Biogen Idec was pleased to announce last week that the FDA has approved an update to the prescription labeling of the drug Tysabri (natalizumab), their monthly IV monoclonal antibody medication for MS. The prescription label now includes information regarding the increased risk of developing progressive multifocal leukoencephalopathy (PML) in patients who test positive for antibodies of the JC virus (JCV). PML is a rare but serious brain infection associated with use of Tysabri and some other medical treatments (including the Rituxan I use for rheumatoid arthritis).
A patient who tests negative for JC virus antibodies and who uses Tysabri may feel like jumping for joy at this negative test result. However, the the FDA stresses that "patients who test negative for anti-JCV antibodies are still at risk for the development of PML due to the potential for a new JCV infection or a false negative test result." It seems obvious that doctors should consider testing patients prior to beginning treatment or during treatment if the antibody status is unknown. Patients should also consider periodic re-testing for those who previously tested negative for the anti-JCV antibody as a person might later become exposed to the virus.
For the past couple of years, discussions of Tysabri, PML, and the JC virus have been common in the MS community. Medical professionals have known that a reactivation of the JC virus is responsible for the development of PML in some patients. But until now there had not been a commercially-available laboratory test which would reliably test for the presence of anti-JC virus antibodies in a person's blood. Now available through Quest Diagnostics, the Stratify JCV Antibody ELISA test is manufactured by Focus Diagnostics of Cypress, Calif. The test is for professional use and by prescription only and is to be performed only at Focus Diagnostics' Reference Laboratory.
Last summer I, along with a small group of MS advocates, spoke with an employee at Biogen Idec who discussed their ongoing STRATIFY II study. The purpose of the study is to define the serological prevalence of JCV Antibody in the MS population and potentially stratify patients into lower or higher risk for developing PML based on antibody status. The Biogen employee suggested that if any of us at the meeting were interested in participating in the study that we should contact our doctors soon as they were about to close the study to new participants.
At my next neurology appointment, I asked to participate in the study and donate a sample of blood. One benefit of participating in the study is that I would learn my JCV antibody status. I tested NEGATIVE! This was good news, especially since I use a drug which increases one's risk of developing PML. My blood will be tested again next October and once more in the following year. One thing which will be measured in the study is the number of patients who test negative initially and later test positive.
How many MS patients test positive for the anti-JCV antibodies? The answer to this question seems to be changing as more information becomes available. If I remember correctly, it was initially believed that 80 to 90 percent of the adult population would have been exposed to the JC virus at some point in their lives. My MS nurse shared with me that they (in the office) were surprised to see that only 50 to 60 percent of their patients participating in the study tested positive. In an informal survey of the MS advocates present at that meeting last summer (who later contributed to the STRATIFY II study), all four participating patients tested negative. Hopefully Biogen will be able to get a good handle on how prevalent the JC virus antibodies are within the MS community by the time their study is completed.
The clinical significance of knowing one's anti-JCV antibody status is in making a more informed decision on treatment choices. Now that the blood test is commercially available, neurologists and patients will be able to better assess their potential risk of developing PML if they are currently using Tysabri or if they are contemplating Tysabri. Note that the false-negative rate for the new Stratify JCV Antibody ELISA test is about 3 percent.
There are three known risk factors for developing PML when a patient uses Tysabri:
- The presence of anti-JCV antibodies
- Longer duration of Tysabri treatment, especially beyond two years
- Prior treatment with an immunosuppressant medication (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, or mycophenolate mofetil)
The revised label for Tysabri estimates that patients found to be antibody positive, have used Tysabri for less than two years and have no prior use of immune suppressing drugs are estimated to have a risk of PML of less than 1/1000; those with all three known risk factors have an estimated risk of PML of 11/1000. Patients who are antibody positive, have used Tysabri for more than two years, and have no use of immune suppressing drugs are estimated to have a risk of PML of 4/1000; those who are antibody positive, have used Tysabri for less than two years, and have used immune suppressing drugs have an estimated risk of PML of 2/1000.
The FDA notes that these estimates are based on postmarketing PML data and Tysabri use data as of September 1, 2011, at which time 159 confirmed cases of PML were reported. The risk in anti-JCV antibody positive patients was based on the assumptions that 18 percent of Tysabri-treated MS patients have a history of prior immunosuppressant treatment and that 55 percent of Tysabri-treated MS patients are anti-JCV antibody positive.
As of January 4, 2012, there have been 201 confirmed cases of PML among approximately 96,582 Tysabri-treated patients worldwide. According to the NMSS, the death rate remains at approximately 19 percent among the patients who have developed PML. "The degree of disability in the survivors is a wide spectrum: at the milder end, some have recovered enough to return to work, and at the other extreme, some are confined to bed, requiring extensive assistance with activities of daily living, and others were in between this range."
I imagine that the availability of the anti-JCV antibody lab test will help to alleviate some of the fear of using Tysabri in the MS community. Patients and neurologists will be able to apply more personal information when assessing risks and benefits of different treatment choices. As for me, I did feel a minor weight lifted off my shoulders when I learned I tested negative for the anti-JCV antibodies. At least the possibility of developing PML can be moved to the bottom of my list of concerns while balancing a life with MS and RA.