MS Specialists Question Company Disclosure of Natalizumab-Associated PML

Neurology Today
15 October 2009; Volume 9(20); p 5-7

TALAN, JAMIE

MS specialists are concerned about the decision of Biogen Idec, the manufacturer of natalizumab, to stop reporting cases of progressive multifocal leukoencephalopathy on its Web site.

Three years have passed since Biogen Idec created a public online record of new cases of progressive multifocal leukoencephalopathy (PML) caused by infection with the human polyomavirus JC virus in multiple sclerosis (MS) patients treated with natalizumab (Tysabri).

The incidence of PML continues to be rare among MS patients who are given monthly infusions of the monoclonal antibody, and the company continues to monitor and report all cases to the FDA, a mandated responsibility, Biogen Idec spokesperson Jennifer Neiman told Neurology Today.

But, Neiman said, keeping a Web-based count of the numbers is not. And after the initial three-year commitment expired, the company stopped recording PML cases on its Web site this summer; as of July 28, it recorded 11 PML cases in MS patients worldwide.

We are now communicating about the product's benefit-risk profile in a way that is more consistent with communications around other approved drugs, she said. We are no longer providing case-by-case updates on the Web site…If there is a change in the post-marketing risk it will be communicated broadly and proactively. At this time, we have not identified any change to the product's known benefit-risk profile.

As of Sept. 18, the FDA reported 15 cases of natalizumab-associated PML in MS patients worldwide since the drug was reintroduced in mid-2006. (Within a year of the 2004 FDA approval of natalizumab for MS, two patients with MS and one with Crohn disease contracted PML, and the company voluntarily withdrew the drug. But in July 2005 it was reintroduced with a black box warning about the risk of PML, which seemed to be about one in 1,000 patients who had received the infusions for at least one year.)

The discrepancy between the FDA and the company reports has some specialists in the MS community questioning the timeline for the data. In particular, they questioned the company's decision not to post their reports of PML for the public in real time.

Patients and their physicians would like to have the latest information about the risk for PML, said John Corboy, MD, professor of neurology at the University of Colorado-Denver, and co-director of the Rocky Mountain Multiple Sclerosis Center, both at the Anschutz campus. Not knowing the up-to-date risk is disconcerting. It leaves a hole in the information that we pass on to patients.

Daniel Kantor, MD, a neurologist and medical director of Neurologique, a nonprofit research, education, and treatment center in Florida, agreed, adding: PML is a serious risk and patients and doctors should be updated continuously. It can be dangerous not to know the numbers as they happen.

Dr. Corboy said he worries that this new limitation on access to data on a serious and potentially life-threatening side effect may lead some patients to refuse this therapy. To me, it was reassuring knowing what the numbers were, said Dr. Corboy. They were not higher than anticipated. Now, not having this information will remove that reassurance. I like transparency.

According to the FDA, the risk for developing PML appears to increase with the number of natalizumab infusions received. The number of monthly infusions of natalizumab in the 13 patients who developed PML ranged from 12 to 35, with an average of 25.

It is not clear whether the risk increases even more in those who continue receiving infusions. So few patients have had more than 35 infusions. The FDA said that based on available data from the US and worldwide, the current rate of PML in patients who have received at least 24 infusions ranges from 0.4 to 1.3 per 1,000 patients.

The ability to assess risk is made more complicated by the nature of PML itself; PML is another demyelinating disease. Once the ubiquitous JC virus enters the CNS, it affects cerebral oligodendrocytes - the same target that creates the lesions of MS. It is an odd twist of nature where you have two different demyelinating diseases targeting the same cell but these diseases have a very different origin and pathology, said Eugene O. Major, PhD, chief of the NINDS Laboratory of Molecular Medicine and Neuroscience.

Now, we are seeing new cases but it doesn't look like the risk of 1 in 1,000 is changing. We don't know if and when the curve can change. We need to be on our toes in the event that things change as more people take this medicine.

Two independent studies in the Sept. 10 issue of The New England Journal of Medicine (NEJM) offer insight why diagnosing PML is so difficult in patients taking natalizumab.

One study offers details about the fourth patient to be diagnosed with PML who had 14 infusions of the monoclonal antibody before he noted jerking motions of his left arm. Two months later, MRI revealed a small lesion in the subcortical region of the right motor area. The lesion was ascribed to MS. He went through a 15th infusion. By June, the symptoms intensified and his left arm was paretic. MRI then showed that the lesion was growing but again it was attributed to the MS. There was finally a suspicion of JC virus infection but PCR analysis of CSF was negative. He had a 16th infusion. Soon after, with the clinical signs worsening, a diagnosis of PML was made even though the serology remained negative. (Concurrent samples were sent to Dr. Major's lab at NINDS and they performed a quantitative PCR that tested positive for JC virus.)

By this time, the patient had been through many rounds of plasmapheresis and the downward spiraling of his disability sent him into a wheelchair. Eight weeks after the first series of five plasma exchanges, the patient was finally improving. Three months later, he could walk 300 meters with a cane and the myoclonus had subsided. The paresis also improved. A year later, he could walk a little further but still used a cane.

Claes Martin, MD, PhD, and their Swedish colleagues in the neurology department of the Karolinska Institute, who wrote the NEJM paper, said that the case reflects how easy it is to miss PML and to continue natalizumab infusions in the face of worsening symptoms.

In another NEJM study, Yiping Chen, MD, PhD, and colleagues at the Beth Israel Deaconess Medical Center and Harvard Medical School tested blood and urine samples from 19 MS patients just beginning natalizumab therapy and followed them for 18 months to determine whether exposure to the monoclonal antibody caused subclinical reactivation of the JC virus, which could explain how the latent virus gains spreads despite the natalizumab. The therapeutic antibody dampens the immune system and the opportunistic infection becomes active.

At baseline, 19 percent of the patients had evidence of JC virus in urine. After 18 months, the number climbed to 63 percent. (Normally it can be found in urine of a third of healthy people.) It also appeared in 20 percent of the plasma samples tested. It does not usually show up in the plasma of healthy individuals. The JC virus-specific cellular immune response initially climbed and then dropped between six and 12 months of treatment. No one in the small study developed clinical symptoms of PML over the course of the study.

The body's cellular immune response plays a crucial role in the containment of the JC virus, according to Dr. Chen and his colleagues. There is evidence that natalizumab triggers the release of immature leukocytes from the bone marrow and that these cells are known to harbor latent JC virus. In the rare patient, the virus is carried through the blood stream and into the brain, triggering PML.

Monitoring for JC virus in urine of patients and also after 18 months in patients with viruria could provide some insight into viral replication, the scientists wrote. Their findings suggest that natalizumab may in fact directly alter the capacity of T cells to react against JC virus. The fact that the drop in the immune response was concomitant with an increased incidence of JC viruria supports this possibility.

One of the problems in supporting this finding is that the scientists did not measure cellular immune response before treatment with natalizumab began. Until more basic science studies are done, the scientists said that they do not suggest any changes in the management of MS, since the clinical implications of this pilot study are still not known.

Dr. Major, who co-authored a March 2006 paper on PML diagnosis in the New England Journal of Medicine, said there are three consensus criteria for the diagnosis of PML: 1) clinical course of progressive disease including motor dysfunction, cognitive impairments, visual deficits, and seizures; 2) MRI evidence for lesions; and 3) presence of JCV DNA in CSF.

The diagnosis of PML can sometimes be made based on clinical and neuroimaging data, he said, but it is much stronger if brain biopsy shows viral DNA. Presence of viral DNA in the blood can be a good monitoring tool for viral reactivation but is not diagnostic because viremia may be found healthy people.

Still, Dr. Major and others working on PML recommend that neurologists using natalizumab monitor blood for JC virus from patients given natalizumab. He said if the viremic level goes up in the presence of the drug, it is obvious what needs to be done - stop the natalizumab.

• Linda H, von Heijne A, Martin C, et al. Progressive multifocal leukoencephalopathy after natalizumab monotherapy.

• Wenning W, Haghikia A, Gold R, et al. Treatment of progressive multifocal leukoencephalopathy associated with natalizumab.

• Yousry TA, Major EO, Clifford DB, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy.