Natalizumab#Legal status

In the United states, natalizumab is indicated for the treatment of multiple sclerosis and Crohn's disease. 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.

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.{{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 }}{{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 }}{{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 }} Natalizumab is used as a monotherapy.{{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 = European Medicines Agency | 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 }}

In the European Union, natalizumab is indicated as single disease modifying therapy in adults with highly active relapsing remitting multiple sclerosis for the following patient groups:

• People with highly active disease activity despite a full and adequate course of treatment with at least one disease modifying therapy (DMT), or
• 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.

The US prescribing information for natalizumab contains a boxed warning about the increased risk of progressive multifocal leukoencephalopathy, a viral infection of the brain that usually leads to death or severe disability. Risk factors for the development of progressive multifocal leukoencephalopathy include the presence of anti-JCV antibodies (antibodies to the JC virus, a typically harmless virus carried by most humans), longer duration of therapy and prior use of immunosuppressants.

It was first observed in seven patients who received natalizumab in late 2008;{{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 }} three cases were noted in clinical trials in 2006{{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 }} leading to the drug being temporarily pulled from the market; two cases were reported to the FDA in August 2008;{{cite web |url=https://www.fda.gov/cder/drug/InfoSheets/HCP/natalizumab2008HCP.htm |title=Natalizumab Injection for Intraveneous {{sic}} Use (marketed as Tysabri) |access-date=22 December 2008 |author=U.S. Food and Drug Administration |website=U.S. Food and Drug Administration (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 }} and two cases were announced in December 2008. By January 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 package insert accompanying the drug will be updated to include this information.{{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 = FDA | 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 }} 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 [95% CI, 8.3 to 14.5]).{{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 }} 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.{{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}} 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.{{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}}

Postmarketing surveillance in early 2008 revealed that 0.1% of people taking natalizumab experience clinically significant liver injury, leading to the FDA, EMEA and manufacturers recommending that the medication be discontinued in patients with jaundice or other evidence of significant liver damage.{{cite web |url=https://www.fda.gov/medwatch/safety/2008/safety08.htm#Tysabri |title=FDA MedWatch - 2008 Safety Information Alerts |publisher=U.S. Food and Drug Administration (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 }}{{cite web|url=http://emea.europa.eu/humandocs/PDFs/EPAR/tysabri/PR_Tysabri_13948908en.pdf |archive-url=https://web.archive.org/web/20090718101207/http://www.emea.europa.eu/humandocs/PDFs/EPAR/tysabri/PR_Tysabri_13948908en.pdf |url-status=dead |archive-date=18 July 2009 |title=EMEA concludes new advice to doctors and patients for Tysabri (natalizumab) needed |access-date=5 April 2008 |date=20 March 2008 |publisher=European Medicines Agency }}{{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 = European Medicines Agency | date = 20 March 2008 | access-date = 14 April 2008 }}{{Dead link|date=July 2023 |bot=InternetArchiveBot |fix-attempted=yes }} ; [http://www.nelm.nhs.uk/Record%20Viewing/vR.aspx?id=591422 lay-summary] {{webarchive|url=https://web.archive.org/web/20080611111842/http://www.nelm.nhs.uk/Record%20Viewing/vR.aspx?id=591422 |date=11 June 2008 }}, [http://www.medscape.com/viewarticle/570796 second summary] {{webarchive|url=https://web.archive.org/web/20081205071838/http://www.medscape.com/viewarticle/570796 |date=5 December 2008 }} This rate is comparable to other immune-suppressing drugs.{{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 }} Evidence of hepatotoxicity in the form of elevated blood levels of bilirubin and liver enzymes 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.{{cite web | url = https://www.fda.gov/medwatch/safety/2008/Tysabri_dhcp_letter.pdf | title = Important safety information: Dear Healthcare Practitioner letter | publisher = Biogen Idec and Élan | 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 }}; [http://www.medpagetoday.com/ProductAlert/Prescriptions/tb/8522 lay summary] {{webarchive|url=https://web.archive.org/web/20080611133555/http://www.medpagetoday.com/ProductAlert/Prescriptions/tb/8522 |date=11 June 2008 }} Such signs reoccur upon rechallenge in some patients, indicating that damage is not coincidental. In the absence of any blockage these liver function tests are predictors of severe liver injury with possible sequelae of liver transplantation or death.

Common adverse effects include fatigue and allergic reactions with a low risk of anaphylaxis,{{cite journal |vauthors=Horga A, Horga de la Parte JF |title=[Natalizumab in the treatment of multiple sclerosis] |language=es|journal=Rev Neurol |volume=45 |issue=5 |pages=293–303 |year=2007 |doi=10.33588/rn.4505.2007268 |pmid=17876741 }} headache, nausea, colds 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, fever and exacerbation of Crohn's disease.{{medical citation needed|date=November 2018}}

About 6% of the people in studies developed long-lasting antibodies against natalizumab, which reduced the medicine's effectiveness.

File:AntibodyChains.svg]]

Natalizumab is a humanized monoclonal antibody against alpha-4 (α4) integrin, the first drug developed in the class of selective adhesion molecule inhibitors. α4-integrin is required for white blood cells to move into organs, and natalizumab's mechanism of action is believed to be the prevention of immune cells from crossing blood vessel walls to reach affected organs.{{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 }}

The symptom-causing lesions of MS are believed to be caused when inflammatory cells such as T-lymphocytes pass through the blood–brain barrier through interaction with receptors on the endothelial cells. Natalizumab appears to reduce the transmission of immune cells into the central nervous system by interfering with the α4β7-integrin receptor molecules on the surfaces of cells. The effect appears to occur on endothelial cells expressing the VCAM-1 gene, and in parenchymal cells expressing the osteopontin gene. In animals used to model MS and test therapies, repeated administration of natalizumab reduced migration of leukocytes into the brain's parenchyma, and also reduced lesioning, though it is uncertain if this is clinically significant for humans.

Individuals with MS dosed with natalizumab demonstrated increased CD34-expressing cells, with research suggesting a peak in expression after 72 hours.{{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=Blood |volume= 111|issue= 7|pages= 3893–5|year=2008 |pmid=18235044 |doi=10.1182/blood-2007-10-120329 |s2cid=206866717 |doi-access=free }}

The interaction of the α4β7 integrin and the addressin (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 venules in the small intestine and are critical in guiding T-lymphocytes to lymphatic tissues in Peyer's patches. 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. Animal models have found higher levels of VCAM-1 expression in mice with irritable bowel syndrome and the VCAM-1 gene may also play a part in CD but its role is not yet clear.

Natalizumab appears to interact with other immune-modulating drugs to increase the risk of progressive multifocal leukoencephalopathy (PML), an often-fatal opportunistic infection caused by the JC virus. In 2005, two people taking natalizumab in combination with interferon beta-1a developed PML. One died, and the other recovered with disabling sequelae.{{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 }}{{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 }} A third fatal case initially attributed to an astrocytoma was reported in a patient being treated for Crohn's disease. Though the patient was being treated with natalizumab in combination with azathioprine, corticosteroids and infliximab, indications of PML infection appeared only after natalizumab monotherapy was re-introduced. No deaths from progressive multifocal leukoencephalopathy have been linked to natalizumab when it was not combined with other immune-modulating drugs{{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 }} and other rates of opportunistic infections are not increased in patients taking natalizumab possibly due to the drug's mechanism of action.{{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 }} Other than a prior history of PML, there is no known method to identify patients at risk of developing PML.{{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 }} Natalizumab's label indicates that it is contraindicated for immunosuppressed individuals or those with a history of PML. Due to the uncertain risk of PML, natalizumab is only available through a restricted distribution program. By January 2010, the United States Food and Drug Administration reported a total of 31 confirmed cases of PML associated with natalizumab.

Though the small number of cases precludes conclusion on the ability of natalizumab alone to induce PML, its black box warning 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. Corticosteroids 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. The risk of developing PML was later estimated to be 1 in 1,000 (0.1%) over 18 months{{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 }}{{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 }} though the longer term risks of PML are unknown.

Biogen Idec announced the initiation of the first clinical trial of natalizumab as a potential cancer treatment as of September 2008.{{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= The Boston Globe | 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 }}

Natalizumab was originally approved for treatment of multiple sclerosis in 2004, through the FDA's accelerated Fast Track program, due to the drug's efficacy in one-year clinical trials. 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{{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 = The New York Times | 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 }} 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 first-line or second-line therapy.{{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. Food and Drug Administration (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 }}{{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 }} Patients taking natalizumab must enter into a registry for monitoring. Natalizumab is the only drug after alosetron withdrawn for safety reasons that returned to the US market.{{citation needed|date=August 2021}}

In April 2006, the Committee for Medicinal Products for Human Use recommended authorizing natalizumab to treat relapsing-remitting MS, and natalizumab was approved for medical use in the European Union in June 2006.{{cite web | title=Tysabri EPAR | website=European Medicines Agency (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.{{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 = European Medicines Agency (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 }}

Health Canada added natalizumab to Schedule F of the Food and Drug Regulations in April 2008, as a prescription drug requiring oversight from a physician.{{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}}

In 2007, the EMA rejected the application to market natalizumab for Crohn's disease due to concerns over its risk/benefit ratio.{{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 = European Medicines Agency | 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 }} {{small|(78.5 KB)}} In January 2008, the FDA approved it for the induction of remission and maintenance of remission for moderate to severe Crohn's disease.{{cite web | url = https://www.fda.gov/bbs/topics/NEWS/2008/NEW01775.html | publisher = U.S. Food and Drug Administration (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 }}

In July 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 Tyruko, intended for the treatment of multiple sclerosis. The applicant for this medicinal product is Sandoz GmbH.{{cite web | title=Tyruko: Pending EC decision | website=European Medicines Agency (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.{{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 }} Tyruko was approved for medical use in the European Union in September 2023.{{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 }}

In August 2023, the FDA approved approved Tyruko (natalizumab-sztn) and granted approval to Sandoz Inc.{{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. Food and Drug Administration (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}}{{cite web | title=Biosimilar Drug Information | website=U.S. Food and Drug Administration (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 }}

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• {{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 }}

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Category:Monoclonal antibodies

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