Peter L. Salgo, MD: I want to put 1 more drug in this pot and then stir it all together, and that would be cladribine, which is a purine antimetabolite.
Thomas P. Leist, MD, PhD: Yes, cladribine is interesting because it is an agent that will be given to the patient differently. It’s an agent that leads to depletion or transient depletion of B-cells and T-cells. It’s selective for B-cells and T-cells. But unlike other medications, it’s only going to be given in short annual courses. So the patient gets 1 week of treatment in month 1, 1 week of treatment in month 2, and then a year later 1 week and 1 week in the same range. In the prescribing information for cladribine in the United States, there is a single trial, the CLARITY trial, which indicated the significant reduction of relapses and disability progression. There are additional trials with these agents that didn’t make it into the prescribing information. There is actually a CIS [clinically isolated syndrome] trial, or a first event trial, that was very significantly positive when it was studied and prevented not just disability progression, relapse reduction, but also prevented McDonald….
Patricia K. Coyle, MD, FAAN, FANA: But it didn’t get approved for CIS.
Thomas P. Leist, MD, PhD: Yes, correct.
Peter L. Salgo, MD: You guys have used this drug, too, yes? What are your personal experiences with this?
Thomas P. Leist, MD, PhD: Well, most of our experience has been in the clinical trials, and obviously it’s now available since the spring, as is siponimod. These 2 agents were approved a day apart, I think. The early experience with both siponimod and cladribine is that these are well tolerated agents.
Peter L. Salgo, MD: Now, 1 last question about these before we go into money because money is big here. Anything with a ‘mab’ on the end begins to worry me. But they all have different mechanisms of action. Now to me, as an old country doctor, if you mix and match different mechanisms of action, theoretically at least they can have benefits when given together, right?
Patricia K. Coyle, MD, FAAN, FANA: Right.
Peter L. Salgo, MD: Do they? Has anybody tried it?
Patricia K. Coyle, MD, FAAN, FANA: This has been a recurring theme, combination strategies. Thus far they’ve failed in MS [multiple sclerosis]. You have not shown a benefit, a true benefit, sufficient to justify trying to add 2 different agents together. That’s interesting. I think what it says is that you may have a great idea for a combination, but you need to test it. You need to test it formally to make sure it works, and they don’t interfere. And the most logical would be, for example, a treatment for the relapsing focal inflammatory phase, the progressive neurodegenerative therapy or 1 of the disease modifying therapies [DMTs] plus a CNS [central nervous system] repair strategy. These would be very logical combinations. So right now, we don’t really use combination DMT therapy in MS.
Thomas P. Leist, MD, PhD: We are in a different place. For example, with our rheumatology colleagues, where very often a DMARD [disease modifying antirheumatic drug] is used, other agents are then added to this one. But there is a fundamental and important result out of the different modes of action, nevertheless, for us. And that is the fact that if a patient has broken through 1 kind of a DMT, 1 kind of a disease modifying therapy, you really set that disease modifying therapy aside. That means if somebody has broken through an interferon, for example, one shouldn’t go back to an interferon even if that has a different brand name.
Patricia K. Coyle, MD, FAAN, FANA: Plus you should probably go to a higher efficacy, or what you perceive as a higher efficacy agent.
Peter L. Salgo, MD: It would be remiss of me not to ask the obvious, which is, don’t we need B-cells? And if you start turning them off, it’s great for MS; what about the rest of B-cell activity?
Thomas P. Leist, MD, PhD: That was an important point that Pat Coyle made. It depletes to a degree, so this is not full depletion. And B-cells repopulate. With these treatments that take away cell, the idea is that the cells come back very rapidly, but that the character of the cells that come back is different. So that there is a drive against, and I apologize, autoimmunity.
Peter L. Salgo, MD: Wait, are you actually saying—because this is what I’m hearing, correct me if I’m wrong—that you take away these bad B-cells that are busy doing harmful things to your brain, and when they come back, they’re different and they don’t do that?
Thomas P. Leist, MD, PhD: The cells that come back and the cells that repopulate are very often naїve B-cells or naїve T-cells. There is the idea, and I agree that this is an idea, that this drives against autoimmunity. So there are certain things where one is at the edge of our knowledge.
Patricia K. Coyle, MD, FAAN, FANA: There are so-called induction strategies where we hit the immune system very hard, and you can have a long-lasting effect that there may be some change. Now honestly, with the anti-CD20s, that has not been shown to date, in my opinion, that you can stop treatment and still have control for a prolonged period.
Peter L. Salgo, MD: If they come back as what you call naїve B-cells, that implies the old B-cells worked, which implies they were activated, which implies something activated them. And here comes autoimmune again, right? Is that what you’re saying? You’re getting rid of these….
Patricia K. Coyle, MD, FAAN, FANA: Well, immune mediated. It doesn’t have to be autoimmune.
Peter L. Salgo, MD: Immune mediated. But what activated them? What triggered them to brain tissue?
Patricia K. Coyle, MD, FAAN, FANA: That’s a very good question.
Peter L. Salgo, MD: Thank you.
Patricia K. Coyle, MD, FAAN, FANA: We don’t understand what starts that initial attack on the central nervous system organ in individuals. We know activated lymphocytes move into everybody’s CNS and they move out. In the MS patient, there are larger numbers, they move in, they don’t move out. They see something, there’s a signal there, they begin to mount a damaging attack on the CNS tissue.
Peter L. Salgo, MD: Gosh, why does this sound like that ad for a roach motel? They check in, but they don’t check out.
Patricia K. Coyle, MD, FAAN, FANA: They don’t check out.
Peter L. Salgo, MD: In this case it’s bad.