Tysabri..Natalizumab
Natalizumab is a humanized monoclonal antibody against the cellular adhesion molecule a4-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 U.S. Food and Drug Administration (FDA).
It was subsequently withdrawn from the market by its manufacturer after it was linked with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.
By January 2010, 31 cases of PML were attributed to natalizumab.
The FDA has not withdrawn the drug from the market because its clinical benefits outweigh the risks
involved. In the European Union, it has been approved for human use only for the treatment of
multiple sclerosis and only then as a monotherapy because 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 deceased customers.
Biogen Idec announced the initiation of the first clinical trial of Tysabri as a
potential cancer treatment as of September 5, 2008.
Indications
Natalizumab is FDA-approved for the treatment of multiple sclerosis and Crohn's disease and
approved for treatment of multiple sclerosis in Europe,
but is currently under review by the EMEA.
Multiple sclerosis
Further information: Multiple sclerosis and Treatment of 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. 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.
Approximately 6% of individuals receiving natalizumab have been found to develop persistent
antibodies to the drug, which reduces its efficacy and produce reactions during the infusion
of the drug, as well as hypersensitivity.
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.
Adverse effects
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.
This rate is comparable to other immune-suppressing drugs.
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.
Such signs reoccur upon rechallenge in some patients,
indicating that damage is not coincidental.
In the absence of any blockage these liver function tests are predictors of severe liver
injury with possible sequelae of liver transplantation or death.
Natalizumab has also been linked to melanoma, though the association is unclear.
The long-term effects of the drug are unknown and concern has been expressed over the risks
of infection and cancer.
Progressive multifocal leukoencephalopathy, an opportunistic infection caused by the JC virus,
and that typically occurs in patients who are immunocompromised, developed in seven patients
who received natalizumab ; three cases were noted in clinical trials in 2006 leading to the drug
being temporarily pulled from the market; two cases were reported to the FDA in August 2008 ; and,
two cases were announced in December 2008 .
A recent preliminary study suggests that patients on this drug for more than 12 months are at
elevated risk for PML .
Mechanism of action
Structure of a generic antibodyNatalizumab is a humanized monoclonal antibody against
alpha-4 (a4) integrin, the first drug developed in the class of selective adhesion
molecule inhibitors. a4-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.
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 a4ß1-integrin receptor molecules on the surfaces of cells.
The effect 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.
Individuals with MS dosed with natalizumab demonstrated increased CD34-expressing cells,
with research suggesting a peak in expression after 72 hours.
Interactions
Natalizumab appears to interact with other immune-modulating drugs to increase
the risk of progressive multifocal leukoencephalopathy (PML),
an often-fatal opportunistic infection caused by JC virus.
In 2005, two people taking natalizumab in combination with interferon beta-1a developed PML.
One died, and the other recovered with disabling sequelae.
A third fatal case initially attributed to an astrocytoma was reported in a patient being
treated for Crohn's disease.
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. No deaths have been linked to natalizumab when
it was not combined with other immune-modulating drugs and other rates of opportunistic
infections are not increased in patients taking natalizumab possibly due to the drug’s mechanism
of action. Other than a prior history of PML, there is no known method to identify patients
at risk of developing PML. Natalizumab's label indicates that it is contraindicated for
immunosuppressed individuals or those with a history of PML.
Due to the uncertain risk of PML, natalizumab is only available through a restricted distribution
program.
As of June 2009, ten cases of PML associated with natalizumab have been reported.
At least one of them had not previously taken any other inmunomodulator therapy.
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. 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.
The risk of developing PML was later estimated to be 1 in 1,000 (0.1%) over 18 months
though the longer term risks of PML are unknown.
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 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. Patients taking natalizumab must enter into a registry for monitoring.
Natalizumab is the only drug after alosetron withdrawn for safety reasons that returned 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.
Health Canada added natalizumab to Schedule F of the Food and Drug Regulations on
April 3rd, 2008 as a prescription drug requiring oversight from a physician.
The information about this subject is edited, and shortened. The subject is based on this article
editor: H.m.Hanse copyright in accordance with the GNU licence