Two More Patients on Natalizumab Develop PML
Within a year of approval of natalizumab (Tysabri) for multiple sclerosis (MS), two patients with MS and one with Crohn disease developed a life-threatening brain infection; this serious and puzzling adverse effect led to removal of the drug from the market.
It returned a year later, in 2006, after a federal advisory panel concluded that it was worth the risk with the proper precautions in place. Now, another two years later, two more patients — Europeans — were diagnosed with the same infection, progressive multifocal leukoencephalopathy, or PML, for which there is no effective treatment.
It is not clear what the FDA will do. With the reintroduction of the MS drug, the drug company Biogen Idec, Inc. agreed to an extensive training and monitoring program in the US to quickly identify symptoms that could be signs of PML. But the program, called TOUCH (TYSABRI Outreach: Unified Commitment to Health), is not being used outside of the United States. In the US, 17,800 patients have received the drug and almost 14,000 of them have taken it for more than 12 months. PML developed in patients taking the drug for more than a year.
Natalizumab is a monoclonal antibody that targets the immune system and stops the inflammatory process that leads to MS symptoms. Given monthly by intravenous infusion, the drug binds to integrins expressed on the surface of leukocytes (except neutrophils), preventing the immune cells from entering the brain.
The revised recommendation was to use natalizumab without interferon therapy; depending on the interferon, injections range from once a week to every other day to three times a day. The first two MS patients who had PML had been taking a beta interferon at the same time they were receiving infusions of natalizumab. It was impossible to tell what triggered PML, which is caused by the ubiquitous JC virus.
One of the two Europeans has already had five rounds of plasmapheresis over a 10-day period to wash out any drug in his body and help the immune system reconstitute. He had been taking the drug for 14 months before developing weakness and fasciculation on his left side that grew progressively worse. MRI revealed an atypical lesion in the pre-central gyrus. Suspecting PML, a lumbar puncture was done and the CSF was normal. The symptoms got worse.
The company held a round of briefings with neurologists during the first week of August and said that the patient's condition was stable, he was ambulatory, and he was well enough to remain at home. The other was hospitalized. Both are off the medicine.
The second patient had MS since 1992 and had been taking azathioprine for the first decade, followed by a stint on beta-interferon. MRI showed nonenhancing lesions suggestive of PML and CSF analysis showed JCV DNA. He developed PML after taking natalizumab for 17 months.
No one is exactly sure how or why these individuals developed this rare condition. By early adulthood, about 70 percent of the general population has antibodies to JC virus, which seems to reside quietly in the body unless provoked by a run-down immune system.
Doctors are mixed on the next move. “I have been increasingly comfortable with the drug after several thousands more patients have been taking it with no sign of PML,” said Joseph Berger, MD, the Ruth L. Works Professor and chairman of neurology at the University of Kentucky. “While we think we are perturbing one action, there may be other downstream effects that we didn't expect.”
He said that it is critical to ensure that a patient has MS and that it is the relapsing and remitting form before prescribing the drug. Patients should be given beta-interferon and glatiramer acetate (Copaxone), and fail both treatments, before moving on to natalizumab. They should not have diseases that suppress the immune system and open the door to opportunistic infections. “Natalizumab should be used for six months and then be re-evaluated,” said Dr. Berger. “It does not make sense to leave patients on it if they don't show a response.”
IS NATALIZUMAB SAFE?
But is natalizumab safe? Karen Roos, MD, the John and Nancy Nelson Professor of Neurology at Indiana University School of Medicine, worries that these cases may be just the beginning of things to come. She specializes in infectious diseases, including PML.
She suspects that the drug may create a functionally deficient T-lymphocyte response as it is designed to put a break on the brain's immune surveillance system. She explained that the JC virus is part of the normal brain and body flora and that the virus is reactivated in the brain or in the periphery and then travels into the brain. She wonders what it is about the JC virus that makes it sensitive to natalizumab, while other latent infections are not showing up in patients on the monoclonal antibody.
“We just don't understand normal brain surveillance,” she said. “The JC virus is really attracted to oligodendrocytes and that is where the infection occurs.” These white matter cells are necessary for making myelin. Patients with PML get limb weakness, visual field impairments, and gait problems. There are no treatments.”
“When we see these patients, is it even clear that it is another MS attack or could it be PML?” Dr. Roos asked. When the first three patients with PML emerged, she said she knew it was only a matter of time.
“Many neurologists who treat MS will say that patients are desperate and willing to take a risk of a fatal disease. But it requires more study to know what the drug is doing. I'm not sure patients can give informed consent about a progressive brain infection.”
Eugene Major, PhD, chief of the laboratory of molecular medicine and neuroscience at the NINDS, and his colleagues have tested blood and spinal fluid from about 1,000 patients taking natalizumab. His laboratory has been investigating the JC virus for 25 years. They did not identify any new cases of PML among the natalizumab users studied, but he said that he was not surprised by the new reports. “It merits a strong concern about how we can better monitor patients.”
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 that is diagnostic given clinical and neuroradiological evidence.
PML diagnosis sometimes can be made based on strong clinical and neuroimaging data, he said, but much stronger with evidence of viral DNA in the brain — through biopsy, which is not done much — or in the CSF. Presence of viral DNA in the blood can be a good monitoring tool for viral reactivation but is not diagnostic since viremia may occur in a non-PML patient or healthy person. PML is rare, even in patients with incompetent immune systems. For instance, the incidence of PML among HIV patients is 3 percent. Dr. Major and Sidney Houff, MD, a former federal scientist who now works at the University of Kentucky, said there is growing evidence that the virus may take up residence in immune cells of the bone marrow, and this could be key to triggering PML.
A study published in Blood in April found an increase of blood progenitor cells that leave bone marrow and enter the blood stream in natalizumab users. The drug prevents these blood stem cells from staying put in the bone marrow. In the blood stream, they can differentiate into mature B cells and the JC virus, if it is present in bone marrow, could latch on to these B cells and make their way into the brain. “But a lot of biological circumstances have to take place for all of this to occur,” Dr. Major said. “Nature is telling us something that we need to understand.”
He thinks that neurologists using natalizumab should monitor blood for the presence of the JC virus, which may be present in small amounts normally. He said the risk for developing PML in natalizumab users is not yet known, but if the viremic level goes up in the presence of the drug, “it is obvious what needs to be done.” Dr. Houff added that “it's only a matter of time before more cases surface.” •