Fred D. Lublin, MD: We’re going to move on to discuss the clinical courses of multiple sclerosis [MS]. We defined these in 1996 and then we modified them again in 2014, although it’s called the 2013 modification. We now look at 4 different clinical courses. And this has some importance on how we approach patients and their therapy. There’s clinically isolated syndrome, which is the terribly inelegant term for what is the first attack of MS. And just as an aside, we tried to change that term at one point, but what we came up with was worse, and no editor wanted to hear it, so I won’t bother you with that. So we’re stuck with clinically isolated syndrome.
First attack of someone, if the MRI [magnetic resonance imaging] is consistent, then we have very good data, which we’ll discuss the support in treating those individuals. Now when we came up with McDonald Criteria 2010, where we made it easier to declare dissemination in time, and now even easier because we’ve added spinal fluid in 2017, about 50% of what used to be clinically isolated syndrome became diagnosable as MS. That’s that.
But then there’s relapsing-remitting MS, which is the most common form, with acute attacks and a period of quiescence in between, or at least clinically quiescence. Secondary progressive MS, or a percentage of individuals, and I don’t know the percentage but I’ll be curious of your thoughts, with relapsing-remitting MS, after a period of time, they start to gradually worsen in between attacks, with or without superimposed attacks.
And then there’s primary progressive MS, which starts out with this gradual worsening, not an identifiable clinical attack, and that may or may not have superimposed relapses later on. And then we subcategorized all this as to whether there was activity. And I thought we made this pretty clear in the paper, that activity was either having had a relapse, or new activity on the MRI—a new T2 or gadolinium enhancing lesion. But it had to be framed in time. You had to pick a time frame. And we didn’t really care what time frame you want. Just like if I see someone in clinic, when I get done with my note, I’ll say, “Impression: relapsing-remitting MS, active over the past year,” because they have had a flare-up or maybe a new MRI.
The second subcategorization was for patients who were in a progressive phase of MS, so whether they were truly progressing or not; again, over some period of time. Because in both primary progressive and secondary progressive, progression is not inexorable; it fluctuates, and they can plateau for long periods. And when we do clinical trials, you want to get people who are actually worsening, progressing, so you can measure a change. That also needed to be framed in time.
Those were the 4 types, the 2 characterizations we did, and 1 other suggestion that we made, which is worth noting, was that one shouldn’t use the term, “the patient is progressing,” unless they’re in a progressive phase of MS, and worsening, independent of a relapse. Whereas a worsening patient may be progressing, or they may be a relapsing-remitting patient who’s developing stepwise changes.
Despite those definitions, and the strong admonition that they must be framed in time, we’re going to talk about siponimod. But when siponimod was approved, it was approved for clinically isolated syndrome, relapsing-remitting MS, and secondary progressive with activity, full stop. And that’s a problem because they didn’t define activity; and more importantly, they didn’t define the time frame. And so theoretically every secondary progressive patient had activity at some point because they had to be in a relapsing-remitting phase first.
And they were only talking about clinical activity. This is for the FDA. The European authorities have also just approved a drug. They went 1 step further and said activity could be on the MRI, or clinical, but they still failed to give a time frame. This is causing some confusion, and so we’re hoping to at least straighten out that confusion now, with those comments.