WEBVTT
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It's November 3rd, and we have a lot to talk about.
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Our coverage of MS Toronto 2026 continues this week, and in just a couple of
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minutes, you'll hear from two of the top MS experts in the world.
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Doctors Jeffrey Cohen and Robert Fox are both neurologists at the Cleveland Clinic,
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and they each led two very important sessions at MS Toronto 2026.
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But before we get to my conversations with Drs. Cohen and Fox,
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we have to talk about Christina Applegate.
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If you've been anywhere near social media, the news, or podcast feeds recently,
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then you heard all about Christina's stunning revelation that after years of
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publicly, courageously navigating what she was told was multiple sclerosis,
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her doctors recently informed her that she had been misdiagnosed.
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Christina's raw honesty was heartbreaking to hear. She talked about feeling
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like she was back at square one,
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still dealing with very real, disabling physical symptoms, but suddenly stripped
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of the explanation and the medical roadmap she thought she had.
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Here, I'll just add that Christina did not let anyone down.
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The vulnerability she shared, the light she shone on invisible disability,
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and the comfort she brought to so many living with chronic neurological conditions,
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well, that remains invaluable.
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Misdiagnosis is a failure of diagnostic limits, not a personal failing.
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Now I want to address the elephant in the room, because over the past week,
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my inbox has been flooded with messages from our listeners, and the dominant
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emotion isn't just sympathy for Christina.
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It's sheer panic. People are asking, if Christina Applegate had an entire team
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of top specialists and was wrong for five years, how do I know my diagnosis is real?
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Could I be taking the wrong medication? Could I be next?
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So let's take a breath, break down why this happened, and talk about what it actually means for you.
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Neurologists often call multiple sclerosis the great imitator,
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but the inverse is just as true.
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Dozens of conditions imitate MS.
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There is still no simple single blood draw or pregnancy-style test that lights up positive for MS.
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An MS diagnosis relies on putting puzzle pieces together, including clinical
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history, neurological exams, spinal fluid analysis for oligoclonal bands,
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evoked potentials, and importantly, MRI imaging.
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The reason this picture gets cloudy is because nonspecific white matter lesions
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on brain MRIs can look very similar to MS plaques.
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Some of the conditions that frequently mimic MS symptoms and imaging include
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neuromyelitis optica spectrum disorder, systemic autoimmune and rheumatologic diseases like lupus,
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severe chronic migraines or microvascular disease,
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severe B12 deficiency, copper deficiency, or late-stage Lyme disease,
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and functional neurological disorder, or FND.
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Studies from specialized MS centers, including Cedars-Sinai and UCLA,
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have shown that an estimated 15-20% of the patients referred to tertiary MS
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clinics with an initial diagnosis
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actually end up having one of these mimic conditions. It happens.
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Now, if you're currently questioning your own diagnosis, please hang on.
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Here are some things I'd like you to think about.
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First, your response to treatment tells a story.
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If you've been on a disease-modifying therapy and your routine MRIs show stable
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disease, no new active lesions and reduced relapse rates, your treatment is
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doing its job biologically.
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That stability is functional proof of an active-responsive mechanism.
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Also, consider that diagnostic tools have radically advanced.
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The revised McDonald criteria, the wider adoption of spinal fluid analysis,
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and specialized imaging techniques, like looking for the central vein sign or cortical lesions,
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they make modern MS diagnoses far more rigorous and precise than they were even a few years ago.
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And specialist care can make a difference.
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Misdiagnoses most often occur when someone is diagnosed by a general practitioner
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or even a general neurologist who sees nonspecific white spots on an MRI and
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just stops looking further.
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If your diagnosis was confirmed by an MS specialist or comprehensive neuroimmunology
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team using the full diagnostic criteria, the likelihood of an error,
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well, it drops significantly.
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If you're genuinely unsure of your MS diagnosis, rule number one is please don't
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alter your treatment regimen based on a headline.
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While your anxiety is understandable, do not stop your disease-modifying therapy.
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Abruptly discontinuing certain MS treatments can trigger severe disease rebound.
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This is especially true if you're on Gilenya, Mazent, Zeposia,
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Ponvary, Tysabri, and Tyruko.
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And at your next routine visit, ask your neurologist to walk you through the
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specific criteria that solidified your diagnosis.
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A good clinician will be happy to review your Spinal Tap results,
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the specific location and architecture of your lesions, and your clinical timeline with you.
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If you're someone who was diagnosed years ago after a single MRI scan,
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you've never seen an MS specialist, or you have symptoms and atypical MRI features
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that have persistently surprised or confused your care team,
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getting a second opinion at an accredited MS center is always a reasonable,
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proactive step for you to take.
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Christina's journey is a sobering reminder of how nuanced an MS diagnosis can be.
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But please know that her story does not invalidate your reality,
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your care plan, or the stability and quality of life you work hard to maintain every day.
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Few sessions generated more buzz
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at ms toronto 2026 than the discussions surrounding car t cell therapy.
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Dr. Jeffrey Cohen of the Cleveland Clinic co-chaired one of the standout presentations
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exploring its potential in treating multiple sclerosis and we sat down with
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dr cohen directly following the session for an update on the latest clinical findings
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Dr. Jeffrey Cohen is a neurologist at the Cleveland Clinic's Mellon Center for
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Multiple Sclerosis Treatment and Research, where he also serves as a director
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of the Experimental Therapeutics Program.
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And one of the things Dr. Cohen is doing at MS Toronto 2026 is moderating a session
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focused on CAR T-cell therapy and immune system reset in MS.
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It's good to see you, Dr. Cohen.
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It's good to see you.
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I hope you'll start us off by briefly explaining what CAR-T cell therapy is
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and what's meant by an immune reset.
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Yeah, so CAR-T therapy is an area where there's a great deal of interest.
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It's early days, but so far the results have been very encouraging.
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So what a CAR-T cell is, a so-called effector T lymphocyte that's been engineered
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to express a CAR or chimeric antigen receptor.
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So this is an artificial receptor that's able to target specific antigens or
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other molecular targets on other cells.
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And then what it allows for is for antigen recognition that doesn't require
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MHC, which is one of the requirements of typical antigen recognition by the immune system.
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Then activation of that CAR-T cell, proliferation, and ultimately killing of the target cell.
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So that approach has really revolutionized the treatment of hematologic malignancies,
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lymphoma, leukemia, multiple myeloma.
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And the CAR-T cell products that are already approved to treat those malignancies
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target antigens that are expressed on B lymphocytes.
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And so So the thought was, is that because we know that B lymphocytes play such
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an important role in the MS process, that maybe we could utilize this approach to treat MS.
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So, among our most potent MS therapies are monoclonal antibodies that target B cells.
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The advantage of CAR-T therapy that does somewhat the same thing is that whereas
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monoclonal antibodies only target and kill B cells circulating in the blood,
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CAR T cells have the ability to migrate throughout the body and kill those B
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cells in the tissues, including within the central nervous system,
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which antibodies can't penetrate.
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So you asked about immune reset. So the idea is that CAR T cells may have very
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potent benefit by killing B cells, deeply depleting them in the blood and in the tissues.
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And then, as they
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reconstitute, repopulate, that the B cell population may come back with a more
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normal characteristics, a
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more normal regulatory phenotype, and a more naive phenotype characteristics,
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the idea being that the immune system may
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be in a more normal state after reconstitution. So that's the reset.
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So the hope, the goal is, is that CAR-T therapy may be a very potent treatment,
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and it also may be a very durable treatment.
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You know, as you mentioned, CAR-T therapy is already used to treat some cancers.
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Early oncology treatment, CAR-T cell therapy targeted a disease that was highly
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resistant to other forms of treatment.
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In multiple sclerosis trials today, we see cohorts spanning both treatment-resistant
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relapsing disease and non-active progressive MS.
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Where do you believe CAR-T cell therapy has the highest likelihood of providing
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transformative clinical benefit, and who represents the ideal candidate?
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Right. As I said earlier, it's still very early days with CAR T.
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So far, the published data really only includes several small case series.
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There are a number of more formal phase one studies that are ongoing,
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actually quite a large number of those.
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And several of those are going to be reported out. Some preliminary ongoing
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data from those studies is going to be reported out at this meeting.
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I think it's very likely that CAR-T therapy directed against B cells will be
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effective in treatment refractory relapsing MS,
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because it's pretty likely that the CAR-T will accomplish at least the same
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thing that the B cell monoclonal antibodies do.
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But that's a population for whom we already have a sizable number of treatments.
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Now, there are a few people that don't benefit from that, from those therapies,
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still have ongoing disease activity, but I think that's going to be a relatively small population.
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I think the population that I'm most excited about is people with non-active,
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non-relapsing, progressive MS.
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Our current therapies don't target that effectively almost at all for most people.
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And so the hope is that CAR T cells,
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through their ability to get into the nervous system and address the mechanisms
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that drive progression within the nervous system, that they'll be effective in that population.
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And so far, very early results look very promising in that regard.
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In hematologic oncology, CAR-T therapy carries some significant risk of side
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effects like severe cytokine release syndrome, immune effector cell-associated
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neurotoxicity syndrome.
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What are early safety and tolerability signals revealing among people with MS?
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And how are conditioning protocols being modified to minimize toxicity for neurological patients?
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Yeah, so there's several questions in there. So, one is there's actually quite
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a lot of experience with CAR-T to treat hematologic malignancy.
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So, the range of potential complications is pretty well defined.
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And so, as neurologists, we, in fact, see some of those patients because some
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of those toxicities are neurologic, even though they're cancer patients.
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Some of the same toxicities have been seen in autoimmune diseases,
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including multiple sclerosis.
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However, actually, thankfully, it looks like they're less frequent and less
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severe, in part because the target cell burden is lower.
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Cancer patients have a huge number of the target cells that the CAR-Ts see and
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get activated by and kill, whereas
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the number of immune cells that are killed in a patient with autoimmune disease is much smaller.
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So, there isn't quite as frenetic a response by the CAR T cells.
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And as a result, some of these well-known toxicities seem to be less common.
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Now, we were concerned that someone that already has an immune condition,
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where their immune system may be overactive, or that already has a neurologic
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disease, might be more prone to those complications.
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But thankfully, that so far has not been the case. You asked about a couple of other things.
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Currently, low-dose chemotherapy prior to the CAR-T is a standard part of the regimen.
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That's mostly to make room, as it were, in the immune system for these CAR-T cells.
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There are some considerations about whether that's really necessary in an autoimmune disease.
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You don't need quite as robust a CAR-T response, or whether at least the regimen
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could be toned down a little bit.
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And then there's also a development called in vivo CAR-T. So the current approach to CAR-T is
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you produce them in the laboratory, then re-infuse them into the patient.
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But there is a technology for creating them within the patient,
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and that may not require this lymphodepleting chemotherapy.
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So that's really exciting. The field's moving really quickly,
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so we'll see how that goes.
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That is really exciting. We have to bring up two pharmaceutical manufacturers
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not too long ago paused their CAR-T clinical trials after three trial participants passed away.
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What's the readout from those deaths, and how have those paused trials impacted
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the work going on in this area?
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Yeah, so it's…
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You know, first of all, you know, the tolerance for risk is lower in autoimmune diseases.
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You know, in patients with hematologic malignancies who may die because of their
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disease in the near future, you know, the oncologists and the people with cancer
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are sometimes willing to put up with bigger risks.
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We're not going to tolerate that in treating MS and autoimmune diseases.
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So, those two instances that you mentioned did give us pause.
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They did remind us that CAR-T therapy is a very novel experimental therapy.
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I don't know all the details from one of those, but I think in both cases,
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probably the main cause related to the manufacturing protocol.
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What we're finding is that the shorter manufacturing procedures lead to CAR
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T cells that are more active,
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and the dose of the CAR T may need to be decreased with these newer manufacturing protocols.
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You have extensive experience as an expert in autologous hematopoietic stem cell transplantation.
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Both approaches aim for an immune reset, but through very different biological routes.
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How do you compare the curative or long-term remission potential,
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durability, and practical delivery of an engineered living CAR T-cell product
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versus high-dose chemotherapy followed by stem cell transplantation?
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Yeah, so the situation is really different for those two treatment approaches.
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For hematopoietic stem cell transplant, we actually now have a sizable amount of experience.
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We know the good points and the bad points. It's a very effective approach in
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appropriate candidates, but it's a pretty rough procedure.
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So, whereas CAR-T is a promising approach with very encouraging early experience,
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but very limited experience so far.
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So, on the good side, it's a much less rough approach.
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So, I would say that if CAR-T pans out, it may obviate the need for a metapoietic
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stem cell transplant in many people.
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But unfortunately, our experience in the field has been that some things that
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seemed like a good idea didn't work out as well as we had hoped.
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I guess that's what science is all about. Well, Dr. Cohen, I want to thank you
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for all you do to improve the lives of people who are living with MS.
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I can honestly say I learn something new every time we talk.
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And thanks so much for making time to talk with us today.
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It was great talking to you.
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Progressive MS was front and center at MS Toronto 2026, where Cleveland Clinic's
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Dr. Robert Fox led a packed session highlighting the global collaborative work
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of the International Progressive MS Alliance.
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Prior to this session, Dr. Fox talked with us about the impressive portfolio
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of work being driven by the Alliance.
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I'm here with Dr. Robert Fox, and I have to say, it's difficult for me to attend
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a major MS research conference anywhere in the world and not want to talk with Dr. Fox.
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He's a neurologist at the Cleveland Clinic's Mellon Center for Multiple Sclerosis
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Treatment and Research, as well as a vice chair of research at the Cleveland
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Clinic Neurological Institute.
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But Dr. Fox also serves as a principal investigator for some of the most high-profile
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clinical trials for multiple sclerosis.
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He chairs the International Progressive MS Alliance Scientific Steering Committee,
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and Dr. Fox is the Managing Director of the NARCOMS Patient Registry.
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So when you consider his leadership role in so many aspects of multiple sclerosis
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research and care, there's always a good reason to catch up with Dr.
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Fox. Thanks for joining me in Toronto.
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Well, thanks, Jon. It's always good to be with you.
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One of the things you'll be doing at this meeting is delivering sort of an update
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on the International Progressive MS Alliance.
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When the Alliance first set out its agenda, treating progressive MS was,
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was widely considered one of neurology's hardest challenges.
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And the strength of the Alliance came from its global collaborative model,
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which was a novel concept when the Alliance was launched.
00:20:42.250 --> 00:20:47.070
So as you present this update here at MS Toronto 2026, where,
00:20:47.070 --> 00:20:53.210
or how do you see this global collaborative model has moved the research needle the fastest?
00:20:53.950 --> 00:20:59.170
So this global collaboration truly has brought together academics,
00:20:59.610 --> 00:21:05.420
nonprofits, industry, people affected by MS like yourself. You were a part of
00:21:05.420 --> 00:21:07.730
the Scientific Steering Committee for many years.
00:21:08.000 --> 00:21:10.020
Thank you for your contributions to that.
00:21:11.260 --> 00:21:15.770
Pulled together to try to solve the riddle of progressive MS.
00:21:16.190 --> 00:21:21.260
And there were three main areas that were identified and continue to be our
00:21:21.260 --> 00:21:25.480
central core focus to solve the riddle of progressive MS.
00:21:25.750 --> 00:21:29.130
One is what is the true biology?
00:21:29.430 --> 00:21:34.470
What are the pathogenic mechanisms that are driving progressive MS?
00:21:34.910 --> 00:21:38.200
There are many different things that are thought to be a part of it.
00:21:38.200 --> 00:21:39.640
It's probably not all of them.
00:21:40.030 --> 00:21:43.590
What is the real pathology? We're still trying to figure that out.
00:21:43.950 --> 00:21:46.230
Secondly, how do we accelerate
00:21:46.870 --> 00:21:51.850
The discovery of new therapies? How do we make clinical trials faster and more
00:21:51.850 --> 00:21:55.990
efficient so we can identify the promising therapies and carry them forward
00:21:56.240 --> 00:22:01.300
and reject the therapies that don't have any promise moving forward?
00:22:01.560 --> 00:22:05.210
We don't have a good way of separating the wheat and the chaff,
00:22:05.210 --> 00:22:08.050
if you will, and we need to figure that out better.
00:22:08.220 --> 00:22:15.320
And thirdly, people affected by MS have a lot of symptoms, a lot of issues with
00:22:15.320 --> 00:22:20.430
their just everyday function, whether it be fatigue, bladder dysfunction.
00:22:21.030 --> 00:22:26.970
Walking difficulties, spasticity, all these symptom problems that we might be
00:22:26.970 --> 00:22:29.430
able to address the disease mechanisms.
00:22:29.750 --> 00:22:34.150
But if we don't help them function in their everyday life, we will not really
00:22:34.150 --> 00:22:36.270
have helped them in a way that they want to be helped.
00:22:36.600 --> 00:22:39.650
So we continue to focus in those three areas.
00:22:40.100 --> 00:22:46.580
We have funded research in each of those areas to try to identify solutions
00:22:46.580 --> 00:22:48.800
and overcome some of the barriers.
00:22:49.020 --> 00:22:56.300
We have convened groups to pull together to try to brainstorm and identify better solutions.
00:22:56.540 --> 00:23:00.450
We've even met with the regulators. We had a meeting with the U.S.
00:23:00.810 --> 00:23:08.110
FDA to talk about fluid biomarkers and to develop further progress in understanding
00:23:08.110 --> 00:23:12.470
fluid biomarkers that may reflect progressive MS.
00:23:12.740 --> 00:23:16.170
So there are many different areas that we have been involved,
00:23:16.460 --> 00:23:18.340
and we're just getting started.
00:23:19.110 --> 00:23:23.880
The Alliance's scientific mandate focuses heavily on accelerating drug discovery,
00:23:24.460 --> 00:23:28.040
identifying novel targets, refining clinical trials.
00:23:28.640 --> 00:23:32.630
What are the top priorities the Scientific Steering Committee is driving right now?
00:23:33.570 --> 00:23:38.760
So at the beginning of this year, the beginning of 2026, we took a step back
00:23:39.160 --> 00:23:42.770
and we said, OK, we've been doing a lot of things over a lot of years.
00:23:43.140 --> 00:23:47.220
Let's take a step back and see where we really need to go.
00:23:47.570 --> 00:23:52.730
We stayed with our three focuses, the biology of progressive MS,
00:23:52.730 --> 00:23:58.060
accelerating trials and improving the quality of life of people living with MS.
00:23:58.460 --> 00:24:07.080
And we convened task groups that did a deep dive to identify what are the remaining unmet needs?
00:24:07.390 --> 00:24:11.380
What are the remaining problems and what should be done? What are the critical
00:24:11.380 --> 00:24:15.320
things that need to be done now to help us make progress?
00:24:15.770 --> 00:24:19.520
And so over the course of the last nine months, we brainstorm,
00:24:20.370 --> 00:24:26.030
we put together those ideas, we refine them in person this past summer in a
00:24:26.030 --> 00:24:29.180
convening effort, And we continue to do that now.
00:24:29.180 --> 00:24:34.680
And we have identified some of the critical barriers in understanding the biology
00:24:34.680 --> 00:24:38.960
and accelerating the trials and improving quality of life that we will then
00:24:38.960 --> 00:24:41.370
implement over the next three to five years.
00:24:41.370 --> 00:24:47.570
So taking a step back and saying what really needs to be figured out and then
00:24:47.570 --> 00:24:49.590
identifying the steps to go figure it out.
00:24:50.210 --> 00:24:54.790
Well, speaking of accelerating clinical trials, in an effort to accelerate research,
00:24:54.990 --> 00:25:00.660
we're seeing multi-armed trials like Octopus and the Platypus trial that test
00:25:00.660 --> 00:25:03.300
multiple drug candidates simultaneously.
00:25:03.680 --> 00:25:08.080
How is the Alliance collaborating with academic groups and industry sponsors
00:25:08.350 --> 00:25:13.520
to make trial screening faster, cheaper, and less burdensome on the trial participants?
00:25:14.040 --> 00:25:17.920
Well, we are supporting these multi-armed trials.
00:25:17.920 --> 00:25:22.360
One, we also identified through this strategic reflection
00:25:22.800 --> 00:25:27.060
that the alternative trial structures of
00:25:27.500 --> 00:25:33.520
different ways of doing trials, like the multiple arm adaptive trial design,
00:25:33.520 --> 00:25:35.740
like the octopus and the platypus trials,
00:25:36.150 --> 00:25:42.780
they are important aspects of what we need to get out into the world for people to know them.
00:25:43.100 --> 00:25:48.170
There are some other designs of doing trials, such as futility design trial,
00:25:48.170 --> 00:25:52.760
which is a little bit different than a superiority, a benefit trial.
00:25:54.180 --> 00:25:57.530
And so what we've come to realize is we need to promote them.
00:25:57.530 --> 00:26:02.010
We need to let the field know about them more, particularly the sponsors,
00:26:02.010 --> 00:26:04.890
like industry sponsors and government sponsors,
00:26:05.330 --> 00:26:10.800
So they realize that those are useful and valid trial formats that can test
00:26:11.090 --> 00:26:13.900
new therapies faster and more efficiently.
00:26:15.060 --> 00:26:19.930
Stopping progression is critical. At the same time, as you started to point
00:26:19.930 --> 00:26:24.760
out, day-to-day life for someone with MS is dictated by symptoms like fatigue,
00:26:24.870 --> 00:26:27.080
mobility loss, cognitive fog.
00:26:27.600 --> 00:26:31.660
What updates can you share regarding the Alliance's work in non-pharmacological
00:26:31.660 --> 00:26:33.840
interventions and neurorehabilitation? .
00:26:34.570 --> 00:26:42.180
Well, we are actively supporting several trials that are exploring non-drug
00:26:42.180 --> 00:26:45.870
approaches to improve quality of life of people living with MS.
00:26:46.200 --> 00:26:51.550
And so we are directly supporting those trials and helping to identify those
00:26:51.550 --> 00:26:55.410
potential treatment methods that don't involve drugs.
00:26:55.810 --> 00:27:02.160
In addition, through the strategic planning, we have identified a need to establish
00:27:02.160 --> 00:27:08.350
a new conceptual model of quality of life and what that means to people living with MS.
00:27:08.620 --> 00:27:15.750
And so over the coming year, we will be trying to develop that and establish
00:27:15.750 --> 00:27:21.450
that, a new conceptual model of living with MS and progressive MS particularly.
00:27:22.010 --> 00:27:26.800
The Alliance has made, including people affected by MS, a cornerstone of its work.
00:27:27.080 --> 00:27:31.300
As you were kind enough to point out, it was my privilege to serve as a member
00:27:31.300 --> 00:27:33.570
of the Alliance Scientific Steering Committee.
00:27:33.900 --> 00:27:38.250
So I know how I would answer this question. I'm curious from your perspective,
00:27:38.610 --> 00:27:43.250
how have you seen the direct involvement of people affected by MS impact the
00:27:43.250 --> 00:27:47.360
Scientific Steering Committee's clinical or research priorities over the years?
00:27:48.030 --> 00:27:54.220
We value deeply the ongoing continued input of people living with MS.
00:27:54.220 --> 00:28:00.340
That's why we have three people affected by MS on our scientific steering committee.
00:28:00.650 --> 00:28:04.010
And we have even more that are on an engagement committee.
00:28:04.340 --> 00:28:10.980
Because if we don't listen to, pay attention to, and get input from people living
00:28:10.980 --> 00:28:15.040
with MS and affected by MS, we are not going to be on the right course.
00:28:15.450 --> 00:28:20.090
And so we are continually getting input. As late as our Scientific Steering
00:28:20.090 --> 00:28:21.790
Committee yesterday, we had many,
00:28:22.390 --> 00:28:28.220
inputs from the Scientific Steering Committee members who are living with MS
00:28:28.220 --> 00:28:32.330
to help guide us, to focus us, to refine us.
00:28:32.570 --> 00:28:37.570
It keeps us on target and makes sure we know that we're going in the right direction.
00:28:38.380 --> 00:28:43.340
While we're talking, I'm wondering if we can switch gears for a minute and talk
00:28:43.340 --> 00:28:47.150
about something called the MONARCH trial and the Primrose clinical trial,
00:28:47.600 --> 00:28:51.710
both focused on an experimental medication called orelabrutinib.
00:28:52.310 --> 00:28:54.780
Orelabrutinib. Yeah, it's a tongue twist.
00:28:55.190 --> 00:28:59.620
The MONARCH trial will test the drug among people with secondary progressive MS.
00:29:00.000 --> 00:29:04.090
Primrose trial will test the same drug among people with primary progressive MS.
00:29:04.820 --> 00:29:09.480
Orelabrutinib falls under a category of disease-modifying therapies called Bruton's
00:29:09.480 --> 00:29:12.490
tyrosine kinase, or BTK, inhibitors.
00:29:12.830 --> 00:29:17.640
And BTK inhibitors have gained significant attention for their dual mechanism,
00:29:17.970 --> 00:29:22.890
modulating B cells in the peripheral nervous system, but also crossing the blood-brain
00:29:22.890 --> 00:29:27.240
barrier to attacks targets like microglia in the central nervous system.
00:29:27.610 --> 00:29:31.750
How does olabrutinib compare with earlier BTK inhibitors?
00:29:32.310 --> 00:29:38.820
Well, in the past, before BTK inhibitors, we have found the effect of one drug
00:29:38.820 --> 00:29:42.960
in a class to be very similar to other drugs in the same class.
00:29:43.370 --> 00:29:50.860
Whether it's an S1P modulator like fungolamide or an interferon or a B cell
00:29:50.860 --> 00:29:55.850
depleting therapy, within the same class, they all work kind of similarly.
00:29:56.160 --> 00:30:01.420
What we are finding with BTK inhibitors is that if you understand how one BTK
00:30:01.420 --> 00:30:06.000
inhibitor works, you only understand how one BTK inhibitor works.
00:30:06.430 --> 00:30:09.920
They work very differently from one drug to another.
00:30:10.250 --> 00:30:15.530
And we haven't yet figured out how to predict how one drug will work.
00:30:16.390 --> 00:30:22.830
In terms of their effect on B cells or microglia, also their effect on the relapsing
00:30:22.830 --> 00:30:27.550
pathology, which we think is mediated by the immune system out in the periphery,
00:30:27.550 --> 00:30:29.690
out in the circulating blood and the lymph nodes,
00:30:30.130 --> 00:30:35.100
versus the compartmentalized inflammation, meaning the inflammation within the brain.
00:30:35.670 --> 00:30:40.060
And what we found is different BTK inhibitors work differently on that relapsing
00:30:40.060 --> 00:30:42.640
pathology and the progressive pathology.
00:30:43.020 --> 00:30:48.880
What has me excited about oral abrutinib is that it appears to have a strong
00:30:48.880 --> 00:30:51.000
effect on the relapsing pathology.
00:30:51.370 --> 00:30:56.110
That effect continues for a long period of time, which was a problem that we
00:30:56.110 --> 00:31:01.050
had with some of the previous BTK inhibitors like evobrutinib and that its effect
00:31:01.050 --> 00:31:03.970
on relapsing pathology was brief and short-lived.
00:31:04.560 --> 00:31:09.960
With orelabrutinib, it seems to continue long-term, and it crosses the blood-brain
00:31:09.960 --> 00:31:13.370
barrier in a biologically relevant concentration.
00:31:13.630 --> 00:31:17.820
So we think it will have an impact within the central nervous system on that
00:31:17.820 --> 00:31:21.770
compartmentalized inflammation that we think drives progression.
00:31:22.170 --> 00:31:28.160
So we have a bunch of reasons to believe that it should work in progressive MS.
00:31:28.490 --> 00:31:34.570
And I'm happy to see that the sponsor is doing a trial in secondary progressive
00:31:34.570 --> 00:31:38.540
MS and primary progressive so we can learn in those two different
00:31:38.900 --> 00:31:42.160
forms of MS, which are probably more similar than they are different,
00:31:42.450 --> 00:31:44.230
but nonetheless, they are still considered
00:31:44.630 --> 00:31:48.980
different forms of MS and we'll understand the effect from those two trials.
00:31:49.410 --> 00:31:54.090
I'm trying to recall, am I right, that orelabrutinib is an oral medication?
00:31:54.090 --> 00:31:58.900
Yes. So, you know, that's interesting in itself Because people who are living
00:31:58.900 --> 00:32:04.120
with progressive forms of MS have largely been left out of the oral medication
00:32:04.120 --> 00:32:05.990
options for a lot of time.
00:32:06.710 --> 00:32:13.450
How do you think the possibility of having a once-daily oral medication is going
00:32:13.450 --> 00:32:15.600
to impact things like adherence?
00:32:16.150 --> 00:32:20.170
Well, at one level, I think people living with progressive MS aren't going to
00:32:20.170 --> 00:32:25.870
be too picky about how they get their effective therapy, whether it is an injection,
00:32:25.870 --> 00:32:27.670
an infusion, or an oral pill.
00:32:27.670 --> 00:32:32.120
But, of course, a once-a-day oral pill is going to be much more convenient and
00:32:32.120 --> 00:32:33.830
easier for patients to take.
00:32:34.230 --> 00:32:40.690
So I think it's going to be much more embraced and preferred by people with MS.
00:32:40.930 --> 00:32:46.320
Are these two clinical trials for this new medication currently recruiting participants?
00:32:46.550 --> 00:32:51.210
They are. They are recruiting both in primary progressive and in secondary progressive
00:32:51.210 --> 00:32:53.650
MS, and recruitment is all around the world.
00:32:54.510 --> 00:33:02.580
So those who might be interested in participating can look around a Google search, a clinicaltrials.gov.
00:33:02.580 --> 00:33:05.860
There are many websites that can help direct them to a site,
00:33:06.080 --> 00:33:10.160
hopefully close to them, where they can explore whether they could participate.
00:33:10.160 --> 00:33:14.000
You know, we'll try to make that easier. We'll include some of those links in
00:33:14.000 --> 00:33:15.550
the show notes for our episode.
00:33:16.250 --> 00:33:19.510
I would say the other thing that's exciting about BTK inhibitors,
00:33:19.890 --> 00:33:23.460
and we don't know if oralibrutinib falls under this category,
00:33:23.460 --> 00:33:30.050
but it very well may, is that some of the BTK inhibitors suppress B-cell function.
00:33:30.560 --> 00:33:35.570
And so they may work on the relapsing pathology in part similar to what the
00:33:35.570 --> 00:33:39.820
B-cell depleting therapies do, but without depleting the B-cells.
00:33:40.110 --> 00:33:45.680
So it's pointed us towards some of the potential mechanisms that the B2K inhibitors
00:33:45.680 --> 00:33:50.250
may work on relapsing pathology while still allowing them to go into the brain
00:33:50.440 --> 00:33:54.840
and downregulate some of the compartmentalized inflammation within the brain.
00:33:55.420 --> 00:34:00.940
Dr. Robert Fox, I want to thank you for all that you do in all of the many roles
00:34:00.940 --> 00:34:05.940
that you managed to excel at filling. Thanks so much for talking with me today.
00:34:06.100 --> 00:34:09.550
Well, thank you, John, and thank you for translating the very complex field
00:34:09.550 --> 00:34:13.140
of MS into something that's very understandable. So thank you for that.
00:34:14.140 --> 00:34:18.680
That's going to wrap up this episode of Real Talk MS. Real Talk MS is powered
00:34:18.680 --> 00:34:20.450
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00:34:20.890 --> 00:34:25.000
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it right into an email or a text.
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And you'll find those links in today's show notes or at realtalkms.com.
00:35:25.030 --> 00:35:30.170
Next week, we're wrapping up our coverage of MS Toronto 2026 with a deep dive
00:35:30.170 --> 00:35:33.560
into a subject that seemed to be everywhere at this meeting.
00:35:34.140 --> 00:35:40.230
It was even embedded in the theme of the meeting itself, and that subject is unifying MS.
00:35:41.080 --> 00:35:44.010
We're going to look at what that really means, and most importantly,
00:35:44.250 --> 00:35:47.720
how this kind of a change will impact your MS care.
00:35:48.520 --> 00:35:52.340
This is a subject that's going to affect every person living with MS,
00:35:52.710 --> 00:35:55.620
and that makes this an episode you won't want to miss.
00:35:56.650 --> 00:36:03.530
I'm Jon Strum. Thanks for listening. Stay safe and make healthy choices.
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