Host – Dan Keller
Hello, and welcome to Episode Eighty-four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.
People with MS take disease modifying therapies, or DMTs, for years. But is it possible to stop the drugs at some point or at least take a drug holiday? I spoke last fall at the ECTRIMS meeting in Barcelona with Dr. Ilya Kister, an assistant professor in the MS Care Center at the New York University School of Medicine. He has looked at various studies and registries that shed light on the question, and he discusses the utility and limitations of using observational data from big data sets.
Interviewer – Dan Keller
People know a lot about starting DMTs, but not about stopping. And, I take it, there's not much been looked at yet in terms of could you stop and what happens.
Interviewee – Ilya Kister
Yes, that’s a question that patients often ask, and clinicians certainly wonder about. Is it safe to stop the drug? When is it safe to stop it? And all the literature that I’ve seen on stopping the DMTs has basically analyzed the reasons for stopping them. The reasons for non-adherence—why did patient not want to continue—but there is very little data on actually what happened in terms of disease course. It’s just an observational study, you know. Do those patients continue to have relapses? Do they have more relapses or less? The only exception is natalizumab, where we have, you know, more than a dozen—probably two dozen—articles looking at what happens when you stop the drug. But that’s a little kind of almost an exceptional circumstance. There is a question of disease rebound and such. With the other drugs, very little to no data. So, so one wonders whether it’s an okay thing to do.
What are the pros versus cons of stopping?
I think you can make almost equally appealing arguments on both sides. The arguments to continue the drugs, the main ones, are that relapses are unpredictable, and even though they’re less common as people age, we do see patients in practice, even in their 60s, who have relapses. And there was a recent study that showed that about 30% of secondary progressive MS patients have relapses. So, presumably, the drugs which work to decrease the risk of relapse would be helpful to reduce the risk of relapse even in those circumstances as well. But that’s not entirely clear, because they were never shown to be beneficial, truly, in the secondary progressive patients or in the older patients, because older patients are, by and large, excluded from all the studies. So we really don’t have any high-level data on these subpopulations.
So the reasons to continue would be to try to prevent relapses, even in older patients. And the reasons to stop would be that the relapses are kind of few and far between. It may be not worth the hassle, and maybe the disadvantages of continuing in DMT long-term outweigh the theoretical risk of decreasing relapse rates. So it’s in a clinical equipoise situation, as far as I am concerned.
How have you looked at this issue?
This is just kind of our individual practice, and many people may agree or not agree with it. This is not really based on our studies, but generally speaking, patients after age 60 who haven’t had relapses or MRI activity for at least five years, I do have a discussion with them and kind of feel them out whether they’re interested in stopping or not. And the reactions vary widely. You know, some people are very attached to their drug. They feel like it’s helping them and protecting them and has done good for them, and they don’t even want to think about stopping. And some people are very tired from being treated for many years. They don’t necessarily see the advantages of it, and they’re very willing to consider stopping and take you up on the offer. They just need a blessing to do this, because the doctor says to stop. You know, there are people in between who are kind of vacillating and not sure. But this is a population that I would consider stopping the drug.
But now, about two weeks ago, we received the news that we have funding for study, wherein we’ll randomize patients. Some will continue on whatever drug they were on, and some will stop. And then this way we’ll actually collect, in a more rigorous fashion, the data of actually what happens to those patients. And that’s a study where the primary investigator is Dr. John Corboy from the University of Colorado in Denver. And there are six sites across the states that were approved for this, and where NYU is one of the six sites, and maybe a few more sites will be added. So this is our best hope, I think, to conduct, not a randomized clinical trial of starting a drug, but a randomized clinical trial of stopping a drug, which has been done in other fields, most important in oncology, a little bit in psychology, but not in neurology or in MS, as far as I know.
But short of that, you've done a database study and looked at people who have stopped?
Yes, though that was a study that was just presented at this ECTRIMS meeting. And there we used a very large international registry called the MS Base, which has over 30,000 patients enrolled in it, so, and dozens of countries. And it's open to any investigator in the world who is interested, and he can contribute patient data. Obviously, it's patient consent, and many patients are interested in contributing their data to the registry.
So because the registry is so large, we were able to include for this study almost 500 patients who met our criteria, which were fairly rigorous. We required that patients be on some drug for three years; have no relapses for at least five years, because we want to exclude active patients; and be followed for at least three years. Three years is more than most clinical trials, which are one to two years. But we really wanted to see what happened to them this time. And we excluded people who went from one DMT to another within three months. So this was the crux of this study. We looked at this—485 patients to be exact—and we followed them. And the minimum was three years, but the median was almost five years.
And we found that in this population during this followup of almost five years, 36% of patients had at least one relapse. And 31% of patients had a confirmed disability progression, meaning three months apart they had a worsening of EDSS. And almost half of the patients have restarted a DMT, but not right after stopping, but two years or more after. That was the average time to restart. So that was the main kind of result. So when you talk to the patient, you try to kind of lay out the data for them, you know, this is the numbers you can use, I think. Even though somebody hasn't had relapses for five years or more, they still are at risk of relapses. And what we found was a predictor of relapses was age and EDSS. The younger patient and less disabled patients who we think are typically probably more in the relapsing phase, rather than in the secondary progressive phase, were more at risk for relapses. So for younger patients, I would be much more wary of stopping the drug, even if they have been relapse-free for years, than in an older patient. So that's one result of the study.
But there was a second component of this study which was interesting, I thought, wherein we compared the people who stopped the drug with the people who continued on the drug, and we matched them. There is a technique called propensity score matching. So we matched the people who stopped and the people who stayed. And the two groups were almost identical. All the parameters, like age, disability, how long they've been on the drugs, proportion of times they've been on the drug, their gender—very, very similar according to most of the variables. And we followed them through time, and the mean followup for both groups was about five years.
And we found, a little bit counterintuitively, that people who stopped the drugs did not have any more relapses than people who did not stop the drug. If you think that the drugs are protective, you will expect some effect; we didn't see any effect whatsoever. There was absolutely no effect.
But interestingly enough, the people who stayed on the drug tended to progress, to show confirmed disability progression, a little less. They were at less risk of disability progression, about 40% compared to people who stopped. So it's a little hard to interpret this data. It may be that the drugs actually have some cumulative effect and maybe continue, and that does delay disability progression. That would be a very favorable interpretation as far as clinicians are concerned and the rational to continue.
But it may be that people who stayed on the drug were really in some what we call unmeasured confounders. They had some reasons why they stayed, and they are not really entirely comparable to the people who stopped. Maybe they were a little more, for whatever reasons, considered to be more active by the clinician, and that's why they kept them on the drugs. So maybe there're intrinsically different groups with intrinsically different disability progression, and that is the reason for the finding.
So this is where we stand right now, and this goes to show kind of the utility and the limitations of using observational data sets. The utility is that we're able to basically run that kind of a pseudo-trial, if you will, comparing the stoppers and stayers, and run it for many years. We actually have data six, seven years after stopping the drug, which is almost not possible with randomized clinical trials. And we're able to use this data. In fact, to power the clinical trial that I talked about earlier, because we can predict how many people are expected to have relapses at this age and such. And the limitation that there are known unmeasured confounders, and that there're biases in who continues to be observed and who is not, and we cannot control for that without randomization.
Now, from your study, it looked like people who had been off of a DMT for more than two years had a higher relapse rate. Is there any possibility of having a drug holiday? Or, when someone comes off drug, a silent insult happens that you only see later, so you really have to not give them a holiday?
Well, it's a hard question to answer. They had a higher risk of disability progression, not relapses in this study. The curves begin to diverge after about two years. It was more of a long-term effect. So, you know, one wonders. But the counter argument to what you are describing is maybe there's a cumulative effect, that you really have to stay on the drug for long periods of time in order to see. And if you stop and have a holiday, you kind of wash out that possibility. So the answer is, we really don't know whether it's okay or not to give holidays. It's definitely not okay in actively relapsing patients, especially if they're on strong drugs like natalizumab or even Gilenya or even interferon. That's pretty clear. So but as far as the patients who hadn't had relapses for a long period of time, we don't know. It remains to be seen.
Is there a continuing effect of any drugs, such as monoclonals, like alemtuzumab, where you might get a tail effect even after stopping it, which would essentially be your accumulative effect?
I think that is, you know, a very important point that we talked about stopping the drugs, but we really have to specify which drug we're stopping. Because drugs like alemtuzumab have been shown to have an effect that lasts for four years or more. And I think at this conference they will show data for even longer term effect of alemtuzumab. I've seen some posters to that effect. So those drugs have an effect on the immune system that persists. Some chemo treatments as well, you know, a stem-cell transfer. It's not something you do every year; it's something you've done once, and you see the effect that lasts for a long period of time. So I think a lot depends on the mechanisms of the drug, you know, how long they're expected to affect the immune system for. Something like natalizumab that washes out within three months or so, and you don't really see, you know, effect on the receptor level than you'll be after about three or four months. We don't really…you wouldn't expect it to work beyond that time, and it really doesn't. It only lasts that long. And other drugs, there is a sustained loss of T cells and B cells for a long period of time, and perhaps that's why there's a clinical effect that lasts for many years.
Have we missed anything? Or is there anything important or interesting to add on the topic?
I think your interest was in observational data sets, and I think MS Base registry and others, like NARCOMS registry, they show the power of, kind of all of the people power. It's not the big pharma who is collecting the data, which is very important and has a big role, obviously. It's actual clinicians and actual patients who volunteer their data. And I think patients should be gratified to see that their data is used to actually come up with some insight as to advantage them, come back to the patients and answer some of the questions they had. So I think those databases are very important.
I appreciate it. Thank you.
Thank you very much.
Thank you for listening to Episode Eighty-four of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.
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For Multiple Sclerosis Discovery, I'm Dan Keller.