Patricia K. Coyle, MD: There is an awareness of progressive multifocal leukoencephalopathy, or PML, in taking care of patients with multiple sclerosis [MS]. PML is an infection of the brain that’s caused by a papovavirus called John Cunningham [JC] virus. Normally JC virus, which is ubiquitous—25% of the population is shedding JC virus in their urine at any point in time—causes no issues whatsoever. It’s basically a benign agent unless you are immunocompromised, particularly with cell-mediated immunity. Then you are at risk of having the JC virus cause an infection of the brain that can be fatal in a significant proportion of individuals.
Clyde E. Markowitz, MD: Natalizumab was approved in 2004, and approximately 3 months after it got approved, it was pulled off the market because of a couple of cases of PML that came up in clinical trials. It came back on the market in 2006 with a black box warning concerning PML risk. I have to be honest, this drug probably would be changing the entire methodology of how we treat MS if it didn’t have that risk. It’s a very effective drug, but this concern for PML is a big problem.
Still, over the years, we have learned how to manage it to some degree. The way this drug works is that it binds to a molecule on your lymphocytes and prevents them from migrating into the central nervous system. It can’t cross through the blood-brain barrier. In essence, what happens is the tissue becomes immunosuppressed. Because of that, we get a concern for certain kinds of infections, particularly PML.
There has been an evolution of a test, the JC virus antibody test, over the last 8 years or so that really gives us the capability to provide patients a risk profile based on data from the number we get back from the test. If they’re negative, we would feel more comfortable that this patient is at low risk—not that they’re at no risk, but they’re at low risk—of developing PML. If they come back positive, we worry that this is somebody who you might have to take off the drug at some point.
Because of that, we think that natalizumab has a place in the treatment algorithm, but it really is at this point mostly for the relapsing group of patients who are JC virus antibody–negative. Or you could keep patients on it if they’re positive with a low index for some period of time. But after 2 years, you worry that’s going to be a problem because that’s when the risk of PML goes up: after 2 years of continuous use of that drug. So this has not really been able to show a huge benefit in patients of the progressive phenotype, but at least in the relapsing phenotype, it’s a very good drug.
We’re still left with the idea that we don’t have any treatments for secondary-progressive MS. The natalizumab ASCEND trial was trying to address the possibility that natalizumab could be used to treat secondary-progressive disease. They enrolled patients into that trial with the idea that we can slow the rate of progression, independent of patients who are having clinical attacks. Unfortunately, it did not show a benefit in terms of slowing the rate of progression. It did show a benefit with regard to the other typical relapsing markers, things such as clinical relapses and preventing MRI lesions; but it did not show a slowing of the rate of disability progression, which is very disappointing because it’s a very powerful drug in the relapsing population. We thought maybe it would help here as well. Unfortunately, it does not.
You could ask the question, Is it a wise idea to keep a patient who had relapsing disease—and now has secondary-progressive MS—on natalizumab, particularly if they’re JC virus antibody–negative? I don’t know if that makes a lot of sense at this point, and that’s an unknown. Based on the data from the trial, we’d say it’s probably not a great idea because the data didn’t really support it.
What are the safety concerns that you would need to be concerned about? We know that there are infusion reactions. There are some other issues that go on with natalizumab, even though it’s a fairly safe drug outside of the PML risk. There are some concerns out there regarding small case reports on a variety of different things. What people have started to think about at this point is, Can you change the dosing frequency to some degree? Instead of using it every 4 weeks, maybe you could go to every 6 or 8 weeks. They did some studies looking at that and found that at 12 weeks, it’s too long a period of time between infusions, and the disease activity starts to come back. At 4 weeks, you’re good. At 6 weeks, it seems to be OK. At 8 weeks, there may be a little bit of breakthrough disease activity, but it’s minor.
Can you change the safety profile by changing the frequency of infusions? That was looked at and is currently being looked at. A small group of clinicians around the country did an extended dosing schedule like that, and they were able to show that it may reduce the risk of PML. They didn’t have enough patients to really answer that question, but there is a large trial starting up now to really address whether moving patients to every-6-week dosing could be more beneficial in terms of reducing risk for PML and keeping the efficacy of the compound. But when it comes to patients with progressive disease, I don’t know that this is going to be the right approach. That’s the problem.