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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.