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Template:Drugbox-mab Natalizumab is a prescription drug co-marketed by Biogen Idec and Élan as Tysabri. It was previously named Antegren. Natalizumab is administered by infusion every 28 days and is used in the treatment of multiple sclerosis and Crohn's disease. In combination with interferon beta-1a the drug has also been linked to two cases of progressive multifocal leukoencephalopathy, one of which was fatal.

As of January 2008, in the European Union and United States natalizumab is prescribed for the treatment of multiple sclerosis; in the United States it is also used to treat Crohn's disease.

Indications

Multiple sclerosis

Natalizumab was evaluated in two randomized, double-blind, placebo-controlled trials in patients with multiple sclerosis. Both studies enrolled patients who experienced at least one clinical relapse during the prior year and had a Kurtzke EDSS score between 0 and 5. In these trials natalizumab was shown to reduce relapses in MS patients by 68% vs. a placebo, a margin far greater than had been seen for other approved MS therapies.

Also in these trials natalizumab slowed the progression EDSS scores by approximately 50% (the US and EU medical authorities use slightly different measures of disability progression leading to reported values varying between 42% and 54%). Natalizumab also appeared to reduce reduces visual loss, maintained cognitive function, reduced the use of steroids and hospitalization and improved quality of life in relapsing multiple sclerosis patients.

Natalizumab was approved in November 2004, and again re-approved in June 2006 by the U.S. Food and Drug Administration for treatment of all forms of relapsing multiple sclerosis (i.e. Relapsing/Remitting, Progressive Relapsing, and Secondary Progressive with relapses). It was also approved in Europe in 2006 for treatment of RES (Rapidly Evolving Severe Relapsing/Remitting multiple sclerosis).

Crohn's Disease

Several randomized controlled trials have demonstrated that natalizumab is effective in increasing rates of remission and maintaining symptom-free status in patients with Crohn's disease.

Adverse effects

In early 2008, Biogen and Elan reported to the FDA that natalizumab can cause liver damage as early as six days after an initial dose, potentially leading to death or necessity of a liver transplant, and the FDA has recommended the medication be discontinued in patients with jaundice or other evidence of liver damage.

Physical and chemical properties

Natalizumab is a humanized monoclonal antibody against integrin-α4 that has proven efficacy in the treatment of two serious autoimmune disorders: multiple sclerosis (MS) and Crohn's disease (CD).

Natalizumab is the first alpha-4 antagonist in a new class of agents called selective adhesion-molecule (SAM) inhibitors. Alpha-4 integrin is required for leukocytes to migrate into the body's organs such as the brain and gut; natalizumab prevents leukocytes from doing so.

Mechanism of action in MS

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 α4β1-integrin receptor molecules on the surfaces of cells. The affect 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.

Mechanism of action in CD

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 4β7 integrin and addressin at sites of inflammation. Animal models have found higher levels of VCAM-1 expression in mice with irritable bowel disease and the VCAM-1 gene may also play a part in CD but its role is not yet clear.

Pharmacokinetics

The mechanism of action of natalizumab is believed to involve the inhibition of immune cells from crossing blood vessel walls to reach various tissues, including the brain.

Interactions

Natalizumab has been linked to fatal progressive multifocal leukoencephalopathy (PML) when used in combination with interferon beta-1a, which led to its withdrawal from various markets. It has since been re-instated for natalizumab-alone treatment.

History

It was announced on February 28, 2005 that one fatal and one non-fatal case of progressive multifocal leukoencephalopathy were found in patients given natalizumab in combination with interferon beta-1a over a two year period. Natalizumab was voluntarily withdrawn from the market that day after the first two confirmed cases, so that an intensive safety evaluation could be conducted to determine the prevalence of PML and course of action., During the safety review, a second PML death was attributed to natalizumab in March of 2005, in a clinical trial Crohn’s disease patient who had died in December 2003 from what was thought at that time to be a brain tumor, but was subsequently re-evaluated as having been PML. The Crohn’s disease patient who had received eight doses of natalizumab over an 18-month period had a prior medication history which included multiple courses of immunosuppressant agents, which are thought to have contributed significantly to the PML.

The MS community lobbied for the return of natalizumab to the market, in part because of its efficacy and also because roughly half of MS patients eventually fail other disease-modifying drugs. The withdrawal of the drug's availability for MS patients was particularly controversial as each of the PML cases occurred in combination therapies with other immuno-modulating drugs, and none of the 2,500 patients on natalizumab mono-therapy in the clinical trials had developed PML.

On June 5, 2006, after reviewing two years of safety and efficacy data and an Advisory Committee hearing ending in a unanimous recommendation for reapproval, FDA reapproved natalizumab for patients with relapsing forms of MS as a first- or second-line therapy.

They also included a special restricted distribution program known as the Tysabri Outreach: Unified Commitment to Health (TOUCH) Prescribing Program. Under this program, only prescribers, infusion centers, and specialty pharmacies trained and enrolled in the program can prescribe and administer natalizumab. Additionally, patients must also be enrolled in the TOUCH program for education and periodical evaluation.

In April of 2006 the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMEA), issued a positive opinion recommending marketing authorization for natalizumab as a treatment for relapsing-remitting multiple sclerosis. Several weeks later on June 29, the EMEA also approved natalizumab in the European Union for rapidly evolving severe relapsing remaining MS, but not subject to the TOUCH restrictions.

In recognition of the fact that the link of natalizumab to PML is unclear, the medication's owing to the fact that all three incidents were in combination therapy with other immuno-modulating drugs, natalizumab black box warning states both that the medication was linked only to combination therapy with immunomodulators, and that the number of cases precludes conclusions on the ability of natalizumab alone to induce PML.

In January 2008 the U.S. Food and Drug Administration approved natalizumab for both induction of remission and maintenance of remission for moderate to severe Crohn's Disease.

References

1. Polman CH, O'Connor PW, Havrdova E; et al. (2006). "A randomized, placebo-controlled trial of natalizumab for relapsing forms of multiple sclerosis". N. Engl. J. Med. 354 (9): 899–910. doi:10.1056/NEJMoa044397. PMID 16510744. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
2. http://www.emea.europa.eu/humandocs/PDFs/EPAR/tysabri/H-603-PI-en.pdf
3. http://www.neurology.org/cgi/content/abstract/68/16/1299
4. http://www.pslgroup.com/dg/265832.htm
5. http://www.webwire.com/ViewPressRel.asp?aId=21727
6. http://www.bioportfolio.com/april_06/10_04_2006/Demonstrate_Significant.html
7. Ghosh S, Goldin E, Gordon F, Malchow H, Rask-Madsen J, Rutgeerts P, Vyhnálek P, Zádorová Z, Palmer T, Donoghue S (2003). "Natalizumab for active Crohn's disease". N. Engl. J. Med. 348 (1): 24–32. PMID 12510039.{{cite journal}}: CS1 maint: multiple names: authors list (link)
8. Feagan BG, Sandborn WJ, Hass S, Niecko T, White J (2007). "Health-related quality of life during natalizumab maintenance therapy for Crohn's disease". Am. J. Gastroenterol. 102 (12): 2737–46. doi:10.1111/j.1572-0241.2007.01508.x. PMID 18042106.{{cite journal}}: CS1 maint: multiple names: authors list (link)
9. "2008 Safety Alerts for Drugs, Biologics, Medical Devices, and Dietary Supplements". Food and Drug Administration. 2008-02-28. Retrieved 2008-03-04.
10. ^ "TYSABRI product information" (pdf). Biogen Idec. 2008-01-01. Retrieved 2008-03-05.
11. {{cite web |url=http://www.neurology.org/cgi/content/abstract/64/8/1336?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=natalizumab+significantly+reduced+the+proportion+of+multiple+sclerosis&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT |title=Anti-{alpha}4 integrin therapy for multiple sclerosis: Mechanisms and rationale -- Rice et al. 64 (8): 1336 -- Neurology |accessdate=2008-01-28 |format= |work=}}
12. ^ Kleinschmidt-DeMasters BK, Tyler KL (2005). "Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis". N. Engl. J. Med. 353 (4): 369–74. doi:10.1056/NEJMoa051782. PMID 15947079.
13. ^ Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D (2005). "Progressive multifocal leukoencephalopathy in a patient treated with natalizumab". N. Engl. J. Med. 353 (4): 375–81. doi:10.1056/NEJMoa051847. PMID 15947078.{{cite journal}}: CS1 maint: multiple names: authors list (link)
14. "Pharmaceuticals: Restrictions in use and availability" (pdd). World Health Organization. Retrieved 2007-07-23.
15. Van Assche G, Van Ranst M, Sciot R; et al. (2005). "Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease". N. Engl. J. Med. 353 (4): 362–8. doi:10.1056/NEJMoa051586. PMID 15947080. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
16. ^ Yousry TA, Major EO, Ryschkewitsch C; et al. (2006). "Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy". N. Engl. J. Med. 354 (9): 924–33. doi:10.1056/NEJMoa054693. PMID 16510746. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
17. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4313b1-02-FDA-Errata.pdf
18. "TYSABRI Patient Safety, tysb". Retrieved 2008-01-28.
19. Tysabri FDA Label: http://www.tysabri.com/en_US/tysb/footer/TYSABRI-pi.pdf
20. FDA news release: http://www.fda.gov/bbs/topics/NEWS/2008/NEW01775.html

External links

• Tysabri Natalizumab
• Elan's Tysabri information center
• Biogen's Tysabri information center

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• Immunosuppressive agents