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Template:Drugbox-mab Natalizumab is a monoclonal antibody used in the treatment of multiple sclerosis and Crohn's disease. It is co-marketed by Biogen Idec and Élan as Tysabri, and was previously named Antegren. Natalizumab is administered by intravenous infusion every 28 days. The drug is believed to work by reducing the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestines and blood-brain barrier. Natalizumab has proven very effective in treating a wide variety of the symptoms of both diseases, preventing relapse, vision loss, cognitive decline and improving quality of life in multiple sclerosis patients and increasing rates of remission and preventing relapse in Crohn's disease.

Natalizumab was approved in 2004 in the United States, then withdrawn from the market after it was linked with a fatal neurological disorder when used in combination with another immune-modulating drug. After a review of its safety information and no further deaths, the drug has been approved for use in the US and in the European Union.

Indications

Multiple sclerosis

Natalizumab was evaluated in two randomized, double-blind, placebo-controlled trials in people with multiple sclerosis. Both studies enrolled individuals with MS 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 individuals with MS by 68% vs. placebo, a margin far greater than had been seen for other approved MS therapies.

Also in these trials natalizumab slowed the progression of disability (measured as 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%). In addition, natalizumab has been shown to reduce visual loss in individuals with relapsing multiple sclerosis, reduce the severity of MS, significantly increase the proportion of disease-free individuals with relapsing MS,, significantly improve assessments of health-related quality of life in relapsing improvements,, reduce the cognitive decline of a portion of individuals with MS, reduce hospitalizations and steroid use, and in individuals with relapsing MS, prevented the formation of new lesions.

Approximately 6% of individuals receiving natalizumab may develop persistent antibodies to natalizumab, which can reduce its efficacy.

Natalizumab was re-approved in June 2006 by the U.S. Food and Drug Administration for treatment of all forms (relapse-remitting, secondary-progressive, and progressive-relapsing) of relapsing multiple sclerosis. It was also approved in Europe in 2006 for treatment of highly active 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.

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.

Contraindications

In early 2008, Biogen, Elan and the FDA notified healthcare professionals that within as little as six days from initial dose, there have been reports of elevated liver enzymes and bilirubin. In the absence of any blockage, such poor liver function tests are a predictor of severe liver injury potentially leading to transplant or death and the FDA recommended the medication be discontinued in patients with jaundice or other evidence of liver damage. The removal, then reinstatement of natalizumab resulted in the disappearance, then reappearance of liver injury, evidence that the cause of injury may have been natalizumab.

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

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.

In multiple sclerosis

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.

In Crohn's disease

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 disease and the VCAM-1 gene may also play a part in CD but its role is not yet clear.

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 when not used in combination with other drugs.

Natalizumab's black box warning states that currently the drug has only been linked to PML when combined with other immune-modulating drugs, though the small number of cases precludes conclusion on the ability of natalizumab alone to induce PML.

History

Natalizumab was originally approved for treatment of multiple sclerosis in 2004, and the approval was hastened due to its efficacy in the drug's one-year clinical trials. In February, 2005, four months after its approval, it was withdrawn voluntarily due to PML-related deaths (though no deaths were linked to the drug when it was not combined with other immune-modulating drugs). Groups representing individuals with MS lobbied to have the drug returned to the US market and in June, 2006, after the 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 (relapse-remitting, secondary-progressive, and progressive-relapsing) of MS as a first-line or second-line therapy.

In April, 2006 the Committee for Medicinal Products for Human Use recommended authorizing natalizumab to treat relapsing-remitting MS, and several weeks later the European Medicines Agency approved natalizumab in the European Union for highly-active relapsing remitting MS.

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. "TYSABRI: ANNEX I - SUMMARY OF PRODUCT CHARACTERISTICS" (pdf). European Medicines Agency. Retrieved 2008-03-09.
3. Balcer LJ, Galetta SL, Calabresi PA; et al. (2007). "Natalizumab reduces visual loss in patients with relapsing multiple sclerosis". Neurology. 68 (16): 1299–304. doi:10.1212/01.wnl.0000259521.14704.a8. PMID 17438220. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
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11. Calabresi PA, Giovannoni G, Confavreux C; et al. (2007). "The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL". Neurology. 69 (14): 1391–403. doi:10.1212/01.wnl.0000277457.17420.b5. PMID 17761550. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
12. 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)
13. 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)
14. "FDA Approves Tysabri to Treat Moderate-to-Severe Crohn's Disease". Food and Drug Administration. 2008-01-14. Retrieved 2008-03-09.
15. "2008 Safety Alerts for Drugs, Biologics, Medical Devices, and Dietary Supplements". Food and Drug Administration. 2008-02-28. Retrieved 2008-03-04.
16. ^ "TYSABRI product information" (pdf). Biogen Idec. 2008-01-01. Retrieved 2008-03-05.
17. Rice GP, Hartung HP, Calabresi PA (2005). "Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale". Neurology. 64 (8): 1336–42. doi:10.1212/01.WNL.0000158329.30470.D0. PMID 15851719.{{cite journal}}: CS1 maint: multiple names: authors list (link)
18. 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.
19. 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)
20. 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)
21. "Errata to FDA Background document for the Tysabri (natalizumab) Advisory Committee on July 31, 2007" (pdf). Food and Drug Administration. 2007-07-20. Retrieved 2008-03-09.
22. Fiore D (2007). "Multiple sclerosis and Natalizumab". Am J Ther. 14 (6): 555–60. doi:10.1097/MJT.0b013e31804bfa6a. PMID 18090880.

External links

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

Template:Humanizedmonoclonals

• Immunosuppressive agents
• Monoclonal antibodies