Natalizumab

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Natalizumab
Humanized (from mouse)
Targetalpha-4 integrin
Clinical data
Trade namesTysabri, others
Other namesAN100226M, Antegren
Biosimilarsnatalizumab-sztn,[1] Tyruko[1]
AHFS/Drugs.comMonograph
MedlinePlusa605006
License data
Pregnancy
category
Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailabilityn/a
Elimination half-life11 ± 4 days
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Molar mass149 kg/mol
 ☒NcheckY (what is this?)  (verify)

Natalizumab, sold under the brand name Tysabri among others, is a medication used to treat

intestines and blood–brain barrier.[medical citation needed
]

Natalizumab, is a monoclonal antibody which targets a protein called α4β1 integrin on white blood cells involved in inflammation.[9] By attaching to integrin, natalizumab is thought to stop white blood cells from entering the brain and spinal cord tissue, thereby reducing inflammation and the resulting nerve damage.[9]

The most common side effects are urinary tract infection, nasopharyngitis (inflammation of the nose and throat), headache, dizziness, nausea, joint pain and tiredness.[9]

Natalizumab was approved for medical use in the United States in 2004. It was subsequently withdrawn from the market by its manufacturer after it was linked with three cases of the rare neurological condition progressive multifocal leukoencephalopathy (PML) when administered in combination with interferon beta-1a, another immunosuppressive drug often used in the treatment of multiple sclerosis. After a review of safety information and no further deaths, the drug was returned to the US market in 2006 under a special prescription program. As of June 2009, ten cases of PML were known. However, twenty-four cases of PML had been reported since its reintroduction by October 2009, showing a sharp rise in the number of fatalities and prompting a review of the chemical for human use by the European Medicines Agency.[11] By 2010, 31 cases of PML were attributed to natalizumab while by 2018 this had risen to 757 cases.[12][13] The US Food and Drug Administration (FDA) did not withdraw the drug from the market as benefits outweigh the risks.[14] In the European Union, it has been approved only for multiple sclerosis and only by itself as the initial cases of PML, and later the fatalities, were said by the manufacturers to be linked to the use of previous medicines by the person.[15]

Medical uses

In the United states, natalizumab is

indicated for the treatment of multiple sclerosis and Crohn's disease.[1][8] 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.[1][8][16]

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.

monotherapy.[20]

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[9]
  • 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.[9]

Adverse effects

The US prescribing information for natalizumab contains a

JC virus, a typically harmless virus carried by most humans), longer duration of therapy and prior use of immunosuppressants.[9][16]

It was first observed in seven patients who received natalizumab in late 2008;

package insert accompanying the drug will be updated to include this information.[24] 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]).[25] 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.[26] 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.[27]

rechallenge in some patients, indicating that damage is not coincidental.[32] In the absence of any blockage these liver function tests are predictors of severe liver injury with possible sequelae of liver transplantation or death.[32]

Common adverse effects include

fatigue and allergic reactions with a low risk of anaphylaxis,[33] headache, nausea, colds and exacerbation of Crohn's disease in a minority of patients with the condition.[medical citation needed] Adolescents with Crohn's disease experience headache, fever and exacerbation of Crohn's disease.[medical citation needed
]

About 6% of the people in studies developed long-lasting antibodies against natalizumab, which reduced the medicine's effectiveness.[9]


Mechanism of action

Structure of a generic antibody

Natalizumab is a

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.[34]

Multiple sclerosis

The

leukocytes into the brain's parenchyma, and also reduced lesioning, though it is uncertain if this is clinically significant for humans.[8]

Individuals with MS dosed with natalizumab demonstrated increased CD34-expressing cells, with research suggesting a peak in expression after 72 hours.[35]

Crohn's disease

The interaction of the α4β7 integrin and the

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.[8]

Interactions

Natalizumab appears to interact with other immune-modulating drugs to increase the risk of

United States Food and Drug Administration reported a total of 31 confirmed cases of PML associated with natalizumab.[12]

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.[8] 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.[8] The risk of developing PML was later estimated to be 1 in 1,000 (0.1%) over 18 months[18][40][43] though the longer term risks of PML are unknown.[18]

History

Biogen Idec announced the initiation of the first clinical trial of natalizumab as a potential cancer treatment as of September 2008.[44]

Society and culture

Legal status

Natalizumab was originally approved for treatment of

first-line or second-line therapy.[46][47] Patients taking natalizumab must enter into a registry for monitoring.[45] Natalizumab is the only drug after alosetron withdrawn for safety reasons that returned to the US market.[citation needed
]

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.[9][48]

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.[49]

In 2007, the EMA rejected the application to market natalizumab for Crohn's disease due to concerns over its risk/benefit ratio.[50] In January 2008, the FDA approved it for the induction of remission and maintenance of remission for moderate to severe Crohn's disease.[51]

Biosimilars

On 20 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.[52] The applicant for this medicinal product is Sandoz GmbH.[52][53] Tyruko was approved for medical use in the European Union in September 2023.[10]

In August 2023, the FDA approved approved Tyruko (natalizumab-sztn) and granted approval to Sandoz Inc.[16][54]

References

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Further reading
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