Misplaced Pages

Natalizumab: Difference between revisions

Article snapshot taken from Wikipedia with creative commons attribution-sharealike license. Give it a read and then ask your questions in the chat. We can research this topic together.
Browse history interactively
Page 1
Page 2
← Previous editContent deleted Content addedVisualWikitext
Revision as of 12:12, 31 October 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'DrugBank', 'ChEMBL').← Previous edit Latest revision as of 02:35, 27 September 2024 edit undoKaltenmeyer (talk | contribs)Extended confirmed users118,581 editsm clean upTag: AWB 
(194 intermediate revisions by 88 users not shown)
Line 1: Line 1:
{{Short description|Medication used to treat multiple sclerosis and Crohn's disease}}
{{Drugbox
{{more medical citations needed|date=November 2018}}
{{Use dmy dates|date=June 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Verifiedfields = changed | Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 403143828
| verifiedrevid = 458283255
| image =

<!--Monoclonal antibody data-->
| type = mab | type = mab
| image = Natalizumab 4IRZ.png
| width =
| alt =
| caption = Natalizumab ] bound to the headpiece of an α4-integrin. From ] {{PDB2|4IRZ}}.

<!-- Monoclonal antibody data -->
| mab_type = mab | mab_type = mab
| source = zu/o | source = zu/o
| target = alpha-4 ] | target = alpha-4 ]


<!--Clinical data--> <!-- Clinical data -->
| tradename = Tysabri | pronounce =
| tradename = Tysabri, others
| Drugs.com = {{drugs.com|monograph|natalizumab}} | Drugs.com = {{drugs.com|monograph|natalizumab}}
| MedlinePlus = a605006 | MedlinePlus = a605006
| licence_EU = Natalizumab | DailyMedID = Natalizumab
| licence_US = Natalizumab
| pregnancy_AU = C | pregnancy_AU = C
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Natalizumab (Tysabri) Use During Pregnancy | website=Drugs.com | date=24 September 2019 | url=https://www.drugs.com/pregnancy/natalizumab.html | access-date=4 May 2020 | archive-date=23 November 2020 | archive-url=https://web.archive.org/web/20201123230620/https://www.drugs.com/pregnancy/natalizumab.html | url-status=live }}</ref>
| pregnancy_US = C
| pregnancy_category=
| routes_of_administration = ]
| class =
| ATC_prefix = L04
| ATC_suffix = AG03
| ATC_supplemental =
| biosimilars = natalizumab-sztn,<ref name="Tyruko FDA label" /> Tyruko<ref name="Tyruko FDA label">{{cite web |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761322s000lbl.pdf |title=Tyruko (natalizumab-sztn) injection, for intravenous use |access-date=25 August 2023 |archive-date=25 August 2023 |archive-url=https://web.archive.org/web/20230825141810/https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761322s000lbl.pdf |url-status=live }}</ref><ref name="Tyruko EPAR" />

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment = <ref>{{cite web | title=Tysabri natalizumab 150 mg/1 mL injection solution pre-filled syringe (353845) | website=Therapeutic Goods Administration (TGA) | date=12 August 2022 | url=https://www.tga.gov.au/resources/artg/353845 | access-date=25 August 2023 | archive-date=25 August 2023 | archive-url=https://web.archive.org/web/20230825201145/https://www.tga.gov.au/resources/artg/353845 | url-status=live }}</ref><ref>{{cite web | title=Tysabri Product and Consumer Medicine Information Licence | website=TGA eBS | url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2012-PI-01015-3 | access-date=25 August 2023 | archive-date=3 July 2022 | archive-url=https://web.archive.org/web/20220703232029/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2012-PI-01015-3 | url-status=live }}</ref>
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| legal_BR_comment =
| legal_CA = Rx-only
| legal_CA_comment = Schedule D<ref>{{cite web | title=Tysabri Product information | website=] | date=22 October 2009 | url=https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=77184 | access-date=25 August 2023 | archive-date=25 August 2023 | archive-url=https://web.archive.org/web/20230825215958/https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=77184 | url-status=live }}</ref>
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK_comment = <ref>{{cite web | title=Tysabri 300 mg concentrate for solution for infusion - Summary of Product Characteristics (SmPC) | website=(emc) | date=14 November 2019 | url=https://www.medicines.org.uk/emc/product/222/smpc | access-date=4 May 2020 | archive-date=22 October 2020 | archive-url=https://web.archive.org/web/20201022071043/https://www.medicines.org.uk/emc/product/222/smpc | url-status=live }}</ref>
| legal_US = Rx-only
| legal_US_comment = <ref name="Tysabri FDA label" /><ref name="Tyruko FDA label" />
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Tysabri EPAR" /><ref name="Tyruko EPAR" />
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment =
| legal_status = Rx-only | legal_status = Rx-only
| routes_of_administration = ]


<!--Pharmacokinetic data--> <!-- Pharmacokinetic data -->
| bioavailability = n/a | bioavailability = n/a
| protein_bound = | protein_bound =
| metabolism = | metabolism =
| metabolites =
| onset =
| elimination_half-life = 11 ± 4 days | elimination_half-life = 11 ± 4 days
| duration_of_action =
| excretion =


<!--Identifiers--> <!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}} | CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 189261-10-7 | CAS_number = 189261-10-7
| ATC_prefix = L04 | CAS_supplemental =
| ATC_suffix = AA23 | PubChem =
| ATC_supplemental = | IUPHAR_ligand =
| PubChem =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00108 | DrugBank = DB00108
| UNII_Ref = {{fdacite|changed|FDA}} | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = none
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 3JB47N2Q2P | UNII = 3JB47N2Q2P
| KEGG_Ref =
| KEGG = D06886
| ChEBI_Ref =
| ChEBI =
| ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = <!-- blanked - oldvalue: 1201607 --> | ChEMBL = 1201607
| NIAID_ChemDB =
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = NA | PDB_ligand =
| synonyms = AN100226M, Antegren

<!--Chemical data-->
| chemical_formula =


<!-- Chemical and physical data -->
| molecular_weight = 149 ]
| IUPAC_name =
| chemical_formula =
| C= | H= | Ag= | Al= | As= | Au= | B= | Bi= | Br= | Ca= | Cl= | Co= | F= | Fe= | Gd= | I=
| K= | Li= | Mg= | Mn= | N= | Na= | O= | P= | Pt= | S= | Sb= | Se= | Sr= | Tc= | Zn= | charge=
| molecular_weight = 149
| molecular_weight_comment = kg/mol
| SMILES =
| StdInChI =
| StdInChI_comment =
| StdInChIKey =
| density =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}} }}
'''Natalizumab''' is a ] ] against the ] ]. Natalizumab is used in the treatment of ] and ]. It is co-marketed by ] and ] as '''Tysabri''', and was previously named '''Antegren'''. Natalizumab is administered by ] every 28 days. The drug is believed to work by reducing the ability of ] ] to attach to and pass through the cell layers lining the ]s and ]. Natalizumab has proven effective in treating the symptoms of both diseases, preventing relapse, vision loss, cognitive decline and ] improving ] in people with multiple sclerosis, as well as increasing rates of remission and preventing relapse in Crohn's disease.


'''Natalizumab''', sold under the brand name '''Tysabri''' among others, is a medication used to treat ] and ].<ref name="Tysabri FDA label">{{cite web | title=Tysabri- natalizumab injection | website=DailyMed | date=12 August 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c5fdde91-1989-4dd2-9129-4f3323ea2962 | access-date=4 May 2020 | archive-date=27 March 2020 | archive-url=https://web.archive.org/web/20200327105652/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c5fdde91-1989-4dd2-9129-4f3323ea2962 | url-status=live }}</ref> It is a ] ] against the ] ].<ref name="Tysabri FDA label" /> It is given by ].<ref name="Tysabri FDA label" /> The drug is believed to work by reducing the ability of ] ] to attach to and pass through the cell layers lining the ]s and ].{{medical citation needed|date=August 2023}}
Natalizumab was approved in 2004 by the ] (FDA). It was subsequently ] by its manufacturer after it was linked with three cases of the rare neurological condition ] (PML) when administered in combination with ], another ] often used in the treatment of multiple sclerosis. After a review of safety information and no further deaths, the drug was returned to the US market in 2006 under a special prescription program. As of June 2009, ten cases of PML were known. However, twenty-four cases of PML had been reported since its reintroduction by October 2009, showing a sharp rise in the number of fatalities and prompting a review of the chemical for human use by the ].<ref>{{cite web | url = http://www.emea.europa.eu/pdfs/human/press/pr/67119009en.pdf | format = pdf | title = Meeting highlights from the Committee for Medicinal Products for Human Use | accessdate = 2010-08-31 | publisher = ] | date = 2009-10-22 }}</ref><ref>{{cite news | url = http://www.reuters.com/article/companyNewsAndPR/idUSLT39797520091029 | date = 2009-10-29| accessdate = 2010-08-31 | agency = ] | title = EU agency reports 24th case of Tysabri infection | last = Hirschler | first = B | coauthors = Cowell D }}</ref><ref name=June2009>{{cite news |title=Biogen reports 10th case of PML brain infection |agency= ] |author=Clarke T; Orlofsky S; Von Ahn L |date=2009-06-29 | url = http://www.reuters.com/article/idUSTRE55S39X20090629 | accessdate = 2010-08-31 }}</ref> By January 2010, 31 cases of PML were attributed to natalizumab.<ref name = Medscape>{{cite web | url = http://www.medscape.com/viewarticle/716536 | title = PML Risk Increases With Repeated Natalizumab Infusions: FDA | last = Jeffrey | first = S | date = 2010-02-05 | accessdate = 2010-08-31 | publisher = ] }}</ref> The FDA did not withdraw the drug from the market because its clinical benefits outweigh the risks involved.<ref>{{cite web | url = http://www.webmd.com/multiple-sclerosis/news/20080801/ms-drug-tysabri-tied-to-brain-infection | title = MS Drug Tysabri Tied to Brain Infection | publisher = ] | last = Hitti | first = M | accessdate = 2010-08-31 | date = 2008-08-01 }}</ref> In the ], it has been approved for human use only for the treatment of multiple sclerosis and only then as a monotherapy because the initial cases of PML, and later the fatalities, were said by the manufacturers to be linked to the use of previous medicines by the deceased customers.


Natalizumab, is a monoclonal antibody which targets a protein called α4β1 integrin on white blood cells involved in inflammation.<ref name="Tysabri EPAR" /> By attaching to integrin, natalizumab is thought to stop white blood cells from entering the brain and spinal cord tissue, thereby reducing inflammation and the resulting nerve damage.<ref name="Tysabri EPAR" />
Biogen Idec announced the initiation of the first clinical trial of natalizumab as a potential cancer treatment as of September 5, 2008.<ref>{{cite news|url=http://www.boston.com/business/ticker/2008/09/biogen_idec_tes.html | title= Biogen Idec testing Tysabri as a cancer treatment | date=2008-09-05 | accessdate=2008-09-05 | work= ] }}</ref>


The most common side effects are urinary tract infection, nasopharyngitis (inflammation of the nose and throat), headache, dizziness, nausea, joint pain and tiredness.<ref name="Tysabri EPAR" />
==Indications==
Natalizumab is FDA-approved for the treatment of ] and ] and approved for treatment of multiple sclerosis in Europe, but is currently under review by the EMEA.<ref>http://www.fiercepharma.com/story/tysabri-safety-falls-under-emea-scrutiny/2009-10-26</ref><ref name = PREU>{{cite web | url = http://www.emea.europa.eu/pdfs/human/press/pr/15260806en.pdf | title = Press release - European Medicines Agency: Committee for Medicinal Products for Human Use 24–27 April 2006 | date = 2006-04-28 | publisher = ] | format = PDF | accessdate = 2008-04-02 }}</ref>


Natalizumab was approved for medical use in the United States in 2004. It was subsequently ] by its manufacturer after it was linked with three cases of the rare neurological condition ] (PML) when administered in combination with ], another ] often used in the treatment of multiple sclerosis. After a review of safety information and no further deaths, the drug was returned to the US market in 2006 under a special prescription program. As of June 2009, ten cases of PML were known. However, twenty-four cases of PML had been reported since its reintroduction by October 2009, showing a sharp rise in the number of fatalities and prompting a review of the chemical for human use by the ].<ref>{{cite web | url = http://www.emea.europa.eu/pdfs/human/press/pr/67119009en.pdf | title = Meeting highlights from the Committee for Medicinal Products for Human Use | access-date = 31 August 2010 | publisher = ] | date = 22 October 2009 | archive-url = https://web.archive.org/web/20091227131325/http://www.emea.europa.eu/pdfs/human/press/pr/67119009en.pdf | archive-date = 27 December 2009 | url-status = dead }}</ref> By 2010, 31 cases of PML were attributed to natalizumab while by 2018 this had risen to 757 cases.<ref name = Medscape>{{cite web | url = http://www.medscape.com/viewarticle/716536 | title = PML Risk Increases With Repeated Natalizumab Infusions: FDA | vauthors = Jeffrey S | date = 5 February 2010 | access-date = 31 August 2010 | publisher = ] | archive-date = 26 January 2012 | archive-url = https://web.archive.org/web/20120126061534/http://www.medscape.com/viewarticle/716536 | url-status = live }}</ref><ref name = ECTRIMS>{{cite web | url = https://onlinelibrary.ectrims-congress.eu/ectrims/2018/ectrims-2018/228448/gavin.giovannoni.incidence.of.natalizumab-associated.progressive.multifocal.html6 | title = Incidence of natalizumab-associated progressive multifocal leucoencephalopathy and its relationship with the pattern of natalizumab exposure over time | date = 10 October 2018 | access-date = 18 July 2019 | publisher = ] | archive-date = 28 October 2021 | archive-url = https://web.archive.org/web/20211028140946/https://onlinelibrary.ectrims-congress.eu/ectrims/portal_navbar | url-status = dead }}</ref> The US ] (FDA) did not withdraw the drug from the market as benefits outweigh the risks.<ref>{{cite web | url = http://www.webmd.com/multiple-sclerosis/news/20080801/ms-drug-tysabri-tied-to-brain-infection | title = MS Drug Tysabri Tied to Brain Infection | publisher = ] | vauthors = Hitti M | access-date = 31 August 2010 | date = 1 August 2008 | archive-date = 20 November 2018 | archive-url = https://web.archive.org/web/20181120221058/https://www.webmd.com/multiple-sclerosis/news/20080801/ms-drug-tysabri-tied-to-brain-infection | url-status = live }}</ref> In the ], it has been approved only for multiple sclerosis and only by itself as the initial cases of PML, and later the fatalities, were said by the manufacturers to be linked to the use of previous medicines by the person.<ref>{{cite news |vauthors=Staton T |title=Tysabri safety falls under EMEA scrutiny |url=https://www.fiercepharma.com/pharma/tysabri-safety-falls-under-emea-scrutiny |work=Fierce Pharma |date=26 October 2009 |access-date=20 November 2018 |archive-date=23 January 2021 |archive-url=https://web.archive.org/web/20210123025327/https://www.fiercepharma.com/pharma/tysabri-safety-falls-under-emea-scrutiny |url-status=live }}</ref>
===Multiple sclerosis===
{{further|] and ]}}


==Medical uses==
Natalizumab was evaluated in two randomized, double-blind, placebo-controlled trials in people with multiple sclerosis. The studies, supported and analyzed by Biogen Idec and Elan Pharmaceuticals, the makers of the drug,<ref name = Polman /><ref name=Galetta /> enrolled individuals with MS who experienced at least one clinical relapse during the prior year and had a Kurtzke ] score between 0 and 5. In these trials natalizumab was shown to reduce relapses in individuals with MS by 68% vs. ], a margin far greater than had been seen for other approved MS therapies.<ref name = Polman>{{cite journal |author=Polman CH, O'Connor PW, Havrdova E, ''et al.'' |title=A randomized, placebo-controlled trial of natalizumab for relapsing forms of multiple sclerosis |journal=] |volume=354 |issue=9 |pages=899–910 |year=2006 |pmid=16510744 |doi=10.1056/NEJMoa044397 |last12=Lynn |first12=F |last13=Panzara |first13=MA |last14=Sandrock |first14=AW |last15=Affirm |first15=Investigators}}</ref> Natalizumab also slowed the progression of disability in patients with relapsing MS.<ref name = Polman/><ref name = EU>{{cite web | url = http://www.emea.europa.eu/humandocs/PDFs/EPAR/tysabri/H-603-PI-en.pdf | format = PDF | title = TYSABRI: ANNEX I&nbsp;– SUMMARY OF PRODUCT CHARACTERISTICS | publisher = ] | accessdate = 2008-03-09 }}</ref> In combination with ] (IB1A), relapsing and disability progression were reduced more than IB1A alone.<ref name="pmid18354844"/> Other benefits of natalizumab use by patients with relapsing MS shown in manufacturer-funded studies included reduced visual loss,<ref>{{cite journal |author=Balcer LJ, Galetta SL, Calabresi PA, ''et al.'' |title=Natalizumab reduces visual loss in patients with relapsing multiple sclerosis |journal=Neurology |volume=68 |issue=16 |pages=1299–304 |year=2007 |url=http://www.neurology.org/content/68/16/1299.abstract|pmid=17438220 |doi=10.1212/01.wnl.0000259521.14704.a8 |last12=Phillips |first12=JT |last13=Polman |first13=CH |last14=Radue |first14=EW |last15=Rudick |first15=RA |last16=Stuart |first16=WH |last17=Wajgt |first17=A |last18=Weinstock-Guttman |first18=B |last19=Wynn |first19=DR |last20=Lynn |first20=F |last21=Panzara |first21=MA}}</ref> a significant increase in the proportion of disease-free individuals,<ref name=Galetta>{{cite conference | first = S | last = Galetta | coauthors = ''et al.'' | title = Natalizumab Increases the Proportion of Patients Free of Clinical or MRI Disease Activity in Relapsing Multiple Sclerosis | date = 2008-04-18 | booktitle = unpublished/unpresented conference poster | url = http://www.abstracts2view.com/aan2008chicago/view.php?nu=AAN08L_P02.156 | accessdate = 2008-03-11}}; industry publication - {{cite web | url = http://www.elan.com/news/full.asp?ID=1061738 | title = New TYSABRI Data to Be Presented at the European Committee for Treatment and Research in Multiple Sclerosis | publisher = ] | accessdate = 2008-03-09 | date = 2007-10-11 |archiveurl = http://web.archive.org/web/20071029041416/http://www.elan.com/news/full.asp?ID=1061738 <!-- Bot retrieved archive --> |archivedate = 2007-10-29}}</ref> significantly improved assessments of health-related quality of life in relapsing individuals,<ref>{{cite journal |author=Rudick RA, Miller DM |title=Health-related quality of life in multiple sclerosis : current evidence, measurement and effects of disease severity and treatment |journal=CNS drugs |volume=22 |issue=10 |pages=827–39 |year=2008 |pmid=18788835 |doi= 10.2165/00023210-200822100-00004|url=}}</ref><ref>{{cite journal |author=Rudick RA, Miller D, Hass S, ''et al.'' |title=Health-related quality of life in multiple sclerosis: effects of natalizumab |journal=Ann. Neurol. |volume=62 |issue=4 |pages=335–46 |year=2007 |pmid=17696126 |doi=10.1002/ana.21163 |last12=Miller |first12=DH |last13=O'connor |first13=PW |last14=Phillips |first14=JT |last15=Polman |first15=CH |last16=Radue |first16=EW |last17=Stuart |first17=WH |last18=Wajgt |first18=A |last19=Weinstock-Guttman |first19=B |last20=Wynn |first20=DR |last21=Lynn |first21=F |last22=Panzara |first22=MA |last23=Affirm And Sentinel |first23=Investigators}}</ref> reduced cognitive decline of a portion of individuals with MS,<ref>{{cite web | url = http://www.pslgroup.com/dg/265832.htm | title = New Data on Natalizumab Demonstrate Significant Improvement in Cognitive Function in Patients With Multiple Sclerosis | publisher = Doctor's Guide | date = 2006-09-28 | accessdate = 2008-03-09 }}</ref> reduced hospitalizations and ] use,<ref>{{cite web | url = http://www.webwire.com/ViewPressRel.asp?aId=21727 | title = New Pharmacoeconomic Data On TYSABRI Demonstrate Significant Reduction In Steroid Use And Hospitalizations In Patients With Multiple Sclerosis | publisher = webwire | date = 2006-10-06 | accessdate = 2008-03-09 }}</ref> and prevention of the formation of new ]s.<ref name = Polman/><ref>{{cite journal |author=Miller DH, Soon D, Fernando KT, ''et al.'' |title=MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS |journal=Neurology |volume=68 |issue=17 |pages=1390–401 |year=2007 |pmid=17452584 |doi=10.1212/01.wnl.0000260064.77700.fd |last12=Hutchinson |first12=M |last13=Havrdova |first13=E |last14=Lublin |first14=FD |last15=Giovannoni |first15=G |last16=Wajgt |first16=A |last17=Rudick |first17=R |last18=Lynn |first18=F |last19=Panzara |first19=MA |last20=Sandrock |first20=AW |last21=Affirm |first21=Investigators}}</ref> Approximately 6% of individuals receiving natalizumab have been found to develop persistent ] to the drug, which reduces its efficacy<ref name="pmid18354844">{{cite journal |author= |title=Natalizumab: new drug. Multiple sclerosis: risky market approval |journal=Prescrire Int |volume=17 |issue=93 |pages=7–10 |year=2008 |pmid=18354844 |doi= |url=}}</ref><ref name="pmid18360634">{{cite journal |author=Hutchinson M |title=Natalizumab: A new treatment for relapsing remitting multiple sclerosis |journal=Ther Clin Risk Manag |volume=3 |issue=2 |pages=259–268 |year=2007 |pmid=18360634 |doi=10.2147/tcrm.2007.3.2.259| accessdate = 2008-04-22 |pmc=1936307}}</ref><ref>{{cite journal |author=Calabresi PA, Giovannoni G, Confavreux C, ''et al.'' |title=The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL |journal=Neurology |volume=69 |issue=14 |pages=1391–403 |year=2007 |pmid=17761550 |doi=10.1212/01.wnl.0000277457.17420.b5 |last12=Radue |first12=EW |last13=Rudick |first13=RA |last14=Stuart |first14=WH |last15=Lublin |first15=FD |last16=Wajgt |first16=A |last17=Weinstock-Guttman |first17=B |last18=Wynn |first18=DR |last19=Lynn |first19=F |last20=Panzara |first20=MA |last21=Affirm And Sentinel |first21=Investigators}}</ref> and produce reactions during the ] of the drug, as well as hypersensitivity.<ref name="pmid18354844"/> Natalizumab is approved in the United States and the European Union. It is indicated as ] (not combined with other drugs) for the treatment of highly active relapsing remitting MS in spite of prior treatments.<ref name = EU>{{cite web | url = http://www.emea.europa.eu/humandocs/PDFs/EPAR/tysabri/H-603-Annex-en.pdf | format = PDF | title = Annex: Conditions or restrictions with regard to the safe and effective use of the medicinal product to be implemented by the member states | publisher = ] | accessdate = 2008-03-09 }}</ref> Natalizumab offers a limited improvement in efficacy compared to other treatments for MS, but due to the lack of information about long-term use, as well as potentially fatal adverse events, reservations have been expressed over the use of the drug outside of comparative research with existing medications.<ref name="pmid18354844"/>
In the United states, natalizumab is ] for the treatment of multiple sclerosis and Crohn's disease.<ref name="Tyruko FDA label" /><ref name="Tysabri FDA label" /> It is indicated to treat clinically isolated syndrome – a single, first occurrence of multiple sclerosis symptoms; relapsing-remitting disease – a type of multiple sclerosis that occurs when people have episodes of new neurological symptoms followed by periods of stability; and active secondary progressive disease – when, following a relapsing-remitting course, patients experience gradual disability worsening with continued relapses.<ref name="Tyruko FDA label" /><ref name="Tysabri FDA label" /><ref name="FDA PR 20230824" />


Natalizumab offers a limited improvement in efficacy compared to other treatments for multiple sclerosis, but due to the lack of information about long-term use, as well as potentially fatal adverse events, reservations have been expressed over the use of the drug outside of comparative research with existing medications.<ref name="pmid18354844">{{cite journal | vauthors = | title = Natalizumab: new drug. Multiple sclerosis: risky market approval | journal = Prescrire International | volume = 17 | issue = 93 | pages = 7–10 | date = February 2008 | pmid = 18354844 }}</ref><ref name="pmid18360634">{{cite journal | vauthors = Hutchinson M | title = Natalizumab: A new treatment for relapsing remitting multiple sclerosis | journal = Therapeutics and Clinical Risk Management | volume = 3 | issue = 2 | pages = 259–268 | date = June 2007 | pmid = 18360634 | pmc = 1936307 | doi = 10.2147/tcrm.2007.3.2.259 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Pucci E, Giuliani G, Solari A, Simi S, Minozzi S, Di Pietrantonj C, Galea I | title = Natalizumab for relapsing remitting multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | issue = 10 | pages = CD007621 | date = October 2011 | pmid = 21975773 | doi = 10.1002/14651858.CD007621.pub2 }}</ref> Natalizumab is used as a ].<ref name = EU>{{cite web | url = http://www.emea.europa.eu/humandocs/PDFs/EPAR/tysabri/H-603-Annex-en.pdf | title = Annex: Conditions or restrictions with regard to the safe and effective use of the medicinal product to be implemented by the member states | publisher = ] | access-date = 9 March 2008 | archive-url = https://web.archive.org/web/20070820005225/http://www.emea.europa.eu/humandocs/PDFs/EPAR/tysabri/H-603-Annex-en.pdf | archive-date = 20 August 2007 | url-status = dead }}</ref>
===Crohn's disease===
{{Further|]}}


In the European Union, natalizumab is indicated as single ] in adults with highly active relapsing remitting multiple sclerosis for the following patient groups:
Several ]s have demonstrated that natalizumab is effective in increasing rates of ]<ref name="pmid12510039">{{cite journal |author=Ghosh S, Goldin E, Gordon F, Malchow H, Rask-Madsen J, Rutgeerts P, Vyhnálek P, Zádorová Z, Palmer T, Donoghue S |title=Natalizumab for active Crohn's disease |journal=N. Engl. J. Med. |volume=348 |issue=1 |pages=24–32 |year=2003 |pmid=12510039 |doi=10.1056/NEJMoa020732}}</ref> and maintaining symptom-free status<ref>{{cite journal |author=Feagan BG, Sandborn WJ, Hass S, Niecko T, White J |title=Health-related quality of life during natalizumab maintenance therapy for Crohn's disease |journal=Am. J. Gastroenterol. |volume=102 |issue=12 |pages=2737–46 |year=2007 |pmid=18042106 |doi=10.1111/j.1572-0241.2007.01508.x}}</ref> in patients with ]. Natalizumab may be appropriate in patients who do not respond to medications that block ] such as ],<ref>{{cite journal |author=Michetti P, Mottet C, Juillerat P, ''et al.'' |title=Severe and steroid-resistant Crohn's disease |journal=Digestion |volume=76 |issue=2 |pages=99–108 |year=2007 |pmid=18239400 |doi=10.1159/000111023}}</ref> with some evidence to support combination treatment of Crohn's disease with natalizumab and infliximab may be helpful in inducing remission.<ref name = Sands>{{cite journal |author=Sands BE, Kozarek R, Spainhour J, ''et al.'' |title=Safety and tolerability of concurrent natalizumab treatment for patients with Crohn's disease not in remission while receiving infliximab |journal=Inflamm. Bowel Dis. |volume=13 |issue=1 |pages=2–11 |year=2007 |pmid=17206633 |doi=10.1002/ibd.20014 |url=}}</ref> Treatment of adolescent patients with natalizumab demonstrates an effectiveness similar to that of adult patients.<ref name = Hyams>{{cite journal |author=Hyams JS, Wilson DC, Thomas A, ''et al.'' |title=Natalizumab therapy for moderate to severe Crohn disease in adolescents |journal=J. Pediatr. Gastroenterol. Nutr. |volume=44 |issue=2 |pages=185–91 |year=2007 |pmid=17255829 |doi=10.1097/01.mpg.0000252191.05170.e7 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?an=00005176-200702000-00006}}</ref>
* People with highly active disease activity despite a full and adequate course of treatment with at least one disease modifying therapy (DMT), or<ref name="Tysabri EPAR" />

* People with rapidly evolving severe relapsing remitting multiple sclerosis defined by two or more disabling relapses in one year, and with one or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.<ref name="Tysabri EPAR" />
In January 2008, the FDA approved natalizumab for both induction of remission and maintenance of remission for moderate to severe Crohn's disease,<ref>{{cite web | url = http://www.fda.gov/bbs/topics/NEWS/2008/NEW01775.html | publisher = ] | title = FDA Approves Tysabri to Treat Moderate-to-Severe Crohn's Disease | date = 2008-01-14 | accessdate = 2008-03-09 }}</ref> though it has not been approved for this use in the European Union due to concerns over its risk/benefit ratio.<ref>{{cite web | url = http://www.emea.europa.eu/humandocs/PDFs/EPAR/natalizumab/H-624-RAR-en.pdf | title = Refusal CHMP assessment report for natalizumab | format = PDF | date = 2007-11-15 | publisher = ] | accessdate = 2008-04-02 }} {{PDF||78.5&nbsp;KB}}</ref>


== Adverse effects == == Adverse effects ==
The US prescribing information for natalizumab contains a ] about the increased risk of ],<ref name="FDA PR 20230824" /> a viral infection of the brain that usually leads to death or severe disability.<ref name="Tysabri EPAR" /><ref name="FDA PR 20230824" /> Risk factors for the development of progressive multifocal leukoencephalopathy include the presence of anti-JCV antibodies (antibodies to the ], a typically harmless virus carried by most humans), longer duration of therapy and prior use of immunosuppressants.<ref name="Tysabri EPAR" /><ref name="FDA PR 20230824" />
Common adverse effects include ] and ] with a low risk of ],<ref name="pmid17876741">{{cite journal |author=Horga A, Horga de la Parte JF |title= |language=Spanish; Castilian |journal=Rev Neurol |volume=45 |issue=5 |pages=293–303 |year=2007 |pmid=17876741 |doi= |issn=}}</ref> ], ], ] and exacerbation of Crohn's disease in a minority of patients with the condition.<ref name = Sands/> Adolescents with Crohn's disease experience headache, ] and exacerbation of Crohn's disease.<ref name = Hyams/> Natalizumab is ] for people with known hypersensitivity to the drug or its components and in patients with a history of PML (see ]).

It was first observed in seven patients who received natalizumab in late 2008;<ref name="BloombergDec152008">{{cite news | vauthors = Greene RT | title = Biogen, Elan Report Brain Illness in Tysabri Patient | url = https://www.bloomberg.com/apps/news?pid=20601087&sid=ahUhAZaAQqgs&refer=home | agency = Bloomberg.com | date = 15 December 2008 | access-date = 21 December 2008 }}</ref> three cases were noted in clinical trials in 2006<ref name="pmid15947080">{{cite journal | vauthors = Van Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M, Verbeeck J, Geboes K, Robberecht W, Rutgeerts P | title = Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease | journal = The New England Journal of Medicine | volume = 353 | issue = 4 | pages = 362–368 | date = July 2005 | pmid = 15947080 | doi = 10.1056/NEJMoa051586 | doi-access = free }}</ref> leading to the drug being temporarily pulled from the market; two cases were reported to the FDA in August 2008;<ref name="FDAAug2008">{{cite web |url=https://www.fda.gov/cder/drug/InfoSheets/HCP/natalizumab2008HCP.htm |title=Natalizumab Injection for Intraveneous <nowiki>{{sic}}</nowiki> Use (marketed as Tysabri) |access-date=22 December 2008 |author=U.S. Food and Drug Administration |website=U.S. ] (FDA) |date=August 2008 |url-status=dead |archive-url=https://web.archive.org/web/20081219002812/https://www.fda.gov/cder/drug/InfoSheets/HCP/natalizumab2008HCP.htm |archive-date=19 December 2008 }}</ref> and two cases were announced in December 2008.<ref name=BloombergDec152008/> By January 2010, the FDA noted a total of 31 confirmed cases of PML,<ref name = Medscape/> with the chance of developing the infection increasing as the number of infusions received by a patient increased. Because of this association, the drug label and ] accompanying the drug will be updated to include this information.<ref>{{cite web | url = https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm199872.htm | title = FDA Drug Safety Communication: Risk of Progressive Multifocal Leukoencephalopathy (PML) with the use of Tysabri (natalizumab) | publisher = ] | date = 2 May 2010 | access-date = 31 August 2010 | archive-date = 24 April 2019 | archive-url = https://web.archive.org/web/20190424013210/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm199872.htm | url-status = live }}</ref> As of February 2012, there were 212 confirmed cases of PML among 99,571 patients treated with natalizumab (2.1 cases per 1000 patients). All 54 patients with PML for whom samples were available before the diagnosis were positive for anti–JC virus antibodies. When the risk of PML was evaluated according to three risk factors, it was lowest among the patients who had used natalizumab for the shortest periods, those who had used few if any immunosuppressant drugs to treat MS in the past, and lastly who were negative for anti–JC virus antibodies. The incidence of PML in the low risk group was estimated to be 0.09 cases, or less, per 1000 patients. Patients who had taken natalizumab for longer, from 25 to 48 months, who were positive for anti–JC virus antibodies, had taken immunosuppressants before the initiation of natalizumab therapy had the highest risk of developing PML. Their risk is fully 123 times higher than the low risk group. (incidence, 11.1 cases per 1000 patients ).<ref name="BloomgrenRichman2012">{{cite journal | vauthors = Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, Lee S, Plavina T, Scanlon JV, Sandrock A, Bozic C | title = Risk of natalizumab-associated progressive multifocal leukoencephalopathy | journal = The New England Journal of Medicine | volume = 366 | issue = 20 | pages = 1870–1880 | date = May 2012 | pmid = 22591293 | doi = 10.1056/NEJMoa1107829 | doi-access = free }}</ref> While none of them had taken the drug in combination with other disease-modifying treatments, previous use of MS treatments increases the risk of PML between 3 and 4-fold.<ref name="pmid21777829">{{cite journal |vauthors=Kappos L, Bates D, Edan G, Eraksoy M, Garcia-Merino A, Grigoriadis N, Hartung HP, Havrdová E, Hillert J, Hohlfeld R, Kremenchutzky M, Lyon-Caen O, Miller A, Pozzilli C, Ravnborg M, Saida T, Sindic C, Vass K, Clifford DB, Hauser S, Major EO, O'Connor PW, Weiner HL, Clanet M, Gold R, Hirsch HH, Radü EW, Sørensen PS, King J |title=Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring.|journal=Lancet Neurology|date=August 2011|volume=10|issue=8|pages=745–58|doi=10.1016/S1474-4422(11)70149-1|pmid=21777829|s2cid=15639613}}</ref> In 2016, EMA recommended all people taking natalizumab should undergo full MRI scans at least once a year due to concerns of progressive multifocal leukoencephalopathy (PML). In addition, more frequent MRI scans (e.g. every 3 to 6 months) should be performed using simplified protocols should be considered for those at higher risk of PML.<ref>{{cite web|url=https://www.ema.europa.eu/en/medicines/human/referrals/tysabri|title=EMA confirms recommendations to minimise risk of brain infection PML with Tysabri|date=25 April 2016|website=European Medicines Agency|access-date=29 November 2019|archive-date=23 January 2021|archive-url=https://web.archive.org/web/20210123035529/https://www.ema.europa.eu/en/medicines/human/referrals/tysabri|url-status=live}}</ref>

] in early 2008 revealed that 0.1% of people taking natalizumab experience clinically significant ] injury, leading to the FDA, EMEA and manufacturers recommending that the medication be discontinued in patients with ] or other evidence of significant liver damage.<ref name="FDA Safety Alerts for Drugs">{{cite web |url=https://www.fda.gov/medwatch/safety/2008/safety08.htm#Tysabri |title=FDA MedWatch - 2008 Safety Information Alerts |publisher=U.S. ] (FDA) |access-date=5 April 2008 |date=28 February 2008 |archive-date=25 May 2009 |archive-url=https://web.archive.org/web/20090525085008/http://www.fda.gov/medwatch/safety/2008/safety08.htm#Tysabri |url-status=live }}</ref><ref name="EMEA press release">{{cite web|url=http://emea.europa.eu/humandocs/PDFs/EPAR/tysabri/PR_Tysabri_13948908en.pdf |title=EMEA concludes new advice to doctors and patients for Tysabri (natalizumab) needed |access-date=5 April 2008 |date=20 March 2008 |publisher=] }}{{dead link|date=August 2020|bot=medic}}{{cbignore|bot=medic}}</ref><ref name=Q&A>{{cite web | url = http://emea.europa.eu/humandocs/PDFs/EPAR/tysabri/Q&A_Tysabri_14590808en.pdf | title = Questions and answers on Tysabri and liver injury | publisher = ] | date = 20 March 2008 | access-date = 14 April 2008 }}{{Dead link|date=July 2023 |bot=InternetArchiveBot |fix-attempted=yes }} ; {{webarchive|url=https://web.archive.org/web/20080611111842/http://www.nelm.nhs.uk/Record%20Viewing/vR.aspx?id=591422 |date=11 June 2008 }}, {{webarchive|url=https://web.archive.org/web/20081205071838/http://www.medscape.com/viewarticle/570796 |date=5 December 2008 }}</ref> This rate is comparable to other immune-suppressing drugs.<ref name="titleMultiple Sclerosis - Natalizumab (Tysabri) Can Rarely Cause Liver Problems">{{cite web |url=http://www.healthcentral.com/multiple-sclerosis/c/6639/21073/liver/ |title=Multiple Sclerosis - Natalizumab (Tysabri) Can Rarely Cause Liver Problems |vauthors=Gross K |date=3 March 2008 |access-date=5 April 2008 |archive-date=7 November 2016 |archive-url=https://web.archive.org/web/20161107034051/http://www.healthcentral.com/multiple-sclerosis/c/6639/21073/liver |url-status=live }}</ref> Evidence of ] in the form of elevated blood levels of ] and ] can appear as soon as six days after an initial dose; reactions are unpredictable and may appear even if the patient does not react to previous treatment.<ref name=DHP>{{cite web | url = https://www.fda.gov/medwatch/safety/2008/Tysabri_dhcp_letter.pdf | title = Important safety information: Dear Healthcare Practitioner letter | publisher = ] and ] | date = 1 February 2008 | access-date = 11 April 2008 | vauthors = Panzara M, Francis V | archive-date = 12 May 2009 | archive-url = https://web.archive.org/web/20090512083812/http://www.fda.gov/medwatch/safety/2008/Tysabri_dhcp_letter.pdf | url-status = live }}; {{webarchive|url=https://web.archive.org/web/20080611133555/http://www.medpagetoday.com/ProductAlert/Prescriptions/tb/8522 |date=11 June 2008 }}</ref> Such signs reoccur upon ] in some patients, indicating that damage is not coincidental.<ref name = DHP/> In the absence of any blockage these ] are predictors of severe liver injury with possible ]e of ] or ].<ref name = DHP/>


Common adverse effects include ] and ] with a low risk of ],<ref name="pmid17876741">{{cite journal |vauthors=Horga A, Horga de la Parte JF |title= |language=es|journal=Rev Neurol |volume=45 |issue=5 |pages=293–303 |year=2007 |pmid=17876741 }}</ref> ], ], ] and exacerbation of Crohn's disease in a minority of patients with the condition.{{medical citation needed|date=November 2018}} Adolescents with Crohn's disease experience headache, ] and exacerbation of Crohn's disease.{{medical citation needed|date=November 2018}}
] in early 2008 revealed that 0.1% of people taking natalizumab experience clinically significant ] injury, leading to the FDA, EMEA and manufacturers recommending that the medication be discontinued in patients with ] or other evidence of significant liver damage.<ref name="FDA Safety Alerts for Drugs">{{cite web |url=http://www.fda.gov/medwatch/safety/2008/safety08.htm#Tysabri |title=FDA MedWatch - 2008 Safety Information Alerts | publisher = ] |accessdate=2008-04-05 | date = 2008-02-28}}</ref><ref name="EMEA press release">{{cite web |url=http://emea.europa.eu/humandocs/PDFs/EPAR/tysabri/PR_Tysabri_13948908en.pdf |format=PDF|title=EMEA concludes new advice to doctors and patients for Tysabri (natalizumab) needed |accessdate=2008-04-05 |date=2008-03-20 |publisher=] |pages= |quote=}} {{Dead link|date=October 2010|bot=H3llBot}}</ref><ref name=Q&A>{{cite web | url = http://emea.europa.eu/humandocs/PDFs/EPAR/tysabri/Q&A_Tysabri_14590808en.pdf | format = PDF | title = Questions and answers on Tysabri and liver injury | publisher = ] | date = 2008-03-20 | accessdate = 2008-04-14 }} {{Dead link|date=October 2010|bot=H3llBot}}; , </ref> This rate is comparable to other immune-suppressing drugs.<ref name="titleMultiple Sclerosis - Natalizumab (Tysabri) Can Rarely Cause Liver Problems">{{cite web |url=http://www.healthcentral.com/multiple-sclerosis/c/6639/21073/liver/ |title=Multiple Sclerosis - Natalizumab (Tysabri) Can Rarely Cause Liver Problems |author=Kenneth Gross, M.D. |date=2008-03-03 |accessdate=2008-04-05 |format= |work=}}</ref> Evidence of ] in the form of elevated blood levels of ] and ] can appear as soon as six days after an initial dose; reactions are unpredictable and may appear even if the patient does not react to previous treatment.<ref name = DHP>{{cite web |url=http://www.fda.gov/medwatch/safety/2008/Tysabri_dhcp_letter.pdf| format = PDF | title = Important safety information: Dear Healthcare Practitioner letter | publisher =] and ] | date = 2008-02-01 | accessdate = 2008-04-11 | last = Panzara | first = M | coauthors = Francis V }}; </ref> Such signs reoccur upon ] in some patients, indicating that damage is not coincidental.<ref name = DHP/> In the absence of any blockage these ] are predictors of severe liver injury with possible ]e of ] or ].<ref name = DHP/>


About 6% of the people in studies developed long-lasting antibodies against natalizumab, which reduced the medicine's effectiveness.<ref name="Tysabri EPAR" />
Natalizumab has also been linked to ], though the association is unclear.<ref>{{cite journal |author=Mullen JT, Vartanian TK, Atkins MB |title=Melanoma complicating treatment with natalizumab for multiple sclerosis |journal=N. Engl. J. Med. |volume=358 |issue=6 |pages=647–8 |year=2008 |pmid=18256405 |doi=10.1056/NEJMc0706103}}</ref> The long-term effects of the drug are unknown<ref name="pmid18389881">{{cite journal |author=van Bronswijk H, Dubois EA, van Gerven JM, Cohen AF |title= |language=Dutch; Flemish |journal=Ned Tijdschr Geneeskd |volume=152 |issue=9 |pages=499–500 |year=2008 |pmid=18389881 |doi= |url=}}</ref> and concern has been expressed over the risks of ] and ].<ref name="pmid18354844"/>


], an opportunistic infection caused by the ], and that typically occurs in patients who are ], developed in seven patients who received natalizumab;<ref name="BloombergDec152008">{{cite news |first = Robert T. |last = Greene |title = Biogen, Elan Report Brain Illness in Tysabri Patient | url = http://www.bloomberg.com/apps/news?pid=20601087&sid=ahUhAZaAQqgs&refer=home | agency = Bloomberg.com | date = December 15, 2008 | accessdate = December 21, 2008 }}</ref> three cases were noted in clinical trials in 2006<ref name="pmid15947080">{{cite journal |author=Van Assche G, Van Ranst M, Sciot R, ''et al.'' |title=Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease |journal=N. Engl. J. Med. |volume=353 |issue=4 |pages=362–8 |year=2005 |month=July |pmid=15947080 |doi=10.1056/NEJMoa051586 |url=}}</ref> leading to the drug being temporarily pulled from the market; two cases were reported to the FDA in August 2008;<ref name="FDAAug2008">{{Cite web| url= http://www.fda.gov/cder/drug/InfoSheets/HCP/natalizumab2008HCP.htm | title= Natalizumab Injection for Intraveneous <nowiki></nowiki> Use (marketed as Tysabri)| accessdate= December 22, 2008 | author= U.S. Food and Drug Administration| month= August | year= 2008}} {{Dead link|date=October 2010|bot=H3llBot}}</ref> and, two cases were announced in December 2008.<ref name=BloombergDec152008/> A recent preliminary study suggests that patients on this drug for more than 12 months are at elevated risk for PML.<ref>{{cite pmid | 19741227 }}</ref> By January 21, 2010 the FDA noted a total of 31 confirmed cases of PML, with the chance of developing the infection increasing as the number of infusions received by a patient increased. Because of this association, the drug label and ] accompanying the drug will be updated to include this information.<ref>{{cite web | url = http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm199872.htm | title = FDA Drug Safety Communication: Risk of Progressive Multifocal Leukoencephalopathy (PML) with the use of Tysabri (natalizumab) | publisher = ] | date = 2010-05-02 | accessdate = 2010-08-31 }}</ref>
<!-- == Overdose == --> <!-- == Overdose == -->
<!-- == Physical and chemical properties == --> <!-- == Physical and chemical properties == -->
Line 82: Line 143:


== Mechanism of action == == Mechanism of action ==
]]] ]]]
Natalizumab is a ] ] against alpha-4 (α4) ], the first drug developed in the class of selective adhesion molecule inhibitors. α4-integrin is required for ]s to move into ]; natalizumab's ] is believed to be the inhibition these immune cells from crossing blood vessel walls to reach affected organs.<ref name=Rice2005>{{cite journal |author=Rice GP, Hartung HP, Calabresi PA |title=Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale |journal=Neurology |volume=64 |issue=8 |pages=1336–42 |year=2005 |pmid=15851719 |doi=10.1212/01.WNL.0000158329.30470.D0}}</ref> Natalizumab is a ] ] against alpha-4 (α4) ], the first drug developed in the class of selective adhesion molecule inhibitors. α4-integrin is required for ]s to move into ], and natalizumab's ] is believed to be the prevention of immune cells from crossing blood vessel walls to reach affected organs.<ref name=Rice2005>{{cite journal |vauthors=Rice GP, Hartung HP, Calabresi PA |title=Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale |journal=Neurology |volume=64 |issue=8 |pages=1336–42 |year=2005 |pmid=15851719 |doi=10.1212/01.WNL.0000158329.30470.D0|s2cid=39916466 }}</ref>


=== In multiple sclerosis === === Multiple sclerosis ===
The ]-causing ]s of MS are believed to be caused when ] cells such as ]s pass through the ] through interaction with receptors on the ]. Natalizumab appears to reduce the transmission of immune cells into the ] by interfering with the ] on the surfaces of cells. The effect appears to occur on endothelial cells expressing the ] gene, and in ]l cells expressing the ] gene. In animals used to model MS and test therapies, repeated administration of natalizumab reduced migration of ]s into the brain's parenchyma, and also reduced lesioning, though it is uncertain if this is clinically significant for humans.<ref name="Tysabri label">{{cite web |url=http://tysabri.com/en_US/tysb/footer/TYSABRI-pi.pdf |format=PDF|title=Final TYSABRI PI |accessdate=2008-03-13 |work=}} {{Dead link|date=October 2010|bot=H3llBot}}</ref> The ]-causing ]s of MS are believed to be caused when ] cells such as ]s pass through the ] through interaction with receptors on the ]. Natalizumab appears to reduce the transmission of immune cells into the ] by interfering with the ] on the surfaces of cells. The effect appears to occur on endothelial cells expressing the ] gene, and in ]l cells expressing the ] gene. In animals used to model MS and test therapies, repeated administration of natalizumab reduced migration of ]s into the brain's parenchyma, and also reduced lesioning, though it is uncertain if this is clinically significant for humans.<ref name="Tysabri FDA label" />


Individuals with MS dosed with natalizumab demonstrated increased ]-expressing cells, with research suggesting a peak in expression after 72 hours.<ref name="pmid18235044">{{cite journal |author=Zohren F, Toutzaris D, Klarner V, Hartung HP, Kieseier B, Haas R |title=The monoclonal anti-VLA4 antibody natalizumab mobilizes CD34+ hematopoietic progenitor cells in humans |journal=] |volume= 111|issue= 7|pages= 3893|year=2008 |pmid=18235044 |doi=10.1182/blood-2007-10-120329 |url=http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=18235044}}</ref> Individuals with MS dosed with natalizumab demonstrated increased ]-expressing cells, with research suggesting a peak in expression after 72 hours.<ref name="pmid18235044">{{cite journal |vauthors=Zohren F, Toutzaris D, Klarner V, Hartung HP, Kieseier B, Haas R |title=The monoclonal anti-VLA4 antibody natalizumab mobilizes CD34+ hematopoietic progenitor cells in humans |journal=] |volume= 111|issue= 7|pages= 3893–5|year=2008 |pmid=18235044 |doi=10.1182/blood-2007-10-120329 |s2cid=206866717 |doi-access=free }}</ref>


=== In Crohn's disease === === Crohn's disease ===
The interaction of the α4β7 integrin and the ] (also known as MADCAM1) endothelial cell receptor is believed to contribute to the chronic bowel inflammation that causes Crohn's disease. Addressin is primarily expressed in the endothelium of ] in the small intestine and are critical in guiding T-lymphocytes to ] in ]. In CD patients, sites of active inflammation of the bowel in CD patients have increased expression of addressin, suggesting a connection between the inflammation and the receptor. Natalizumab may block interaction between the α4β7 integrin and addressin at sites of inflammation. ]s have found higher levels of VCAM-1 expression in mice with ] and the VCAM-1 gene may also play a part in CD but its role is not yet clear.<ref name = "Tysabri label"/> The interaction of the α4β7 integrin and the ] (also known as MADCAM1) endothelial cell receptor is believed to contribute to the chronic bowel inflammation that causes Crohn's disease. Addressin is primarily expressed in the endothelium of ] in the small intestine and are critical in guiding T-lymphocytes to ] in ]. In CD patients, sites of active inflammation of the bowel in CD patients have increased expression of addressin, suggesting a connection between the inflammation and the receptor. Natalizumab may block interaction between the α4β7 integrin and addressin at sites of inflammation. ]s have found higher levels of VCAM-1 expression in mice with ] and the VCAM-1 gene may also play a part in CD but its role is not yet clear.<ref name="Tysabri FDA label" />


== Interactions == == Interactions ==
Natalizumab appears to interact with other immune-modulating drugs to increase the risk of ] (PML), an often-fatal ] caused by the ]. In 2005, two people taking natalizumab in combination with ] developed PML. One died, and the other recovered with disabling ]e.<ref name = "nejm-pml1">{{cite journal |author=Kleinschmidt-DeMasters BK, Tyler KL |title=Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis |journal=N. Engl. J. Med. |volume=353 |issue=4 |pages=369–74 |year=2005 |pmid=15947079 |doi=10.1056/NEJMoa051782}}</ref><ref name = "nejm-pml2">{{cite journal |author=Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D |title=Progressive multifocal leukoencephalopathy in a patient treated with natalizumab |journal=N. Engl. J. Med. |volume=353 |issue=4 |pages=375–81 |year=2005 |pmid=15947078 |doi=10.1056/NEJMoa051847}}</ref> A third fatal case initially attributed to an ] was reported in a patient being treated for Crohn's disease.<ref name=Van_Assche>{{cite journal |author=Van Assche G, Van Ranst M, Sciot R, ''et al.'' |title=Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease |journal=N. Engl. J. Med. |volume=353 |issue=4 |pages=362–8 |year=2005 |pmid=15947080 |doi=10.1056/NEJMoa051586 | url = http://content.nejm.org/cgi/content/full/353/4/362 }}</ref> Though the patient was being treated with natalizumab in combination with ], ]s and ], indications of PML infection appeared only after natalizumab monotherapy was re-introduced.<ref name=Van_Assche/> No deaths have been linked to natalizumab when it was not combined with other immune-modulating drugs<ref name = Yousry>{{cite journal |author=Yousry TA, ], Ryschkewitsch C, ''et al.'' |title=Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy |journal=N. Engl. J. Med. |volume=354 |issue=9 |pages=924–33 |year=2006 |pmid=16510746 |doi=10.1056/NEJMoa054693 |last12=Radue |first12=EW |last13=Jäger |first13=HR |last14=Clifford |first14=DB |pmc=1934511}}</ref> and other rates of opportunistic infections are not increased in patients taking natalizumab<ref name="pmid17136224"/> possibly due to the drug’s mechanism of action.<ref name="pmid17521672">{{cite journal |author=Ransohoff RM |title="Thinking without thinking" about natalizumab and PML |journal=J. Neurol. Sci. |volume=259 |issue=1–2 |pages=50–2 |year=2007 |pmid=17521672 |doi=10.1016/j.jns.2006.04.011}}</ref> Other than a prior history of PML, there is no known method to identify patients at risk of developing PML.<ref name="pmid17122725">{{cite journal |author=Aksamit AJ |title=Review of progressive multifocal leukoencephalopathy and natalizumab |journal=Neurologist |volume=12 |issue=6 |pages=293–8 |year=2006 |pmid=17122725 |doi=10.1097/01.nrl.0000250948.04681.96}}</ref> Natalizumab's label indicates that it is ] for ] individuals or those with a history of PML.<ref name="Tysabri label"/> Due to the uncertain risk of PML, natalizumab is only available through a restricted distribution program.<ref name="Tysabri label" /> As of June 2009, ten cases of PML associated with natalizumab have been reported.<ref name=June2009/> At least one of them had not previously taken any other inmunomodulator therapy.<ref name="WSJ08">{{cite news|url=http://blogs.wsj.com/health/2008/08/01/brain-infections-return-for-multiple-sclerosis-drug-tysabri/?mod=googlenews_wsj | title= Brain Infections Return for Multiple Sclerosis Drug Tysabri | date=2008-08-01 | accessdate=2008-08-01 | work=The Wall Street Journal | first=Jacob | last=Goldstein}}</ref> By Jaunary 21st, 2010 the ] reported a total of 31 confirmed cases of PML associated with natalizumab.<ref name = Medscape/> Natalizumab appears to interact with other immune-modulating drugs to increase the risk of ] (PML), an often-fatal ] caused by the ]. In 2005, two people taking natalizumab in combination with ] developed PML. One died, and the other recovered with disabling ]e.<ref name = "nejm-pml1">{{cite journal | vauthors = Kleinschmidt-DeMasters BK, Tyler KL | title = Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis | journal = The New England Journal of Medicine | volume = 353 | issue = 4 | pages = 369–374 | date = July 2005 | pmid = 15947079 | doi = 10.1056/NEJMoa051782 | doi-access = free }}</ref><ref name = "nejm-pml2">{{cite journal | vauthors = Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D | title = Progressive multifocal leukoencephalopathy in a patient treated with natalizumab | journal = The New England Journal of Medicine | volume = 353 | issue = 4 | pages = 375–381 | date = July 2005 | pmid = 15947078 | doi = 10.1056/NEJMoa051847 | doi-access = free }}</ref> A third fatal case initially attributed to an ] was reported in a patient being treated for Crohn's disease.<ref name="pmid15947080"/> Though the patient was being treated with natalizumab in combination with ], ]s and ], indications of PML infection appeared only after natalizumab monotherapy was re-introduced.<ref name="pmid15947080"/> No deaths from progressive multifocal leukoencephalopathy have been linked to natalizumab when it was not combined with other immune-modulating drugs<ref name = Yousry>{{cite journal | vauthors = Yousry TA, Major EO, Ryschkewitsch C, Fahle G, Fischer S, Hou J, Curfman B, Miszkiel K, Mueller-Lenke N, Sanchez E, Barkhof F, Radue EW, Jäger HR, Clifford DB | title = Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy | journal = The New England Journal of Medicine | volume = 354 | issue = 9 | pages = 924–933 | date = March 2006 | pmid = 16510746 | pmc = 1934511 | doi = 10.1056/NEJMoa054693 }}</ref> and other rates of opportunistic infections are not increased in patients taking natalizumab<ref name="pmid17136224"/> possibly due to the drug's mechanism of action.<ref name="pmid17521672">{{cite journal | vauthors = Ransohoff RM | title = "Thinking without thinking" about natalizumab and PML | journal = Journal of the Neurological Sciences | volume = 259 | issue = 1–2 | pages = 50–52 | date = August 2007 | pmid = 17521672 | doi = 10.1016/j.jns.2006.04.011 | s2cid = 28808262 }}</ref> Other than a prior history of PML, there is no known method to identify patients at risk of developing PML.<ref name="pmid17122725">{{cite journal | vauthors = Aksamit AJ | title = Review of progressive multifocal leukoencephalopathy and natalizumab | journal = The Neurologist | volume = 12 | issue = 6 | pages = 293–298 | date = November 2006 | pmid = 17122725 | doi = 10.1097/01.nrl.0000250948.04681.96 | s2cid = 25003597 }}</ref> Natalizumab's label indicates that it is ] for ] individuals or those with a history of PML.<ref name="Tysabri FDA label" /> Due to the uncertain risk of PML, natalizumab is only available through a restricted distribution program.<ref name="Tysabri FDA label" /> By January 2010, the ] reported a total of 31 confirmed cases of PML associated with natalizumab.<ref name = Medscape/>


Though the small number of cases precludes conclusion on the ability of natalizumab alone to induce PML, its ] states that the drug has only been linked to PML when combined with other immune-modulating drugs and natalizumab is contraindicated for use with other immunomodulators.<ref name="Tysabri label" /> ]s may produce immunosuppression, and the Tysabri prescribing information recommends that people taking corticosteroids for the treatment of Crohn's disease have their doses reduced before starting natalizumab treatment.<ref name="Tysabri label" /> The risk of developing PML was later estimated to be 1 in 1,000 (0.1%) over 18 months<ref name="pmid18360634"/><ref name="pmid17136224">{{cite journal |author=Berger JR |title=Natalizumab |journal=Drugs Today |volume=42 |issue=10 |pages=639–55 |year=2006 |pmid=17136224 |doi=10.1358/dot.2006.42.10.1042190}}</ref><ref name="pmid17434098">{{cite journal |author=Kappos L, Bates D, Hartung HP, ''et al.'' |title=Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring |journal=Lancet Neurol |volume=6 |issue=5 |pages=431–41 |year=2007 |pmid=17434098 |doi=10.1016/S1474-4422(07)70078-9 |last12=King |first12=J |last13=Radue |first13=EW |last14=Yousry |first14=T |last15=Major |first15=EO |last16=Clifford |first16=DB}}</ref> though the longer term risks of PML are unknown.<ref name="pmid18360634"/> Though the small number of cases precludes conclusion on the ability of natalizumab alone to induce PML, its ] states that the drug has only been linked to PML when combined with other immune-modulating drugs and natalizumab is contraindicated for use with other immunomodulators.<ref name="Tysabri FDA label" /> ]s may produce immunosuppression, and the Tysabri prescribing information recommends that people taking corticosteroids for the treatment of Crohn's disease have their doses reduced before starting natalizumab treatment.<ref name="Tysabri FDA label" /> The risk of developing PML was later estimated to be 1 in 1,000 (0.1%) over 18 months<ref name="pmid18360634"/><ref name="pmid17136224">{{cite journal | vauthors = Berger JR | title = Natalizumab | journal = Drugs of Today | volume = 42 | issue = 10 | pages = 639–655 | date = October 2006 | pmid = 17136224 | doi = 10.1358/dot.2006.42.10.1042190 }}</ref><ref name="pmid17434098">{{cite journal | vauthors = Kappos L, Bates D, Hartung HP, Havrdova E, Miller D, Polman CH, Ravnborg M, Hauser SL, Rudick RA, Weiner HL, O'Connor PW, King J, Radue EW, Yousry T, Major EO, Clifford DB | title = Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring | journal = The Lancet. Neurology | volume = 6 | issue = 5 | pages = 431–441 | date = May 2007 | pmid = 17434098 | doi = 10.1016/S1474-4422(07)70078-9 | s2cid = 18131415 }}</ref> though the longer term risks of PML are unknown.<ref name="pmid18360634"/>


== Legal status == ==History==
Biogen Idec announced the initiation of the first clinical trial of natalizumab as a potential cancer treatment as of September 2008.<ref>{{cite news | url= http://www.boston.com/business/ticker/2008/09/biogen_idec_tes.html | title= Biogen Idec testing Tysabri as a cancer treatment | date= 5 September 2008 | access-date= 5 September 2008 | work= ] | archive-date= 29 October 2013 | archive-url= https://web.archive.org/web/20131029201555/http://www.boston.com/business/ticker/2008/09/biogen_idec_tes.html | url-status= live }}</ref>
Natalizumab was originally approved for treatment of ] in 2004, through the FDA's accelerated ], due to the drug's efficacy in one-year ]s. In February 2005, four months after its approval, natalizumab was withdrawn voluntarily by the manufacturer after two cases of progressive multifocal leukoencephalopathy. Groups representing individuals with MS lobbied to have the drug returned to the US market<ref name = NYT>{{cite news | url = http://www.nytimes.com/2006/03/09/business/09drug.html?_r=1&scp=2&sq=natalizumab&st=nyt&oref=slogin | title = F.D.A. Panel Recommends M.S. Drug Despite Lethal Risk | last = Pollack | first = A | work = ] | date = 2006-03-09 | accessdate = 2008-03-13 }}</ref> and in June, 2006, after recommendation by an advisory committee and a review of two years of safety and efficacy data, the FDA re-approved natalizumab for patients with all relapsing forms of MS (relapse-remitting, secondary-progressive, and progressive-relapsing) as a ] or second-line therapy.<ref>{{cite web | url = http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4313b1-02-FDA-Errata.pdf | format = PDF | title = Errata to FDA Background document for the Tysabri (natalizumab) Advisory Committee on July 31, 2007 | date = 2007-07-20 | accessdate = 2008-03-09 | publisher = ] }}</ref><ref>{{cite journal |author=Fiore D |title=Multiple sclerosis and natalizumab |journal=Am J Ther |volume=14 |issue=6 |pages=555–60 |year=2007 |pmid=18090880 |doi=10.1097/MJT.0b013e31804bfa6a}}</ref> Patients taking natalizumab must enter into a registry for monitoring.<ref name = NYT/> Natalizumab is the only drug after ] withdrawn for safety reasons that returned to the US market.


== Society and culture ==
In April, 2006 the ] recommended authorizing natalizumab to treat relapsing-remitting MS, and several weeks later the ] approved natalizumab in the European Union for highly-active relapsing remitting MS.<ref name = PREU/>
=== Legal status ===
Natalizumab was originally approved for treatment of ] in 2004, through the FDA's accelerated ], due to the drug's efficacy in one-year ]s. In February 2005, four months after its approval, natalizumab was withdrawn voluntarily by the manufacturer after two cases of progressive multifocal leukoencephalopathy. Groups representing individuals with MS lobbied to have the drug returned to the US market<ref name = NYT>{{cite news | url = https://www.nytimes.com/2006/03/09/business/09drug.html?_r=1&scp=2&sq=natalizumab&st=nyt&oref=slogin | title = F.D.A. Panel Recommends M.S. Drug Despite Lethal Risk | vauthors = Pollack | work = ] | date = 9 March 2006 | access-date = 13 March 2008 | archive-date = 11 January 2016 | archive-url = https://web.archive.org/web/20160111132257/http://www.nytimes.com/2006/03/09/business/09drug.html?_r=1&scp=2&sq=natalizumab&st=nyt&oref=slogin | url-status = live }}</ref> and in June 2006, after recommendation by an advisory committee and a review of two years of safety and efficacy data, the FDA re-approved natalizumab for patients with all relapsing forms of MS (relapse-remitting, secondary-progressive, and progressive-relapsing) as a ] or second-line therapy.<ref>{{cite web | url = https://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4313b1-02-FDA-Errata.pdf | title = Errata to FDA Background document for the Tysabri (natalizumab) Advisory Committee on July 31, 2007 | date = 20 July 2007 | access-date = 9 March 2008 | publisher = U.S. ] (FDA) | archive-date = 17 May 2017 | archive-url = https://web.archive.org/web/20170517112105/https://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4313b1-02-FDA-Errata.pdf | url-status = live }}</ref><ref>{{cite journal | vauthors = Fiore D | title = Multiple sclerosis and Natalizumab | journal = American Journal of Therapeutics | volume = 14 | issue = 6 | pages = 555–560 | year = 2007 | pmid = 18090880 | doi = 10.1097/MJT.0b013e31804bfa6a | s2cid = 22339176 }}</ref> Patients taking natalizumab must enter into a registry for monitoring.<ref name = NYT/> Natalizumab is the only drug after ] withdrawn for safety reasons that returned to the US market.{{citation needed|date=August 2021}}


In April 2006, the ] recommended authorizing natalizumab to treat relapsing-remitting MS, and natalizumab was approved for medical use in the European Union in June 2006.<ref name="Tysabri EPAR">{{cite web | title=Tysabri EPAR | website=] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/tysabri | access-date=4 May 2020 | archive-date=6 August 2020 | archive-url=https://web.archive.org/web/20200806180356/https://www.ema.europa.eu/en/medicines/human/EPAR/tysabri | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref><ref name = PREU>{{cite press release | url = https://www.ema.europa.eu/documents/press-release/european-medicines-agency-committee-medicinal-products-human-use-24-27-april-2006_en.pdf | title = European Medicines Agency: Committee for Medicinal Products for Human Use 24–27 April 2006 | date = 28 April 2006 | publisher = ] (EMA) | access-date = 2 April 2008 | archive-url = https://web.archive.org/web/20070710205028/http://www.emea.europa.eu/pdfs/human/press/pr/15260806en.pdf | archive-date = 10 July 2007 | url-status = live }}</ref>
] added natalizumab to Schedule F of the Food and Drug Regulations on April 3, 2008 as a ] requiring oversight from a ].<ref>{{cite journal |url=http://www.gazette.gc.ca/rp-pr/p2/2008/2008-04-16/pdf/g2-14208.pdf | journal = ] Part I | title = SOR/2008-101: Food and Drug Act; Regulations Amending the Food and Drug Regulations (1528—Schedule F) |volume=142|issue=8|page=649| date = 2008-04-16}}</ref>

] added natalizumab to Schedule F of the Food and Drug Regulations in April 2008, as a ] requiring oversight from a ].<ref>{{cite journal|url=http://www.gazette.gc.ca/rp-pr/p2/2008/2008-04-16/pdf/g2-14208.pdf|journal=Canada Gazette Part I|title=SOR/2008-101: Food and Drug Act; Regulations Amending the Food and Drug Regulations (1528—Schedule F)|volume=142|issue=8|page=649|date=16 April 2008|access-date=18 December 2010|archive-date=18 August 2011|archive-url=https://web.archive.org/web/20110818110635/http://gazette.gc.ca/rp-pr/p2/2008/2008-04-16/pdf/g2-14208.pdf|url-status=live}}</ref>

In 2007, the EMA rejected the application to market natalizumab for Crohn's disease due to concerns over its risk/benefit ratio.<ref>{{cite web | url = http://www.emea.europa.eu/humandocs/PDFs/EPAR/natalizumab/H-624-RAR-en.pdf | title = Refusal CHMP assessment report for natalizumab | date = 15 November 2007 | publisher = ] | access-date = 2 April 2008 }}{{Dead link|date=April 2020 |bot=InternetArchiveBot |fix-attempted=yes }} {{cite web |url= http://www.emea.europa.eu/pdfs/human/opinion/Natalizumab_Q%26A_53096407en.pdf |title= lay-summary |access-date= 4 April 2008 |archive-date= 18 July 2009 |archive-url= https://web.archive.org/web/20090718104014/http://www.emea.europa.eu/pdfs/human/opinion/Natalizumab_Q%26A_53096407en.pdf |url-status= live }}&nbsp;{{small|(78.5&nbsp;KB)}}</ref> In January 2008, the FDA approved it for the induction of remission and maintenance of remission for moderate to severe Crohn's disease.<ref>{{cite web | url = https://www.fda.gov/bbs/topics/NEWS/2008/NEW01775.html | publisher = U.S. ] (FDA) | title = FDA Approves Tysabri to Treat Moderate-to-Severe Crohn's Disease | date = 14 January 2008 | access-date = 9 March 2008 | archive-date = 23 May 2009 | archive-url = https://web.archive.org/web/20090523235718/http://www.fda.gov/bbs/topics/NEWS/2008/NEW01775.html | url-status = live }}</ref>

=== Biosimilars ===
In July 2023, the ] (CHMP) of the ] (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Tyruko, intended for the treatment of multiple sclerosis.<ref name="Tyruko: Pending EC decision" /> The applicant for this medicinal product is Sandoz GmbH.<ref name="Tyruko: Pending EC decision">{{cite web | title=Tyruko: Pending EC decision | website=] (EMA) | date=21 July 2023 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/tyruko | access-date=25 August 2023 | archive-date=25 August 2023 | archive-url=https://web.archive.org/web/20230825215745/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/tyruko | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref><ref>{{cite web |date=24 July 2023 |title=Sandoz granted positive CHMP opinion for multiple sclerosis biosimilar |url=https://www.pmlive.com/pharma_news/sandoz_granted_positive_chmp_opinion_for_multiple_sclerosis_biosimilar_1495148 |access-date=24 July 2023 |website=PMLive |archive-date=24 July 2023 |archive-url=https://web.archive.org/web/20230724114851/https://www.pmlive.com/pharma_news/sandoz_granted_positive_chmp_opinion_for_multiple_sclerosis_biosimilar_1495148 |url-status=live }}</ref> Tyruko was approved for medical use in the European Union in September 2023.<ref name="Tyruko EPAR">{{cite web | title=Tyruko EPAR | website=European Medicines Agency | date=28 September 2023 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/tyruko | access-date=6 October 2023 | archive-date=28 October 2023 | archive-url=https://web.archive.org/web/20231028174855/https://www.ema.europa.eu/en/medicines/human/EPAR/tyruko | url-status=live }}</ref>

In August 2023, the FDA approved approved Tyruko (natalizumab-sztn) and granted approval to Sandoz Inc.<ref name="FDA PR 20230824">{{cite press release |date=24 August 2023 |title=FDA Approves First Biosimilar to Treat Multiple Sclerosis |url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-biosimilar-treat-multiple-sclerosis |access-date=25 August 2023 |website=U.S. ] (FDA) |archive-date=25 August 2023 |archive-url=https://web.archive.org/web/20230825094543/https://www.fda.gov/news-events/press-announcements/fda-approves-first-biosimilar-treat-multiple-sclerosis |url-status=live }} {{PD-notice}}</ref><ref>{{cite web | title=Biosimilar Drug Information | website=U.S. ] (FDA) | date=1 November 2023 | url=https://www.fda.gov/drugs/biosimilars/biosimilar-product-information | access-date=26 November 2023 | archive-date=28 August 2021 | archive-url=https://web.archive.org/web/20210828185647/https://www.fda.gov/drugs/biosimilars/biosimilar-product-information | url-status=live }}</ref>


==References== ==References==
{{reflist|2}} {{reflist}}


==Further reading==
== External links ==
* {{cite journal |vauthors=Clerico M, Artusi CA, Liberto AD, Rolla S, Bardina V, Barbero P, Mercanti SF, Durelli L |title=Natalizumab in Multiple Sclerosis: Long-Term Management |journal=Int J Mol Sci |volume=18 |issue=5 |date=April 2017 |page=940 |pmid=28468254 |pmc=5454853 |doi=10.3390/ijms18050940 |doi-access=free }}
*
*
*


{{Demyelinating diseases of CNS}}
{{Immunosuppressants}} {{Immunosuppressants}}
{{Monoclonals for immune system}} {{Monoclonals for immune system}}
{{Portal bar | Medicine}}
{{Authority control}}


] ]
] ]
]

]
]
]
]
]
]
]
]
]
]
]