JC Virus, Immunosuppressants Up Risk for PML With Natalizumab

Daniel M. Keller, PhD

July 17, 2012

July 17, 2012 (Prague, Czech Republic) — JC virus (JCV) exposure is a known risk factor for progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) treated with natalizumab, and the risk is increased depending on the presence of other factors.

A study presented here at the 22nd Meeting of the European Neurological Society (ENS) by Gary Bloomgren, MD, vice president of drug safety at Biogen Idec, Inc, in Weston, Massachusetts, estimated the risk from JCV, natalizumab treatment duration, and exposure to immunosuppressant (IS) drugs.

Natalizumab can significantly reduce the MS relapse rate, reduce disability progression, and increase the proportion of patients free of disease activity. But PML, a rare but often fatal inflammation of the white matter of the brain, is thought to result from the interaction of host factors and the presence of a neurotropic form of JCV in patients on natalizumab.

Dr. Bloomgren and colleagues set out to quantify the risk for PML according to patients' anti-JCV antibody status, prior IS therapy, and duration of natalizumab exposure. Postmarketing data through March 2012 shows that 99,600 patients have received natalizumab, with a total of 211,243 patient-years of exposure.

Immunosuppressants, Natalizumab Duration Increase PML Risk

A history of IS use (mitoxantrone, methotrexate, cyclophosphamide, azatioprine, and mycophenolate mofetil) increased the risk for PML in natalizumab-treated patients. One observational study had shown that 20.3% of patients had been treated with an IS before receiving natalizumab. However, of natalizumab-treated patients who developed PML, 42% had received prior IS therapy.

Infection with JCV is very common in the general population. Dr. Bloomgren reported that anti-JCV antibody seroprevalence in MS patients is about 55%, based on clinical trial data from 5896 patients, and the rate was not affected by natalizumab or prior IS use. This seroprevalence rate is within the range for the general population.

Serum samples were available for 54 patients who were later diagnosed with PML. All 54 (100%) had anti-JCV antibodies at least 6 months (range, 6 - 187 months) prior to the PML diagnosis. "This finding is significantly different from what we've seen as an overall seroprevalence of about 55%, and it's clinically and statistically significant, suggesting that there is some validity to this as a tool to be added to the armamentarium for further risk stratification (P < .001)," Dr. Bloomgren said.

In a sensitivity analysis of the estimated PML incidence by anti-JCV antibody status, the investigators found a 44-fold elevated risk (relative risk [RR], 44.2; 95% confidence interval [CI], 7.63 - 1784; P < .001) of PML if a patient was anti-JCV antibody–positive. Of the natalizumab-treated patients who were JCV antibody–seropositive, 54 of 14,209 had PML, for an incidence of 3.80/1000 patients (95% CI, 2.86 - 4.96/1000 patients).

For patients who were seronegative, possibly 1 out of 11,625 developed PML, for an incidence of 0.09/1000 patients (95% CI, 0 - 0.48/1000 patients), and that 1 patient is being investigated to validate or invalidate the seronegative result. If this 1 patient is actually seropositive, then JCV positivity would confer a relative risk that would be calculated to be infinite.

Assuming that PML risk is concentrated in patients who have been exposed to JCV and that these patients make up 55% of the natalizumab-treated population, Dr. Bloomgren calculated that the risk of PML in anti-JCV antibody–positive patients is 1.8 times higher than in the overall natalizumab-treated population, which includes a majority of seropositive patients.

The lowest risk for PML was for patients who were JCV antibody–seronegative, and the highest risk was among seropositive patients who had a history of IS use and natalizumab exposure for 25 to 48 months.

Stratifying risk using a combination of the 3 risk factors, based on natalizumab exposure and 212 confirmed cases of PML, the risk of PML was 120 times greater (11.1/1000 vs 0.09/1000 incidence) for a JCV-seropostive patient with MS who had received IS drugs and used natalizumab for 25 to 48 months compared with an anti-JCV–seronegative patient (see Table, below).

Dr. Bloomgren concluded that anti-JCV antibody status is an important biomarker for assessing risk vs benefit for individual MS patients, and he said the test for JCV antibodies is currently available in the United States, Europe, Australia, Brazil, and Mexico. But because of a false-negative rate and seroconversions, he recommended periodic testing of patients.

Session moderator Eva Havrdová, MD, PhD, professor of neurology at Charles University in Prague, Czech Republic, who was not involved in the study, explained that many people in the general population have been infected with JCV, and it usually stays in the kidneys or bone marrow. "Then, under some conditions, like, for example, immunosuppression, or it may be something else, the virus mutates and acquires new characteristics which lead the virus to the central nervous system, making harm," she said.

With so many patients seropositive for antibodies against JCV, she said she discusses the risk of PML with all her MS patients going on natalizumab, and her practice is to ask them if they want to continue on the drug after 1 year. Unfortunately, because interferon or glatiramer acetate has necessarily already failed before a patient can go on natalizumab, there are really no other second-line therapies, such as fingolimod, available in the Czech Republic. Only about 10% of patients in her practice, who have very aggressive disease, start on natalizumab.

"More and more clinicians stop treatment with natalizumab if they have 1 year of therapy [and] they have Gilenya [fingolimod] on the market, and so they can offer another treatment," Dr. Havrdová said, "But nobody has proven that Gilenya is effective in this high [disease] activity population...after switching." She noted that the manufacturer organized a trial, but for reasons she does not know, the trial never came about.

She looks forward to some new drugs or current drugs approved for other indications to be approved for MS. "I think that these patients who are JC virus–positive in the future will not be offered natalizumab at all or will be offered natalizumab for 1 year and then switched to another treatment," Dr. Havrdová predicted.

As for the prospect of using antiviral drugs, she said it is difficult to organize clinical trials to test such drugs in PML because it is such a rare disease and the diagnosis is often made very late. Some clinicians have tried drugs off-label that are approved for treatment of HIV, she said.

Table. PML Incidence After Exposure to Natalizumab*

    Incidence (/1000) 95% Confidence Interval
Anti-JCV antibody–negative   ≤0.09 0 - 0.48
       
Anti-JCV antibody–positive Prior IS Use    
Natalizumab 1 - 24 months No 0.56 0.36 - 0.83
Natalizumab 1 - 24 months Yes 1.6 0.91 - 2.6
Natalizumab 25 - 48 months No 4.6 3.7 - 5.6
Natalizumab 25 - 48 months Yes 11.1 14.5

*Assumes all patients received at least 1 dose of natalizumab; limited data beyond 4 years of treatment.

The study was supported by Biogen Idec, Inc, and Elan Pharmaceuticals, Inc. Dr. Bloomgren is an employee of Biogen Idec. Dr. Havrdová was a principal investigator of the first natalizumab clinical study, published in 2006. She has disclosed no relevant financial relationships.

22nd Meeting of the European Neurological Society (ENS). Abstract O-260. Presented June 11, 2012.

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