TYSABRI (natalizumab) is a recombinant humanized IgG4k monoclonal antibody produced in murine myeloma cells. In development, TYSABRI was originally slated to be named Antegren, but FDA regulators forced a change due to name confusion with existing products such as Integrilin and Edecrin.
TYSABRI is indicated for the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations. This indication is based on results achieved after approximately one year of treatment in ongoing controlled trials of two years in duration. The safety and efficacy of TYSABRI beyond one year are unknown.
The recommended dose of TYSABRI is 300 mg IV infusion every four weeks.
On February 28, 2005, Biogen Idec and Elan announced a voluntary suspension of the marketing of TYSABRI.
On June 5, 2006 Biogen Idec and Elan announced the approval of a supplemental Biologics License Agreement (sBLA) by the FDA, for the reintroduction of TYSABRI as a monotherapy treatment for relapsing forms of multiple sclerosis. This approval for reintroduction was based on the review of TYSABRI trial data, a revised labeling with enhanced safety warnings and a risk management plan (TOUCH Prescribing Program) designed to inform of the potential risk of progressive multifocal leukoencephalopathy (PML).
FDA approval of TYSABRI for the treatment of MS was based on two
randomized, double-blind, placebo-controlled trials with over 2,000
subjects. Subjects were enrolled if they had experienced at least
one relapse during the prior year and had a score of between 0 -
5.0 on the Kurtzke Expanded Disability Status Scale (EDSS). In both
studies, neurological evaluations were performed every 12 weeks and
at times of suspected relapse. Magnetic resonance imaging
evaluations for T1-weighted gadolinium (Gd)-enhancing lesions and
T2-hyperintense lesions were performed annually.
All 942 subjects enrolled in this study had not received any interferon-beta or glatiramer acetate for at least the previous 6 months. In fact, roughly 94% had never been treated with these agents. The median age was 37, with a median disease duration of 5 years. Subjects were randomized to receive TYSABRI (300mg IV infusion) or placebo every 4 weeks for up to 28 months. Results showed that subjects who received TYSABRI had a relapse rate (annualized) of .25 compared with .74 for subjects taking placebo. 76% of subjects taking TYSABRI had remained relapse free compared with 53% of subjects taking placebo.
All 1,171 subjects enrolled in this study had experienced one or more relapses while on treatment with Interferon beta-1a (30 mcg intramuscularly) once weekly during the year prior to study entry. The median age was 39, with a median disease duration of 7 years. Subjects were randomized to receive TYSABRI (300mg IV infusion) or placebo every 4 weeks for up to 28 months. Subjects continued taking Interferon beta-1a at their normal dosing once weekly. Results showed that subjects who received TYSABRI had a relapse rate (annualized) of .36 compared with .78 for subjects taking placebo. Data demonstrated that 67% of subjects taking TYSABRI had remained relapse free compared with 46% of subjects taking placebo.
Adverse events associated with the use of TYSABRI may include (but are not limited to) the following:
MS is an auto-immune disease that damages and prevents the creation of the tissues that protect nerves, called myelin. This creates lesions, or scar tissue known as sclerosis. Lesions are believed to occur when activated inflammatory cells, including T-lymphocytes, cross the blood-brain barrier. Leukocyte migration involves interaction between adhesion molecules on inflammatory cells, and their counter-receptors present on endothelial cells of the vessel wall. The drug works by blocking the integrin molecule and preventing immune cells from migrating through blood vessels in the brain to areas of inflammation; however the specific mechanism by which TYSABRI exerts its effects in multiple sclerosis have not been fully defined.
Preclinical results from animal models of autoimmune encephalitis of multiple sclerosis demonstrated a reduction of leukocyte migration into brain parenchyma and reduction of plaque formation detected by magnetic resonance imaging (MRI) following repeated administration of natalizumab. The clinical significance of these animal data is unknown.
Elices MJ. Natalizumab. Elan/Biogen. Curr Opin Investig Drugs. 2003 Nov;4(11):1354-62. Review.
O'Connor PW, Goodman A, Willmer-Hulme AJ, Libonati MA, Metz L, Murray RS, Sheremata WA, Vollmer TL, Stone LA Natalizumab Multiple Sclerosis Trial Group. Related Articles, Links Randomized multicenter trial of natalizumab in acute MS relapses: clinical and MRI effects. Neurology. 2004 Jun 8; 62(11):2038-43.
Vollmer TL, Phillips JT, Goodman AD, Agius MA, Libonati MA, Giacchino JL, Grundy JS. An open-label safety and drug interaction study of natalizumab (Antegren) in combination with interferon-beta (Avonex) in patients with multiple sclerosis. Mult Scler. 2004 Oct; 10(5):511-20.
For additional information regarding TYSABRI or multiple sclerosis, please contact The Tysabri web page