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Episode 441: The 2026 ACTRIMS Forum with Dr. Manuel Friese, Dr. Amit Bar-Or, and Dr. Haritha Desu
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- [00:01]
A
I'm john strum, and this is real talk, mississippi. It's February 10th, and we have a lot to talk about. Last week, over 1400 scientists and clinicians gathered in San Diego, California at the 2026America's Committee for Treatment and Research in Multiple Sclerosis Annual Meeting, better known as the actrooms Forum. I had an opportunity to talk with some of the top Ms. Experts in the world, as well as some of the young investigators in attendance. And this week, in Part one of our coverage, we're going to dive right into some of those conversations. First, I want to remind you that this episode of Real Talk, Miss. Is sponsored by Able now, a Tax Advantage savings program for people with disabilities. If you're living with multiple sclerosis, this is important news. Expanded federal rules mean more adults with disabilities, including many people with ms, can open an ablenow account. ABLE now lets individuals save and invest money without affecting their eligibility for certain public benefits, such as SSI or Medicaid. For many of you, Able to it can be an essential financial tool. To learn more and understand if you're eligible to open an account, visit ablenow.com and you'll find that link in today's show. Notes Dr. Manuel Friesa is a clinician scientist at the Institute of Neuroimmunology and Multiple Sclerosis at the University Medical Center Hamburg, Eppendorf in Hamburg, Germany, where he serves as the Director of the center for Molecular Neurobiology and the Director of the Institute of Neuroimmunology and multiple sclerosis. Dr. Friesa is also this year's recipient of the Barancik Prize for Innovation in Multiple Sclerosis Research in recognition of his pioneering work in uncovering how inflammation links to nerve cell death in Ms. And how this interaction drives disease progression. I met up with Dr. Friesa on the first day of the ACTROMS Forum and discussed some of his truly remarkable research. In a moment, you'll meet Dr. Manuel Frise. Doctor Manuel Frisa is a clinician scientist at the Institute of Neuroimmunology and Multiple Sclerosis at the University Medical Center, Hamburg, Eppendorf in Hamburg, Germany, where he serves as the Director of the center for Molecular Neurobiology, Director of the Institute of Neuroimmunology and Multiple Sclerosis, a professor of neuroimmunology, and a consulting neurologist at the University Medical center, Hamburg, Eppendorf. Dr. Friesa is also this year's recipient of the Vrancik Prize for Innovation in Multiple Sclerosis Research in recognition of his Pioneering work in uncovering how inflammation links to nerve cell death in Ms. And how this interaction actually drives disease progression. Welcome and congratulations, Dr. Frise.
- [03:13]
B
Thank you very much.
- [03:15]
A
You have famously said that nerve cells aren't just passive victims of the immune system. For someone living with ms, what does it mean to change the focus from stopping the attacker, the immune system, to fortifying the house, protecting that nerve cell?
- [03:33]
B
Yeah, so one of the key, really, elements in my research is that we try to readjust our understanding of how Ms. Is progressing. And then I think that progression of Ms. Is still the most unmet clinical need in Ms. And that is where we need to understand how that comes about. And the focus so far has been looking at the immune system, trying to modulate that. But we think that we might come too late in doing that, because when the diagnosis has been established, maybe everything has already been adjusted in the house. And therefore we try to understand what has been adjusted in the house, in the brain, in the spinal cord, to maybe readjust it. And this adjustment is mostly done properly in the nerve cells themselves. It's not so much that certainly the immune cells are still there, but the neurons, the nerve cells, they respond to it. And this response we want to understand.
- [04:47]
A
Much of your work addresses the slow progression that happens even when there are no new relapses. How does your research into neuronal stress help us understand why some people still get worse even when their MRIs look stable?
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B
That is exactly the point we want to understand is that we think that neurons or nerve cells are putting on a track. And this track probably has been defined very early on. So they have seen the inflammation, and the inflammation has done something to the nerve cells, and they probably have a response, a memory for the inflammation, and this is somehow what is determining their further outcome and this outcome. First of all, we want to understand how these nerve cells are responding and then to maybe readjust and trying to put on where they were in the beginning. And that could maybe stop in that they eventually die, these nerve cells. And it's probably in comparison to other primary neurodegenerative diseases, where we also see that in Alzheimer's disease and Parkinson's disease, the nerve cells themselves somehow respond to something, could be different stressors. In ms, we have the stressor of inflammation and other diseases, we might have other stressors like protein aggregates or protein misfolding of proteins, but the nerve cells probably respond to it in different fashions. And then they are putting on a track, and we want to understand this track. What determines then their Long term outcome.
- [06:32]
A
You've identified that inflammation forces neurons to shut down their energy production. Is there a way we can reboot the energy centers of a nerve cell to keep it from dying?
- [06:44]
B
Yeah, so that's one of the key questions I think in many neurodegenerative diseases that in the end the neurons try to modulate the energy. And it's. One needs to take a step back and try to understand why do we have this inflammation in the central nervous system. It is probably not because evolution has primed us to actually get ms, but evolution has primed us to be really resilient and resistant to infections. And somehow this is kind of has been gone into disarray and now we have upholding this inflammation. But the brain, the nerve cells still think that there is an infection around. That's why we have inflammation. And they try to, to respond to something which they think there's an ongoing infection. At least that is what I believe how things are happening. And one way to really modulate infections is to shut down energy, not to give pathogens a lot of energy, because the pathogens should not kind of unfold themselves. And we still see that. I mean, if we have a very dramatic flu, we don't eat. We try to really not take up any energy to fuel the pathogen. And that I believe is something which is at the core of our problem. And now the question is how does that actually on a molecular level happen? And these switches and key elements at hubs we try to understand to then and give the neuron kind of, or lift the brake to then again consume energy and to then thrive Again.
- [08:39]
A
You mentioned when we have a flu, for instance, we don't eat. I'm curious, does your research suggest that certain dietary nutrients might actually provide the raw materials neurons need to maintain energy and resist stress?
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B
I believe, I mean there's always the hope that you can just readjust your.
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A
Food.
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B
Your nutrition and then you can somehow modulate the outcome of Ms. Certainly there's components to it which might be absolutely true. We have not entirely understood what the components are. But I think at the moment the picture which unfolds is more the contrary, is that neurons consume too little energy actually because they are primed not to consume too much. Right. Because inflammation is around and they should somehow modulate their energy uptake. So we just need to give the neuron, the nerve cell a stimulus that they should actually again take all the energy up which they are getting provided. Having said that, one of them, the, the major caveats we think is that because they change the energy. And because there's inflammation around, a lot of reactive oxygen species are getting produced and that certainly damage also the neurons because they are doing a different kind of energy production and inflammation is around. And having an idea of how to modulate these reactive oxygen species, I think could be something which could also be then positively modulated by the nutrition. However, it's very early days, people look into that, how to actually scavenge the reactive oxygen species and how to somehow give really good nutrients which are then also passing to the brain, to the spinal cord. But these are early days. And if I just give you one example, vitamin E is one of those. But vitamin E is plentiful in the brain. So if you just give more vitamin E, there will not be more vitamin E in the brain. So therefore this could not be a solution. So we need to find other modes of action and other really drugs properly which can then reach the central nervous system to an extent that it can modulate this reactive oxygen species.
- [11:12]
A
Speaking of drugs, we have over 20 drugs that target the immune system. How close are we to a drug that targets neuroprotection? And do you think we might be looking at a future where someone living with Ms. Takes one drug to stop relapses and a second neuroprotective drug to keep their brain healthy?
- [11:32]
B
Yeah. So if you look back of how these drugs have been discovered, most of them were either serendipitous finding or they were are still not understood why we actually have a modulation of the immune system and what it really does good to, to the, to the immune system so that it is modulating the the relapses. So if you look at how this has been discovered, there is a bit of frustration because the immune system is very complex. And what we give, we give actually drugs which take out a large chunk of immune cells, which we have not understood why that actually is of beneficial effect to the relapses. So even that, so what we do there is very coarse in terms of intervening and that has somehow some beneficial effect. I believe that the nervous system is even more complex than the immune system. So taking out large chunks or courses of the nervous system is just not possible as it is in the immune system. So therefore we need to understand first all the delicate balances in the nervous system to really intervene that. So I think this is even a much larger task than it is in the immune system because you can live with certain and you have a very high redundancy in the immune system and you can live by just Taking out a large chunk of the immune system, but it's not possible for the nervous system. So will in the future be two drugs been taken, one really to modulate the immune system and one to the nervous system? I believe that will be the future. However, how close are we to that? I think it will still be quite some time and that we have really fast, well understood how the workings are of the nervous system to then really fine tune the nervous system.
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A
You're both a researcher and a clinician and a researcher who really lives on the cutting edge of developments. When you're sitting across from a patient in Hamburg and they're worried about their future, how does what you're seeing in the lab change the way you respond to them in the clinic?
- [13:56]
B
Well, first I explained them how Ms. Comes about. So this is just a stochastic event where there's nothing. Where there are certain things which come together and some of that already is a relief for the patient. So that there's a very depth understanding of how actually this disease comes about. And there is no fault in having that disease, nothing which has been done wrong by the patient. And so that sometimes is already a relief and it's a very unfortunate event. Right. In something which is ingrained in being human because we have kind of. That is our trait of which we have in our humankind is that we are getting autoimmune diseases as a trade off of fighting infections. And if we don't have that and if we don't have these individuals who develop autoimmune diseases. And this is something which is. Which I try to understand, which I try to explain to patients, is that they carry the burden of. That everybody lives and can survive against infections and they carry the burden for humankind pretty much. Right? So this is something which we should also kind of support or heavily support these individuals because they are living or showing a disease which is kind of giving the other individuals the allowance to really live and cherish without a disease. And that is something which I think is a totally different view on diseases. It's a collective, so it's not individuals. We try to understand diseases as a collection of individuals which are living together. And I think that can already, for some patients, give a relief and a totally different understanding of disease itself.
- [16:09]
A
That is a remarkable perspective. Thank you for sharing with us. Thank you for sharing with all your patients. Thank you for all you do, both in the laboratory and the clinic. Congratulations again on being this year's winner of the Barancik Prize. And thanks so much for spending a few minutes talking with me today.
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B
Thank you so much for having me here.
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A
The final session of the ACTROMS forum is always reserved for late breaking research news. In this case, we heard updates on four different clinical trials. Dr. Amit Bar, or the Director of the center for Neuroinflammation and Experimental Therapeutics and Chief of the Division of Multiple Sclerosis and Related Disorders at the University of Pennsylvania provided two of those updates. First, reporting on the week 12 results of Moonstone, a phase 2 clinical trial for obexilumab, and then sharing the results of the phase three trial that compared BTK inhibitor phenobrutinib to Ocrevus among people with primary progressive Ms. I caught up with Dr. Bar or right after his presentation and we talked about the results of both of these trials. In a moment you'll hear my conversation with Dr. Amit Bahor. Doctor Amit Bahor holds the Melissa and Paul Anderson's President's Distinguished Chair at the University of Pennsylvania where he directs the center for Neuroinflammation and Experimental Therapeutics and serves as Chief of the Division of Multiple Sclerosis and Related Disorders. Good to see you.
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C
Good to see you.
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A
John, you've spent your career looking at how the immune system behaves in Ms. How has our understanding of what causes Ms. Progression changed in just the last few years?
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C
Well, we've first come to realize that there are two processes that contribute to injury of the central nervous system in Ms. One involves these immune cell interactions and waves of immune cells trafficking from outside the central nervous system to around vessels in the cns. That's the relapse biology. But the non relapsing progressive biology is based on processes that are taking place within the central nervous system. They include inflammatory mechanisms, both immune cells from the periphery that come in and stay and set up shop there and appear to propagate ongoing inflammation as well as brain cells themselves, particularly microglia and probably also astrocytes whose chronic activation is almost certainly also contributing to non relapsing progressive injury of the cns. And ideally we want to be able to target both those different aspects of the disease and perhaps ideally with a single agent.
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A
Lately we've heard a lot about BTK inhibitors. We certainly have over the last few days here at the ACTROMS forum. For someone living with ms, how is this class of drug different from the B cell therapies like Ocrevus or Qsimta that many of our listeners are already familiar with?
- [18:59]
C
So the anti CD 20s like the ocrelizumab the Ocrevus and QSIMTA are are highly effective at limiting relapsing Ms. Activity, but they don't typically get into the CNS at concentrations that in fact change the face of the central nervous system inflammation, including the B cells that are there. BTK inhibitors, and particularly the ones that are what we call CNS penetrant that get into the central nervous system are being viewed as having the potential to impact the B cells as well as other cells of the immune system called myeloid cells in the periphery and impact their contribution to relapsing disease, but also within the central NE system to impact B cells that set up shop there as part of the chronic inflammation as well as importantly the chronically activated microglial cells which are also targets of the BTK inhibitors and are also thought to be relevant for progressive disease.
- [19:50]
A
Just a few minutes ago you presented data from the Moonstone clinical trial. Can you explain what that trial is focused on and what these Week 12 results tell us about how quickly these treatments might actually start working in the body?
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C
Yeah, so the Moonstone trial is a trial of obexilimab and Obexilimab is another what's called monoclonal antibody. It binds to two different parts of the B cell surface. One is the CD19 molecule which is similar to the CD20, the target of the anti CD20 therapies. But CD19 is expressed on somewhat larger range of B cells. But interestingly, this molecule also binds to another receptor on the surface of the B cells and delivers a negative signal into the cell which means it's gonna get less activated. And rather than just killing the cell, which is what the anti CD20 therapies do, this treatment, this antibody engaging the B cell changes its response to be less of a bad guy, less pro inflammatory. So it's a different way of thinking of targeting the range of B cells with a monoclonal antibody.
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A
And would that leave the immune system more intact for the person receiving that therapy?
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C
Quite possibly. I mean we need to see the larger cohorts and subsequent phase three data. But yes, the idea here is that if it's indeed efficacious, you may achieve that benefit without getting rid of as many B cells and that that might be safer over time.
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A
So what were the Week 12 results of the Moonstone trial?
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C
So the primary outcome measure of the Moonstone trial was the number of new brain lesions assessed through contrast enhancing gadolinium lesions. Looking at the scans eight weeks and 12 weeks after the initiation of the study. The study was having Oboxilumab and placebo as a control. And the orxilumab arm decreased the development of new lesions by over 90%. It was highly effective at decreasing both gadolinium enhancing lesions as well as another way of looking at focal lesions, new or enlarging T2 lesions.
- [21:53]
A
Well, that's encouraging.
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C
That is certainly encouraging.
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A
You also presented the results of the Phase 3 phentropid study which compared a BTK inhibitor called phenobrutinib with ocrevus among people with primary progressive Ms. Can you share some of the results from that study?
- [22:09]
C
Yes. This is a study that I must say many of us thought was incredibly brave to pit a BTK inhibitor against the highly active ocrelizumab. Anti CD20. Anti CD20, as you probably know, is the only approved therapy for primary progressive Ms. And so the idea here is to look at whether this BTK inhibitor, how it compares to the ocrelizumab. And the study was designed to be what's called a non inferiority trial, which was, let's see whether this BTK inhibitor, phenibrutinib is at least as good as ocrelizumab because if it is, it would provide a great alternative for some people who may not be able to access anti CD 20s, may not be able to take or tolerate them, and so on.
- [22:51]
A
What did you learn in this study?
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C
Well, what we learned is the study achieved its primary outcome, so it established non inferiority of phenibrutinib compared to ocrelizumab. And while while one doesn't report on the statistical testing of superiority, what's important to note is that throughout the course of the study, people on fenibrutinib did a little bit better nominally than those on the ocrelizumab with about a 12% decrease in the proportion of individuals who met that outcome. The primary outcome of confirmed disability progression on the composite measure.
- [23:26]
A
I know that a major concern for people who are living with Ms. Is maintaining their brain health in the face of long term progression. It sounds like we are getting closer to not just stopping the relapses, but actually protecting the nervous system from compartmentalized inflammation in Ms.
- [23:45]
C
I think we're getting there. I think we have just kind of gotten beyond the cusp and for the first time really with the class of the CNS penetrant BTKIs for those that get into the CNS, the prospect of impacting the non relapsing progressive disease. And I think the field is excited about that and different modalities moving forward to make sure that we can really cover the broad spectrum for people living.
- [24:05]
A
With Ms. That's really, really great. I know you attend a great many research conferences and meetings over the course of the year. What makes the Actrooms forum unique?
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C
I love the actroms meeting. Several reasons. One, it is an Ms. Dedicated meeting. The size is excellent, but I think importantly it has a one track design which means that sessions happen one after the other as opposed to multiple parallel sessions. So you get to enjoy the full content of the meeting. It also is highly interactive with the good opportunities for discussion and it emphasizes young emerging investigators and trainees in the field, which is a top priority for us in terms of training the next generation of researchers and clinicians in the field of multiple sclerosis. It also this year had really focused on having speakers for the oral sessions be new faces to the field and younger people than some of the stuffy old people like myself.
- [24:58]
A
Well, we're always happy to hear from stuffy old people like you, but I will say we were also hearing from some of the people who are going to be the stuffy old people tomorrow. Tomorrow's experts who are going to take everything that you have developed and your colleagues have developed and take it to the next level.
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C
Certainly hope so.
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A
John Dr. Ramit Bar Oar, it is always such an honor to speak with you. I appreciate all that you do on behalf of the Ms. Community. Thanks for making time today.
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C
John. The pleasure and honor of mine. Thank you.
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A
As Dr. Baror pointed out during our conversation, one of the things that really sets the Actriums Forum apart from is the young investigators in attendance not only to hear the latest Ms. Research, but to present their own cutting edge research. I had an opportunity to talk with Dr. Haritha Desu, a young investigator whose work is already making a difference. In a moment you'll hear my conversation with Dr. Desu. Doctor Haritha Destination Desu is a postdoctoral neuroscientist at the Centre Hospitalier de l' Universit de Montreal Centre de richarche in Montreal. Dr. Desu's research has focused on how immune cells like T cells interact with the cells already resident in the brain to drive damage or potentially promote repair. And Dr. Desu is at the ACTRIMS forum presenting research that focuses on how these so called sticky immune cells stay in the brain to keep inflammation going. Your presentation here at actrims discusses how ICAM1 helps immune cells stick around in the brain. For someone living with ms, why is it so important to break that Stickiness.
- [26:45]
D
The reason Ms. Or people living with Ms. Are experiencing the symptoms they are is because their immune cells are attacking their central nervous system or their brain. And this is what's causing the damage that's there. And in later, more progressive stages of the disease, the damage doesn't get repaired. And so by making the cells less sticky and preventing them from staying in the brain, that means that we can hopefully stop the damage that's occurring and maybe even help the brain repair itself.
- [27:19]
A
That was kind of my follow up, whether this is kind of a key to stopping that compartmentalized inflammation that causes progression.
- [27:27]
D
Yeah, hopefully. That would be really wonderful. And that's what my data suggests so far at least.
- [27:33]
A
We often hear about drugs that stop immune cells from entering the brain. Your work looks at what they do once they're already inside.
- [27:42]
D
Exactly.
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A
How might your research help us develop treatments for people who already have active inflammation within their central nervous system?
- [27:49]
D
Yeah, so I am looking at what they do in the brain, but at the end of the day, they are originating from the peripheral body and they're sort of circulating in the blood. And one of the difficulties with developing therapies for Ms. Is that most drugs can't cross into the brain to do their therapeutic effect or to have their therapeutic effect. So if we are able to find targets on the peripheral immune cells that can potentially stop them from sticking around once they're there. And that means that we have found a marker that or a target that would be accessible through the outside system. And that is really an amazing finding if it ends up being true.
- [28:37]
A
Most Ms. Drugs work by turning off parts of the immune system. However, your work on what's called tumor necrosis Factor Receptor 2, or TNFR2, which is a specific target that might actually help the brain heal itself. Your work suggests we could turn on a receptor that actually protects the brain. How close are we to a therapy that doesn't just stop damage, but actively promotes myelin repair?
- [29:05]
D
Yeah. So the TNFR2 results are from my PhD work and it is very exciting because when we remove this receptor, it actually makes in preclinical models of Ms. With animal studies and cell cult, we can see that it makes things worse. And when we add a activating antibody, it can help reduce the inflammation. However, there is still a lot to be done because the activation that we would want to see is within the brain. As I mentioned, it's hard to get therapeutic targets into the brain, and so we would have to do a lot more, I think, studies in the lab before we identify A molecule that could activate TNFR2 and really enhance the protective effects of this receptor. But it is certainly very promising and I was really excited about my graduate work when I was doing it.
- [29:59]
A
You've also spent a lot of time looking at NFL levels. NFL is short for neurofilament light chain, a protein that's released into the bloodstream as a result of nerve cell damage. And you've looked at NFL levels in different clinical subtypes. Can these fluid biomarkers eventually tell a patient sitting in a clinic what their disease course might look like? And maybe more importantly, which drug will work best for them?
- [30:26]
D
Hopefully. I can't comment on whether or not NFL would be the biomarker that would do that because there's still a lot more ongoing studies that are trying to determine exactly that. At least from what is published so far. It seems to be that NFL is not just a marker of more disease severity, but it's also something that increases with age. And there's a lot of other factors that could be influencing its levels. So it's not Ms. Specific. However, there were some very interesting presentations this morning on protein biomarkers that could be predictive or that could potentially be involved in continuing or Ms. Progression.
- [31:13]
A
I would say, yeah, people living with Ms. Are often confused by the labels primary and secondary progressive Ms. From a biological standpoint, does your research show that these are actually two different subtypes or are we just seeing the same fire burning at different speeds?
- [31:32]
D
I think the consensus in the field now is that it's the same fire just burning at different speeds. It's definitely both are progressive forms of the disease. It's just that the people that are affected with SPMS are diagnosed with it after they have relapsing attacks. And people who are diagnosed with primary progressive Ms. Usually have their progression starting from their disease onset. But when it comes to the underlying biology, it is pretty similar. And yeah, I would say there's not many key differences that we have now.
- [32:07]
A
Dr. Haritha Desu, I want to thank you for all you do to improve the lives of people who are living with Ms. And thanks so much for talking with me today.
- [32:14]
D
Thank you for having me.
- [32:16]
A
That's going to wrap up this episode of Real Talk Ms. Real Talk Ms. Is powered by the National Ms. Society and you can share this episode of the podcast by letting your friends or family members know that all they have to do is point their web browser@realtalkms.com 441. You'll find that link in today's show notes, so you can easily copy and paste it right into an email or a text. And I hope you plan on joining me next week on Real Talk. Ms. For part two of our coverage of the 2026 Actrooms forum, I'm John Strum. Thanks for listening. Stay safe and make healthy choices.