PML Reported in MS Patient on Fingolimod

Susan Jeffrey

April 13, 2012

April 13, 2012 — A case of progressive multifocal leukoencephalopathy (PML) has been reported in a patient with multiple sclerosis (MS) taking fingolimod (Gilenya, Novartis).

Novartis AG confirmed that the company has been informed of a PML diagnosis in a patient on fingolimod, but points out that the patient was treated with natalizumab (Tysabri, Biogen Idec/Elan) for approximately 3 ½ years before being started on fingolimod. The patient is also JC virus (JCV) antibody–positive, a company statement notes.

Natalizumab treatment is associated with a known risk for PML, particularly in JCV antibody–positive patients and those treated longer than 2 years.

"The current assessment is that Tysabri is the drug most likely associated with this case of PML," the company notes in their statement. "However, a contribution of Gilenya to the evolution of this case cannot be excluded."

"This is the first and only reported PML case in approximately 36,000 fingolimod-treated patients," the statement adds. "Novartis believes Gilenya provides a benefit for appropriate MS patients when used in accordance with approved labelling."

Details on the case will continue to be submitted to health authorities "according to regulations as they become available," the company concludes.

Health authorities have already been paying attention to fingolimod of late. The agent won the race for first oral treatment for MS, with approval by the US Food and Drug Administration (FDA) in September 2010, and the European Medicines Agency (EMA) in March 2011. However, since the death of a patient soon after receiving the first dose in December 2011, both the FDA and the EMA are looking more closely at the risks and benefits of fingolimod. Those reviews are still underway; the EMA is expected to report their findings as soon as April 20.

A recent report from the Institute for Safe Medication Practices (ISMP) urged the FDA to put restrictions on the use of fingolimod after a review of adverse event reports sent to the FDA's MedWatch program in the second quarter of 2011. "Problems of widespread toxicity that were already evident in clinical testing of fingolimod are now producing strong signals in postmarket adverse event data," the group said in their report.

"Notable" among them were 68 reports of serious infections, including eye, skin, urinary, and upper respiratory tract infections, and 60 reports of eye-related problems, including macular edema and vision disruptions, the report said. In 14 cases, patients experienced generalized symptoms, including heart-rhythm problems and liver damage.

"The signals for fingolimod raise the question whether enough is known about the troubling safety profile of this drug to justify its continued unrestricted use. Its array of known adverse effects on the eyes, heart, liver, and immune response, as well as patient deaths in testing and postmarket surveillance, raise the question about its long-term use at the current approved dose," the ISMP report concludes.

The risk for PML with natalizumab is well known, but because it is also very effective, measures have been taken to try to mitigate the risk. The manufacturers have a postmarketing surveillance in place for these cases, and in January 2012, the FDA approved a test (Stratify JCV, Biogen Idec/Elan Pharmaceuticals) for the presence of JCV, with the aim of reducing the risk of treatment with natalizumab.


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