Fred D. Lublin, MD: So an agent such as this, I could see 2 different potential positionings for it. One is as 1 of the highly active agents, such as natalizumab, alemtuzumab, ocrelizumab, or 1 of the orals. It may be top of the orals. What do you think, positioning?
Clyde E. Markowitz, MD: It’s a difficult question because the efficacy looks robust. The question ultimately is, is this an induction treatment? It has the flavor, to some degree, of depleting out your immune cells and then having a different functioning immune system come back, which is kind of our definition, to some degree, of what an induction treatment would be. So I like that idea, particularly for this compound. Then the other side to that is, what are the safety concerns? How are we going to monitor these patients? What is the next agent if somebody breaks through? Is there any concern for the sequencing of drugs? And that’s really what it’s going to come down to. And so far, based on the data that were available in 2010 and now that we have follow-up extension data, there really wasn’t a huge safety concern that came out. There was a concern for possible malignancies.
You look at all the drugs that we’re using these days and they all have a little bit of that going on. So I don’t know that it’s going to distinguish anything. It may end up being just another really good, high efficacy drug with a fairly benign mechanistic, take a couple of pills for a week, and another month later, take another, and you don’t really have to keep doing that. I think it’s very attractive. Where we will learn more is, what are the concerns if somebody is breaking through on that? Where do you go at that point? What’s your next option, safety-wise, to put somebody on without a concern?
James M. Stankiewicz, MD: I think we’re going to have to have 4 tiers. I would say that we have the orals, like a second tier of the injectables where, arguably, depending on how people look at it, teriflunomide is in the first tier. The second tier would be the orals outside of teriflunomide. The third tier would be cladribine, and the fourth tier would be the infusion agents. Of course, part of what makes this very hard is that we don’t have a lot of head-to-head data sometimes to fully establish this. But, based on the pivotal trials, we make our best guess. And so, I think ultimately the answer is the efficacy is between the orals and the infusions.
These comments are not asynchronous with what’s been said, but I think a concern that I have is, arguably with all of the agents, when you give the drug, MS [multiple sclerosis] can recur. That’s for sure. We saw this with cyclophosphamide which is, I would argue, a stronger drug than cladribine. Mechanistically, admittedly, it’s a little different. But if you follow these patients for long enough, even after giving them a good slug of cyclophosphamide, you’d see that the disease comes back. So I think it’s a matter of time and also interplays with the overall disease severity of the patient.
But I think it would be a mistake to say we’re giving 2 courses of cladribine and we’re taking care of the patient’s MS. Of course, you’d want to continue to monitor them. But I think another hard part about continuing to monitor them is, are you waiting until you have a new change on the MRI [magnetic resonance imaging] and they’ve had damage in the meantime? Having said that, I think that this is a drug for which the safety profile looks good. It seems pretty tolerable. I think another interesting little feature is that there are some patients who will lose oligoclonal bands when they’re treated with cladribine. So what is that mechanistically doing? It’s sort of an interesting thing to wonder. I think it will be nice to have this new addition, for sure.
Patricia K. Coyle, MD: I’m not a big fan of tiering at all. To me, the interest in cladribine is that it’s an oral induction agent. You clearly use it and it had very good data when used early, at the time of CIS [clinically isolated syndrome]. And you seem to have a prolonged effect. Can you have a sustained drug-free period, or can you change the course of MS? Could you use this induction therapy very early on, at the time of CIS, and convert an active MS to a much milder form of MS that then could be treated very well with very safe, easy-to-take therapies? So I’d like to see data on how long the effect lasts, and some data suggesting whether you can change the course early on of what appears to be aggressive MS. Will it then respond to other agents? To me, that would make it, intellectually, a very attractive agent to use.
Suhayl S. Dhib-Jalbut, MD: To me, the direction of cladribine is the convenience of use. In addition to that, and this is more of an economic question, the cost of treatment may be theoretically less than with comparable drugs, in addition to what has already been said.
Fred D. Lublin, MD: Tom, in the CLARITY extension, were there any hints or markers of the durability, other than the clinical outcomes—white count, or something like that?
Thomas P. Leist, MD, PhD: No. That’s a very interesting question. In general, the white cell count, even in the CLARITY study, did not correlate with the disease attenuation in individual patients. So stratifying the patients on the level of lymphocyte reductions that they experienced didn’t correlate with the disease activity. I agree with what’s being said. Obviously, our patients will have new disease activity at some point. And so, how we recognize these patients is going to be an important question. For example, the question is, in such patients, neurofilament light will be a monitoring tool that indicates more subtle disease reoccurrence. So this certainly will need to be looked at.
Also keep in mind that obviously different individuals may need different doses or repeat dosing of this agent. Individuals may have an immunologic response in multiple sclerosis that may be more or less accessible to an oral treatment, depending on whether the immune aberration is already present—whether it’s present within the central nervous system, to a larger degree, or whether it’s present perhaps in areas that are less reachable.