accessible. PMID 23176611.
  8. Sánchez-Fernández, Elena M.; García Fernández, José M.; Mellet, Carmen Ortiz (2016). "Glycomimetic-based pharmacological chaperones for lysosomal storage disorders: lessons from Gaucher, GM1-gangliosidosis and Fabry diseases". Chem. Commun. 52 (32): 5497. doi:10.1039/C6CC01564F.
  9. Yam, G. H.; Bosshard, N; Zuber, C; Steinmann, B; Roth, J (2006). "Pharmacological chaperone corrects lysosomal storage in Fabry disease caused by trafficking-incompetent variants". AJP: Cell Physiology. 290 (4): C1076–82. doi:10.1152/ajpcell.00426.2005. PMID 16531566.
  10. Benjamin, E. R.; Flanagan, J. J.; Schilling, A; Chang, H. H.; Agarwal, L; Katz, E; Wu, X; Pine, C; Wustman, B; Desnick, R. J.; Lockhart, D. J.; Valenzano, K. J. (2009). "The pharmacological chaperone 1-deoxygalactonojirimycin increases alpha-galactosidase A levels in Fabry patient cell lines". Journal of Inherited Metabolic Disease. 32 (3): 424–40. doi:10.1007/s10545-009-1077-0. PMID 19387866.
  11. Sigma-Aldrich Co., product no. D9641.
  12. 1 2 Asano, N (2007). "Naturally occuring iminosugars and related alkaloids: structure, activity and applications". In Compain, P; Martin, OR. Iminosugars: from synthesis to therapeutic applications. Wiley and Sons. p. 17. ISBN 0-470-03391-6.
  13. Miyake, Y; Ebata, M (1988). "The structures of a β-galactosidase inhibitor, Galactostatin, and its derivatives". Agric Biol Chem. 52: 661–666. doi:10.1271/bbb1961.52.661.
  14. 1 2 "Galafold". European Medicines Agency. 1 April 2016.
  15. "Public summary of opinion on orphan designation". European Medicines Agency. 29 April 2014.
  16. Clinical trial number NCT00925301 for "Study of the Effects of Oral AT1001 (Migalastat Hydrochloride) in Patients With Fabry Disease" at ClinicalTrials.gov
  17. Clinical trial number NCT01218659 for "Study to Compare the Efficacy and Safety of Oral AT1001 and Enzyme Replacement Therapy in Patients With Fabry Disease" at ClinicalTrials.gov
  18. "Amicus Therapeutics Plans to Submit NDA for Migalastat for Fabry Disease Following Positive Pre-NDA Meeting With FDA". Drugs.com. 15 September 2015.
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