NEW YORK (Reuters Health) – A company-sponsored study of natalizumab has confirmed that the drug raises the risk of progressive multifocal leukoencephalopathy (PML), and that the risk can be as high as 1.11% when used for a long time in multiple sclerosis (MS) patients who have been exposed to immunosuppressant drugs and the John Cunningham (JC) virus, which causes PML.
The research, published online today in the New England Journal of Medicine, was designed to tease out the risk factors for the rare but often-fatal brain infection in MS patients, a problem that led to the drug being temporarily withdrawn from the market in 2005.
“This is an important study which allows us to better inform our patients about the risk of progressive multifocal leukoencephalopathy associated with the use of natalizumab,” said Dr. Emily Poole Pharr, a neurologist at Wake Forest Baptist Medical Center in North Carolina who was not connected with the study. “This information could lead to a reduction in the incidence of PML as a result of early identification of patients at greatest risk.”
“Because of the risk of PML, natalizumab had been reserved for those who failed other treatments,” she told Reuters Health in an e-mail. “Now, we are able to discuss its use earlier in those who are without these identified risk factors.”
In January, the U.S. Food and Drug Administration, noting the risk posed by the virus, announced approval of a test for the JC infection, which affects over half the world’s population, usually causing no symptoms.
Biogen Idec of Cambridge, Mass., sells natalizumab under the brand name Tysabri. The drug is given monthly by infusion.
The new study’s chief author, Biogen’s Dr. Gary Bloomgren, told Reuters Health that the new estimates are in line with earlier attempts to assess the risk. However the New England Journal numbers include data from as recently as February.
“The nice thing is, this applies to not only patients who are on the drug, but some patients may have avoided the drug because of the PML risk,” he said. “Now that we can characterize who is at greater risk and at low risk, it’s helped make better treatment decisions across the board.”
The estimates come from clinical studies, an independent Swedish registry and postmarketing information, along with blood samples from 5,896 MS patients, including 54 who developed PML after treatment with the drug.
The rate of confirmed PML cases among natalizumab recipients was 0.21%, or 212 out of 99,571. Among those 212, 22% died and 40% ended up severely disabled.
All of the 54 blood samples showed evidence of a previous JC infection.
The researchers estimated that the risk of PML was lowest — probably 0.009% or lower — for people who have not been exposed to the virus (according to the imperfect test for the virus) and highest — 1.11% — among people who tested positive for anti-JC virus antibodies, had taken immunosuppressant drugs before getting natalizumab and had been on the drug for 25 to 48 months.
With shorter exposure to the drug, the risk was 0.16%.
Among patients who tested positive for the JC virus but who had not been treated with immunosuppressants, the risk was 0.056% with less than two years of exposure to natalizumab, and 0.46% with three or four years of exposure.
The test did not look at natalizumab exposure lasting longer than four years.
In addition to being approved in more than 50 countries for relapsing-remitting MS, it is also used in the U.S. against Crohn’s disease.
Although Biogen withdrew the drug in 2005 following initial reports of the brain infection, it returned to the market, with restrictions, in 2006.
“What makes it so effective in the management of MS may be the same mechanisms by which the complications of PML can develop,” said Bloomgren.
The new results were originally released in April at the annual meeting of the American Academy of Neurology.
Biogen makes the drug with Irish drugmaker Elan Corp Plc., which also helped pay for the study.
N Engl J Med 2012; 366:1870-1880.