Evaluation of patients treated with natalizumab finds no new cases of PML

An independent clinical and laboratory study of more than 3000 people treated with the drug natalizumab (Tysabri®) for multiple sclerosis (MS), Crohn’s disease, and rheumatoid arthritis has found no evidence of new cases of the often-fatal disorder called progressive multifocal leukoencephalopathy (PML). The laboratory component of the study was coordinated by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH), working in conjunction with the NIH Clinical Center. Clinical and neuroradiological experts from other institutions also participated. Results of the study will be published in the March 2, 2006, issue of the New England Journal of Medicine.*

Natalizumab, an immune system-modifying drug, was approved by the U.S. Food and Drug Administration in November 2004 to treat relapsing-remitting MS. Studies have shown that it can substantially reduce the frequency of relapses in that disease. However, the drug was withdrawn from the market and from clinical trials in February 2005 after the manufacturer identified 2 cases of PML in MS patients who had received the drug. A person with Crohn’s disease who had received natalizumab was also diagnosed with PML. The current study was conducted to determine whether other people treated with natalizumab were at risk of PML. Symptoms of PML include mental deterioration, problems with vision, speech, balance, and movement, and, in most cases, coma and death.

“This was an important opportunity for NIH to use its specialized expertise in cooperation with the private sector to address a pressing and unanticipated risk of a devastating disorder,” said NIH Director Elias A. Zerhouni, M.D.

“This study was designed to address a critical, immediate need for patient safety in the people who participated in clinical trials of this drug,” says Eugene Major, Ph.D., of NINDS. “We had to assess who else might be at risk.” Dr. Major served as the chair of the independent adjudication committee (IAC) that was established to evaluate the risk of PML in natalizumab-treated patients after it was withdrawn from the market. He is chief of the NINDS’ Laboratory of Molecular Medicine and Neuroscience and an expert on the virus (known as JC virus) that causes PML. Other members of the IAC were neurologist David B. Clifford, M.D., of Washington University School of Medicine in St. Louis, and neuroradiologist Tarek Yousry, M.D., of the Institute of Neurology, Queens Square in London, U.K.

While the study did not find any evidence for new cases of PML, the researchers cannot say for certain that the patients who received natalizumab will not develop the disease in the future, Dr. Major cautions. The risk associated with longer-term treatment with natalizumab is also unknown.

Most people in the world are exposed to JC virus during childhood, and antibodies to the virus are detectable throughout life. However, the initial infection usually does not cause noticeable symptoms. PML is extremely rare and, when it occurs, it is almost always in people whose immune systems are compromised.

The researchers invited patients who had received natalizumab in clinical trials for MS, Crohn’s disease, and rheumatoid arthritis to take part in the evaluation. A total of 3,116 patients exposed to natalizumab participated. They underwent a detailed clinical history, physical examination, and brain magnetic resonance imaging (MRI) scans. Some patients’ cerebrospinal fluid was tested for JC virus DNA. The IAC reviewed the clinical information and MRIs of patients who were identified as having signs of possible PML. Dr. Major’s research team at NINDS, in conjunction with the Department of Laboratory Medicine at NIH, analyzed the cerebrospinal fluid samples for JC virus DNA. The manufacturers of natalizumab, Biogen Idec and Elan Pharmaceuticals, provided support for the clinical procedures and MRIs. The companies also provided some reagents and supplies for laboratory testing.

A total of 44 patients were referred to the IAC because of clinical findings of possible PML, abnormalities on MRI, or a high blood level of JC virus. None of them had detectable JC virus DNA in the cerebrospinal fluid. Only the three previously reported cases of PML were confirmed. The data suggested that the risk of PML associated with natalizumab was approximately 1 in 1000 among these patients, who had been treated with natalizumab for an average of 17.9 months.

The study did not formally include patients who were treated with natalizumab outside of clinical trials. However, since PML is a very severe disease, it is likely that any PML in other patients who received natalizumab would have been diagnosed, the researchers say.

The results of this study are important not only for natalizumab, but also for similar drugs that are now in development, says Dr. Major. “Even under close evaluation, PML remains a rare disease. But as we alter the immune system, we need to understand what unintended effects it might have. This experience tells us that we need to understand more about how the JC virus causes disease in order to find ways to intervene.” In the future, it might be possible to monitor people given natalizumab and similar drugs for activation of the JC virus in order to prevent PML, he adds.