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Assessing the Withdrawal of Natalizumab

What does the withdrawal of this MS drug mean for patients?

Natalizumab (Tysabri) was approved by the U.S. FDA to treat relapsing forms of multiple sclerosis (MS) in November 2004. On February 28, 2005, the manufacturer (Biogen Idec) suspended all use of the drug after discovering progressive multifocal leukoencephalopathy (PML; an opportunistic brain infection caused by JC virus) in two people who received natalizumab in clinical trials.

Natalizumab, a monoclonal antibody directed against the 4 subunit of 4ß1 and 4ß7 integrins, prevents immune cells from docking with the VCAM receptor on the vascular endothelium and penetrating the CNS. The FDA had expedited approval of the drug on the basis of highly positive 1-year efficacy data from two Phase III placebo-controlled clinical trials. In both the AFFIRM trial (natalizumab monotherapy) and the SENTINEL trial (natalizumab added to weekly interferon beta-1a), marked reduction of clinical relapse rate and MRI activity occurred in the active-drug arms. In both studies, natalizumab was very well tolerated (hypersensitivity reactions in <4% of patients).

Both PML patients had been taking the combination of IFNB-1a and natalizumab for more than 2 years. One died; the other remains alive at this writing. Subsequent to these two cases, another fatal case of PML was uncovered in a man who had originally been misdiagnosed with a malignant astrocytoma. That patient had received only eight treatments of natalizumab (in a clinical trial for Crohn disease) but had also received azathioprine early in his natalizumab treatment course. These three cases (abstracts available at http://content.nejm.org/early_release/index.shtml#6-9-05) have now been published (case 1; case 2; and case 3).

Comment: The stunning chain of events concerning natalizumab has dealt a shocking blow to many patients who had pinned their hopes on what appeared to be an extremely effective new agent. It also has dashed the hopes of clinicians and discouraged hundreds of natalizumab investigators worldwide. Why PML emerged in patients without other opportunistic infections remains a mystery. JC virus, believed to reside in as many as 80% of clinically asymptomatic adults, probably is harbored in B cells within the bone marrow. It is frequently shed in urine. The mechanism by which it is activated to cause neurologic disease in natalizumab recipients remains unclear and is being investigated.

The initial possibility that PML development depended on the combination of interferon with natalizumab was refuted by the discovery of the third patient, who had not received interferon. However, that patient had received other immune-suppressing drugs, so a glimmer of hope remains that natalizumab might safely be used as the sole immunologically active agent. Whether the FDA will permit the drug to reenter the marketplace remains to be seen and will undoubtedly depend on the results of further investigations. If the drug is allowed back, it would likely be with substantial warnings, probably with restriction to use in patients in whom other approved treatments fail, and with procedures to ensure close monitoring of patients.

— Aaron Miller, MD

Dr. Miller is Professor of Neurology, Mount Sinai School of Medicine, and Medical Director, Corinne Goldsmith Dickinson Center for Multiple Sclerosis, New York City.

Published in Journal Watch Neurology July 7, 2005