How Tysabri works
Multiple sclerosis (MS) is a progressive immune-mediated neurodegenerative disorder. Immune cells cross the blood-brain barrier (the endothelial cells that form the blood vessels in the brain and provide a barrier between the brain and the blood) and attack the protein coat called myelin that protects the nerve cells. Without myelin, nerve impulses are interrupted or poorly transmitted, which results in impaired vision and loss of muscle control and balance, among other symptoms. RRMS is the most common form of MS where patients go through periods of worsening neurological symptoms (relapse) followed by periods of partial or complete recovery (remission).
Tysabri is an antibody therapy which treats relapsing MS by blocking the entry of immune cells into the brain.
Ordinarily, in order to cross the blood-brain barrier, immune cells must interact with a protein complex found on the surface of endothelial cells that make up blood-brain barrier. This complex is made up of two proteins, VCAM-1 and alpha-4-beta-1-integrin. Tysabri contains an antibody that recognizes and binds to alpha-4-beta-1-integrin, preventing binding to VCAM-1 and blocking entry of immune cells to the brain.
Tysabri is administered by intravenous (into-a-vein) or subcutaneous (under-the-skin) injection, at a dosage of 300 mg, once every 28 days.
Tysabri in clinical trials
A literature review of a Phase 3 clinical trial data of Tysabri in patients with RRMS was published in the journal Therapeutics and Clinical Risk Management. The study found that, after two years of Tysabri treatment, the average relapse rate was reduced by 68 percent in patients with RRMS compared to placebo. Moreover, the number of new or enlarging MS lesions was decreased by 83 percent compared to placebo. Six percent of patients developed an immune response to the treatment itself, which resulted in a loss of treatment effectiveness.
An observational clinical trial (NCT00493298) is currently recruiting 6,000 RRMS patients in Europe, Australia, Canada, and Argentina to assess Tysabri’s long-term safety and effect on disease activity and progression. The number of patients who experience severe adverse events will be recorded, as well as the annual relapse rate (a measure of disease progression), for 10 years after beginning Tysabri treatment.
Preliminary results from the first five years of the trial were published in the Journal of Neurology, Neurosurgery, and Psychiatry. Of the 4,821 patients enrolled, 468 were followed for at least four years, and 2,496 for at least two years. No new safety concerns have been raised, and a lower annual relapse rate was observed, which remained low at five years. Many patients discontinued treatment (25 percent) or withdrew from the study (15 percent). The most common reason for patients withdrawing from the study was an infection. Fifty-one patients discontinued treatment following serious adverse events.
Tysabri increases the risk of a rare type of brain infection called progressive multifocal leukoencephalopathy (PML). Patients with a weakened immune system (either through an illness like HIV or from taking immune-suppressing medications) are at higher risks to develop PML. Patients who previously have been or are currently infected with John Cunningham Virus (JCV) also are at higher risk. Long-term treatment with Tysabri (more than two years) may increase the risk of developing PML.
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