Miglustat

Miglustat, sold under the brand name Zavesca, is a medication used to treat type I Gaucher disease (GD1). It is also known as N-butyldeoxynojirimycin, and is a derivative of the anti-diabetic 1-deoxynojirimycin. It was developed by Oxford GlycoSciences and is marketed by Actelion.

Miglustat
Clinical data
Trade namesZavesca, Brazaves
Other namesOGT 918, 1,5-(butylimino)-1,5-dideoxy-D-glucitol, N-butyl-deoxynojirimycin
AHFS/Drugs.comMonograph
MedlinePlusa604015
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability97%
Protein bindingNil
MetabolismNil
Elimination half-life6–7 hours
ExcretionKidney, unchanged
Identifiers
IUPAC name
  • (2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.216.074
Chemical and physical data
FormulaC10H21NO4
Molar mass219.281 g·mol−1
3D model (JSmol)
SMILES
  • OC[C@H]1N(CCCC)C[C@H](O)[C@@H](O)[C@@H]1O
InChI
  • InChI=1S/C10H21NO4/c1-2-3-4-11-5-8(13)10(15)9(14)7(11)6-12/h7-10,12-15H,2-6H2,1H3/t7-,8+,9-,10-/m1/s1 Y
  • Key:UQRORFVVSGFNRO-UTINFBMNSA-N Y
  (verify)

Miglustat has been approved in the EU, Japan, and Canada for treating progressive neurological complications in people with Niemann–Pick disease, type C (NPC).

It was approved for medical use in the European Union in November 2002,[4][5] and for medical use in the United States in July 2003.[6][7]

Medical uses

Miglustat is indicated to treat adults with mild to moderate type I Gaucher disease for whom enzyme replacement therapy is unsuitable.[8]

Contraindications

Miglustat is contraindicated for people with neurological conditions, kidney problems, women who are pregnant, and men and women planning to conceive a child.[9]

Adverse effects

Serious side effects include pain, burning, numbness or tingling in the hands, arms, legs, or feet; shaking hands that cannot be controlled; changes in vision; and easy bruising or bleeding. Common side effects include gastrointestinal effects (including diarrhea, stomach pain or bloating, gas, loss of appetite, weight loss, upset stomach, vomiting, constipation), dry mouth, muscular effects (including weakness, muscle cramps, especially in the legs, feeling of heaviness in the arms or legs, unsteadiness when walking), back pain, dizziness, nervousness, headache, memory problems, and difficult or irregular menstruation (period).[9]

Mechanism of action

Type I Gaucher's disease is an autosomal recessive disorder; parents are generally healthy carriers with one functional and one mutated (nonfunctioning) copy of the Gaucher disease gene, GBA. People with type I Gaucher have a defect in the enzyme called glucocerebrosidase (also known as acid β-glucosidase). Glucocerebrosidase is an enzyme, and its function is to convert glucocerebroside (also known as glucosylceramide) into ceramide and glucose. When this enzyme doesn't work, glucocerebroside accumulates, which in turn causes liver and spleen enlargement, changes in the bone marrow and blood, and bone disease. It functions as a competitive and reversible inhibitor of the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions which results in the synthesis of most glycosphingolipids.[10][11]

Earlier treatments on the market (imiglucerase (approved in 1995),[12] velaglucerase (approved in 2010),[13] taliglucerase alfa (Elelyso) (approved in 2012)[14]) are enzyme replacement therapy - they are functioning versions of the enzyme that doesn't work. Miglustat works differently - it prevents the formation of the substance that builds up when the enzyme doesn't work; this is called substrate reduction therapy.[15]

Chemistry

Miglustat is an iminosugar, a synthetic analogue of D-glucose[16] and a white to off-white crystalline solid that has a bitter taste.[17]

Society and culture

Miglustat has been approved in the EU, Canada, and Japan for treating progressive neurological complications in people with Niemann–Pick disease, type C (NPC). Miglustat has not received approval for this indication outside of these countries and use for this disease, including the US, is off-label.[18][19][20][21][22]

Research

In July 2004, Actelion started a clinical trial of miglustat to treat Tay–Sachs disease, particularly late-onset Tay–Sachs with an estimated enrollment of 10 subjects; the trial ended August 2007.[23]

In November 2007, Actelion initiated a clinical trial with miglustat in people with cystic fibrosis (CF) who have the ΔF508 in both copies of the cystic fibrosis transmembrane conductance regulator (CFTR) gene; the study ended in March 2008.[24] The cystic fibrosis trial showed no effect.[25]

See also
  • Migalastat, a drug for the treatment of Fabry disease, with a similar structure
  • Miglitol, an oral antidiabetic drug with a similar structure

References
  1. "Miglustat (Zavesca) Use During Pregnancy". Drugs.com. 4 February 2020. Retrieved 7 August 2020.
  2. "Summary for ARTG Entry:122957 Zavesca miglustat 100 mg capsules blister pack". Therapeutic Goods Administration.
  3. "Zavesca (miglustat) 100 mg hard capsules - Summary of Product Characteristics (SmPC)". (emc). Retrieved 7 August 2020.
  4. "Zavesca EPAR". European Medicines Agency (EMA). Retrieved 7 August 2020.
  5. European Medicines Agency. Human Medicines Database. Zavesca (miglustat) Page Accessed 1 September 2014.
  6. "Drug Approval Package: Zavesca (Miglustat) NDA #021348". U.S. Food and Drug Administration (FDA). 4 April 2002. Retrieved 9 August 2020.
  7. Actelion Press Release August 2003. Zavesca approved -- first oral treatment option for type 1 Gaucher disease
  8. Cox TM, Aerts JM, Andria G, Beck M, Belmatoug N, Bembi B, et al. (2003). "The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: a position statement". Journal of Inherited Metabolic Disease. 26 (6): 513–26. doi:10.1023/a:1025902113005. PMID 14605497. S2CID 6681399.
  9. American Society of Health-System Pharmacists, Inc. for the Public Library of Medicine. Miglustat on MedlinePlus Accessed 1 September 2014
  10. Grabowski, GA (2012). "Gaucher disease and other storage disorders". Hematology Am Soc Hematol Educ Program. 2012: 13–8. doi:10.1182/asheducation.v2012.1.13.3797921. PMID 23233555.
  11. Huddleston, Richard D. (July 1999). "FDA Clinical Investigator Site Inspections: The Sponsor's Role". Drug Information Journal. 33 (3): 965–968. doi:10.1177/009286159903300338. ISSN 0092-8615. S2CID 72975032.
  12. Deegan, PB; Cox, TM (2012). "Imiglucerase in the treatment of Gaucher disease: a history and perspective". Drug Design, Development and Therapy. 6: 81–106. doi:10.2147/DDDT.S14395. PMC 3340106. PMID 22563238.
  13. "Shire Announces FDA Approval Of VPRIV(TM) (velaglucerase Alfa For Injection) For The Treatment Of Type I Gaucher Disease". Medicalnewstoday.com. Retrieved 2012-08-13.
  14. Yukhananov, Anna (1 May 2012). "U.S. FDA approves Pfizer/Protalix drug for Gaucher". Chicago Tribune. Reuters. Retrieved 2 May 2012.
  15. Actelion. FDA Advisory Briefing Book for Miglustat (Ogt 918, Zavesca) in Niemann-Pick Type C Disease NDA 021-348/S-007 Prepared for the Endocrinologic and Metabolic Drugs Advisory Committee meeting, 1 December 2009
  16. Abian O, Alfonso P, Velazquez-Campoy A, Giraldo P, Pocovi M, Sancho J (December 2011). "Therapeutic strategies for Gaucher disease: miglustat (NB-DNJ) as a pharmacological chaperone for glucocerebrosidase and the different thermostability of velaglucerase alfa and imiglucerase". Molecular Pharmaceutics. 8 (6): 2390–7. doi:10.1021/mp200313e. PMID 21988669.
  17. European Medicines Agency 1 April 2003 Scientific discussion related to approval of Zavesca.
  18. UK Medicines Information. New Drugs Online Report for miglustat Archived 2016-03-04 at the Wayback Machine
  19. Staff, The Pharma Letter. 4 April 2012. Actelion drops setipiprant, gets miglustat approval in Japan
  20. Kevin Grogan for PharmaTimes. 10 March 2010. FDA rejects Actelion's Zavesca for rare NP-C disease Archived 2014-09-03 at the Wayback Machine
  21. Actelion Press Release. 23 March 2010 Zavesca (Miglustat) First Treatment Available in Canada for Rare Progressive Niemann-Pick Type C Disease
  22. Solomon BI, Smith AC, Sinaii N, Farhat N, King MC, Machielse L, Porter FD. Association of Miglustat With Swallowing Outcomes in Niemann-Pick Disease, Type C1. JAMA Neurol. 2020 Sep 8;77(12):1–6. doi: 10.1001/jamaneurol.2020.3241. Epub ahead of print. PMID: 32897301; PMCID: PMC7489403.
  23. Clinicaltrials.gov Pharmacokinetics, Safety and Tolerability of Zavesca (Miglustat) in Patients With Infantile Onset Gangliosidosis: Single and Steady State Oral Doses Accessed 1 September 2014
  24. Clinicaltrials.gov Miglustat / OGT 918 in the Treatment of Cystic Fibrosis Accessed 1 September 2014
  25. Leonard, A; et al. (May 2012). "A randomized placebo-controlled trial of miglustat in cystic fibrosis based on nasal potential difference". Journal of Cystic Fibrosis. 11 (3): 231–6. doi:10.1016/j.jcf.2011.12.004. PMID 22281182.
  • "Miglustat". Drug Information Portal. U.S. National Library of Medicine.
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