Natalizumab is a humanized monoclonal antibody against the cellular adhesion molecule α4-integrin. Natalizumab is 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 effective in treating the symptoms of both diseases, preventing relapse, vision loss, cognitive decline and significantly improving quality of life in people with multiple sclerosis, as well as increasing rates of remission and preventing relapse in Crohn's disease.
Natalizumab was approved in 2004 by the
Indications
Natalizumab is FDA-approved for the treatment of multiple sclerosis and Crohn's disease and approved for treatment of multiple sclerosis in
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.[2] Natalizumab also slowed the progression of disability in patients with relapsing MS. In combination with interferon beta-1a (IB1A), relapsing and disability progression were reduced more than IB1A alone. Other benefits of natalizumab use by patients with relapsing MS included reduced visual loss,a significant increase in the proportion of disease-free individuals, significantly improved assessments of health-related quality of life in relapsing individuals, reduced cognitive decline of a portion of individuals with MS, reduced hospitalizations and steroid use, and prevention of the formation of new lesions.[2][10] Approximately 6% of individuals receiving natalizumab have been found to develop persistent antibodies to the drug, which reduces its efficacy[11][12][4] and produce reactions during the infusion of the drug, as well as hypersensitivity.[4] Natalizumab is approved in the United States and the European Union. It is indicated as monotherapy (not combined with other drugs) for the treatment of highly active relapsing remitting MS in spite of prior treatments. 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.
Crohn's disease
Several randomized controlled trials have demonstrated that natalizumab is effective in increasing rates of remission[13] and maintaining symptom-free status[14] in patients with Crohn's disease. Natalizumab may be appropriate in patients who do not respond to medications that block tumor necrosis factor-alpha such as infliximab,[15] with some evidence to support combination treatment of Crohn's disease with natalizuma and infliximab may be helpful in inducing remission.[16] Treatment of adolescent patients with natalizumab demonstrates an effectiveness similar to that of adult patients.[17]
In January 2008, the FDA approved natalizumab for both induction of remission and maintenance of remission for moderate to severe Crohn's disease,[18] though it has not been approved for this use in the European Union due to concerns over its risk/benefit ratio.[19]
Adverse effects
Common adverse effects include fatigue and allergic reactions with a low risk of anaphylaxis,[20] headache, nausea, colds and exacerbation of Crohn's disease in a minority of patients with the condition.[16] Adolescents with Crohn's disease experience headache, fever and exacerbation of Crohn's disease.[17] Natalizumab is contraindicated for people with known hypersensitivity to the drug or its components and in patients with a history of PML (see interactions).
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.[21][22][23] This rate is comparable to other immune-suppressing drugs.[24] 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.[25] Such signs reoccur upon rechallenge in some patients, indicating that damage is not coincidental.[25] In the absence of any blockage these liver function tests are predictors of severe liver injury with possible sequelae of liver transplantation or death.[25]
Natalizumab has also been linked to melanoma, though the association is unclear.[26] The long-term effects of the drug are unknown[27] and concern has been expressed over the risks of infection and cancer.[4]
Mechanism of action
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; natalizumab's mechanism of action is believed to be the inhibition these immune cells from crossing blood vessel walls to reach affected organs.[28]
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.[29]
Individuals with MS dosed with natalizumab demonstrated increased CD34-expressing cells, with research suggesting a peak in expression after 72 hours.[30]
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 syndrome and the VCAM-1 gene may also play a part in CD but its role is not yet clear.[29]
Interactions
Natalizumab appears to interact with other immune-modulating drugs to cause progressive multifocal leukoencephalopathy (PML), an often-fatal opportunistic viral infection. In 2005, two people taking natalizumab in combination with interferon beta-1a developed PML. One died, and the other recovered with disabling sequelae.[31][32] A third fatal case initially attributed to an astrocytoma was reported in a patient being treated for Crohn's disease.[33] 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.[33] No deaths have been linked to natalizumab when it was not combined with other immune-modulating drugs[34] and other rates of opportunistic infections are not increased in patients taking natalizumab[35] possibly due to the drug’s mechanism of action.[36] Other than a prior history of PML, there is no known method to identify patients at risk of developing PML.[37] Natalizumab's label indicates that it is contraindicated for immunosuppressed individuals or those with a history of PML.[29] Due to the uncertain risk of PML, natalizumab is only available through a restricted distribution program.[29] As of 2008, no other cases of PML associated with natalizumab have been reported.[37]
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.[29] 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.[29] The risk of developing PML was later estimated to be 1 in 1,000 (0.1%) over 18 months[11][35][38] though the longer term risks of PML are unknown.[11]
Legal status
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[39] 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.[40][41] Patients taking natalizumab must enter into a registry for monitoring.[39] Natalizumab is the only drug after alosetron withdrawn for safety reasons that returns to the US market.
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.[1]
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