ARTICLE IN BRIEF
Investigators reported that the risk for progressive multifocal leukoencephalopathy in MS patients taking natalizumab is most heightened for patients who test positive for anti-JC virus antibodies, have a prior history of using immunosuppressants, and have been on natalizumab for more than two years.
A new study has identified those subgroups of multiple sclerosis (MS) patients taking natalizumab who are most at risk for developing progressive multifocal leukoencephalopathy (PML), a rare and often deadly brain infection caused by the JC virus.
It's been known that MS patients treated with natalizumab (Tysabri), a humanized monoclonal antibody, are at risk for PML, but this study shows that the risk is most heightened for patients who test positive for anti-JC virus antibodies, have a prior history of using immunosuppressants, and have been on natalizumab for more than two years. For patients who meet those three criteria, the risk of developing PML is about 1 in 90. The risk is lowest in patients who test negative for anti-JC virus antibodies, according to the paper published in the May 17 edition of The New England Journal of Medicine.
“The algorithm presented in this analysis, which can discern a difference by a factor of 120 in the risk of PML across the patient subgroups, allows for better characterization of risk than that observed with previous methods, and should assist clinicians in making more informed, individualized treatment decisions,” the study authors wrote.
The research was done by scientists at Biogen Idec, which developed the drug and co-markets it in the US with Elan Pharmaceuticals.
Because of the associated risk of PML, natalizumab is usually reserved for patients who have not been helped by other therapies or cannot tolerate them, said Gary Bloomgren, MD, who is vice president of drug safety and benefit risk management at Biogen Idec and the lead author for the study. Dr. Bloomgren said it's possible that the new risk stratification might lead some physicians and their patients to consider treatment with natalizumab sooner.
At the time of this latest study, 212 confirmed cases of PML had been identified globally — an incidence of 2.1 cases per 1,000 patients. (Dr. Bloomgren said the number of confirmed PML cases was up to 242 as of May 3.) Of the 212 patients with PML, 46, or 22 percent, died. Data as of October 2011 on PML survivors showed that approximately 40 percent of those who reported their disability status and who had at least six months of follow-up after diagnosis were severely disabled, while 60 percent were mildly to moderately disabled.
To carry out their risk-stratification study, Dr. Bloomgren and his team drew on data from multiple sources, including post-marketing data from the Biogen Idec global safety database, clinical studies, and an independent Swedish registry. At the time of the study, 99,571 patients had been exposed to natalizumab, a number that translates into 209,123 years of patient experience.
The research team looked at three key factors: anti-JC virus antibodies (yes or no prior to developing PML); prior use of immunosuppressants (yes or no; prior use of glucocorticoids, interferons or glatiramer was not included); and duration of natalizumab treatment (1 to 24 months versus 25 to 48 months).
“Since infection with JC virus is required for the development of PML, the risk of PML was lowest among patients who were negative for anti-JC virus antibodies, with a conservatively estimated risk of 0.09 cases or fewer per 1,000 natalizumab-treated patients,” the researchers reported.
Patients who had all three risk factors — positive serologic status to anti-JC virus antibodies, history of immunosuppressants, and at least a two-year history of natalizumab infusions — were at the highest risk, with an incidence of 11.1 cases of PML per 1,000 patients.
OTHER FACTORS TO CONSIDER
The researchers cautioned, however, that this new risk analysis should not be the only information that drives treatment choice.
“Other factors to consider in determining whether natalizumab is an appropriate treatment include the severity of the multiple sclerosis in the patient, the patient's prior experience with disease-modifying drugs (e.g., neutralizing antibodies), the efficacy and safety of alternative therapies, and the manner in which risks are conveyed to patients,” the researchers wrote.
The researchers noted their analysis was limited by several factors, including the fact that most patients had not had long-term exposure to natalizumab. Only 46 percent of patients had used the drug at least two years and only 14 percent had been on it for four years or more. Biogen Idec is continuing to track the incidence of PML in patients using its on-going pharmacovigilance program.
An editorial accompanying the study said that patients who test negative for anti-JC virus antibodies prior to treatment may feel reassured by the risk analysis. But it noted that blood tests can produce a false negative and patients may become exposed to the JC virus after starting the drug. He said retesting during treatment is advisable.
“Because multiple sclerosis and PML have similar characteristics on magnetic resonance imaging (MRI), serologic screening should not be confused with tests to establish the diagnosis of PML, such as measurement of JC virus in cerebrospinal fluid,” wrote Allan H. Ropper, MD, executive vice chair of neurology at Harvard's Brigham and Women's Hospital. He also noted that while immune-modulating treatments, such as natalizumab, reduce the rate of MS relapses, they don't prevent chronic disease progression.
Eugene Major, PhD, chief of the NINDS Laboratory of Molecular Medicine and Neuroscience, told Neurology Today that researchers are working to better understand the mechanisms that lead to a heightened risk for PML in MS patients taking natalizumab. His laboratory is also focusing on ways to make certain assays are as sensitive as possible to the JC virus.
Dr. Major said he agrees with current guidelines that physicians need to practice “clinical vigilance” to pick up possible signs of PML in MS patients and to make sure that patients understand they also need to be alert for any changes in neurological status. Possible problematic signs include changes in thinking, balance, strength and eyesight.
“Serologic status will only tell you so much,” he said.
David Clifford, MD, the Melba and Forest Seay Professor of Clinical Neuropharmacology in Neurology at Washington University School of Medicine in St. Louis, MO, said this new study showing degrees of risk associated with taking natalizumab is important because “people will go onto the drug with their eyes wide open.”
He said clinicians might decide to adjust their use of blood screening for JC antibodies or MRI scans based on what risk group a patient falls into. “If you decide to go ahead and treat a patient who has a JC-positive status, then monitoring much more frequently with MRI may be attractive,” Dr. Clifford said.
Patients who are suspected of having PML are typically taken off the drug and further evaluated using brain MRI and CSF testing for the presence of the JC virus. Blood plasma exchange is usually done to remove natalizumab and restore the immune system to aid the body in fighting this viral infection, he said.
NATALIZUMAB: HISTORY OF APPROVAL AND WITHDRAWAL
Natalizumab is approved for the treatment of relapsing-remitting MS in more than 50 countries and for the treatment of moderate-to-severe Crohn's disease in the US. As of February 2012, more than 100,000 patients worldwide have been treated with the drug.
In the so-called AFFIRM trial, “natalizumab monotherapy decreased the risk of progression of disability by 42 to 54 percent and reduced the annualized rate of relapse by 68 percent,” according to this latest paper.
But natalizumab was temporarily withdrawn from the market in 2005 after three cases of PML had been identified in clinical trials. PML can cause profound disability and death.
“PML appears to occur after a complex interaction between host and viral factors, leading to the development of a pathogenic form of JC virus that can infect and destroy oligodendrocytes in the central nervous system,” the researchers wrote in this latest paper.
After a safety review and the initiation of an intensive global risk-management program by Biogen Idec, the drug was the reintroduced in 2006.