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AAN REPORT 2: PML risk, viruses and a new treatment in development

American Academy of Neurology highlights

Over 200 people with multiple sclerosis (MS) treated with Tysabri have developed PML (progressive multifocal leukoencephalopathy), a frequently fatal brain infection caused by reactivation of the JC virus. Since PML was first identified in MS, three key risk factors have been identified. They are exposure to the JC virus, treatment with Tysabri for longer than two years, and prior treatment with an immunosuppressant drug. If all three risk factors are present, the risk of developing PML is slightly higher than 1%.

A first step in determining PML risk is to see if a person has been exposed to the JC virus. This can be done by taking a blood sample to test for antibodies to the virus. (A more expensive method is to look for viral DNA in cerebrospinal fluid or urine.) An assay, called STRATIFY, was first approved in 2012 for anti-JCV antibody testing and an improved two-step test has now been developed.

According to the most recent results, 55% of people with MS have been exposed to the JC virus at some point in their lives (Plavina and colleagues. AAN 2013; abstract S30.001). With repeat testing, 52% were consistently positive (i.e. antibodies always detectable), and 38% were consistently negative (never detected). That leaves about 10% of people in a grey zone. Some are occasionally positive, some are initially negative then become positive (which may indicate a new exposure to the virus), and some are positive and become negative. Since the body can’t clear the virus, what this probably means is that the results are fluctuating around the cutoff point of the test. The accuracy of a test always depends on how sensitive it is to the thing being measured. This 10% grey zone is different from the error rate of the test, which is about 2.4% (i.e. the test says you’re negative when you’re actually positive).

An emerging issue with Tysabri is the dose that’s used. At one MS clinic, an analysis of 29 people who developed PML showed that 83% weighed 75 kilograms (165 pounds) or less (Foley J. AAN 2013; abstract S30.002).  People with a smaller body mass had significantly higher levels of the drug in their bloodstream. This suggests that a lower dose may be advisable in people with a smaller body mass – which is probably most people taking the drug. But these findings will need to be confirmed by other studies before Tysabri dosing is adjusted.

The JC virus is just one of the many viruses we encounter in our lives, although it doesn’t appear to be associated with a higher risk of developing MS. But many studies have suggested that exposure to a virus may be involved in MS. The most common suspect is EBV (Epstein-Barr virus, which can cause mononucleosis). A new study has looked at people with clinically isolated syndrome (CIS) to see if viral exposures have an impact on their neurological signs and symptoms (Horakova and colleagues. AAN 2013; abstract P05.134).

Study participants were tested for exposure to EBV and CMV (cytomegalovirus, a herpesvirus that generally doesn’t cause illness in healthy people). People with the highest antibody response to EBV had greater evidence of inflammation on their brain MRIs. People with CMV antibodies had more relapses than those who hadn’t been exposed to the virus.

More is now known about a new drug in development called ocrelizumab (Hauser and colleagues. AAN 2013; abstract S31.004). Unlike other MS therapies which target T cells, ocrelizumab targets B cells (which produce antibodies) in the immune system. The drug is a reboot of the Roche drug Rituxan, which will soon lose patent protection, and is being investigated in relapsing MS and progressive MS.

The phase II study included 220 people. All received one of two doses of ocrelizumab given by infusion every six months. Results are available for 69 people who have been on treatment for two years. Only three people had new or enlarging lesions on their brain MRI. The annualized relapse rate (relapses averaged over 2 years) ranged from 0.035 to 0.18 (i.e. 1 relapse every 28 years to 1 relapse every 5-6 years). So overall, people showed very little MS activity with respect to relapses or MRI. Larger studies will now be needed to determine the drug’s effectiveness and safety in people with MS.


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