ARTICLE IN BRIEF
Data from the manufacturer of natalizumab suggest that better monitoring and clinical vigilance for progressive multiple leukoencephalopathy (PML) has led to improved clinical outcomes for MS patients who develop PML.
SEATTLE-The incidence of progressive multifocal leukoencephalopathy (PML) appears to be much lower in real-world patients taking natalizumab, which is FDA-approved for relapsing-remitting multiple sclerosis (MS), and their outcomes are better than those participating in clinical trials, according to new safety data described here at the AAN annual meeting.
We found six cases of PML [in post-marketing surveillance], and five of the six patients are alive. Although there are too few cases to make firm conclusions, these data suggest that PML is not a uniformly fatal disease, Carmen Bozic, MD, vice president and global head of drug safety and risk management at Biogen-Idec, told Neurology Today in a telephone interview.
The five survivors have deficits that range from being bedridden and able to speak to being ambulatory with a cane, cognitively intact, and able to return to work, Dr. Bozic said. Biogen-Idec has submitted data on these patients to the FDA.
Dr. Bozic suggested that improved outcomes with these six cases are most likely due to factors that include heightened clinical vigilance and earlier intervention at first signs of PML.
The current analysis was based on data on patients being monitored through two disease-management and surveillance programs: the TOUCH (TYSABRI Outreach Unified Commitment to Health) and TYGRIS (TYSABRI Global Observation Program in Safety), established in 2006 after three patients developed PML and died after taking natalizumab in clinical trials. Two patients had had relapsing-remitting MS and were taking natalizumab and interferon-beta 1, and the third person had Crohn disease and had been treated previously with azathioprine, another immunosuppressant.
But several experts interviewed for this article, who were not involved with the analysis, were more reserved about endorsing the safety of natalizumab.
STUDY DETAILS
The analysis comes from data on 52,000 patients taking natalizumab in the post-marketing setting worldwide, including those enrolled in both the TOUCH and TYGRIS monitoring programs. Of these, 24,900 received the drug for at least 12 months; 14,400 received the drug for at least 18 months; and 6,800 received the drug for at least two years, Dr. Bozic said.
The incidence of PML in post-marketing surveillance to date is approximately 1 in 10,000, whereas it was 1 in 1,000 in clinical trials, she said. With 52,000 patients in treatment, that is more than 10 times the amount of exposure in the clinical trials setting, she commented. Five of the cases were in the European Union and one was in the US, she added.
The duration of natalizumab monotherapy in the six cases of PML varied, ranging from 12 to 31 months. Four were treated with plasma exchange, three received immunoadsorption (two, in addition to plasma exchange), and four were treated with mefloquine, an anti-malarial drug.
Dr. Bozic said that there are no standard treatments and no consensus guidelines for PML. Three sessions of plasma exchange, or plasmapheresis, seemed to accelerate clearance of natalizumab, and this information was added to the product label in 2008. A phase I study co-sponsored by Elan is currently exploring the effects of mefloquine in patients with PML.
Five patients developed immune reconstitution inflammatory syndrome (IRIS) approximately four weeks after plasma exchange or immunoadsorption; three of them were given corticosteroids.
IRIS involves paradoxical worsening of the patient's neurological condition and can include worsening fever or other signs of infection, Dr. Bozic explained. IRIS is usually transient, and recovery is attributed to recovery of the immune system. It is often accompanied by gadolinium enhancement on MRI. IRIS has been described previously in the medical literature as a feature of the clinical course of PML in non-MS patients. It means the body's immune system is attacking the infection, Dr. Bozic said. There are no consensus guidelines on how to treat IRIS, but patients seemed to get better on corticosteroids, she added.
Figure. DR. KAREN L....Image Tools
Dr. Bozic pointed out that in the AFFIRM trial of patients with relapsing remitting MS, those taking natalizumab had a 68 percent reduction in the rate of relapses annually and a 54 percent reduction in the risk of disability progression, as measured by the Expanded Disability Status Scale compared to those taking placebo. By contrast, other multiple sclerosis therapies such as beta interferons and glatiramer acetate achieve about a 30 percent reduction in annualized relapse rate and up to a 30 percent reduction in risk of disability progression, she said.
SAFETY CONCERNS
Karen L. Roos, MD, a neuroinfectous disease expert, is not particularly reassured by these data. The new immunosuppressive agents blast one receptor, subunit, or T- or B-cell type of the immune system without really taking into consideration what effect this will have on the overall biological function of the immune system. I think that with natalizumab, and other new immunomodulating drugs like fingolimod, we are speeding down a road but don't know what's around the bend, she said. Dr. Roos is the John and Nancy Nelson Professor of Neurology at the University of Indiana in Indianapolis.
She pointed out that the safety data on natalizumab and PML were not based on a prospective study. The new cases of PML occurred since July 2008, which is really short term, Dr. Roos continued. The risk of PML may very well be associated with the duration of treatment. It may be overly optimistic to say only one year later that there won't be more cases of PML in patients who receive natalizumab, Dr. Roos said.
Patients who develop PML have permanent deficits, Dr. Roos said. They may improve but the deficits won't resolve, she said. The complications depend on where the lesions are, she continued, and could include hemiparesis, visual field deficits, cortical blindness, memory loss, gait abnormalities, and seizures.
She also questioned the use of plasmapheresis as a life-saving measure for PML. This is early anecdotal information, she said.
Finally, other opportunistic infections can occur in those taking natalizumab, including mycobacterium avium complex infection and shingles. What about these other infections? Dr. Roos asked.
I have been cautious about the use of natalizumab, even when it was first approved, said Gary Birnbaum, MD, director of the MS Treatment and Research Clinic at the Minnesota Clinic of Neurology in Minneapolis and adjunct professor of neurology at the University of Minnesota School of Medicine. The drug has a broad spectrum of activity and can cause other side effects besides PML, he said.
The TOUCH and TYGRIS programs focus on PML, Dr. Birnbaum continued, but provide no information about the other adverse events that can occur with natalizumab. These include eosinophilic syndromes, opportunistic infections, and malignancy, especially melanoma.
My concern is that there may be other side effects and complications that are not being disseminated by Biogen-Idec. This is a lack of transparency. No one would argue that natalizumab is effective, but is the drug's efficacy sufficiently better than the other disease-modifying therapies to balance safety concerns? he said.
THE NATALIZUMAB RISK MANAGEMENT PROGRAM
The global risk management program for natalizumab - which was established in 2006 after three patients taking the therapy developed PML and died - stipulates that natalizumab be given as monotherapy and that it not be given to immunocompromised patients.
Physicians are educated about the signs and symptoms of PML, including subtle weakness in the hands or legs, difficulty concentrating, and lack of coordination. As PML progresses, later symptoms include headache, speech and vision changes, and seizures.
Physicians are asked to discontinue the therapy at the first sign of PML. The program recommends that plasma exchange be considered to remove natalizumab more rapidly from the body. Prescribers are also educated about the probability of developing IRIS after plasma exchange and the need for vigilance.
MS patients taking natalizumab, as well as those in clinical trials, are monitored monthly for signs and symptoms of PML when they get their infusions and also every three to six months by their treating physicians. Physicians should be alert for any new or worsening neurological symptoms - in thinking, eyesight, balance, or strength - that last for more than several days.
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