New Cases of PML Found in MS Patients Taking Natalizumab

August 1, 2008

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By Lily Jung, MD, FAAN, Swedish Neuroscience Institute, Seattle, WA

Author Disclosure

Biogen Idec notified physicians on Thursday, July 31, that two new cases of progressive multifocal leukoencephalopathy (PML) have been identified in multiple sclerosis patients receiving natalizumab (Tysabri) in the European Union. Close clinical surveillance associated with the drug allowed for the identification of the two new cases reported.

  • In the first case, a treatment-naive male was started on natalizumab after being diagnosed with an aggressive clinical course of multiple sclerosis. A subacute presentation of left upper extremity twitching and weakness resulted in a diagnosis of PML after JC Virus (JCV) DNA was identified in cerebrospinal fluid (CSF) analysis. MRI scan showed a nonenhancing lesion not consistent with demyelination, and initial CSF sampling was negative for JCV DNA. Natalizumab was discontinued and he was treated with plasma exchange over ten days. He is currently clinically stable and ambulatory.
  • In the second case of PML, a patient with a remitting-relapsing course of MS treated with azathioprine for ten years in conjunction with beta-interferon, developed subacute left sided weakness with cognitive changes. MRI showed nonenhancing lesions suggestive of PML and CSF analysis showed JCV DNA. Plasma exchange will be initiated.

The identification of three cases of PML soon after the drug was initially released resulted in natalizumab being voluntarily removed from the market in 2005. The FDA approved its re-release in 2006 on the condition that a risk map be implemented involving close monitoring of the drug and its clinical indications.

In these earlier cases of PML, two MS patients had been treated with natalizumab and interferon-beta 1-a, while a Crohn's patient had received natalizumab after having received immunosuppressive therapies in the past. No patients who had been treated with natalizumab alone had been identified as having PML. As a result of this, an FDA physician advisory panel had recommended that natalizumab be used as monotherapy for MS patients. Natalizumab was re-released in June 2006 with the TOUCH program in place to monitor patients while on therapy. Of particular concern for neurologists at this time is that one of the newly diagnosed PML cases had not previously received immunosuppressive therapies and had no known risk factors for immunocompromise.

At the AAN Annual Meeting in April, Biogen Idec released safety data showing that over thirty-two thousand patients had received the drug worldwide, with more than thirteen thousand having been on the drug longer than 12 months, and 6,600 having been on treatment for over 18 months, with no new cases of PML identified. This resulted in a change of perception that the risk of developing PML with natalizumab was one-in-a-thousand to one-in-ten-thousand.

At this time, no recommendations around the management of patients who are currently on natalizumab therapy have been made. In Thursday's phone conference with MS neurologists, Al Sandrock, MD, PhD, of Biogen Idec stated that it was due to clinical vigilance that the two cases in the EU were diagnosed definitively. He also noted that, as always, the risks and benefits of natalizumab therapy should be carefully discussed with patients prior to initiating or continuing therapy.

Search for abstracts presented at the 2008 AAN Annual Meeting that address treatment with natalizumab.

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Author Disclosure

Within the past 24 months, Dr. Jung has received personal compensation as a consultant for the Speaker's Bureau of Biogen, as well as from Glaxo Smith Kline, Chromos, and VLST Corporation. She has also served as an expert witness for medical liability, personal injury, and felony cases, and has received support for clinical research from Novartis and Biogen.