To mark the 50th episode of the international MS Perspective podcast, I have invited my neurologist Prof. Dr. Tjalf Ziemssen to talk to me about the future of MS treatment. As he is one of the most innovative MS specialists, he can give a good overview of what is coming soon and which goals are still difficult to achieve at the moment.
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Table of Contents
[00:00:01] Nele Handwerker: Hello Tjalf, nice to have you on the show and a warm welcome to just another position of the lovely Elbflorenz.
[00:00:12] Prof. Dr. Tjalf Ziemssen: Yeah, Nele, it’s a great pleasure to be here number 50.
[00:00:16] Nele Handwerker: Yes.
[00:00:17] Prof. Dr. Tjalf Ziemssen: I always booked the special anniversaries here and number 50, I think it’s great, yeah, so that even the whole world can listen to you.
[00:00:29] Nele Handwerker: Yes, and the good thing is you are getting these booked spots, because you are my doctor since a long time. But before we start into the interview, it would be lovely if you could introduce yourself to the audience, because I know you, I know you since many years, but maybe some of them, unfortunately, don’t know you yet.
Introduction – Who is Prof. Tjalf Ziemssen?
[00:00:47] Prof. Dr. Tjalf Ziemssen: Yeah, so the most important thing is that I’m the neurologist of Nele Handwerker.
[00:00:53] Nele Handwerker: But there’s a bit more to you.
[00:00:55] Prof. Dr. Tjalf Ziemssen: Yeah, and by the way, I’m heading the MS Center in Dresden, so I have a long-term interest in multiple sclerosis. So I decided not to get head of a neurological department, but to really specialize quite a lot in the care and in the research of multiple sclerosis patients. And I think I’m very happy, because I don’t have to fight a lot with administration, with hospital guys, so I can really concentrate on the care of my patients and on research. And that’s, of course, I think, the nice thing of my life.
[00:01:39] Nele Handwerker: Yes, absolutely. And you do a great job.
Personal motivation for your career choice?
[00:01:45] Prof. Dr. Tjalf Ziemssen: I think there’s no other choice, because the brain is the most interesting organ. That’s why I think there’s no choice to neurologists, they are the smartest doctors. Although the whole family consists of ophthalmologists. So I am the only person in my family, who escaped the retina.
[00:02:04] Nele Handwerker: Yeah. But you are still with the OCT and with the opticus neuritis, you are still a little bit connected.
[00:02:11] Prof. Dr. Tjalf Ziemssen: I have a certain interest in ophthalmology as well. Yeah, I think it’s very nice to have this combination. On the other side, I think, I had… Among the friends of my parents, I had a case of multiple sclerosis, when I was, I think, 14, 15. That was really impressive to me. At that time, I really decided to, yeah, to do something against this disease. And then at the end, then of course, in the study of medicine, it was very interesting, neuroautonomy, then neurology. And at the end, yeah, you ended really up in neuroinformation.
[00:02:56] Nele Handwerker: Very good. And today, as we want to talk about future treatment, we should probably talk at the beginning about the status, who we are right now.
Status of MS treatment
Can you provide an overview of the current landscape of MS treatments, and how has it evolved over the years?
[00:03:12] Prof. Dr. Tjalf Ziemssen: Yeah, I think we can be very happy. If we compare our situation in the MS field with other fields of neurology, I think we can be very happy that we can offer treatments. I think, especially I have discussed today a lot with my colleagues treating Parkinson’s disease and they still are looking for treatment options to really shape, to really change the course of disease. And so we are very happy that we have this medication.
Now, I think the big challenge is that the number of medicines available to fight against MS is increasing. And so it’s getting more and more challenging to select the right treatment for the specific patient. And of course, I think we have treatments, especially for certain subtypes of multiple sclerosis, which are really very potent. But when we are very successful to treat one subtype, especially the relapsing-remitting subtype of multiple sclerosis, it’s of course very evident that in some scenarios, which are not so rare, it’s very difficult to really get this positive extraordinary treatment effects, we have in relapsing remitting. And that’s progressive, primary progressive, small ring MS, I think there we have lots of things to be done and lots of things to be developed.
That’s of course a challenge, because on the one side we have a lot of treatment options, which are quite efficient and we can really stabilize the majority of our patients, but nevertheless I think we have unmet needs and it’s usually, you know, it’s usually difficult if you… In the beginning with all new medication, you have huge steps and now I think we need to increase our outcomes. I think it will it will take a while and it’s of course painful, because to improve yourself now in a quite established treatment landscape, it will be difficult.
[00:05:31] Nele Handwerker: Yeah, absolutely. And just half an hour before our interview, we were discussing about escalation therapies in our multiple sclerosis management study program, which you, by the way, initiated as well. A very good thing.
[00:05:45] Prof. Dr. Tjalf Ziemssen: Absolutely. So I think education is very important. I think everybody, who is listening to your podcast, is benefiting from this program. I think it’s very important to offer education and I think that is a good sign that you can fill two years full of information about one disease. Because a lot of my colleagues they were critical and said, yeah, you cannot study MS for two years. I think you recognize it and I think your experience is really live and you recognize it. I think it’s really, we have a lot of problems to be solved and that’s why I think that the way really to have such a master, I think it’s a great idea.
[00:06:33] Nele Handwerker: Absolutely. And it’s important for a disease that can be devastating, if you don’t treat it and that you have until the end of your life.
[00:06:43] Prof. Dr. Tjalf Ziemssen: That is, of course, a nice thing that on the one side, I think you have to really develop a concept. So it’s not as a researcher. So for me, it’s not so fashioned as other fields of research. So I have really a program which is directed into 10 years time of development. So you really look forward. On the other side, same sustainable care, I think, is with our patients. So I don’t treat patients only for one or two years, like, for example, in oncology. So you have, in oncology you have probably quite stressful two or three years, but then everything is solved. And in MS, it’s really a lifelong disease. So, you know, how long we know each other?
[00:07:36] Nele Handwerker: 16 years. It is already.
[00:07:40] Prof. Dr. Tjalf Ziemssen: I think that’s really very nice, really, to know another person very well. And so from my perspective is, of course, to know the patient. I think for the patient it’s quite nice to know the doctor quite well. Because usually in a patient and physician relationship, it’s very important not to start every time from the beginning, because it’s really annoying if you’re like, oh, I have now to talk again from the beginning on. And if you meet, it’s like with good friends, then you can start again, where you left. And I think that’s very important in psychology and I think in the ability to fight against this disease.
[00:08:25] Nele Handwerker: Absolutely, yes, to fight as a team against it. And we are doing quite well.
Emerging Therapies in Multiple Sclerosis
What promising new therapies or treatment approaches are currently in development for MS?
[00:08:41] Prof. Dr. Tjalf Ziemssen: Yeah, of course. Of course, there are several, several therapies, which are in the development process. Of course, we have this different type of clinical studies. So we have medications, which are quite far away. Usually, you have an idea which starts in your animal experiments and MS animal models. And that’s usually very, very tricky, because then patients, they’re usually published then in the newspapers and then patients are asking, yeah, here in this mice experiment it was possible to demonstrate that that there is a potential effect in a mess. And you know if you read something about an animal experiment where there is a potential effect which could be relevant for MS. I think it will last at least 10 years time and we have seen so many drugs failing. That’s why an animal experiment is interesting, but we have to be careful.
On the other side, then we have, I think, quite interesting new principles. I think if we do it in a more systematic way. I think we have of course treatments, which are more aggressive and then we have treatments, which have a different mechanism of action, which are not so aggressive as we it. And then we have, I think, potential treatments, which take known drugs, so repurposing of drugs, so drugs, which have been developed for other indications. And now it’s trying to apply these medications to multiple sclerosis. So that’s in principle the landscape we have to follow.
And I think the big challenge is, because we have still some patients in relapsing-emitting disease, we have to be probably more aggressive and we have to think about what is among the available or potential therapies, what is better to be very, very aggressive or to be more specific, less aggressive. And then on the other side, I think the big challenge will be, as we have already discussed, will be the treatment of really progressive disease, whether it’s primary or secondary progressive. I think that is still a challenge, where we have to go. But on the other side, it will be very difficult, because still the mechanisms are not well known. And especially this phase of chronic MS resembles a lot what is happening in Alzheimer’s disease, in Parkinson’s disease, so in the classical neurodegenerative disease. And you know very well that we are not very successful in these types of diseases. So, I think we have a significant way to go.
[00:11:57] Nele Handwerker: But as I prefer to look on the positive side of things, let’s say, it’s in a way good that there are the same mechanisms happening, because Alzheimer’s is interesting, Parkinson’s is interesting and multiple sclerosis is compared to them, just a few patients. So I guess, if people combine their research activities in a smart way worldwide, hopefully there will be these small steps coming one after another.
[00:12:27] Prof. Dr. Tjalf Ziemssen: The big challenge is that, so the classical relapsing-emitting MS that is really characterized by the immune system moving into the brain, so that this mechanism is crucial. And I think there we have identified certain strategies, how to inhibit migration, how to kill cells, how to increase regulatory cells, how affecting immune regulation, for example, with the classical first-line therapies to avoid this. But we know very well what happens. I think the problem is in the case of the more advanced progressive disease that the exact mechanisms are not well known. We don’t have really a good animal model, so it’s very difficult to simulate and to understand what is happening and that I think is a challenge. And even then I think, so we will come later on to it, if we would have a drug, which is effective in progressive MS or a drug which is probably regenerative or which encourages myelination, remyelination, so that the myelin sheet is restored.
The big question would be, which study design is able to prove that this drug is effective. I think it’s very easy, the classical relapsing-emitting MS, it’s quite easy, because you count MRI lesions, you count relapses, yeah, so that’s really quite simple. But we have to admit that especially looking at progressive deficits at the moment, the tools we have and you know it very well, because you’re part of it, that we are working on ideas, how we can make especially the assessment of progression more reliable, more objective to avoid classical outcomes like the expanded disability status scale, the neurological examination. I think that’s very relevant that we have to work on outcomes to prove this. And then I think medication will be visible. Because potentially, I don’t know whether really at least small treatment effect by certain medication will be visible with our current tools. Maybe, because we don’t have really the right outcomes that we wouldn’t see it.
[00:15:06] Nele Handwerker: Yeah, absolutely.
Are there specific breakthroughs or advances in the pipeline that you find particularly exciting?
[00:15:14] Prof. Dr. Tjalf Ziemssen: Of course, everyone is, of course, looking at the bruton tyrosine kinase inhibitors. But on the other side, the world is quite brutal, because the first candidate failed, you know, so we had, so the first candidate which was developed by Merck in this family. It was not successful, so we got in early December, we got the notice that Evobrutinib, so all these BDKAs, they have the -brutinib at the end. That it did not show a different relapse rate than Teriflunomide. So both relapse rates were low, but there was no difference. And as it was the primary endpoints, the relapse rate difference between Evoprutinib and Teriflunomide. That’s why, yeah, so the study failed and there will be no further development of Evobrutinib. And that’s why we are, of course, very curious to look at the, yeah, to look at the family members of the BDKI family. So Tolebrutinib will be probably the next one.
Tolebrutinib is a drug, which is now developed by Sanofi. And the difference is that it’s run in a quite huge study program. So it’s not tested only in relapsing-emitting patients, but it’s really tested in a group of primary progressive patients and in a very interesting group, which I think it’s very relevant. It’s a group of non-active secondary progressive MS patients. So that means patients with secondary progressive MS, but without acute signs of, so without this pathophysiology, which we discussed with the relapsing-remitting MS, so immune system moving from the outside into the inside. And that will be interesting.
On the other side, then we will go to Fenebrutinib, which is a little bit behind, but that is a drug, which is developed by Roche, again, relapsing, relapsing remitting study. And then, of course, that is, of course, the advantage of Roche as they have Ocrelizumab available for primary progressive patients that they have a study in primary progressive patient, comparing Oculizumab versus Fenebrutinib. And that’s, of course, quite interesting that we don’t have a placebo-controlled trials in this setting.
And then a little bit, unfortunately, not in Europe available, because in Europe or in Germany we have not been allowed to run a phase 3 trial, when no phase 2 trial was performed. That is Remibrutinib, that is the other family member developed by Novartis. So that is in the same family member, which is now evaluated. So all these drugs have demonstrated there is a good treatment effect. And of course, the interesting thing is that it’s a new mechanism of action. So it’s a drug which acts on microglial cells and which acts on B-cells. So the B-cell action is quite well known from the B-cell depleting therapies.
But inhibiting kinase, which is quite typical for cancer treatment there, this kinase, they have a cascade of events in the cells. By inhibiting this cascade, you stop downstream effects. And one effect is, for example, the B-cell activation and so on. And by stopping this by a small molecule, of course, the advantage is that you can really regulate much better than a depletion. A depletion usually lasts for a certain time and by really having an on-off mechanism, taking the drug off and if you stop the drug, it’s on again. Of course, the regulation, it’s much different. But of course, it could be of benefit.
On the other side if you have a non-compliant patient, it could be a problem. Because then one medication given once a year or every half year, could be better, but that we have to learn. But, you know, you see, I think, by having four drugs and probably other BTKIs are coming as well, but by having four family members shows, so what are the expectations for this class of drugs?
[00:20:37] Nele Handwerker: And it would be so lovely to have something for the neurodegeneration part, which is…
[00:20:42] Prof. Dr. Tjalf Ziemssen: I think that is still the holy grail and, yeah, hopefully we don’t have this fate, which we had in Parkinson’s disease and Alzheimer’s, that a lot of drugs failed there.
[00:20:54] Nele Handwerker: Yeah, let’s see. We have to wait a bit longer. Let’s come to the topic of precision medicine in MS.
Precision Medicine in MS
How does precision medicine play a role in tailoring MS treatments to individual patients?
[00:21:08] Prof. Dr. Tjalf Ziemssen: I think precision medicine, it’s a very nice, yeah, it’s a very nice concept. Of course, if you talk about precision medicine, you have to have something how precision can be developed. So precision means that you have to measure something, because this measurement or this characterization counts then in favor of a treatment decision. And the problem is, if we don’t have a high quality data set, it will be very difficult. So there is no precision without high quality data. You know very well, because you’re part of it as well, that we are fighting a lot to get high quality data. And I think that’s the challenge we have at the moment. I don’t think that the data quality we know from the registries, which is standard, which is used for a lot of publications, just counting relapses, just putting some EDSS together. At the end, I don’t think that it will answer reliable, that it can be used for a reliable treatment decision.
I think we need much more data from MRI, so from other biomarkers. We have now neurofilament coming up, so to include this information as well. Then probably the lesion localization, which is not relevant, for example, if you collect just relapses and EDSS. Yeah, I think we have to work hard to improve data quality and then I think precision medicine is possible. So precision medicine is nicely already introduced in the field of oncology, but the big advantage is in oncology that the first thing you do in oncology is remove the tumor or biopsy the tumor. And that we don’t have.
So we don’t have really something which we could rely on. So in the tumor, of course, you can look for genetic changes. You can look for histopathology changes. You can look for dysregulation, which is there. So we don’t have this. That’s why we have to use things, which can provide us information, of course, the cause of disease, imaging, biomarkers, CSF, probably could be quite interesting. And this information has to be collected. And only if you collect this information and you link it with your treatment, then it’s possible to go to a more personalized treatment. So it’s a long way to go for us.
[00:24:09] Nele Handwerker: Yes, but I prefer this collection instead of getting a biopsy. This is only for a few cases important, I think.
[00:24:17] Prof. Dr. Tjalf Ziemssen: The big problem is, and you know it very well, so it’s a big question whether this lesion you biopsy is really a representative lesion. And you know by Christine Stadelman who is really doing an excellent job to moderate the first module of our master program and so she usually says, so in most of the cases, if you biopsy an inactive lesion then it’s very difficult to go there. So you have to go, if you would like to biopsy and get more information out of it, you have to have really an active lesion, but that’s not easy to identify. And it may be that if you take the wrong lesion or a non-active lesion, then the gain in information is very low. Yeah.
[00:25:05] Nele Handwerker: Yeah. But can you maybe still share an example of how personalized or precision medicine has improved the treatment outcomes of MS patients? As you said, I’m taking part in all these different kinds of studies, because I think information is so valuable and I want to be part of the improvement.
Can you share examples of how personalized or precision medicine has improved treatment outcomes for MS patients?
[00:25:24] Prof. Dr. Tjalf Ziemssen: Yeah, one simple example is, for example, that not only the clinical deficits are relevant, but especially in the beginning when you go for a treatment decision, of course, the MRI plays a significant role. And if you realize, for example, that a patient has really a high lesion load, so high lesion load means that you have more than 10 lesions, or if you have 50, 60 lesions, then we do know that classical first line therapy in the long term, it’s probably problematic, because we do know that we need more effective treatment from the beginning on. So that’s an example that the initial MRI could be included.
On the other side, we know very well that especially if you have an highly inflammatory phenotype, so usually you see that, especially in the first MRI, you have a lot of contrast enhancement, so a lot of gadolinium-enhanced lesions and then a drug which can stop the migration of these inflammatory cells could be very, very effective. For example, a patient with more than 100 gadolinium-enhancing lesions I think it calls for Natalizumab, which inhibits the migration. On the other side, if you have a nasty relapse with a lot of deficit and the recovery is not so well, although you have used steroids. I think it calls for more induction therapy, because we know that induction therapy or depleting therapies, that these are the only ones which can really provide some probability that this disability could be reversed or at least a little bit decreased. That is very difficult to have this effect with a drug which needs a lot of time until the full efficacy is available. So that are examples, but that’s more gut feeling. We need really hard data and we need really a large data set of well-controlled and well-characterized patients to draw this conclusion.
What role do biomarkers play in the future of MS treatment, and how are they being used to guide therapy choices?
[00:28:05] Prof. Dr. Tjalf Ziemssen: Yes, I think the MRIs play a significant role, but even talking about MRI, so there is MRI and MRI. So MRI with standard reporting, so in some MRI reports the information we get is multiple MS lesions, so it’s very interesting for me, because I wouldn’t have expected multiple MS lesions if it’s an MS patient. Yeah. So I’m of course very interested, so what is the evolution of lesions, so we have to do, you know very well. We try to have a yearly MRI and then compare it. And I’m of course interested about the phenotype of the lesions. So what is the potential of neurodegeneration in this lesion, so what is the percentage of lesions developing to black holes, what is the localization of lesions, yeah.
So because I think we have some different phenotypes, especially, you know, infratentorial lesions, so lesions in the brainstem or lesions in the spinal cord, they indicate a more negative prognosis in this. And, yeah, that’s why we have to quantify the MRI and we have as we do it using artificial intelligence to really compare and we should get rid of sliced MRIs, so the 3D MRIs are much better, because then you can do an analysis in the volume scans and you can identify, of course, three tests. I think it’s at the moment still, I think still the MRI of choice. It’s better than if you have a low field MRI. Yeah, so even if you have an MRI, so it could be done and it could be reported in a way that’s not very helpful.
Then on the other side, it’s now moving into the field of other biomarkers. So we are very happy that we have, of course, differential diagnostic biomarkers, like, for example, aquaporin, mock antibodies, which indicate a little bit more that it’s not MS, but a subtype. But we have then other markers, which can tell us about the disease activity, like neurofilaments or factors, which are released by the neurons itself, which are not specific for MS, but which can tell us what is the amount of the neuro destruction, which is taking place. And that’s why, yeah, so that’s for the first time that we have something in blood, which we can use to, yeah, to identify the degree of neuro destruction.
[00:31:02] Nele Handwerker: Yeah. And are there any… Sorry.
[00:31:03] Prof. Dr. Tjalf Ziemssen: All these digital biomarkers which can measure function. So we know very well that cognition plays a significant role. I think cognition is very nice, because you can really quantify it. It’s much easier to measure cognitive function in a quantitative way, than for example, to have a motor function. So measuring upper extremity function, it’s quite tricky, because you have to have certain tests and, of course, a cohort. But with cognition, neuropsychological testing, we have a lot of experience and especially that it’s done by very, very quantitative persons that are the neuropsychologists, which are prone to look in a quantitative way.
And in contrast to us, I think the problem is, in neurology, that we are too kind to our patients. So if you do a neurological examination, it’s like holiday on the Maldives. But if you are, and I think Nele you have been there, if you are at neuropsychological testing, you feel after the testing a little bit demented, you feel very sad, because you think, oh my brain is completely gone. I did it myself, because they have this strategy of stress testing, so they really move to the limit to understand what is happening at the limit. And that I think is something probably we have to do, to be a little bit more quantitative, so we have to challenge more.
And we have, you know, we do this gait analysis for for long-term gait tests, so for one hour yeah and then of course you see certain abnormalities. And the stress testing, neurological stress testing, I think that is what we have to do, because that’s the only way already at very low or very early stages of multiple sclerosis to detect abnormalities. Because a big problem is that for early patients, our instruments we have at the moment, they’re not sensitive enough. So if a patient, for example, is able to run a marathon two years ago and this year, this patient is only able to run half the marathon distance. So in principle, in neurological examination, I would not see the difference, because we are not sensitive enough.
But I think we would agree that it’s a significant change we have there. If you have half the distance, in such a running event, yeah. So that of course has to tell us that we have to be more sensitive. And their cognition I think it’s a nice way, because it’s very quantitative and it’s, yeah, it’s very stressy, but on the other side that’s what we would like to know. So what is your reserve capacity, what is your compensatory power, because that is very relevant, because when I know that your neurological reserve is limited then of course I would probably treat more aggressive, yeah, then if if I would know, oh there’s a lot of reserve fuel in the tank, so we we can really, yeah… But that’s why I think it’s very important really to understand the mechanism and the potential of compensation
[00:34:43] Nele Handwerker: Yeah. And yes, this test felt a bit stressful. And yes, it’s more putting it to the edge than the, I don’t know, what is it?
[00:34:57] Prof. Dr. Tjalf Ziemssen: Then neurological…
[00:34:58] Nele Handwerker: I mean the very short walking. I mean, that doesn’t show you too much. The six minute walk test is already a bit better.
[00:35:06] Prof. Dr. Tjalf Ziemssen: You know it very well. So what we are doing, for example, to do jump tests.
[00:35:09] Nele Handwerker: The jump test is very, I think the jump test is good. The jump test is helpful.
[00:35:13] Prof. Dr. Tjalf Ziemssen: Because really you have to be a ballet dancer, so to really have it in the right way. So that’s why we have, I think, to improve. We have to, I think, what is necessary, we have to adapt our examination technology to the status of the patient. And some patients, they are annoyed. So two minutes walking for you, boring. So we have to talk about the whole hiking way in the Saxonian Switzerland. So a hiking way with 3000 meters altitude. That’s something for Nele Handwerker, yeah. But we could do a test after this 100 km crossing Saxonian Switzerland.
[00:35:58] Nele Handwerker: Yeah, I would probably, yeah, mountain biking or badminton, something like that with the hiking, but hiking is okay as well, yes. There are good options, but I know what you mean.
Are there new technologies or methods for monitoring MS progression that you find promising?
[00:36:17] Prof. Dr. Tjalf Ziemssen: I think what I haven’t mentioned besides motor function is of course our new baby, which is related to speech. So speech is… So that’s why we have this podcast here, yeah. How efficient speech can be, how speech can tell us a lot about functions. So we try to combine speech and cognition. I think it’s very nice, because then you don’t have to analyze by yourself if speech is recognized, especially in cognitive tasks. It’s of course supporting the neuropsychologist as well. On the other side, we get a lot of information out of it.
And I think what is at the moment my favorite, which I would say is the best test really to do a quantitative evaluation, is everything which is related to multitasking. So if you do two tests at one time, it’s, of course, very challenging. But I think it’s, at the moment, the best way and the most sensitive way. So we see it, for example, in our walking analysis. So walking may be normal. But if you do a cognitive task during this walking, we see that there is a deterioration of walking. And that’s why, at the moment, I think it’s a dual task or multitask paradigm. I think that is at least a stressy, a neurological stress test per se. And I think the most sensitive way to identify small, in principle, invisible deficits.
[00:38:01] Nele Handwerker: Yeah. When they ask me to give words starting with D or counting back or whatsoever, but still walking, yes.
[00:38:13] Prof. Dr. Tjalf Ziemssen: I think it sounds very… See, our problem is, of course, that especially if you have this really very special test, then the question is, is it only MS, which is causing problems? Or could it be another mechanism, which can cause it? So that, I think, is the challenge.
[00:38:38] Nele Handwerker: Yeah. And that’s why the neuropsychologists always ask about your education and what you are doing, so they can then…
[00:38:52] Prof. Dr. Tjalf Ziemssen: Yeah, that’s very relevant. Yeah.
Stem Cell Therapies
Stem cell therapies have gained attention in recent years. Can you explain their potential role in treating MS, and where research stands?
[00:39:03] Prof. Dr. Tjalf Ziemssen: Yeah, first of all, I think we have to differentiate. So we have stem cell therapies, which are really stem cells, so mesenchymal stem cells, which are really given IV or some approaches given intrathecally, so injected into the CSF space. That are principles, where one hopes that you provide stem cells, which can change the milieu in the brain or which can develop into neurons or other cells. So there is a really restoration stories. And we had, in the past year, we had the publication of a first, phase 1 mesenchymal stem cell trial, but at the moment I think the important message is that they seem to be safe, no side effects are there. And especially if you use stem cells of course there’s always a risk that tumors can develop, because stem cells usually have the potency of dividing and developing themselves. So that is, of course, a thing.
I’m not sure what will be the development. So there is some information from the animal experiment that it’s not the cell itself, but the cell migrating into the tissue can change the milieu and it’s an indirect effect. So that’s not only the cell, which is… or the cell you provide which can develop. But of course that is I think a concept, where we have to run trials. Big problem is of course that there are high quality centers, like for example the Italian colleagues, who have published this really well-performed phase 1 study. But the big problem is, there are the black sheep as well, so there are centers around which offer stem cell treatments, but it’s nothing scientific, it’s really earning money.
And so we have, it depends on the country. So in Germany, it’s, for example, quite difficult because dealing with cells, of course, it’s limited. But then you go to other countries, where it’s more flexible and their treatment options are there. So to inject some stem cells and yeah, I think that is problematic. I think especially such very experimental studies, they should be restricted to protocols which are okay, which are approved and not to centers, which in principle are only interested to earn money.
And then the second treatment is of course in the bone marrow stem cell transplantation. So at the moment it’s among the most aggressive treatments we have. So you have such a strong chemotherapy-induced depletion of cells, that you wouldn’t survive this depletion. That’s why you need stem cells, which have been collected before, that these stem cells could serve as a repopulation source and so you killed so much inside the immune system, in the bone marrow, that you need something, which is important for repopulation.
The interesting thing is that a lot of patients, so I had just a conversation yesterday with a patient and so they think, oh, I have to look for a donor. No, no, no. No, the stem cell transplantation principle is that you need your own, that you can take your own stem cells. And the interesting thing is that in principle, moving to the, or going for the stem cells means that your immune system starts at a very early point. So probably your immune system, unfortunately not your whole body, but your immune system is going to a point where you have been as a little child, where you have to experience the immune system, where you have to train the immune system, where you have the infections.
And we know very well that this early phase during your childhood, adulthood, so if you’re a teenager, that this infection happening there, they are shaping probably the pathophysiology of multiple sclerosis. So EBV is one important virus which is there, but probably for the immune system, other infections are relevant. And in principle, this development step is put forward. And that, interestingly, by shifting the immune system to a quite earlier time point and even taking your own cells, which have developed later on MS, so it’s very beneficial in most of the patients. Interesting.
What are the key considerations and challenges in using stem cell therapies for MS?
[00:44:45] Prof. Dr. Tjalf Ziemssen: So the difficult thing is to do it not too early and to do it not too late. So the right time point. So that’s really the question of precision medicine. So I think if your disease is well controlled with medication, I think there’s no reason to go for this exercise, because of course now a lot of patients, the majority of patients, they survive. So it’s not anymore associated with a significant mortality. But on the other side, I think it is an experience, which I would try to work. And especially if you have a family. So we had it in our podcast earlier this year, where we had the live conversation with a patient, who has undergone this procedure. And especially if you have small children at home, it’s horrible, because then you have to separate, you have to live in a separate room, mask all the time and so on.
So in principle, I think it should be used early enough, but you have to demonstrate that the current medication is not working. On the other side, I think it’s of course not a treatment when you cannot move any leg in a wheelchair, because then it’s too late. So this medication is extremely effective, if you have a high disease activity, so if you have a lot of inflammation, if you have a lot of influx of the immune system into the brain. And to identify the time point not too early and not too late, that is a difficult thing. And then, ah, we will wait. But of course, we have a certain window. And you wouldn’t do this autologous stem cell transplantation, you wouldn’t do, for example, if you are 60. So there is, of course, an age limit as well. And yeah, I think that is the difficult thing.
And then on the other side, we have very effective treatments. So we see it in our center. So if you have a quite good… So if you would have a lot of patients with bone marrow transplantation, with autologous stem cell transplantation, then it would tell us that our principle would not work very well, our treatment concept. But we haven’t because a lot, the majority of our patients are really very controlled by the selective treatment. And then I think we don’t need it. We would only need it if disease control could not be, could not be, yeah…
[00:47:42] Nele Handwerker: If it’s failing, more or less.
[00:47:49] Prof. Dr. Tjalf Ziemssen: Absolutely.
[00:47:50] Nele Handwerker: Yeah, thank you. And who wants to listen to that? There was a podcast with Roland Martin and he was explaining it quite in detail.
[00:47:55] Prof. Dr. Tjalf Ziemssen: The father of the Switzerland autologous stem cell transplantation, which is very nice, because everything is proved there.
[00:48:05] Nele Handwerker: Yeah. So let’s talk a little bit more about neuroprotection and repair.
Neuroprotection and Repair
Are there any emerging approaches or strategies for neuroprotection and repair in MS?
[00:48:20] Prof. Dr. Tjalf Ziemssen: Yeah, to be very honest, I think there are, of course, data from animal models, but really convincing drugs, which really have a significant effect. I think you have to differentiate between drugs or clinical studies, which you can publish and studies which can really make the difference. I think still there is a lot of discussion around, but on the other side, really a groundbreaking drug, I don’t see it at the moment.
Complementary and Alternative Therapies
Some MS patients explore complementary and alternative therapies. Can you discuss any that show promise or deserve further research?
[00:49:25] Prof. Dr. Tjalf Ziemssen: Yeah, the big problem is, I think, if we are moving to therapies, which are not mainstream, the problem is that the data quality is, of course, decreasing. You know, to run a clinical study program, it’s quite expensive. And of course, drug companies, of course, go this way, but because they have a benefit on it. So if we have a promising drug, but where the drug is not very likely to generate a lot of money, I think it’s very, very difficult how to fund these trials. And then usually we have, I think, a bad situation in the MS arena that then you run trials, but the trials are totally underpowered. And if you have an underpowered trial, I think that’s very bad, because at the end, you have a trial, but you have to say the trial doesn’t answer the question.
And then for me, for example, if I know already in the beginning that this trial will not answer the question, then you shouldn’t perform this trial, because of course, some patients, they will not be able to understand that the study hasn’t the power to answer it. Like, for example, you know, the same problem we have for example in studies investigating different forms of diet. So very small studies and at the end the main result is because of a small sample size we cannot get a relevant outcome, so we cannot evaluate, we cannot say yes or no. And we can only say that it’s, that it’s tolerated very well, but that is not the question to be answered. And yeah, so in this context, probably we have to be more, we have to be better.
At the moment I don’t see really an infrastructure, which helps us to investigate drugs which are not mainstream, which are not introduced by big pharma. But I think it’s necessary and it would be very interesting. But the problem is that the distance between, on the one side, quite promising drugs and then drugs, which are just sold by people who want to earn money only, and who say, okay, this is a drug, we would have to go and the drug is there. Yeah, one example is, for example, you know, the story about high-dose vitamin D, so Cohimba protocol. So you have, so everyone tells and has a personal experience, which is very positive, but we lack significant clinical study data really to say that if you randomize patients, treatment A, treatment B. Treatment A would be probably low dose vitamin D, treatment B would be high dose vitamin D, that you can show the difference.
And I think it’s very bad if you introduce the therapy, but without demonstrating effects and effects are relevant in the positive way and in the negative way as well. So it means we have to look for efficacy on the one side but we have to look for side effects as well. And that, especially if you have a drug like this, which can cause side effects, I think it’s a problem. Because safety is a clue. So I think we don’t have to run such risks like, for example, in oncology. So in oncology, sometimes it’s really the question. So if you are not aggressive, you wouldn’t survive. That is not the case in multiple sclerosis. So in multiple sclerosis, probably it’s the amount of disability, but it’s not dealing with survival. And that’s why I think, because it’s not so urgent and not so life threatening, that we shouldn’t be as aggressive as we are sometimes in cancer.
[00:53:51] Nele Handwerker: Yeah. So can you give any recommendations to people, who are still interested, so they are not doing, let’s say, stupid choices, but at least end up with things, where there’s maybe no proven context, but there’s at least no threatening?
How can patients safely integrate these therapies into their overall treatment plans?
[00:54:13] Prof. Dr. Tjalf Ziemssen: I think the easiest way is really not to go for drugs, but to go for lifestyle. I think it’s better to stop smoking than to go for a vitamin pill or for other ingredients. And then, of course, smoking is one issue. On the other side, the next thing is, of course, the diet. So a healthy diet. Live… eat like the Mediterranean, eat like Italy, eat like a very nice cuisine in Greece and so on. So that is the way. And then of course, I think what is one of the most important issues, especially in our time, is of course to keep mobile. So, to really walk, walk, walk. And I think looking at these factors, that is much better at the moment than taking a pill.
[00:55:11] Nele Handwerker: And then you get your vitamin D on the side. That’s a good thing.
[00:55:17] Prof. Dr. Tjalf Ziemssen: For example, I have a very low vitamin D level, but that’s probably the cause, because I spend too much, too many times…
[00:55:24] Nele Handwerker: With your patients.
Patient-Centered Care
In the future of MS treatment, how do you envision patient-centered care evolving to provide better support for those living with the condition?
[00:55:41] Prof. Dr. Tjalf Ziemssen: No, I think it’s very relevant, especially if you have different choices, especially if you have some time to decide. So for example, if you had a traffic accident, I think and some arms are hanging around, there will be no discussion that the surgeon will do the best. But of course, in the field of MS, we don’t have really this urgency in minutes or in seconds. Resuscitation, for example, is an example, I think in this situation, you shouldn’t discuss, you shouldn’t just start your resuscitation activities. But in MS, of course, it’s relevant. And especially if you have more treatment options available, it’s very relevant to have this, yeah, really common discussion, shared decision, or how it’s called, so that you know the process of how to come to a treatment decision. And that’s why it’s very relevant, really, to have more objective data. Because if the patient asks me why should I do it and the neurologist says, oh, it’s my gut feeling. I had just a feeling or I had a vision, I had a vision. So we have, of course, in Dresden, you know very well, we have the best crystal ball.
[00:57:12] Nele Handwerker: Of course.
[00:57:12] Prof. Dr. Tjalf Ziemssen: Everything is well known. But I think that is the most important thing, because the patient has to live. A patient is confronted with more and more information. You know it very well, because it’s for you when you do your preparation for the podcast, you see what strange information is available on the internet. And that’s why I think the best thing is only to listening to the Nele Handwerker, to avoid fake news. Because that’s really the problem. And especially if you are confronted with more information. So probably I have very, very few patients not using Google to collect information. I think it’s very good that you have an information-seeking behavior.
But on the other side, a big problem is that the quality of information is not there. And if I say, for example, please do not Google, then the patient responds to me, oh, you would like, you don’t want me to be informed and so on. No, that’s not the reason. So I’m very happy if one collects information, but the big problem is that unfortunately the amount of really strange information on the internet is really relevant. So you know what is the most popular thing in social media. It’s really looking at strange cat videos and to demonstrate how successful you are. So with scientific information, it’s very difficult. But if you have a strange cat moving around, so that’s attracting attention. And that’s a problem, that in principle we have to be serious and we have to rely on objective information, but that’s very difficult to get it outside the Nele Handwerker podcast.
[00:59:26] Nele Handwerker: Yes, unfortunately, your podcast is in German only.
Farewell
How and where can interested people follow your research activities?
[00:59:37] Prof. Dr. Tjalf Ziemssen: Yeah, so we have to work on this. So the problem is, of course and we know it very well. So what was the achievement of Nele Handwerker, really to switch it from the German traditional podcast, which is now 2.000?
[00:59:50] Nele Handwerker: Ah, there are 230 something.
[00:59:53] Prof. Dr. Tjalf Ziemssen: Come on three zeros or four zeros.
[01:00:05] Nele Handwerker: More or less all the same.
[01:00:06] Prof. Dr. Tjalf Ziemssen: All the same, all the same. So it doesn’t matter, doesn’t matter. But you know very well that’s of course a big thing and in principle, I have still a normal life as a physician. And of course, it’s interesting as well. So I think I learned it from you and you told it, that’s still a different perspective. And of course, to do it, to make it available in English is, of course, the amount of interesting people, of course, increases significantly and the audience is getting different. So we had the same challenge. So that was our first internalization process that the master course in German, which still I like very much, because the familiar atmosphere there, it’s, of course, different from having really the international, which is endorsed by the Charcot, the Charcot Master in MS management. But that’s really a difference. And to be more international, I think it’s very good. But of course, it’s, as you know very well, it’s a lot of effort.
[01:01:25] Nele Handwerker: It is. And I think, I mean, I will put a link to PubMed, so people can see how busy you are, besides taking care of patients and having a family and sleeping sometimes. I mean, you must sleep sometimes. I don’t know when, but it must happen.
[01:01:41] Prof. Dr. Tjalf Ziemssen: Probably, probably for the audience. Usually our podcast sessions are usually very late.
[01:01:42] Nele Handwerker: Yes, it’s…
[01:01:43] Prof. Dr. Tjalf Ziemssen: … it’s already sleeping. And that’s the best way to chat with Nele Handwerker.
[01:01:53] Nele Handwerker: Yeah, but you trained me for the American or South and North American parts of the world or Asian. So far I had no interviews with Asian colleagues, but I think they will come in the future. And it’s good that we are doing it always 10 p.m. to 11 p.m. or so.
[01:02:10] Prof. Dr. Tjalf Ziemssen: Also what will be a challenge as well is really Australia.
[01:02:07] Nele Handwerker: I did Australia already, Claudia Mark, on smoking, stop smoking.
[01:02:18] Prof. Dr. Tjalf Ziemssen: That’s a challenge as well, because then you have the early time points. So it’s usually for me, I was two years ago, I was at the Australian Neurological Meeting, but virtual. I think I had to get up at two o’clock in the morning. And then you look a little bit pale.
[01:02:40] Nele Handwerker: You have to use filters. Nowadays, you can use a lot of filters.
[01:02:45] Prof. Dr. Tjalf Ziemssen: But then everyone is asking what Mickey Mouse is doing there. So if you have a new avatar, if you have changed to Mickey Mouse.
[01:02:53] Nele Handwerker: Tjalf, thank you a lot. Thanks for sharing all these insights for the future treatment.
[01:02:59] Prof. Dr. Tjalf Ziemssen: And join you at podcast number 100.
See you soon and try to make the best out of your life,
Nele
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