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PML in Suspected MS Patient Taking Fingolimod Raises FDA Concerns

Samson, Kurt

doi: 10.1097/01.NT.0000436532.49183.e0
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The FDA has asked health care professionals and multiple sclerosis patients taking fingolimod to report any adverse effects to its Medwatch program.

Although all of the facts are not yet clear, European health officials have reported that a single patient taking fingolimod for suspected multiple sclerosis (MS) has developed progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain.

The report is reminiscent of early cases of PML in MS patients taking another promising drug, natalizumab (Tysabri), which resulted in several deaths. Like fingolimod, natalizumab suppresses the immune system.

The US Food and Drug Administration is working with the drug's manufacturer Novartis Pharmaceuticals to review all available information about the case and will make its conclusions and recommendations after the evaluation is complete.

In the meantime, the agency has asked health care professionals and MS patients taking fingolimod in the US to report any side effects to its MedWatch program at the agency's website for adverse events at

Patients should not discontinue fingolimod before discussing any questions or concerns with their medical providers, the FDA advised.

When the agency approved fingolimod for MS in September 2010, it was the first oral drug shown in clinical trials to modify the course of the disease by reducing relapse episodes and delaying progression of disability. In two phase 3 studies the immunomodulating drug reduced relapse rates by more than 50 percent by limiting lymphocytes involved in the autoimmune response, a hallmark of MS and other diseases.

The report marks the first case of PML in a patient taking the drug who had not previously taken natalizumab.The diagnosis was made based on clinical symptoms and JC viral DNA in the cerebrospinal fluid, although it is unclear if the condition was present in the patients before they began taking the drug, according to Novartis, which markets the drug under the name Gilenya.

According to the FDA, the patient received nearly eight months of fingolimod treatment before being diagnosed with PML.The patient had also been treated with interferon beta-1a and azathioprine, a drug used to control swelling and pain, for one month before starting fingolimod. Both of the medications were halted when treatment began. In addition, the patient had received multiple courses of intravenous corticosteroids for several months before and during fingolimod treatment.

PML attacks myelin, impeding the function of nerves in white matter. Affected individuals typically become severely disabled or die. While the JC virus is common and harmless in most people, it can cause PML in people with reduced immunity.

Fingolimod weakens the immune system, as does natalizumab, which was approved in 2004 but withdrawn from the market after three cases of PML were reported in patients also talking interferon beta-1a. It was reintroduced in 2006 under a special prescription monitoring program warning against prescribing the drug in patients also taking interferon beta-1a.

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“Several features of this case of PML make it unlikely to be attributable to [fingolimod],” according to the company.

Prior to initiating treatment with fingolimod the patient showed brain lesions that were atypical for MS, however reviewers “could not exclude PML,” Novartis spokesman Michael Billings told Neurology Today.

The patient had also been exposed to repeated courses of corticosteroids before and during fingolimod treatment, and one-month treatment with the azathioprine, both of which are associated with immunosuppression. The patient also only received a relatively short, seven-month, exposure to the fingolimod, he noted.

Mark S. Freedman, MD, professor of medicine (neurology) and director of the Multiple Sclerosis Research Unit of the University of Ottawa, noted that there are important questions about the case that need further examination.

“This was a very unusual case of MS, if it was MS, and we are still awaiting further information in this regard,” he told Neurology Today. “If it was cerebral lymphoma, then PML in association with that disease is not uncommon, so we might be jumping the gun a little.”

Another MS specialist agreed that it was critical to get more information on this case. “There is a lot of information about this patient that we do not know,” said Robert J. Fox, MD, staff neurologist the Mellen Center for Multiple Sclerosis Treatment and Research at Cleveland Clinic.

“It is very important that we know more to further understand the risk profile of this drug, and this is true of other newer MS drugs as well, where we are just beginning to understand rare complications. It takes thousands of patients taking a new drug and a number of years before we understand rare complications of the drug,” he told Neurology Today in a telephone interview.

Although Novartis has contacted MS neurologists stating that the company believes that that patient's PML was not the results of fingolimod treatment, a number of factors make the statement questionable, or at least premature, he said.

First, he noted, PML develops very quickly, which makes it unlikely that it predated fingolimod treatment. Further, the assertion that concurrent treatment with corticosteroids or previous treatment with azathioprine may have somehow contributed to the development of the disease is questionable given the number of patients currently taking the fingolimod who are being or have been regularly treated with these other drugs without developing PML.



But perhaps most troubling, he said, is that the patient's lymphocyte count has not been reported. “It is hard to believe that with all of the treatments and hospitalizations that the patient underwent, no one took a lymphocyte count, or that there is no record of this. A lot of patients have very low lymphocyte counts during fingolimod treatment, but we do not know how low is too low with fingolimod. This will not change the way I treat my patients yet, but it makes me a little nervous, especially with patients with very low lymphocyte counts,” Dr. Fox told Neurology Today.

“My colleagues and I do not believe there are enough data yet for Novartis to say that fingolimod did not contribute to this case of PML, and until there is, we must be very vigilant with our patients taking the drug.”

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•. FDA safety announcement regarding PML in patient taking fingolimod:
    •. Neurology Today archive on fingolimod:
      •. Neurology Today archive on natalizumab:
        © 2013 American Academy of Neurology