[intro music]   Host – Dan Keller Hello, and welcome to Episode Ninety-four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.   Today's interview features Dr. Oscar Fernandez, a senior investigator at the Málaga Regional University Hospital in Málaga, Spain. When we met at a neurology conference in Chile, he reviewed for me some of the elements of risk stratification for second-line therapies for MS. That implies there are first-line therapies and probably third-line ones, as well – terms that Dr. Fernandez is not particularly fond of.   Interviewee – Oscar Fernandez I am very much against that classification, but this is being used for clinicians, so I have to accept that. I believe that there is one drug for one patient, and I don't believe in lines. Because if you use lines, then you must be forced sometimes to do the passing through all these lines. And many times you must go indirectly from the very beginning to second or third line and the case is very severe. Anyhow, lines have been defined more or less just taking into account the benefit and the risk. And first line are those drug who are not terrible beneficial; they have more this efficacy, but they are very safe in the long term. This is the first line, and those are interferons, there are like four interferons so far, and glatiramer acetate, this is first line. And second line are those drug where are more efficacious but more risky also. So there you have natalizumab, fingolimod, alemtuzumab, and mitoxantrone.   And even you can go further for the third line, which is maybe bone marrow transplantation and some experimental therapies by now. There are many new drugs coming, and then we must try to classify these as first, second, or third lines. It's very difficult for clinicians today to image, for instance, ocrelizumab, which drug is that? Is it first, second, or third line? Is it very efficacious, is it very safe until now? So why it should be classified as second line? Probably the agencies will say this is for active relapsing or for active MS and just let the clinicians to use it properly.   Interviewer – Dan Keller So what goes into the risk stratification? What parameters do you consider?   Dr. Fernandez Yeah, the first thing is that most clinicians use a balance, for the balance of efficacy and safety. But then they put numbers. You must put numbers. I mean the numbers are there. I mean for low-risk drugs and for very mild diseases the number is 1 in 10,000. You can have severe adverse events 1 in 10,000. For moderate disease and moderate risk, a drug is 1 in 1,000; and for severe, this is risky drugs, is 1 in 100. Those are the numbers to put in the balance. And we know the numbers from the drugs, and we must tailor our decision based on that.   MSDF Are the risks you're looking at purely progressive multifocal leukoencephalopathy, PML, or are there other risks you're considering in those numbers?   Dr. Fernandez No, PML is just something that appear, but there are many other things to be taken into account. I mean all severe adverse events should be taken into account, and these are the numbers I have mentioned. MS is a very severe disease; it's a risky disease. So we can theorize independent of the severity of the disease and we must look for everything. I mean hematological alteration, hepatic alterations, opportunistic infections, and everything that can be produced by these drugs over these therapies.   MSDF Is it only the drug or do you also take into consideration patient characteristics besides their MS; age, comorbidities, gender, lots of things?   Dr. Fernandez Everything has to be put in the box; I mean all the things have to be consider. And it's not the same to use a drug in a patient which is also a hypothyr