The Food and Drug Administration has identified a new risk factor for progressive multifocal leukoencephalopathy, a life-threatening brain infection associated with the use of natalizumab, an immunomodulatory agent used to treat multiple sclerosis and Crohn’s disease.
Testing positive for anti–John Cunningham virus (JCV) antibodies raises the risk of developing progressive multifocal leukoencephalopathy (PML), particularly when patients have been on natalizumab treatment for more than 2 years and have previously taken immunosuppressant medicines such as mitoxantrone, azathioprine, methotrexate, cyclophosphamide, or mycophenolate mofetil. When all three risk factors are present – 2 or more years of natalizumab therapy, anti-JCV, and prior immunosuppressant use – the incidence of PML is estimated to be 11 in 1,000 patients, FDA said in a drug safety communication Jan. 20.
When patients have anti-JCV antibodies but have been on natalizumab less than 2 years and have no prior immunosuppressant use, PML incidence is less than 1 in 1,000, the FDA said. PML incidence is estimated at 2 of every 1,000 anti–JCV positive patients with less than 2 years on natalizumab and with prior immunosuppressant use. For those with anti-JCV antibodies and more than 2 years treatment but no prior immunosuppressants, incidence is about 4 in 1,000, the FDA communication said. The FDA, which already had a black box warning on natalizumab (Tysabri, Biogen Idec, and Elan) describing increased PML risk, said Jan. 20 that it had changed the product labeling to reflect the newly stratified risk information, and also announced in a news release that it had approved a new test, called the Stratify JCV Antibody ELISA test (Focus Diagnostics), to detect anti-JCV antibodies in people deemed at risk of developing PML.
In most people, JCV is harmless; however, those on immunomodulatory agents like natalizumab are at risk of death or serious disability from PML caused by JCV exposure.
The agency stressed that patients on natalizumab may be at risk for developing PML even without a positive test for JCV antibodies, because the infection can occur at any time, or because false negative results can occur. Patients should be monitored carefully and natalizumab treatment should be stopped at the first sign of PML. While there is no treatment for PML, stopping treatment early may allow the immune system to recover and fight JCV infection.
Natalizumab, a monoclonal antibody administered by intravenous infusion, works by blocking a protein that is found on the surface of leukocytes, preventing their movement from the blood into the brain and reducing the inflammation and nerve damage caused by MS. In Crohn’s disease, it works by blocking adhesion and migration of leukocytes into the gut. For both indications it is administered by intravenous infusion of 300 mg every 4 weeks.
In 2004, the FDA approved natalizumab as a treatment for MS in patients who had failed other therapies; however, it was withdrawn the following year by its manufacturer due to safety concerns related to PML. In 2006, it was returned to market under a restricted prescribing program to treat relapsing forms of MS and was granted marketing authorization by the European Medicines Agency (EMA) to treat highly active relapsing MS. In 2008, it was approved in the United States for the treatment of Crohn’s disease, also under a restricted prescribing program, in patients failing other therapies.
The EMA in 2007 refused to grant marketing authorization to natalizumab for Crohn’s, citing an unfavorable risk-benefit profile. In 2010 the EMA concluded a review of the risks of natalizumab for relapsing MS following increasing reports of PML cases. The EMA retained natalizumab’s marketing authorization for relapsing MS but strengthened its warnings about PML risk.
To listen to a podcast concerning the natalizumab warning, click on the "Listen" button below. Podcast courstesy of the FDA.
