It was approved by the U.S. Food and Drug Administration (FDA) in November 2004 to treat adults with relapsing forms of the disease, including clinically isolated syndrome, relapsing-remitting MS (RRMS), and active secondary progressive MS.
The European Commission also approved Tysabri in June 2006 for the treatment of RRMS in adults with highly active disease. According to Biogen, the therapy is available in more than 80 countries across the globe.
Tysabri can be administered by intravenous (into-the-bloodstream) or subcutaneous (under-the-skin) injection, at a dosage of 300 mg, every four weeks. The subcutaneous formulation, expected to reduce dosing time and treatment burden, was approved in the European Union, but rejected by the FDA. Biogen plans to apply for regulatory approval of this formulation in several other countries.
How Tysabri works
In MS, immune cells cross the blood-brain barrier and mistakenly attack myelin, the fatty molecule surrounding nerve fibers that is key for proper nerve cell communication. The blood-brain barrier is a specialized membrane that prevents large molecules and harmful microorganisms circulating in the blood from entering the brain and spinal cord (central nervous system or CNS). Without myelin, nerve impulses are interrupted or poorly transmitted, leading to MS symptoms.
To reach the CNS, immune cells must interact with the blood vessel cells that make up the blood-brain barrier. This interaction involves the binding of the alpha-4-beta-1-integrin protein at the surface of immune cells to VCAM-1, a protein found at the surface of blood vessel cells.
Tysabri is an antibody that binds to and blocks the activity of alpha-4-beta-1-integrin, preventing its interaction with VCAM-1 and thereby the entry of immune cells into the brain and spinal cord.
Tysabri in clinical trials
The international, placebo-controlled Phase 3 AFFIRM clinical trial (NCT00027300) evaluated the long-term safety and effectiveness of Tysabri in adults with relapsing MS. Participants were assigned randomly to receive Tysabri (627 patients) or a placebo (315 patients), every four weeks, for up to two years.
Results showed that two years of treatment with Tysabri was generally safe and significantly reduced the mean relapse rate by 68% and the number of new or enlarging brain lesions by 83%, compared with a placebo. A total of 6% of patients developed a sustained immune response to the treatment itself, which resulted in a loss of treatment effectiveness.
In another Phase 3 trial, called SENTINEL (NCT00030966), adding Tysabri to the standard regimen of Biogen’s Avonex (interferon beta-1a) in RRMS patients was found to significantly drop the mean annual relapse rate by 55% and the risk of sustained disability progression by 24%, at two years, compared with interferon beta-1a alone.
The Biogen-sponsored Tysabri Observational Program (TOP; NCT00493298) is assessing Tysabri’s long-term safety and effectiveness in 6,620 RRMS patients recruited at sites in Europe, Australia, Canada, and South America. It is the largest ongoing real-world study of Tysabri’s use by RRMS patients. The rate of serious adverse events is being assessed, as well as patients’ annual relapse rate and disability progression — as measured with the expanded disability status scale (EDSS) — for up to 15 years after initiating Tysabri. The trial is expected to conclude in January 2029.
Both five-year and 10-year interim TOP data showed that Tysabri consistently reduced relapse rates and slowed disease progression, with patients showing stable EDSS scores for 10 years. No new safety concerns were identified with long-term treatment. A specific analysis of TOP’s 11-year results demonstrated that nearly one-quarter (23.9%) of patients achieved confirmed disability improvement (CDI) during the study. CDI was defined as a one point or greater drop on the EDSS, indicative of lesser disability. Most (68.1%) of these patients maintained the CDI status over the duration of their follow-up.
The Biogen-sponsored, international REVEAL clinical trial (NCT02342704, EUCTR2013-004622-29-IT) and the France-based BEST-MS study (NCT01981161) compared the effectiveness of Tysabri with that of Novartis’s Gilenya (fingolimod), also available as a generic, in more than 300 adults with RRMS.
Results from the REVEAL study showed that compared with Gilenya, Tysabri reduced the mean number of new active brain lesions by 70% after three months, with this difference being sustained through six months. Patients given Tysabri were also significantly less likely to have a relapse than those on Gilenya (1.9% vs. 22.3%).
BEST-MS data also supported Tysabri’s superiority, with a greater proportion of Tysabri-treated patients achieving no evidence of disease activity (NEDA) after one year of treatment, compared with those given Gilenya (47.8% vs. 30.4%). NEDA was defined by the absence of new or enlarging brain lesions, relapses, and confirmed disability progression. Patients receiving Tysabri also had a significantly lower relapse risk after six months of treatment (0.02 vs. 0.09 for those on Gilenya) and were more likely to have no new brain lesions on MRI at one year (70% vs. 61.6%).
Two clinical trials — the Phase 1 DELIVER study (NCT00559702) and the Phase 2 REFINE trial (NCT01405820) — compared the intravenous and subcutaneous formulations of Tysabri in about 350 people with RRMS and secondary progressive MS. Results highlighted that the two formulations were similar in their effectiveness, safety, pharmacokinetics (movement into, through, and out of the body), and pharmacodynamics (effects on the body).
Common side effects of Tysabri include headaches, nausea, urinary tract infections, depression, and joint pain. Injection site pain may also occur with the under-the-skin formulation. Due to its immunosuppressive effects, more than two years of Tysabri treatment has been associated with an increased risk of progressive multifocal leukoencephalopathy (PML), a rare and often fatal condition caused by the John Cunningham virus.
Increasing evidence suggests that less frequent dosing of Tysabri — every six weeks — can reduce the risk of adverse events, including PML, without compromising efficacy.
Biogen launched the international, Phase 3b NOVA clinical trial (NCT03689972) to compare the effectiveness and safety (including the associated PML risk) of Tysabri when given every four weeks or every six weeks. The trial recruited 500 adults with RRMS who were previously treated with Tysabri’s standard regimen for at least one year before enrollment. Participants were randomly assigned to receive the standard regimen or the extended interval dosing for nearly 1.5 years, after which they could enter the study’s open-label extension and receive the extended interval dosing through nearly three years. Changes in relapse rate, brain lesions, disability, and adverse event rates, among others, will be assessed. The trial is expected to finish by February 2023.
Tysabri is also approved for the treatment of Crohn’s disease.
Last updated: May 10, 2021
Multiple Sclerosis News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.