There is excellent evidence in recently published studies that natalizumab treatment for two years is effective in reducing the rate of clinical relapse of multiple sclerosis. Clinical relapses were reduced by 68 percent. Magnetic Resonance Image (MRI) brain lesions, new or enlarging, were reduced by 83 percent. Our current immunomodulatory treatments with interferon or glatiramer reduce relapses by about one-third. Natalizumab, at least for two years, appears to be about twice as effective.

Perhaps even more exciting, there was a reduction of progression of neurological deficit. The treated patients had a 17 percent incidence of progression. The placebo group’s incidence was 29 percent. If this reduction would be extended over a lifetime… Wow!

No wonder it was hailed as a wonder drug. During the four months it was commercially available, about 7,000 patients received the monthly infusions of natalizumab at least once, and some received it four times. No additional cases of PML have been reported, but scrutiny has been described as casual.

I had one patient who received two doses of natalizumab. She was very disappointed when it was withdrawn. Both before and after her treatment with natalizumab, she declined treatment with our other immunomodulatory agents because of the discomfort of the injections. Natalizumab is given once a month by intravenous infusion.

PML is a rare white matter disease that is difficult in early stages to completely separate from MS. It is a progressive neurological disease, usually occurring in immunosuppressed patients, often resulting in irreversible neurologic deterioration and death. There is no known effective treatment for PML, although reversing immune system suppression may slow or arrest progression of the disease. It is associated with JC virus, which may be latent in kidney or bone tissue. Something appears to trigger the release of the virus, which then enters the nervous system and produces a pathological response.

What should the FDA do? Natalizumab received accelerated approval by the FDA in November 2004 for reducing the frequency of exacerbations in 1,100 patients with remitting-relapsing MS, after one year of treatment. No cases of PML had been reported. Physicians and patients had requested accelerated approval. Was it a wise decision?

On March 11, 2006, an international group of neurologists, immunologists, and radiologists headed by the Institute of Neurology, Queen Square, London, and the National Institute of Health (NIH), Bethesda, Maryland, reported an extensive evaluation to determine whether PML had developed in any other treated patients. They studied 3,417 patients who had received natalizumab for MS, Crohn’s disease, or rheumatoid arthritis. The average length of treatment was 17 months. No other cases of PML were identified.

Is the combination of natalizumab with other immunosuppressant drugs responsible for PML? The two reported cases of PML in natalizumab treated patients with MS were also being treated with interferon beta (Avonex). The case with Crohn’s disease had been treated with azathioprine (Imuran).

The FDA is currently deciding whether or not to release natalizumab again for treatment of MS. Should the FDA release it? The risk appears to be low in patients treated with natalizumab alone, but possibly as high as 1 in 1,000 patients in the first two years of treatment. Should the FDA restrict its use to patients who have never received other immunomodulatory drugs or at least not allow its use concomitantly?

Should the FDA await more information? What is an acceptable occurrence rate for this serious complication? If released, should we have a national registry for treatment requiring close, expensive follow-up? Tough questions! Tough decisions!

Should we give as much information as we can to the patients and their physicians and let them decide?