Natalizumab Injection (Tysabri)
A new agent has received expedited FDA approval for the treatment of relapsing multiple sclerosis (MS). Natalizumab is the first humanized monoclonal antibody to be approved for MS and is believed to work by inhibiting adhesion of molecules to the surface of immune cells, thus preventing these cells from migrating into the brain from the bloodstream. Natalizumab is manufactured by Biogen and marketed by Elan as Tysabri.
Indications
Natalizumab is indicated for the treatment of relapsing multiple sclerosis to reduce the frequency of clinical exacerbation.1
Dosage
The recommended dose is 300 mg by intravenous infusion, over 1 hour, every 4 weeks. The patient should be observed during infusion and 1 hour after completion for signs or symptoms of hypersensitivity-type reactions.1
Potential Advantages
Natalizumab has a different mechanism of action than existing drugs such as interferon beta-1a and 1b and glatiramer. Addition of natalizumab to interferon beta results in further reduction of exacerbations and reduces the number of lesions detected by MRI.1
Potential Disadvantages
Natalizumab requires intravenous infusion over 1 hour while other products can be given by subcutaneous or intramuscular injection. (Mitoxantrone also requires infusion, but is approved for advanced or chronic MS). Serious hypersensitivity reactions have been reported with natalizumab (< 1%). These generally occur within 2 hours of the start of infusion and are characterized by urticaria, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea, and chest pain.1 Patients should be observed for 2 hours after infusion of the drug. Natalizumab increases circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Other side effects include serious infections (2.1% vs 1.3% for placebo), fatigue (24% vs 18%), arthralgia (15% vs 11%), and irregular menstruation/dymenorrhea (7% vs 2%). Anti-natalizumab antibodies have been detected in about 10% of patients. These have been associated with reduction in serum natalizumab and infusion related reactions.1 Long-term effectiveness and safety remains to be established.
Comments
Natalizumab is believed to bind to the 4-subunit, and 4 1 and 4 7 integrins expressed on the surface of all leukocytes except neutrophils.1,2 Integrins on circulating leukocytes bind to vascular cell adhesion molecule that is expressed at high levels in the CNS during MS exacerbations.3 Animal models indicate that the natalizumab reduces leukocyte migration into the brain, reducing MRI detected plaque formation.1 The approval of natalizumab was based on 1-year analysis of 2 phase III, randomized controlled studies. One was a placebo-controlled monotherapy trial (AFFIRM) (n = 942) and the other an add-on study with interferon beta-1a (SENTINEL) (n = 1171). In monotherapy, natalizumab reduced the annualized relapse rate by 66% (0.25 vs 0.74) and resulted in fewer patients with MRI detected and gadolinium-enhancing lesions (60% vs 22% with no new or newly enlarging T2-hyperintense lesions and 96% and 68% with no gadolinium-enhancing). In contrast, in the SENTINEL study, natalizumab or placebo was added to interferon beta-1a in patients who had experienced one or more relapses on interferon beta-1a. Natalizumab reduced the annualized relapse rate by 54%, (0.36 vs 0.78) reduced the number of new or newly enlarging, T2 hyperintense lesions and gadolinium-enhancing lesions detected by MRI (no lesions in 67% vs 40%, 96% vs 76%).1
The wholesale cost of natalizumab is $1808 per 4 weeks. This is 14-47% more expensive than interferon beta and glatiramer.4
Clinical Implications
Multiple sclerosis affects about 1 million individuals, and twice as many women as men. First symptoms generally occur between ages 20 and 40.5 The clinical patterns of the disease include relapsing-remitting, secondary-progressive, primary-progressive, and progressing-relapsing.6 None of the currently approved agents is a cure but all have proven partial success in reducing exacerbations and may slow the disease progression.7 Switching monotherapy or combination therapy may be considered with breakthrough disease.2 Interferon beta and glatiramer are generally first line monotherapy for relapsing remitting disease. Natalizumab provides an alternative agent to interferon beta and glatiramer with a different mechanism of action. Natalizumab has demonstrated efficacy when added-on to interferon beta-1a. The 2-year results of the AFFIRM and SENTINEL trials are expected in the first half of 2005.
References
1. Tysabri Product Information. Biogen Idec Inc and Elan Pharmaceuticals. November 2004.
2. Weinstock-Guttman B and R. Bakshi. CNS Drugs. 2004;18(12):777-792.
3. Adis International. Drugs RD. 2004;5(2):102-107.
4. www.nationalmssociety.org/Research-TysabriQ&A.asp
6. Giovannoni G. CNS Drugs. 2004;18(10):653-669.
7. Calabresi PA. Am Fam Physic. 2004;70:1935-1944.
A new agent has received expedited FDA approval for the treatment of relapsing multiple sclerosis.
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