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Medical Areas: Neurology | Family Medicine
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The following drug information is obtained from various newswires, published
medical journal articles, and medical conference presentations.
Company: Elan Pharmaceuticals / Biogen Idec
Approval Status: Approved November 2004 -- Updated: Suspended February 2005--Updated: sBLA
Treatment Area: Multiple Sclerosis
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
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
Adverse events associated with the use of TYSABRI may include
(but are not limited to) the following:
- Hypersensitivity Reactions
- Cholelithiasis (gallstones)
- Urticaria (hives)
- Irregular menstruation
Mechanism of Action
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;
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