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Episode 436: 3 Questions Your Neurologist Should Be Asking Themselves with Dr. Leorah Freeman
00:34:14
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I'm john strum, and this is real talk, mississippi.
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It's January 6th, and we have a lot to talk about. This is our first episode of 2026, so let me kick things off by wishing each of you a very happy and and a very healthy new year. Dr. Leora Freeman is the Director of the Multiple Sclerosis and Neuroimmunology center at Dell Medical School, the University of Texas at Austin, where she also leads the Ms. And Neuroimmunology Fellowship Program and the Ms. Imaging and Outcomes Research Laboratory. Dr. Freeman has recently launched a substack that I found to be a very worthwhile read. It's entitled the Multiple Sclerosis Insider, and as I was reading one of Dr. Freeman's posts, I thought she would be the ideal guest to kick off 2026 with. But before we get to my conversation with Dr. Leora Freeman, there are a few other things that you should know about. I guess we can classify this as a Public service announcement on December 24, the US Postal Service clarified the rules regarding the way that mail is postmarked. This clarification, which actually amounts to a new rule, affects all of us, and it has a potential to impact health care. Under this new rule, which has already gone into effect, a postmark will reflect the date that a letter is processed at one of the Postal Services Automated Regional processing hubs. This can actually occur days after you've dropped that letter in the mailbox. Postmarks serve as proof that something was mailed on a certain date. So what's the potential impact of this new rule on health care? If you mail your insurance premium, or if you're submitting a response to a letter of denial from your insurance company, or you might be applying for Social Security disability and you have to respond to a challenge from the Social Security Administration, you really can't drop that premium payment or letter into the mailbox at the last minute. If you do, it's going to be postmarked late. So don't wait until the last minute to mail anything important by dropping it into that blue mailbox on the corner. Give yourself a week to account for unknown processing delays, and if you want to be completely sure, mail those important documents using certified mail or take your letter to the post office and request a manual local postmark. Planning ahead is usually a sound strategy for almost anything. In this case, it can make the difference in your ability to access health care without having to jump through a bunch of additional hoops, even when they change the rules on Christmas Eve, when most of us are otherwise distracted, please don't overlook this important change in the way US Mail is now postmarked. 2025 ended with some disappointing news for the Ms. Community, especially for people living with non active secondary progressive Ms. On December 24, the FDA issued a CRL or complete response letter advising drug manufacturer Sanofi that their application for tolebrutinib as a treatment for non active secondary progressive Ms. Was would not be approved. In its current form, Tolebrutinib is the first in a new category of disease modifying therapies called BTK inhibitors to be considered for approval. The BTK stands for Brutons tyrosine kinase, which is a long name for a protein that plays an important role in the development of B cells. A BTK inhibitor blocks the activity of this protein and one thing that makes Tolebrutinib particularly important is that it can cross the blood brain barrier so it can target B cells in the central nervous system, making Tolebrutinib the first and only brain penetrant BTK inhibitor that's been shown in clinical trials to be effective in treating non relapsing secondary progressive Ms. And slowing disability progression independent of relapse activity. In response to this disappointing news, Dr. Human Ashrafian, Sanofi's Executive Vice President and Head of Research and Development, issued this statement and I'm quoting here. Today's FDA decision is a significant and meaningful change in direction from the feedback the agency previously provided to Sanofi. We are very disappointed by the FDA's action. Disability progression remains a large unmet medical need in ms, and tolebrutinib was previously aware awarded Breakthrough Therapy designation by the FDA in recognition of its potential to address this critical gap. We believe that the FDA should also take the advice of scientific experts, clinicians and patients in this matter to ensure all perspectives are considered. We remain committed to working with the FDA to find a path forward for tolebrutinib and ultimately serve the Ms. Community. End quote I think the very beginning of Dr. Ashrafian statement is particularly worth noting, he said. Today's FDA decision is a significant and meaningful change in direction from the feedback the agency previously provided to Sanofi. Reading this part of Dr. Ashrafian statement, I can't help wondering whether the chaotic upheaval at the FDA over the past year, including the leadership changes and significant staff reductions affecting the FDA's drug center, may have played a role in all of this. But that's a mystery that's going to remain unsolved. Sanofi has indicated that they're committed to working with the FDA to find a path forward for Tolebrutinib and will continue to keep you updated as that effort moves forward. One of the more confusing aspects of Ms. Is that it can present differently from one person to the next. We can all probably think of examples of two people who have been diagnosed with relapsing ms, yet they seem to be experiencing very different disease courses. A research team at University College London may have uncovered a reason for that when they identify two new and quite different biologically informed subtypes of Ms. And don't worry, we'll get to that biologically informed part in just a moment. The research team used a form of artificial intelligence called machine learning to analyze MRI scans and levels of a blood based biomarker for nerve cell damage called serum neurofilament light chain from 634 people with relapsing, remitting and secondary progressive Ms. We've discussed Serum neurofilament light chain in previous podcast episodes just as a quick refresher. It's a protein that gets released into the bloodstream as a result of nerve cell damage, and serum neurofilament light chain can be measured through a simple pinprick blood test. This analysis identified two distinct biological trajectories in multiple sclerosis, making them biologically informed subtypes. The first subtype was identified as early snfl, and SNFL is just a much shorter way of saying serum neurofilament light chain. This early SNFL Ms. Subtype was found to exist in people with Ms. Who had high levels of serum neurofilament light chain early on in the disease, coupled with damage to part of the brain called the corpus callosum, which plays a role in how people think, remember and coordinate their movements. The second Ms. Subtype was identified as late snfl, which was characterized by a later increase in serum neurofilament light chain coupled with early volume loss in the cortical and deep gray matter of the brain. It's important to remember that the current Ms. Course descriptors were developed about 30 years ago. Relapsing, remitting, secondary progressive and primary progressive describe how a patient presents in a clinical exam. They are symptom driven descriptions, but since the mid-1990s, scientists have developed a better understanding of the biology of Ms. And that knowledge continues to grow. That's why there's a major effort underway to develop updated course descriptors that better reflect this deeper understanding of the biological complexities of Ms. Because the more specifically those biological mechanisms that are taking place in someone living with Ms. Can be described, the more targeted that individual's treatment plan can be. And that's the ultimate goal here, to be able to describe an individual's Ms. Based upon exactly what's occurring in that person's central nervous system. Stopping Ms. Through Targeted personalized treatment Now, I'm not one for making bold predictions of the new year, but I'll guarantee that we'll be talking about the impact of AI and the path to developing new course descriptors throughout 2026. If you'd like to review the details of this study, you'll find that link in today's show. Notes A team of researchers in Europe, the United States and Iran have published the results of a systematic review of data from more than 3,000 people living with Ms. Showing that fear of a sudden relapse or disease progression is common among people with ms, and those fears are closely tied to poorer mental health, greater fatigue, and a reduced quality of life. Now, sometimes you can look at the results of a study and say to yourself, well, of course, and I'm willing to bet that the results of this research aren't the least bit surprising to most of you listening to this podcast. But I'll remind you that opinions are not the same as facts, and while most of us may have already held this opinion, this research provides evidence facts that in this case validate our opinions. It turns out that fear of disease progression has been studied far less in Ms. Than in other chronic illnesses like cancer, for instance. This study reviewed all the studies published up to October of 2024 that focused on examining fear of relapse progression among people living with ms, and the researchers were able to identify a total of 13 studies representing 3,058 participants. These studies were conducted in countries across Europe, Latin America, and the Middle east between 2017 and 2023. About 40% of the study participants expressed fear of needing help with everyday tasks. Study participants also expressed fear about no longer being able to participate in their hobbies or manage medication side effects. While fear of relapse was common, how that fear might play out varied by geographic region. For example, people living with Ms. In Turkey reported milder levels of fear, while people living with Ms. In Iran had much greater concerns about worsening fatigue and the psychological impact of receiving difficult medical from their doctor. Spanish speaking study participants most often worried about both the psychological and physical consequences of experiencing an Ms. Relapse. Younger people and women had significant higher levels of fear of disease progression. But across all 13 studies, greater fear of relapse or progression was associated with worse depression, anxiety, stress and poorer health related quality of life. I think you'll agree that these results are in no way surprising. I've always believed that living with the uncertainty of Ms. Is the worst part of living with Ms. That uncertainty can drive your imagination. And there's really no end to the ways our imaginations can create absolutely terrifying scenarios. And even though those scenarios only live in our imaginations, they create very real fear. And as these study results show, that fear makes real life worse. So what's the solution? There probably isn't an easy answer, but part of the answer is educating yourself, choosing to rely on facts and not opinions. Which means learning to take everything posted on social media with a huge grain of salt, making sure your sources of Ms. Information are reliable sources. That's why I always share links to every study we discuss on this podcast. I think it's important that you have a clear path to review the scientific evidence for yourself, and if you'd like to review the details of this study, you'll of course find that link in today's show. Notes. Last month, the International Progressive Ms. Alliance announced that it was awarding just over $4.1 million to support two clinical trials as part of its Experimental Medicine Trial Awards initiative. The Experimental Medicine Trial Awards fund new and creative studies that help scientists better understand how Ms. Works. The alliance initially selected five projects for funding as part of these awards. Three One Year Development awards were announced earlier this year, and now two full clinical trials are ready to begin. Both of these trials will be testing drugs that have already received FDA approval for treating other conditions to determine whether they could be effective in slowing or preventing Ms. Progression. One of the clinical trials is being led by Professor Laura Iris and her team at Turku University Hospital in Finland. This trial will test whether hydroxychloroquine, a drug that's used to treat malaria and other autoimmune diseases, can reduce inflammation in the brain. Specifically, whether hydroxychloroquine can reduce the activation of microglial cells that contribute to disease progression in Ms. The researchers will use positron emission tomography, or PET imaging, to measure microglial activation while incorporating advanced MRI techniques as imaging biomarkers and to help accelerate future drug development. The other clinical trial is being led by Dr. Ellen Mowry and her team at Johns Hopkins University in the United States, and in this trial, the researchers will investigate whether GLP1 receptor agonists which are currently used to treat diabetes and quite popularly used to treat obesity, can also reduce brain inflammation and protect neurons, which the researchers believe will reduce the risk of progression in people with Ms. Or slow down disease progress in people with progressive Ms. The two year trial will compare an experimental GLP1 agonist to a placebo using imaging, blood biomarkers, neurological examinations, and patient reported outcomes to assess the effectiveness of the drug. I think it's important to point out that the Experimental medicine trial awards required all projects were to be developed with and informed by the perspectives of people affected by progressive ms, including their input on trial design and identifying key outcomes. We'll keep you updated on both of these trials as they progress. The promise of progress that these clinical trials represent ultimately plays out in the clinic, where neurologists and Ms. Specialists leverage these discoveries to to improve a patient's quality of life. To do that, neurologists and Ms. Specialists should be asking themselves three very important questions. In a moment, Dr. Leora Freeman joins me to discuss what those questions are and why they're so important.
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Doctor Leora Freeman is the Director of the Multiple Sclerosis and Neuroimmunology center at Dell Medical School at the University of Texas at Austin, where she also leads the Ms. And Neuroimmunology Fellowship Program and the Ms. Imaging and Outcomes Research Laboratory. Welcome back to the podcast, Dr. Freeman.
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It's a pleasure to be with you.
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I want to start our conversation by letting our listeners know about your substack called the Multiple Sclerosis Insider, and we'll include that link in today's show notes. In fact, we're having this conversation because I read your post that was entitled three Questions we need to Ask As We Enter the BTK Inhibitor Era. So before we get into those three questions, can you explain what a BTK inhibitor is and what prompted you to write your post now?
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Yeah, absolutely. So the BTK inhibitors are this new class of medication that a lot of us are talking about in the Ms. Space. So it's a new class of drugs. Those are oral medications that block the BTK, as their name suggests, and the BTKs are signaling molecules that are critical for the activations of both B cells and also myeloid cells, which what is relevant for us in the field of Ms. Is that it also targets microglia. So let's take a little bit of a step back. The medications that we have in Ms. Right now all target what we call the peripheral component of the disease, peripheral inflammation. Immune cells that live in the periphery, in the blood, that get into the brain and do damage within the brain. What is very exciting about the BTK inhibitors is that yes, they are going to target this peripheral component of the disease by modulating B cells, but they are able to get into the brain and modulate Immune cells that reside within the BR are resident B cells of the brain or also those famous microglial cells which are thought to contribute to the progressive, you know, disease that can.
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Occur with Ms. You write that clinical trials provide important safety data and you also point out that there's still much left to be learned from the real world use of the new medication. I'm wondering whether you can share an example of this scenario from a disease modifying therapy that's currently in use today.
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Yeah, so we've seen this at least twice and two examples that truly come to mind in my lifetime. When I started as a young resident, Tsavari was approved and it was very exciting because we only had those injectable. We had many people failing these medication or these medications failing many people. And there came a high efficacy treatment. And so a lot of our patients that for whom the platform therapies were not working were switched to Tisabri. And we discovered after the medication was approved that Tisabri could contribute to the development of a condition called pml, which is a brain disease due to the reactivation of a virus. And in many cases this condition can be lethal. So we had very serious complications. So Tsavri was then taken off market and after further studies and findings was put back on the market and became available with more safeguards with additional research to help identify what contributes to the development of this bml. So that was really probably the most significant example. We also saw this with the S1Pmodulators, Gilenia in particular, where drug became available. And soon after the drug became available, we realized that Gilenia could have an impact on the heart and slow down the heart so much that a patient passed away from this complication. So then again, the drug was not taken off market at the time, but there were a lot of safeguards that were put. People were required to have a first dose observation. So it's really shaped the way that we started this medication. And you know, in, in later years.
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You also write that the art and science of Ms. Care, and I'm going to interrupt myself here to say that I found art and science to be a perfect characterization of what Ms. Care should be. You write that the art and science of Ms. Care is pairing innovation with vigilance, optimism with responsibility. What does pairing optimism with Responsibility look like in Ms. Care?
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Well, for me, it's approaching every, every one of our patients that come in the door, you know, asking myself, you know, what is the best decision I can make for this patient today? And, you know, we find that we have to really navigate very specific and individualized decisions with our patients, but we have to really be mindful that our decisions have potential consequences. So we have to be really clear about what do we know, what do we not know, what do we not know yet? And, you know, that means for me, being able to explain to my patients, yes, I think this medication is available and it may be a good choice for you. But here are the things that I don't know from the data that exist. Here are the things that I wish I knew that may be available, and here are the risks that we may be taking. So it's really about engaging in a shared decision making approach where we are able to talk to our patients about, really about this uncertainty and making decisions together with some solid data, because there's a lot of solid data in ms, but with also this approach to uncertainty when it comes to both efficacy and safety.
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Which really brings us to the three.
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Questions that you see confronting neurologists and Ms. Specialists as we enter this BTK inhibitor era. And those questions are, who is the right candidate? When is the optimal window to intervene? And how will you know with confidence whether a treatment is helping someone or not? Now, these are incredibly important questions. And I can hear a lot of our listeners saying, well, isn't that what the clinical trial is for?
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You know, I think it's important for our listeners that clinical, you know, to understand that clinical trials are very important steps in understanding efficacy and safety of medications. But there's a lot still that needs to be learned in the real world as we approach. So they, you know, the clinical trial get us through the door, but it doesn't answer all the questions free. It doesn't answer all the questions because clinical trial participants are very precisely selected. They look a certain way, their age are within a certain bracket, they're free of comorbidities. And depending on where you live in the US this may not look like most people living with ms, because people with Ms. Don't live just with Ms. And so as we approach, you know, bringing a medication that, you know, gets approved or just showed efficacy in a clinical trial into the real world, then, you know, we're kind of left with a question. Well, I know data from the group, you know, clinical trial findings show us group data. Well, what does that mean for an individual person with their own history, with their history of medication that they've used. So I think this is really kind of what I really mean by these questions is how do we go from group level data to individualized decisions? What's very challenging, in particular with the BTK inhibitors, is that we're in a complete different framework from the one that we know, which is medications that target peripheral inflammation and are meant to really be effective on relapse activity and MRI activity. For this, we have good, very obvious markers of whether or not a medication's working. You know, patients stop having relapses, good patients can stop having new lesions on MRIs. I'll be able to see that progression is much more difficult to approach first, because when I see someone who lives with Ms. Who comes to the clinic and tells me I'm getting worse, you know, what I need to really figure out as a clinician with them, in partnership with is this person getting worse because their Ms. Is getting worse? Because there's really such a thing that we don't talk about in trials, which is Progression independent of Ms. You know, when somebody with Ms. Is 55 years old and has arthritis in the knee and needs a knee replacement, their score, their EDSS score, which is a disability score that we use in trial, is going to worsen. But it's not because their Ms. Is necessarily getting worse. The knee needs to be replaced. Then all of a sudden you replace the knee and they walk much better, and suddenly they're far better. So that's really kind of a first step, is identifying who's really progressing. Can we identify this before it is completely obvious and people are using walking aids? Right. We want to be very early in that decision. And I think that's what really I mean by can we identify better who is the right candidate? We need to be able to know who is really progressing or who is at risk of progression based on what's happening within their brains. But we have no windows into that currently. Not like looking at new lesions as a marker of relapse activity. We don't have the right markers to say this person is at risk for progression.
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And one of the things I was so taken with in your post was that you call out what those markers.
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Could very well be.
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You call out digital biomarkers, serum biomarkers, and for our listeners, that those are biomarkers that can be found in your blood, and you call out advanced imaging biomarkers that can add tremendous specificity to characterizing and hopefully treating Ms. And it really points to fitting all the things that experts are learning about identifying progression in Ms. Into clinical practice, which is ultimately going to lead us to a much more patient centric, a more personalized approach to Ms. Care. As you say, the individual in front of you is getting examined.
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If, if they, if, if their issue.
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Is arthritis in the knee, that may not be much of an impact in terms of their Ms. Care. It's impacting their overall health. And we can start teasing. That's one we can tease out, perhaps more obviously than some others. But as we move toward the future, I have to ask, as we're talking about being able to, to make these finer distinctions using tools that are either in development or available today, I have to ask whether you think the current course descriptors for Ms. Relapsing, remitting, secondary progressive and primary progressive, do they still make sense in this new era we're entering?
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I don't think so. I think that. And you can read about this, I've written about this on my substack as well. You know, this is, you know, for me, Ms. Is one disease. It's a spectrum. You know, people experience relapses or disease activity that reflects a certain biology. They may also, at any point in time, experience progression or be at risk for it that reflects a different biology, but those can be completely intertwined. And we see this, you know, with, you know, young patients that have books, you know, that have, you know, relapses at the same time that they experience progression independent of relapse activity. So it's really what, what we truly need is course descriptors that really reflect the underlying biology of Ms. And, and the, this, those different processes that are intertwined within each individual. You know, now not everybody will express, you know, microglial activation or this, these biological processes that lead to progression of disability. Not everybody will have aggressive disease activity. But that's what we need to understand, being able, in the way that we assess patients in the future, being able to understand not just where they've been, you know, oh, they've had this many relapses, they have progressed in this past year, but understand where they are going, what is at play in the brain, in the immune system. And for that, we need those better tools that will be able to tell us with greater precision how a patient's journey may unfold. And interestingly, those same markers and tools that we need to be able to predict the journey of individual patients are the same tools that are going to tell, help, tell us whether a medication has an effect in that one individual. Because this is also the whole issue with, you know, looking at treatments for progression. And, you know, BTK inhibitors are. What's, you know, on the horizon for us is that once we start someone, you know, on these treatments, how do we know it's working? We know that progression is very fickle. You know, it can sometimes slow down and sometimes accelerate. And, you know, does that mean the drug is working or does that mean this is just the journey somebody is on? So being able to have these different tools at our disposal, and I always say it's tools that are always used in collaboration with the individual, the expert who lives with Ms. And the expert who treats Ms. It's not just tools in a vacuum. It's really tools that are used together with, you know, with our patients, with our sound decision making so that we can make individualized decision for each and everyone.
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Well, Dr. Leora Freeman, I want to thank you for all you do to improve the lives of people living with Ms. I want to thank you for deciding to launch your substack. It's called the Multiple Sclerosis Insider. And I just find it to be a wonderful addition to what's available to learn more about what's happening at the forefront of Ms. Treatment and care. Thanks so much for talking with me today.
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C
Thank you so much for having me, John. Always a joy to be with you.
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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 436. 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. I'm John Strum. Thanks for listening. Stay safe and make healthy choices.
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Sam.