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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 has proven effective in the treatment of multiple sclerosis and Crohn's disease.

As of January 2008, in the USA natalizumab is prescribed for the treatment of multiple sclerosis and Crohn's disease; in the EU and several other countries worldwide (including Canada, Australia, etc), it is prescribed for the treatment of multiple sclerosis.

Description

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 that.

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.

The FDA Label for natalizumab describes its putative mechanism of action in multiple sclerosis and Crohn’s disease as follows:

"In multiple sclerosis, lesions are believed to occur when activated inflammatory cells, including T-lymphocytes, cross the blood-brain barrier (BBB). Leukocyte migration across the BBB involves interaction between adhesion molecules on inflammatory cells and their counterreceptors present on endothelial cells of the vessel wall. The clinical effect of natalizumab in multiple sclerosis may be secondary to blockade of the molecular interaction of α4β1-integrin expressed by inflammatory cells with VCAM-1 on vascular endothelial cells, and with CS-1 and/or osteopontin expressed by parenchymal cells in the brain. Data from an experimental autoimmune encephalitis animal model of multiple sclerosis demonstrate reduction of leukocyte migration into brain parenchyma and reduction of plaque formation detected by magnetic resonance imaging (MRI) following repeated administration of natalizumab. The clinical significance of these animal data is unknown".

"In Crohn’s disease, the interaction of the α4β7 integrin with the endothelial receptor MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of the disease. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T lymphocytes to gut lymph tissue found in Peyer’s patches. MAdCAM-1 expression has been found to be increased at active sites of inflammation in patients with CD, which suggests it may play a role in the recruitment of leukocytes to the mucosa and contribute to the inflammatory response characteristic of CD. The clinical effect of natalizumab in CD may therefore be secondary to blockade of the molecular interaction of the α4ß7-integrin receptor with MAdCAM-1 expressed on the venular endothelium at inflammatory foci. VCAM-1 expression has been found to be upregulated on colonic endothelial cells in a mouse model of IBD and appears to play a role in leukocyte recruitment to sites of inflammation. The role of VCAM-1 in CD, however, is not clear."..

Link to a rare brain disease in combination therapy

While the drug was shown to be powerfully effective for both preventing relapses of MS and for induction of and sustaining remission in Crohn's Disease, it was announced on February 28, 2005 that one fatal and one non-fatal case of a rare, often lethal brain disease known as progressive multifocal leukoencephalopathy (PML) were found in two patients given natalizumab in combination with interferon beta-1a (Avonex) 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 clamored for the return of natalizumab to the market, in part because of its powerful 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 acquired PML.

Re-Authorization for MS in USA; Authorization for MS in EU

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 re-approved it for patients with relapsing forms of MS as a first-line or second-line therapy for MS. The FDA stated: "FDA would like to clarify to the reader that the MS indication for Tysabri was carefully written by FDA and the Sponsor to indicate that its use is generally recommended for patients who have had an inadequate response to, or are unable totolerate, alternative multiple sclerosis therapies (e.g., as second-line therapy). However, the indication statement does not explicitly preclude the possibility of first-line therapy in some MS patients as part of the approved use. FDA recognizes that the health care provider needs to consider its use based on the unique circumstances of each patient.

They also included a special restricted distribution program known as the TOUCH Prescribing Program ("TOUCH" stands for "Tysabri Outreach: Unified Commitment to Health"). Under this program, only prescribers, infusion centers, and specialty pharmacies trained and enrolled in the TOUCH program can prescribe and administer Tysabri. Additionally, patients must also be enrolled in the TOUCH program, so that they may be educated on Tysabri as well as periodically evaluated while being treated with Tysabri.

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 relapsing forms of MS, but not subject to the TOUCH restrictions.

In recognition of the fact that the link of Tysabri to PML is unclear owing to the fact that all 3 incidences were in combination therapy with other immuno-modulating drugs, the US Food & Drugs Administration's Black Box label states: "Although the cases of PML were limited to patients with recent or concomitant exposure to immunomodulators or immunosuppressants, there were too few cases to rule out the possibility that PML may occur with TYSABRI monotherapy"

Authorization of Natalizumab for Crohn's in USA

In January 2008 the U.S. Food and Drug Administration approved natalizumab (Tysabri) for both induction of remission and maintenance of remission in Crohn's Disease.

Price

The wholesale price of Tysabri is US$2184.62 per vial. Given that natalizumab is generally administered 13 times a year, the annual costs for Tysabri is approximately US$28,400 (not including costs associated with infusion services), priced at a premium to the older generation drugs.

Natalizumab in Clinical Practice

As of late December 2007, more than 21,000 MS patients were receiving Tysabri mono-therapy without a single incidence of PML occurring..

References

1. {{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=}}
2. FDA Tysabri label http://www.tysabri.com/en_US/tysb/footer/TYSABRI-pi.pdf
3. Kleinschmidt-DeMasters BK, Tyler KL; Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med. 2005 Jul 28;353(4):369-74.
4. Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D; Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med. 2005 Jul 28;353(4):375-81.
5. "PHARMACEUTICALS: RESTRICTIONS IN USE AND AVAILABILITY" (PDF). World Health Organization. Retrieved 2007-07-23.
6. Van Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M, Verbeeck J, Geboes K, Robberecht W, Rutgeerts; "Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease". N Engl J Med. 2005 Jul 28;353(4):362-8.
7. "Evaluation of Patients Treated with Natalizumab for Progressive Multifocal Leukoencephalopathy" Yousry et al - N Engl J Med 2006;354:924-33. http://www.tixx.com/nejm924.pdf
8. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4313b1-02-FDA-Errata.pdf
9. "TYSABRI Patient Safety, tysb". Retrieved 2008-01-28.
10. 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, Jager HR, Clifford DB. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006 Mar 2;354(9):924-33.
11. Tysabri FDA Label: http://www.tysabri.com/en_US/tysb/footer/TYSABRI-pi.pdf
12. FDA news release: http://www.fda.gov/bbs/topics/NEWS/2008/NEW01775.html
13. .http://www.elan.com/News/full.asp?ID=1091942

External links

• Tysabri Natalizumab
• Elan's Tysabri information center
• Biogen's Tysabri information center
• Site created by MS patients

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• Immunosuppressive agents