Miglustat

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Miglustat
Miglustat.svg
Clinical data
Trade names Zavesca, Brazaves, Opfolda
Other namesOGT 918, 1,5-(butylimino)-1,5-dideoxy-D-glucitol, N-butyl-deoxynojirimycin
AHFS/Drugs.com Monograph
MedlinePlus a604015
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 97%
Protein binding Nil
Metabolism Nil
Elimination half-life 6–7 hours
Excretion Kidney, unchanged
Identifiers
  • (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 InfoCard 100.216.074 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C10H21NO4
Molar mass 219.281 g·mol−1
3D model (JSmol)
  • OC[C@H]1N(CCCC)C[C@H](O)[C@@H](O)[C@@H]1O
  • 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 Yes check.svgY
  • Key:UQRORFVVSGFNRO-UTINFBMNSA-N Yes check.svgY
   (verify)

Miglustat, sold under the brand name Zavesca among others, is a medication used to treat type I Gaucher disease [7] and Pompe disease. [10]

Contents

It was approved for medical use in the European Union in November 2002, [7] [11] and for medical use in the United States in July 2003. [12] [13]

Medical uses

Miglustat is indicated to treat adults with mild to moderate type I Gaucher disease for whom enzyme replacement therapy is unsuitable. [14]

In the European Union, miglustat (Opfolda), in combination with cipaglucosidase alfa, is a long-term enzyme replacement therapy in adults with late-onset Pompe disease (acid α‑glucosidase [GAA] deficiency). [10]

Contraindications

Miglustat is contraindicated for people with neurological conditions, kidney problems, women who are pregnant, and men and women planning to conceive a child. [15]

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). [15]

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. Miglustat 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. [16] [17]

Earlier treatments on the market (imiglucerase (approved in 1995), [18] velaglucerase (approved in 2010), [19] taliglucerase alfa (Elelyso) (approved in 2012) [20] ) are enzyme replacement therapy—they are functioning versions of the enzyme that doesn't work. Miglustat, on the other hand, prevents the formation of the substance that builds up when the enzyme doesn't work; this is called substrate reduction therapy. [21]

Chemistry

Miglustat is an iminosugar, a synthetic analogue of D-glucose [22] and a white to off-white crystalline solid that has a bitter taste. [23]

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). [24] [25] [26] [27] [28]

On 26 April 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Opfolda, intended for the treatment of glycogen storage disease type II (Pompe disease) in combination with cipaglucosidase alfa. [10] The applicant for this medicinal product is Amicus Therapeutics Europe Limited. [10] Opfolda is a hybrid medicine of Zavesca which has been authorized in the EU since 2002. [10] Opfolda contains the same active substance as Zavesca but in a lower strength. [10] It is also authorized for a different indication and can only be used in combination with cipaglucosidase alfa. [10] Miglustat (Opfolda) was approved for medical use in the European Union in June 2023. [8] [29]

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. [30]

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. [31] The cystic fibrosis trial showed no effect. [32]

N-butyldeoxynojirimycin interferes with the secretion of hepatitis B virus [33] and reduces the infectivity of HIV virions, in the latter case by preventing proper folding of the gp160 precursor glycoprotein to cause a conformational defect in mature gp120, which interferes with the process of fusion with host membranes. [34] [35]

Related Research Articles

<span class="mw-page-title-main">Gaucher's disease</span> Medical condition

Gaucher's disease or Gaucher disease (GD) is a genetic disorder in which glucocerebroside accumulates in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low blood platelet count and enlargement of the liver and spleen, and is caused by a hereditary deficiency of the enzyme glucocerebrosidase, which acts on glucocerebroside. When the enzyme is defective, glucocerebroside accumulates, particularly in white blood cells and especially in macrophages. Glucocerebroside can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow.

<span class="mw-page-title-main">Niemann–Pick disease</span> Medical condition

Niemann–Pick disease (NP), also known as acid sphingomyelinase deficiency, is a group of rare genetic diseases of varying severity. These are inherited metabolic disorders in which sphingomyelin accumulates in lysosomes in cells of many organs. NP types A, A/B, and B are cause by mutations in the SMPD1 gene, which causes a deficiency of a acid sphingomyelinase (ASM). NP type C is now considered a separate disease, as SMPD1 is not involved, and there is no deficiency in ASM.

<span class="mw-page-title-main">Glycogen storage disease type II</span> Medical condition

Glycogen storage disease type II, also called Pompe disease, and formerly known as GSD-IIa. It is an autosomal recessive metabolic disorder which damages muscle and nerve cells throughout the body. It is caused by an accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme. GSD-II and Danon disease are the only glycogen storage diseases with a defect in lysosomal metabolism, and Pompe disease was the first glycogen storage disease to be identified, in 1932 by the Dutch pathologist J. C. Pompe.

<span class="mw-page-title-main">Glucocerebrosidase</span> Mammalian protein found in humans

β-Glucocerebrosidase is an enzyme with glucosylceramidase activity that cleaves by hydrolysis the β-glycosidic linkage of the chemical glucocerebroside, an intermediate in glycolipid metabolism that is abundant in cell membranes. It is localized in the lysosome, where it remains associated with the lysosomal membrane. β-Glucocerebrosidase is 497 amino acids in length and has a molecular mass of 59,700 Da.

Alglucerase was a biopharmaceutical drug for the treatment of Gaucher's disease. It was a modified form of human β-glucocerebrosidase enzyme, where the non-reducing ends of the oligosaccharide chains have been terminated with mannose residues.

Alglucosidase alfa, sold under the brand name Myozyme among others, is an enzyme replacement therapy (ERT) orphan drug for treatment of Pompe disease, a rare lysosomal storage disorder (LSD). Chemically, the drug is an analog of the enzyme that is deficient in patients affected by Pompe disease, alpha-glucosidase. It is the first drug available to treat this disease.

<span class="mw-page-title-main">Niemann–Pick disease, type C</span> Medical condition

Niemann–Pick type C (NPC) is a lysosomal storage disease associated with mutations in NPC1 and NPC2 genes. Niemann–Pick type C affects an estimated 1:150,000 people. Approximately 50% of cases present before 10 years of age, but manifestations may first be recognized as late as the sixth decade.

<span class="mw-page-title-main">Afegostat</span> Chemical compound

Afegostat was an experimental drug for the treatment of certain forms of Gaucher's disease that was being developed by Amicus Therapeutics and Shire plc until a failed clinical trial in 2009 led to termination of its development. The substance was used in form of the tartrate.

Velaglucerase alfa, sold under the brand name Vpriv, is a medication used for the treatment of Gaucher disease Type 1. It is a hydrolytic lysosomal glucocerebroside-specific enzyme, which is a recombinant form of glucocerebrosidase. It has an identical amino acid sequence to the naturally occurring enzyme. It is manufactured by Shire plc.

Taliglucerase alfa, sold under the brand name Elelyso among others, is a biopharmaceutical medication developed by Protalix and Pfizer. The drug, a recombinant glucocerebrosidase used to treat Gaucher's disease, is the first plant-made pharmaceutical to win approval by the U.S. Food and Drug Administration (FDA). Each vial has 200 units of taliglucerase alfa.

<span class="mw-page-title-main">Ruxolitinib</span> Medication

Ruxolitinib, sold under the brand name Jakafi among others, is a medication used for the treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative neoplasm that affects the bone marrow; polycythemia vera, when there has been an inadequate response to or intolerance of hydroxyurea; and steroid-refractory acute graft-versus-host disease. Ruxolitinib is a Janus kinase inhibitor. It was developed and marketed by Incyte Corp in the US under the brand name Jakafi, and by Novartis elsewhere in the world, under the brand name Jakavi.

<span class="mw-page-title-main">Actelion</span> Swiss biopharmaceutical company

Actelion is a pharmaceuticals and biotechnology company established in December 1997, headquartered in Allschwil near Basel, Switzerland.

<span class="mw-page-title-main">Nintedanib</span> Chemical compound

Nintedanib, sold under the brand names Ofev and Vargatef, is an oral medication used for the treatment of idiopathic pulmonary fibrosis and along with other medications for some types of non-small-cell lung cancer.

<span class="mw-page-title-main">Protalix BioTherapeutics</span> Israeli pharmaceutical company

Protalix BioTherapeutics is an Israeli pharmaceutical company that manufactures a plant-based enzyme, taliglucerase alfa, which has received U.S. Food and Drug Administration approval for the treatment of Gaucher disease.

<span class="mw-page-title-main">Eliglustat</span> Chemical compound

Eliglustat, sold under the brand name Cerdelga, is a medication used for the treatment of Gaucher's disease. It was discovered at the University of Michigan, developed by Genzyme Corp, and was approved by the FDA in August 2014. Commonly used as the tartrate salt, the compound is believed to work by inhibition of glucosylceramide synthase. According to an article in Journal of the American Medical Association the oral substrate reduction therapy resulted in "significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count" in untreated adults with Gaucher disease Type 1.

Vestronidase alfa, sold under brand name Mepsevii, is a drug for the treatment of Sly syndrome. It is a recombinant form of the human enzyme beta-glucuronidase. It was approved in the United States in November 2017, to treat children and adults with an inherited metabolic condition called mucopolysaccharidosis type VII, also known as Sly syndrome. MPS VII is an extremely rare, progressive condition that affects most tissues and organs.

Elexacaftor/tezacaftor/ivacaftor, sold under the brand names Trikafta (US) and Kaftrio (EU), is a fixed-dose combination medication used to treat cystic fibrosis. Elexacaftor/tezacaftor/ivacaftor is composed of a combination of ivacaftor, a chloride channel opener, and elexacaftor and tezacaftor, CFTR modulators.

Avalglucosidase alfa, sold under the brand name Nexviazyme, is an enzyme replacement therapy medication used for the treatment of glycogen storage disease type II.

Olipudase alfa, sold under the brand name Xenpozyme, is a medication used for the treatment of non-central nervous system (CNS) manifestations of acid sphingomyelinase deficiency (ASMD) type A/B or type B.

Cipaglucosidase alfa, sold under the brand name Pombiliti, and used in combination with miglustat, is a medication used for the treatment of glycogen storage disease type II. Cipaglucosidase alfa is a recombinant human acid α-glucosidase enzyme replacement therapy that provides an exogenous source of acid α-glucosidase.

References

  1. ↑ "Miglustat (Zavesca) Use During Pregnancy". Drugs.com. 4 February 2020. Archived from the original on 28 November 2020. Retrieved 7 August 2020.
  2. ↑ "Summary for ARTG Entry:122957 Zavesca miglustat 100 mg capsules blister pack". Therapeutic Goods Administration.[ permanent dead link ]
  3. ↑ "Zavesca (miglustat) 100 mg hard capsules - Summary of Product Characteristics (SmPC)". (emc). Archived from the original on 25 February 2021. Retrieved 7 August 2020.
  4. ↑ "Zavesca- miglustat capsule". DailyMed. 20 April 2023. Retrieved 2 October 2023.
  5. ↑ "Yargesa- miglustat capsule". DailyMed. 12 July 2023. Retrieved 2 October 2023.
  6. ↑ https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215211s000lbl.pdf
  7. 1 2 3 "Zavesca EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 5 August 2020. Retrieved 7 August 2020.
  8. 1 2 "Opfolda EPAR". European Medicines Agency (EMA). 7 July 2023. Retrieved 7 July 2023.
  9. ↑ "Yargesa EPAR". European Medicines Agency. 11 April 2023. Retrieved 2 October 2023.
  10. 1 2 3 4 5 6 7 "Opfolda: Pending EC decision". European Medicines Agency. 26 April 2023. Archived from the original on 27 April 2023. Retrieved 27 April 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  11. ↑ European Medicines Agency. Human Medicines Database. Zavesca (miglustat) Archived 7 January 2016 at the Wayback Machine Page Accessed 1 September 2014.
  12. ↑ "Drug Approval Package: Zavesca (Miglustat) NDA #021348". U.S. Food and Drug Administration (FDA). 4 April 2002. Archived from the original on 27 February 2021. Retrieved 9 August 2020.
  13. ↑ Actelion Press Release August 2003. Zavesca approved -- first oral treatment option for type 1 Gaucher disease Archived 3 March 2016 at the Wayback Machine
  14. ↑ 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): 513–526. doi:10.1023/a:1025902113005. PMID   14605497. S2CID   6681399.{{cite journal}}: CS1 maint: overridden setting (link)
  15. 1 2 American Society of Health-System Pharmacists, Inc. for the Public Library of Medicine. Miglustat on MedlinePlus Archived 5 July 2016 at the Wayback Machine Accessed 1 September 2014
  16. ↑ Grabowski GA (2012). "Gaucher disease and other storage disorders". Hematology. American Society of Hematology. Education Program. 2012: 13–18. doi: 10.1182/asheducation.v2012.1.13.3797921 . PMID   23233555.
  17. ↑ Huddleston RD (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.
  18. ↑ 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.
  19. ↑ "Shire Announces FDA Approval Of VPRIV(TM) (velaglucerase Alfa For Injection) For The Treatment Of Type I Gaucher Disease". Medicalnewstoday.com. Archived from the original on 13 June 2011. Retrieved 13 August 2012.
  20. ↑ Yukhananov A (1 May 2012). "U.S. FDA approves Pfizer/Protalix drug for Gaucher". Chicago Tribune . Reuters . Retrieved 2 May 2012.[ permanent dead link ]
  21. ↑ Actelion. FDA Advisory Briefing Book for Miglustat (Ogt 918, Zavesca) in Niemann-Pick Type C Disease NDA 021-348/S-007 Archived 9 May 2017 at the Wayback Machine Prepared for the Endocrinologic and Metabolic Drugs Advisory Committee meeting, 1 December 2009
  22. ↑ 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): 2390–2397. doi:10.1021/mp200313e. PMID   21988669.
  23. ↑ European Medicines Agency 1 April 2003 Scientific discussion related to approval of Zavesca Archived 24 September 2015 at the Wayback Machine .
  24. ↑ UK Medicines Information. New Drugs Online Report for miglustat Archived 4 March 2016 at the Wayback Machine
  25. ↑ Staff, The Pharma Letter. 4 April 2012. Actelion drops setipiprant, gets miglustat approval in Japan Archived 31 October 2018 at the Wayback Machine
  26. ↑ Kevin Grogan for PharmaTimes. 10 March 2010. FDA rejects Actelion's Zavesca for rare NP-C disease Archived 3 September 2014 at the Wayback Machine
  27. ↑ Actelion Press Release. 23 March 2010 Zavesca (Miglustat) First Treatment Available in Canada for Rare Progressive Niemann-Pick Type C Disease Archived 17 May 2017 at the Wayback Machine
  28. ↑ Solomon BI, Smith AC, Sinaii N, Farhat N, King MC, Machielse L, et al. (December 2020). "Association of Miglustat With Swallowing Outcomes in Niemann-Pick Disease, Type C1". JAMA Neurology. 77 (12): 1564–1568. doi:10.1001/jamaneurol.2020.3241. PMC   7489403 . PMID   32897301.
  29. ↑ "Opfolda Product information". Union Register of medicinal products. 27 June 2023. Archived from the original on 28 June 2023. Retrieved 3 July 2023.
  30. ↑ Clinical trial number NCT00672022 for "Pharmacokinetics, Safety and Tolerability of Zavesca (Miglustat) in Patients With Infantile Onset Gangliosidosis: Single and Steady State Oral Doses" at ClinicalTrials.gov
  31. ↑ Clinical trial number NCT00537602 for "OGT 918 in the Treatment of Cystic Fibrosis" at ClinicalTrials.gov
  32. ↑ Leonard A, Lebecque P, Dingemanse J, Leal T (May 2012). "A randomized placebo-controlled trial of miglustat in cystic fibrosis based on nasal potential difference". Journal of Cystic Fibrosis. 11 (3): 231–236. doi: 10.1016/j.jcf.2011.12.004 . PMID   22281182.
  33. ↑ Block TM, Lu X, Platt FM, Foster GR, Gerlich WH, Blumberg BS, et al. (March 1994). "Secretion of human hepatitis B virus is inhibited by the imino sugar N-butyldeoxynojirimycin". Proceedings of the National Academy of Sciences of the United States of America. 91 (6): 2235–2239. Bibcode:1994PNAS...91.2235B. doi: 10.1073/pnas.91.6.2235 . PMC   43345 . PMID   8134380.
  34. ↑ Fischer PB, Karlsson GB, Butters TD, Dwek RA, Platt FM (October 1996). "N-butyldeoxynojirimycin-mediated inhibition of human immunodeficiency virus entry correlates with changes in antibody recognition of the V1/V2 region of gp120". Journal of Virology. 70 (10): 7143–7152. doi: 10.1128/JVI.70.10.7143-7152.1996 . PMC   190767 . PMID   8794361.
  35. ↑ Pollock S, Dwek RA, Burton DR, Zitzmann N (October 2008). "N-Butyldeoxynojirimycin is a broadly effective anti-HIV therapy significantly enhanced by targeted liposome delivery". AIDS. 22 (15): 1961–1969. doi: 10.1097/QAD.0b013e32830efd96 . PMID   18753929.
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