Natalizumab in Relapsing Multiple Sclerosis—FDA Panel Recommends Use of Drug with Restrictions

Abstracts & Commentary

By Brian R. Apatoff, MD, PhD, Director, Multiple Sclerosis Clinical Care and Research Center, Department of Neurology and Neuroscience, NewYork-Presbyterian Hospital, Cornell Campus. Dr. Apatoff is on the speaker's bureau for Biogen and Teva.

Synopsis: In 2 studies involving more than 2000 relapsing MS patients followed for 2 years, monthly infusions of natalizumab (Tysabri) were shown to be highly effective in reducing the clinical and MRI measures of disease activity. Although voluntarily suspended from the market for more than one year because of 2 cases of Progressive Multifocal Leukoencephalopathy, the FDA advisory panel said the drug should return with certain restrictions, including a mandatory patient registry.

Sources: Polman CH, et al. A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis. N Engl J Med. 2006;354:899-910; Rudick RA, et al. Natalizumab Plus Interferon Beta-1a for Relapsing Multiple Sclerosis. N Engl J Med. 2006;354:911-923; Yousry TA, et al. Evaluation of Patients Treated with Natalizumab for Progressive Multifocal Leukoencephalopathy. N Engl J Med. 2006;354:924-933.

In the study reported by Polman and colleagues, of 942 relapsing multiple sclerosis (MS) patients, 627 were randomized to a monthly infusion of natalizumab, 300mg, while 315 patients received a placebo infusion, for over 2 years. The primary end points were the rate of clinical relapse at one year and the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale (EDSS) at 2 years. Natalizumab reduced the risk of disability progression by 42%. Seventeen percent of patients became disabled in the natalizumab group vs 29% in the placebo group (P < 0.001). Natalizumab reduced the rate of relapse at one year by 68% (P < 0.001), and led to an 83% reduction in new or enlarging brain lesions on MRI (mean number of lesions, 1.9 with natalizumab, 11.0 with placebo; P < 0.001). Hypersensitivity allergic reactions occurred in 4% of patients, and 9% developed detectable antibodies against natalizumab, some of whom lost efficacy from the drug.

In a second study by Rudick and colleagues, 1171 patients on interferon beta-1a, 30mcg IM weekly, who had experienced at least 1 breakthrough attack in the preceding year, were randomized to monthly natalizumab (589 patients) or placebo (582 patients). The combination therapy resulted in a 24% reduction in the relative risk of sustained disability (P = 0.02). Combination therapy was associated with a lower annualized relapse rate than interferon beta-1a alone (0.34 vs 0.75, P < 0.001), and with fewer new or enlarging brain lesions on MRI (0.9 vs 5.4, P < 0.001). Two cases of progressive multifocal leukoencephalopathy (PML), one of whom died, were discovered in natalizumab patients treated for longer than 2 years (Neurol Alert. 2005). Thirty-eight patients (6%) developed persisting antibodies to natalizumab, resulting in a loss of efficacy and an increase in allergic infusion-related adverse events.

Following the reported cases of PML in natalizumab-treated patients, an independent expert panel reviewed the data from 3116 patients who were exposed to a mean of 17.9 monthly doses of natalizumab (including MS, Crohn's disease, or rheumatoid arthritis). Yousry and colleagues reported additional MRI data from all patients, and cerebrospinal fluid (CSF) testing for JC virus DNA in 396 patients. No additional cases of PML were detected, suggesting a risk of PML of roughly one in 1000 patients treated with natalizumab for a mean of 17.9 months.


Natalizumab is a recombinant monoclonal antibody against alpha-4 integrins that blocks the adhesion of activated T cells to the vascular endothelium, and reduces the trafficking of inflammatory lymphocytes into the central nervous system. The premature release of natalizumab by the FDA on incomplete one-year safety-efficacy data from the above 2-year clinical trials was reasonable, given the superior benefits of drug to currently available drugs (interferon-beta and glatiramer acetate), and adverse events similar to other humanized monoclonal antibodies, in terms of allergic hypersensitivity reactions. While natalizumab was heralded as a selective immunomodulating drug for MS and possibly other autoimmune disorders, there was scrutiny toward the possibility of increased infection and neoplasm in treated patients, given that this important function of immune surveillance would be impaired. While there was no obvious increase in conventional infections such as urinary tract infections or sinusitis, the medical community was stunned when the drug was suspended in February 2005, shortly after its release, when 3 cases of PML were reported. Those cases of PML in MS appeared in 2 patients in the combination trial where natalizumab was used in conjunction with interferon beta-1a, for over 24 months. While there is no clear explanation why a natural anti-viral agent such as interferon-beta should increase this risk, it is possible that interferon-beta further reduced lymphocyte entry into the CNS and contributed to a subtle level of lymphopenia, to increase the relative risk of PML. In the case of Crohn's disease, the patient had only been treated for several months with natalizumab, but was on additional immunosuppressants such as azathioprine and corticosteroids.

Given that natalizumab provides a therapeutic advance in the treatment of MS, by reducing relapses, clinical disability, and brain MRI lesions, it is not surprising that the FDA advisory panel recently recommended that sales of the drug should resume with a black box warning if Biogen creates a mandatory patient registry to track adverse events and imposes other controls on its use. The panel was mixed in its view whether natalizumab should be used as a first-line agent for MS, or whether it should just be applied in patients with more refractory disease who had failed other therapies. The panel indicated that natalizumab should not be used in combination with interferon-beta or other immunomodulatory drugs, other than periodic corticosteroid treatment for relapses, and be used only for relapsing forms of MS at centers experienced in the use of natalizumab and its potential complications. Despite these safeguards and its use as a monotherapy, it is likely, however, that additional cases of PML will emerge at some low frequency as patients are treated natalizumab over longer periods of time. Hopefully future cases of PML, if recognized early enough, can be treated by abrupt cessation of the drug. The prescribing neurologist will need to have a complex discussion with prospective patients regarding the risks and benefit of this effective drug, with the unfortunate side-effect of a possible fatal brain infection.