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Natalizumab Fails on Infarct Volume


American Heart Association - February 19, 2016 ACTION临床试验:使用那他珠单抗治疗急性缺血性卒中后神经炎症。 The ACTION trial studied natalizumab to treat neuroinflammation after acute ischemic stroke.

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Dr. Karen Furie, Chief of Neurology, Rhode Island Hospital: I'm Karen Furie at the International Stroke Conference (ISC) in Los Angeles.
Dr. Mitch Elkind, Professor of Neurology, Columbia University: My name is Mitch Elkind at the International Stroke Conference.
KF: Mitch, can you tell us about the ACTION trial?
ME: Sure! So, the ACTION trial was a Biogen-sponsored study of natalizumab (Tysabri), a drug that's used commonly in multiple sclerosis to treat neuroinflammation after acute ischemic stroke. So, it was a randomized trial designed to test whether a dose of natalizumab (Tysabri) that's used in MS (multiple sclerosis), given acutely after stroke within nine hours, could reduce infarct volume and improve outcomes in patients with ischemic stroke.
KF: What did you find?
ME: So, interestingly, what we found was that although natalizumab did not decrease infarct volume based on MRI measures, it did improve functional outcomes measured by the Barthel Index and the ranking scale at longer intervals after the stroke. So, out at 30 and 90 days, there was evidence of a benefit.
KF: If it didn't work by reducing infarct volume, what effect do you think it had?
ME: Yeah, that's a really great question, and we don't really know the answer to that yet, of course, but there are a lot of potential explanations, including the possibility that neuroinflammation may play a role in more long-term effects on the damaged tissue. It may impact neurotransmission. It may even have effects on cognition, energy levels, fatigue [and] other things that are also found in multiple sclerosis, and may similarly play a role in acute stroke. But again, we don't really know the answer to that yet, which is why another study is being conducted.
KF: Why do you think this is an important trial?
ME: Well, the idea that neuroinflammation or inflammatory damage plays an important role in acute stroke, that idea has been around for many years, and so far, we have not had a lot of success, as you know, treating inflammation in the setting of acute stroke, at least in clinical trials. For animal models, we're able to do it quite well. It's important because natalizumab is a drug that's currently used to treat a chronic inflammatory neurological disease. It's approved. It's available. And we think that it could be translated into the stroke realm as well. It's interesting, though, because there are some differences between chronic diseases like multiple sclerosis, and acute stroke. And so, it may be that we need to use different doses or different dosing regimens with natalizumab to get the same kind of benefits we see in other, more chronic conditions. So, I think, additional studies may help us to resolve those questions.
KF: Do you see any implications for the clinical care of stroke patients in the near future?
ME: Well, I think in specific terms, it would be hard to make any concrete recommendations for patients or for physicians caring for them at this time. I think it's something that people may want to be aware of. The general approach to modulating inflammation after acute stroke as a way to reduce acute injury, reduce infarct volume, and improve long-term outcomes, even when the stroke is still present, has important implications. And, over the long term, whether it's natalizumab or another agent that is able to make that advance, will be an interesting thing to see play out. So, I think, the implications at present are really more research-oriented and looking towards the future.
KF: And you've suggested a few potential directions for your research. Do you have any specific plans?
ME: Well, Biogen, who is marketing natalizumab and conducting these studies has plans to do more in this area. Again, the first concrete steps will involve testing different doses to see whether, in the stroke situation, it may require a larger dose to see a change, say, in infarct volume. In other words, it may be that we have the right approach, but we used a dose that was used for multiple sclerosis (MS), again, a chronic disease where the acute inflammatory process and the size of the damage to the brain may be smaller. It may be the case that more natalizumab is needed when you have a larger infarct. So, that's something that will be explored further. In addition, we'll be looking at other outcome measures. So, on the other side, at the end-side of the trial, we'll be looking at cognitive measures, measures of fatigue [and] measures of energy, to try to capture what it is about treating inflammation that leads to this benefit.
KF: Of course, with this class of drugs, there's always concern about infection due to immunosuppression. Did you have any signal of adverse effects or infection in the [patient] population you studied?
ME: No. So, this study was really looking at a single dose given within nine hours of acute ischemic stroke; and the effect does last for several weeks afterwards, but the setting in which the largest infectious complications occur is really chronic use of natalizumab, again, in the setting of MS, with multiple doses every month for a long period of time. The most serious complication, of course, is PML - or progressive multifocal leukoencephalopathy - which has not been reported with fewer than eight doses of natalizumab. So, going into the study, we were fairly confident that we wouldn't see any complications like that. That's the one that's on everybody's mind, of course, but we didn't see any signal of that. Further studies are needed. We're very mindful of the risk of infection, and that could become an issue if we give higher doses and so forth, but we don't think using it in this fashion will lead to major infectious complications.
KF: Great! That seems like a very important and exciting first step to understanding how immunomodulation might help with stroke outcomes. Thank you!
ME: Thank you very much, Karen!

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