Miglustat

Miglustat is indicated to treat adults with mild to moderate type I Gaucher disease for whom enzyme replacement therapy is unsuitable.{{cite journal | vauthors = Cox TM, Aerts JM, Andria G, Beck M, Belmatoug N, Bembi B, Chertkoff R, Vom Dahl S, Elstein D, Erikson A, Giralt M, Heitner R, Hollak C, Hrebicek M, Lewis S, Mehta A, Pastores GM, Rolfs A, Miranda MC, Zimran A | title = The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: a position statement | journal = Journal of Inherited Metabolic Disease | volume = 26 | issue = 6 | pages = 513–526 | year = 2003 | pmid = 14605497 | doi = 10.1023/a:1025902113005 | s2cid = 6681399 }}

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).

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

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).American Society of Health-System Pharmacists, Inc. for the Public Library of Medicine. [https://www.nlm.nih.gov/medlineplus/druginfo/meds/a604015.html Miglustat on MedlinePlus] {{Webarchive|url=https://web.archive.org/web/20160705113110/https://www.nlm.nih.gov/medlineplus/druginfo/meds/a604015.html |date=5 July 2016 }} Accessed 1 September 2014

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.{{cite journal | vauthors = Grabowski GA | title = Gaucher disease and other storage disorders | journal = Hematology. American Society of Hematology. Education Program | volume = 2012 | pages = 13–18 | year = 2012 | pmid = 23233555 | doi = 10.1182/asheducation.v2012.1.13.3797921 | doi-access = free }}{{Cite journal| vauthors = Huddleston RD |date=July 1999|title=FDA Clinical Investigator Site Inspections: The Sponsor's Role|journal=Drug Information Journal|volume=33|issue=3|pages=965–968|doi=10.1177/009286159903300338|s2cid=72975032|issn=0092-8615}}

Earlier treatments on the market (imiglucerase (approved in 1995),{{cite journal | vauthors = Deegan PB, Cox TM | title = Imiglucerase in the treatment of Gaucher disease: a history and perspective | journal = Drug Design, Development and Therapy | volume = 6 | pages = 81–106 | year = 2012 | pmid = 22563238 | pmc = 3340106 | doi = 10.2147/DDDT.S14395 | doi-access = free }} velaglucerase (approved in 2010),{{cite web |url=http://www.medicalnewstoday.com/articles/180630.php |title=Shire Announces FDA Approval Of VPRIV(TM) (velaglucerase Alfa For Injection) For The Treatment Of Type I Gaucher Disease |publisher=Medicalnewstoday.com |access-date=13 August 2012 |archive-date=13 June 2011 |archive-url=https://web.archive.org/web/20110613222314/http://www.medicalnewstoday.com/releases/180630.php |url-status=dead }} taliglucerase alfa (Elelyso) (approved in 2012){{cite news| vauthors = Yukhananov A |title=U.S. FDA approves Pfizer/Protalix drug for Gaucher|url=http://www.chicagotribune.com/health/sns-rt-us-fda-gaucherbre8401jz-20120501,0,5155428.story|access-date=2 May 2012|newspaper=Chicago Tribune|date=1 May 2012|agency=Reuters}}{{dead link|date=January 2018 |bot=InternetArchiveBot |fix-attempted=yes }}) 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.Actelion. [https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM196758.pdf FDA Advisory Briefing Book for Miglustat (Ogt 918, Zavesca) in Niemann-Pick Type C Disease NDA 021-348/S-007] {{Webarchive|url=https://web.archive.org/web/20170509201725/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM196758.pdf |date=9 May 2017 }} Prepared for the Endocrinologic and Metabolic Drugs Advisory Committee meeting, 1 December 2009

Miglustat is an iminosugar, a synthetic analogue of D-glucose{{cite journal | vauthors = Abian O, Alfonso P, Velazquez-Campoy A, Giraldo P, Pocovi M, Sancho J | title = Therapeutic strategies for Gaucher disease: miglustat (NB-DNJ) as a pharmacological chaperone for glucocerebrosidase and the different thermostability of velaglucerase alfa and imiglucerase | journal = Molecular Pharmaceutics | volume = 8 | issue = 6 | pages = 2390–2397 | date = December 2011 | pmid = 21988669 | doi = 10.1021/mp200313e }} and a white to off-white crystalline solid that has a bitter taste.European Medicines Agency 1 April 2003 [http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000435/WC500046721.pdf Scientific discussion related to approval of Zavesca] {{Webarchive|url=https://web.archive.org/web/20150924012010/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000435/WC500046721.pdf |date=24 September 2015 }}.

Miglustat has been approved in the EU, Canada, and Japan for treating progressive neurological complications in people with Niemann–Pick disease, type C (NPC).UK Medicines Information. [http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=4475 New Drugs Online Report for miglustat] {{Webarchive|url=https://web.archive.org/web/20160304032346/http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=4475 |date=4 March 2016 }}Staff, The Pharma Letter. 4 April 2012. [http://www.thepharmaletter.com/article/actelion-drops-setipiprant-gets-miglustat-approval-in-japan Actelion drops setipiprant, gets miglustat approval in Japan] {{Webarchive|url=https://web.archive.org/web/20181031202054/https://www.thepharmaletter.com/article/actelion-drops-setipiprant-gets-miglustat-approval-in-japan |date=31 October 2018 }}Kevin Grogan for PharmaTimes. 10 March 2010. [http://www.pharmatimes.com/article/10-03-10/FDA_rejects_Actelion_s_Zavesca_for_rare_NP-C_disease.aspx FDA rejects Actelion's Zavesca for rare NP-C disease] {{webarchive|url=https://web.archive.org/web/20140903105602/http://www.pharmatimes.com/article/10-03-10/FDA_rejects_Actelion_s_Zavesca_for_rare_NP-C_disease.aspx |date=3 September 2014 }}Actelion Press Release. 23 March 2010 [http://www.marketwired.com/press-release/Zavesca-Miglustat-First-Treatment-Available-Canada-Rare-Progressive-Niemann-Pick-Type-SIX-ATLN-1136457.htm Zavesca (Miglustat) First Treatment Available in Canada for Rare Progressive Niemann-Pick Type C Disease] {{Webarchive|url=https://web.archive.org/web/20170517100902/http://www.marketwired.com/press-release/Zavesca-Miglustat-First-Treatment-Available-Canada-Rare-Progressive-Niemann-Pick-Type-SIX-ATLN-1136457.htm |date=17 May 2017 }}{{cite journal | vauthors = Solomon BI, Smith AC, Sinaii N, Farhat N, King MC, Machielse L, Porter FD | title = Association of Miglustat With Swallowing Outcomes in Niemann-Pick Disease, Type C1 | journal = JAMA Neurology | volume = 77 | issue = 12 | pages = 1564–1568 | date = December 2020 | pmid = 32897301 | pmc = 7489403 | doi = 10.1001/jamaneurol.2020.3241 }}

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. The applicant for this medicinal product is Amicus Therapeutics Europe Limited.{{cite web | title=Opfolda: Pending EC decision | website=European Medicines Agency | date=26 April 2023 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/opfolda | access-date=27 April 2023 | archive-date=27 April 2023 | archive-url=https://web.archive.org/web/20230427003254/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/opfolda | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Opfolda is a hybrid medicine of Zavesca which has been authorized in the EU since 2002. Opfolda contains the same active substance as Zavesca but in a lower strength. It is also authorized for a different indication and can only be used in combination with cipaglucosidase alfa. Miglustat (Opfolda) was approved for medical use in the European Union in June 2023.{{cite web | title=Opfolda Product information | website=Union Register of medicinal products | date=27 June 2023 | url=https://ec.europa.eu/health/documents/community-register/html/h1737.htm | access-date=3 July 2023 | archive-date=28 June 2023 | archive-url=https://web.archive.org/web/20230628222233/https://ec.europa.eu/health/documents/community-register/html/h1737.htm | url-status=live }}

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.{{ClinicalTrialsGov|NCT00672022|Pharmacokinetics, Safety and Tolerability of Zavesca (Miglustat) in Patients With Infantile Onset Gangliosidosis: Single and Steady State Oral Doses}}

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.{{ClinicalTrialsGov|NCT00537602|OGT 918 in the Treatment of Cystic Fibrosis}} The cystic fibrosis trial showed no effect.{{cite journal | vauthors = Leonard A, Lebecque P, Dingemanse J, Leal T | title = A randomized placebo-controlled trial of miglustat in cystic fibrosis based on nasal potential difference | journal = Journal of Cystic Fibrosis | volume = 11 | issue = 3 | pages = 231–236 | date = May 2012 | pmid = 22281182 | doi = 10.1016/j.jcf.2011.12.004 | doi-access = free }}

N-butyldeoxynojirimycin interferes with the secretion of hepatitis B virus{{cite journal | vauthors = Block TM, Lu X, Platt FM, Foster GR, Gerlich WH, Blumberg BS, Dwek RA | title = Secretion of human hepatitis B virus is inhibited by the imino sugar N-butyldeoxynojirimycin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 6 | pages = 2235–2239 | date = March 1994 | pmid = 8134380 | pmc = 43345 | doi = 10.1073/pnas.91.6.2235 | bibcode = 1994PNAS...91.2235B | author-link6 = Baruch Samuel Blumberg | author-link7 = Raymond Dwek | doi-access = free | author-link3 = Frances Platt }} 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.{{cite journal | vauthors = Fischer PB, Karlsson GB, Butters TD, Dwek RA, Platt FM | title = N-butyldeoxynojirimycin-mediated inhibition of human immunodeficiency virus entry correlates with changes in antibody recognition of the V1/V2 region of gp120 | journal = Journal of Virology | volume = 70 | issue = 10 | pages = 7143–7152 | date = October 1996 | pmid = 8794361 | pmc = 190767 | doi = 10.1128/JVI.70.10.7143-7152.1996 | doi-access = free }}{{cite journal | vauthors = Pollock S, Dwek RA, Burton DR, Zitzmann N | title = N-Butyldeoxynojirimycin is a broadly effective anti-HIV therapy significantly enhanced by targeted liposome delivery | journal = AIDS | volume = 22 | issue = 15 | pages = 1961–1969 | date = October 2008 | pmid = 18753929 | doi = 10.1097/QAD.0b013e32830efd96 | doi-access = free }}

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Category:Iminosugars

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