Progressive Multiple Sclerosis: Contemporary Concepts & New Therapies

Podcast Transcript

Neuro Pathways Podcast Series

Release Date: April 15, 2025
Expiration Date: April 14, 2026

Estimated Time of Completion: 30 minutes

Progressive Multiple Sclerosis: Contemporary Concepts & New Therapies
Robert Fox, MD

Description
Each podcast in the Neurological Institute series provides a brief, review of management strategies related to the topic.

Learning Objectives

• Review up to date and clinically pertinent topics related to neurological disease
• Discuss advances in the field of neurological diseases
• Describe options for the treatment and care of various neurological disease

Target Audience
Physicians and Advanced Practice providers in Family Practice, Internal Medicine & Subspecialties, Neurology, Nursing, Pediatrics, Psychology/Psychiatry, Radiology as well as Professors, Researchers, and Students.

ACCREDITATION

In support of improving patient care, Cleveland Clinic Center for Continuing Education is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

CREDIT DESIGNATION

• American Medical Association (AMA)
  Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
  
  Participants claiming CME credit from this activity may submit the credit hours to the American Osteopathic Association for Category 2 credit.

• American Nurses Credentialing Center (ANCC)
  Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.50 ANCC contact hours.

• Certificate of Participation
  A certificate of participation will be provided to other health care professionals for requesting credits in accordance with their professional boards and/or associations.

• American Board of Surgery (ABS)
  Successful completion of this CME activity enables the learner to earn credit toward the CME requirements of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

Credit will be reported within 30 days of claiming credit.

Podcast Series Director
Andreas Alexopoulos, MD, MPH
Epilepsy Center

Additional Planner/Reviewer
Cindy Willis, DNP

Faculty
Robert Fox, MD
Mellen Center

Host
Glen Stevens, DO, PhD
Cleveland Clinic Brain Tumor and Neuro-Oncology Center

Agenda

Progressive Multiple Sclerosis: Contemporary Concepts & New Therapies
Robert Fox, MD

Disclosures

In accordance with the Standards for Integrity and Independence issued by the Accreditation Council for Continuing Medical Education (ACCME), The Cleveland Clinic Center for Continuing Education mitigates all relevant conflicts of interest to ensure CME activities are free of commercial bias.

The following faculty have indicated that they may have a relationship, which in the context of their presentation(s), could be perceived as a potential conflict of interest:

Robert Fox, MD	Biogen Idec Consulting EMD Serono, Inc. Consulting Novartis Pharmaceuticals Consulting Genzyme/Sanofi Consulting Bristol-Myers Squibb Co Consulting Cognito Consulting Galvani Consulting Immunic Consulting INmune Bio Consulting Kiniksa Pharmaceuticals Consulting Siemens Consulting TG Therapeutics, Inc. Consulting AB Science Consulting Astoria Biologica, Inc. Consulting
Glen Stevens, DO, PhD	DynaMed Consulting

All other individuals have indicated no relationship which, in the context of their involvement, could be perceived as a potential conflict of interest.

CME Disclaimer

The information in this educational activity is provided for general medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options of a specific patient's medical condition. The viewpoints expressed in this CME activity are those of the authors/faculty. They do not represent an endorsement by The Cleveland Clinic Foundation. In no event will The Cleveland Clinic Foundation be liable for any decision made or action taken in reliance upon the information provided through this CME activity.

HOW TO OBTAIN AMA PRA Category 1 Credits™, ANCC Contact Hours, OR CERTIFICATE OF PARTICIPATION:

Go to: Neuro Pathways Podcast April 15, 2025 to log into myCME and begin the activity evaluation and print your certificate If you need assistance, contact the CME office at myCME@ccf.org

Copyright © 2025 The Cleveland Clinic Foundation. All Rights Reserved.

Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab and psychiatry.

Glen Stevens, DO, PhD: Progressive multiple sclerosis is a condition characterized by a gradual but relentless worsening of neurologic function and increase in disability over time, creating a critical need for effective treatments. In today's episodes, we're discussing our evolving understanding of progressive multiple sclerosis and new therapies coming to light, uncovering their implications and what they could mean for the future of multiple sclerosis treatment. I'm your host, Glen Stevens, neurologist, neuro-oncologist in Cleveland Clinic's Neurological Institute. Joining me for today's conversation is Dr. Bob Fox, a Neuroimmunologist in the Mellon Center for Multiple Sclerosis and Cleveland Clinic Neurological Institute, Vice Chair of Research. Bob, welcome to Neuro Pathways.

Robert Fox, MD: Glen, it's great to be joining you today.

Glen Stevens, DO, PhD: So Bob, for those out there that don't know you, tell us a little bit about yourself. Why you went into medicine, how you came to Cleveland, and what you do on a regular basis.

Robert Fox, MD: So, I'm a neurologist here at the Cleveland Clinic. I grew an interest in neurology as an undergraduate up at Amherst College. I became a neuroscience major and thought medicine was the right calling. I liked research but I wanted to have research that impacted people, and what better way to do it but by doing clinical research with people themselves.

When I got to med school, I looked for something better than neurology and I couldn't and I had developed an interest in immunology as an undergraduate. And during my neurology residency, I looked for something more interesting than multiple sclerosis, and I couldn't. And so here I am.

Glen Stevens, DO, PhD: Well, I've mentioned on the podcast before, I'm always very interested in multiple sclerosis because my mother had multiple sclerosis.

Robert Fox, MD: Yeah. Right.

Glen Stevens, DO, PhD: So, I'm always very excited. I think when my mother was diagnosed, we had steroids, and we had steroids, and we had steroids - was about it. But to set the table for our audience, MS isn't MS, isn't MS. Why don't you go through the different phenotypes for us? I think we're going to talk mostly about progressive MS today, but can you go through the phenotypes and how they're different?

Robert Fox, MD: Yeah. And, actually, how we've developed new understanding of those phenotypes. So, we used to think that patients started with relapsing MS, which involves episodes of neurologic dysfunction, weakness, numbness, blurry vision, double vision. And those episodes would recur over time, and most episodes would recover fully or almost fully. And then later on, the disease would change and relapsing MS would stop, and it would be replaced by a gradual little by little worsening that we called progressive MS. In patients who had relapsing MS first, we called that secondary progressive MS. And there were some patients who would jump right to the progressive part, the gradual little by little decline without having relapses. And so we call that primary progressive MS. Now we used to think those were very separate and independent aspects or, as you said, phenotypes. What we've come to realize is that these are very overlapping and that progressive MS probably starts very early on even if it's clinically not easily seen and apparent to patients and to their providers.

And relapsing MS can continue long into the progressive phase. So what we've come to realize is that there's this overlapping aspects. There is a peripheral immune driven disease which we think drives the relapsing aspect of MS. And then there is something different, probably something within the central nervous system, within the brain and spinal cord that is set up by that injury in relapsing MS but sets up this cascade of gradual little by little decline. And initially, like in many diseases, it's subclinical. Patients don't know about it and clinicians don't know about it. But over time, once that injury accumulates, the patients start having a gradual little by little decline. And it depends what patients do. For example, I had one patient who was a marathon runner and he developed progressive MS, noticed in the last couple miles of his marathons. Now if he weren't a marathon runner, he wouldn't know he had progressive MS. So, it really depends on what patients do in terms of recognizing and realizing the aspects of progressive MS.

Glen Stevens, DO, PhD: Yeah. It's interesting you mentioned that because I remember back with Lou Gehrig with ALS, and I remember reading papers many years ago where they looked at his batting average month by month to try to predict when the ALS had actually had started, and they could see a break point where things probably started. And how true that is or not, I don't know but...

Robert Fox, MD: Yeah. And we know with all of these neurologic diseases, whether it's Parkinson's disease, or Alzheimer's disease or Lou Gehrig's disease, that the pathology long predates the symptoms that patients notice. And sometimes, these diseases are found incidentally at autopsy and it probably was a less severe manifestation or form of the disease. And so, we've seen all throughout medicine where the conditions start long before the patients notice it.

Glen Stevens, DO, PhD: So one of the things that I've liked is that the MS community will update their diagnostic criteria.

Robert Fox, MD: Yes.

Glen Stevens, DO, PhD: And fortunately it doesn't take decades to do it. They can do it in shorter periods of time. And we had Dr. Antonieta on talking about some of the updates, although it was mostly to do with relapsing remitting multiple sclerosis in our discussion. So from a progressive multiple sclerosis standpoint, the new diagnostic criteria, any significant changes there?

Robert Fox, MD: It's really not change in the progressive aspect. And it's still defined by patients having a little by little decline in the neurologic function that is progressing over one to two years without an obvious alternative cause. So it is important to consider alternative diagnoses to make sure we're not missing something. MS can coexist with other things like B12 deficiency and thyroid dysfunction and things like that. But it is a gradual little by little decline and it can be in whatever function the patient notices. Again, it depends on what the patients do but it's most commonly noticed with exertion. With long-distance walks around the block or climbing the stairs, with things in one's arm, boxes or groceries or things like that. The most common story is a patient will say, "Hey doc, I used to walk around the block with my spouse every night after dinner. And about a year ago, I noticed I had to sit down at a bench about halfway around. About six months ago, I had to stop two or three times around the block. And a couple months ago, I just gave up and said, 'Forget about it.'"

And it's this gradual little by little decline. And for that patient, the exertion was that long distance walk around the block after dinner. But for other patients, it can be something different.

Glen Stevens, DO, PhD: So there's clearly been an explosion in medications for treating multiple sclerosis.

Robert Fox, MD: There have, yeah.

Glen Stevens, DO, PhD: I take it that the vast majority of these have shown benefit in relapsing or emitting. How many of these medications have shown benefit or look specifically at the progressive population?

Robert Fox, MD: So, it is true. We have over 20 FDA-approved therapies now for MS. And it used to be the approvals were for relapsing MS, relapsing remitting MS, and now they become a little bit more generic relapsing forms of MS. And so all of our currently approved therapies are for relapsing forms of MS. And we haven't had effective therapies for the gradual little by little decline of either secondary progressive MS or primary progressive MS. Now one exception is a drug Ocrelizumab which obtained FDA approval for primary progressive MS. But when you actually look pretty deeply, those primary progressive patients were quite different. They were much younger than typical, the ones that were in the trial. They had more active inflammation. And if you look at the subgroup of patients who were on the older end of that trial cohort and the ones without active inflammation on their MRI, they really had little if any benefit from Ocrelizumab. And we've seen in clinical practice that it hasn't really been helping that gradual little by little decline in patients who don't have active inflammation.

So we still use it in primary progressive MS but we have developed a more balanced view that it's not really truly helping the gradual little by little decline. And so that has left a huge unmet need in treating patients with progressive MS, either primary progressive or secondary progressive MS, and that we really are in need of treatment options.

Glen Stevens, DO, PhD: Before we get into the clinical trial that you're involved with, is it more difficult to do trials on progressive MS than relapsing remitting? Does it take longer? Are the biomarkers more difficult to interpret? Is it different?

Robert Fox, MD: It's not necessarily different. Now the outcomes are different. In relapsing MS, the most common targeted outcome would be episodes of MS, relapses. In progressive MS, we're not looking at the relapses so much. We're looking at the gradual little by little decline in the patient's function. Now, we have formalized scales for measuring that, and we look for confirmed progression because there is a bit of variability in how patients are scored on that scale. So, we look for sustained progression of disability or sustained worsening of disability over time. Most of those trials need about eight to 900 patients split between the two treatment arms and following those patients for between 18 months and two and a half years. So, on average, about two years. Now, that's a pretty big undertaking. So that ends up costing many hundreds of millions of dollars to conduct and needs to be done at a hundred or so clinical sites around the world. So, these are very big undertakings that require a large amount of money in order to successfully do these trials.

Glen Stevens, DO, PhD: So we'll get into the primary outcome, what you looked at in the disability scale because I think it's important. In brain tumor, same issue with us. What do we choose our primary endpoint or secondary endpoints? And it may not necessarily be survival for us, it could be progression free survival, maybe more...

Robert Fox, MD: Right.

Glen Stevens, DO, PhD: ...cognitive effects or those types of things. But a new class of drugs have come out that have been looked at. Actually, we've have some similarity because we've looked at some of these drugs in brain tumor as well...

Robert Fox, MD: Sure.

Glen Stevens, DO, PhD: ...but the Bruton's tyrosine kinase drugs, can you discuss that in the trial that you've been involved with?

Robert Fox, MD: Yeah. So Bruton's tyrosine kinase is a protein that has been a target for white blood cells. It was originally targeted so inhibitors to inhibit this enzyme, BTK inhibitors. They've been targeted for blood cancers and blood-based cancer disorders. And so, they have approval for a number of different lymphoma and lymphoid blood disorders. They also have an effect on the immune function. So they can alter how lymphocytes, the circulating white blood cells out in the blood function. They can also alter microglia. So, these are the resident immune cells within the brain. They also may have an impact on some of the other brain cells as well. And so, these have become a target in recent years to treat both the peripheral immune dysfunction that we think drives relapsing MS but also the central compartmentalized inflammation that we think is driving or at least contributing to progressive MS. And so, that led to a couple phase two trials using a couple different BTK inhibitors which found quite a strong result in reducing new lesions on brain MRI. And that is the classic way that phase two trials of proof-of-concept demonstration in relapsing MS, how they are done. And so based on successful phase two trials in relapsing MS, several candidates in this class were carried forward into phase three trials in relapsing MS and with some of the drugs in progressive MS, as well.

Glen Stevens, DO, PhD: I'm always interested in the names that they get for these drugs, we can always discuss that in a minute. But did you see a difference in the relapsing remitting versus the progressive MS patients in the trials?

Robert Fox, MD: Yeah. So based on the success of the relapsing MS trials, the phase two trials, they then went into phase three trials. And the first two drugs that were tried in relapsing MS, they actually had negative trials. So evobrutinib and tolebrutinib, to many people's surprise, they did not have a benefit. Now, the comparison was to an active comparator. Because we have effective therapies in relapsing MS, there are ethical concerns around doing placebo-controlled trials in most of the world. And so, therefore, we have to use an active comparator. So teriflunomide, which is a modestly effective anti-inflammatory therapy approved for use in MS was the active comparator for both the evobrutinib and the tolebrutinib trials. And even though the phase two trials showed a benefit on MRI lesions, that benefit seemed to wear off or decrease in the months and years after starting the therapy. And so, that is what led those two drugs to have negative trials. Now, it doesn't mean they didn't work at all in relapsing MS, it just said they didn't work better than teriflunomide...

Glen Stevens, DO, PhD: Not superior.

Robert Fox, MD: They were not superior. And so the trials were set up as superiority trials, not non-inferiority trials which is a different way of evaluating a drug. And they were not found to be superior. And what it turned out is that the effect of those drugs on the peripheral inflammation seemed to wear off after three, six or more months, or at least decline and become less robust. And that's something we've never seen in MS with the 20 FDA-approved therapies. They don't all work equally effectively but when they do work, they continue doing what they were doing at the group level, at the population level over the long period of time. So this is the first time we've seen a drug that seems to work initially and then wear off after three, six or more months. So that's a new lesson to us that we need to watch the long-term effects on the peripheral inflammation.

Now, one of the drugs, tolebrutinib, was evaluated in secondary progressive MS. And specifically, secondary progressive MS patients who did not have any relapses in the last few years prior to enrollment in the trial. So, it's a subgroup of secondary progressive MS that we're now calling non-relapsing, meaning they just haven't had any relapses in the last couple of years, so non-relapsing secondary progressive MS. These have been the hardest group of patients to find therapies for because they don't have any peripheral-driven inflammation. So, those current therapies don't really work at all, and there's something else that's driving their disease and we have not been able to find a therapy to help them. What was attractive about tolebrutinib is that it crosses the blood-brain barrier and gets into the brain and the hope is that it's impact on the brain would decrease inflammation related to secondary progressive MS. And, indeed, the trial did find a benefit. There was a 31% reduction in the proportion of patients who had sustained worsening of their disability compared to placebo. Now because this was non-active secondary progressive MS patients and we don't have any effective therapies, the comparison in that trial was to placebo.

Glen Stevens, DO, PhD: And you called that the Hercules trial, is that correct?

Robert Fox, MD: Yes.

Glen Stevens, DO, PhD: Where'd the name come from? I'm always curious.

Robert Fox, MD: You know I...

Glen Stevens, DO, PhD: Is it mnemonic for something or...?

Robert Fox, MD: I don't know. It seems to be a star constellation theme because the partner trial in relapsing MS were Gemini, Gemini I and Gemini II.

Glen Stevens, DO, PhD: Right.

Robert Fox, MD: So I guess it's an astrological, astronomical reference.

Glen Stevens, DO, PhD: So let's back up a little bit to your primary endpoint.

Robert Fox, MD: Sure.

Glen Stevens, DO, PhD: Because the primary endpoint here was based on the EDSS, correct?

Robert Fox, MD: Yes.

Glen Stevens, DO, PhD: Why don't you explain that to us a little bit?

Robert Fox, MD: So we developed a scale a long time ago, it was probably about 40 years ago, of measuring disability. And it was taken from a spinal cord injury scale that was used in the military and it was adapted for multiple sclerosis. And it was called the disability status scale. It then got expanded. Now, the disability status scale was zero to 10 in full point increments but that was thought not to be granular enough to really capture the progression of a disability. So, it was revised and expanded and became the expanded disability status scale to reflect now half point increments. Now it's a rather complex and arcane scale. It derives from nominal scoring, nominal scale scoring, of various functional systems like sensory and motor and cranial nerves. And then that's assimilated into an overall EDSS score. And that ranges from zero to 10 in half point increments. And so, what we look for in these trials is a progression on that scale, a progression on the EDSS scale that is sustained for six months or more. And the idea there is because there's some variability in how that score is derived, and there's inconsistency from one examiner to another or from one date to another. So by looking for the six-month confirmation, one can be a little bit more confident that this was truly a progression of the patient's disability.

Glen Stevens, DO, PhD: And the scale goes from zero to 10. Zero you're perfect, 10 you're dead?

Robert Fox, MD: Correct.

Glen Stevens, DO, PhD: And you needed at least a one scale change, is that right?

Robert Fox, MD: Yes. So zero, perfect. No symptoms, no findings on neurologic exam. Ten is death due to MS, so it has to be from MS. And then it's a one point increase up until a certain level and that's 5.5. And after that, the scale patients move a lot more slowly through the scale. And that just emphasizes the arcaneness of it. It's a one point increase on the lower end and a half point increase above 5.5.

Glen Stevens, DO, PhD: And that's the scale that Kurtzke helped, right?

Robert Fox, MD: Yes. And so it's also called the Kurtzke Expanded Disability Status Scale. John Kurtzke was the one who originally devised it and developed the expanded version.

Glen Stevens, DO, PhD: In another lifetime, I almost worked with Kurtzke.

Robert Fox, MD: Oh, really?

Glen Stevens, DO, PhD: Because I was going to do MS originally.

Robert Fox, MD: Okay.

Glen Stevens, DO, PhD: And then decided to go in a different direction. So, I met with him in Georgetown. He was at the VA...

Robert Fox, MD: Oh okay.

Glen Stevens, DO, PhD: ...through Georgetown. Very nice man but decided that wasn't for me.

Robert Fox, MD: One of his last papers was a complaint that the current EDSS used in trials, that is the neuro status certified EDSS, is actually not EDSS. So his dying plea was to no longer have it be called the Kurtzke EDSS because he said, "That's not my scale anymore. I don't want to be connected to it." Yet, he is still connected to it.

Glen Stevens, DO, PhD: Yeah. Well, we could probably also argue about the MRC scale for motor strength testing...

Robert Fox, MD: Sure.

Glen Stevens, DO, PhD: ...in that it goes zero to five. But it's just not granular enough and...

Robert Fox, MD: And the reliability is not and this is getting replaced. And so, there are different ways of measuring disability which are being placed into trials now. And so now, many of the currently in process phase three trials are used in a composite outcome where they combine EDSS with 25 foot walk time and an arm function time of how long it takes to put nine pegs into a hole and back, the nine hole peg test time.

Glen Stevens, DO, PhD: Right.

Robert Fox, MD: And so we are moving beyond just the EDSS, but it's taken us a while.

Glen Stevens, DO, PhD: So we have you here and you have the insight of being very involved with this trial. I think you were even... What was your... Remind me your role?

Robert Fox, MD: I'm chair of the scientific steering committee of the trial.

Glen Stevens, DO, PhD: So I'm curious how much discussion there was on this as the primary end point. Were there thoughts of something else or was this, everybody felt comfortable that...?

Robert Fox, MD: Yeah. So this has been the standard outcome of MS trials ever since the first drug was approved. So the EDSS has been used, the regulators are familiar with it. They're comfortable with it and they like it because it's what they've seen. People have talked to them about changing it and indeed, there are efforts to adapt it in this composite outcome of EDSS. And the walking and the arm function tests is the primary outcome of some licensing trials right now. So clearly, the regulators are open to some progression and some evolution of this outcome but it has historically been the one that the regulators have approved based upon. It's the one that we have the most data to be able to project sample size and study power and things like that. And I guess there's a part of “if it ain't broke, don't fix it.” And although we do need large patient numbers and followed over several years in order to do these trials, we do think it works.

Glen Stevens, DO, PhD: So there's always another trial. What's the next trial?

Robert Fox, MD: Well...

Glen Stevens, DO, PhD: ...Because there's an ongoing trial, right?

Robert Fox, MD: Yes. So there are a couple different things. One is we do have additional drugs. So there are other BTK inhibitors which also penetrate the central system. So we think should have activity against progressive MS since the Hercules trial show that tolebrutinib has activity in slowing disability progression. So we have several BTK inhibitors that are in trials for development. We also have some other class. We have a CD40 ligand inhibitor called “Frex” for short, Frexalimab, which showed good promise in a phase two relapsing MS trial and is being carried forward into phase three trials in relapsing and progressive MS. That's a total new class of drug. And so, we're excited to see new approaches and new ideas being brought to therapies.

Glen Stevens, DO, PhD: When will the first FDA drug be approved for progressive MS?

Robert Fox, MD: Well, the Hercules trial is the first positive trial in non-active secondary progressive MS and it was positive with the 31% slowing of disability progression. So the sponsor of that trial has indicated they're going to seek regulatory approval for the drug. I don't know the timeline of when that would be expected.

Glen Stevens, DO, PhD: And is it the Perseus trial?

Robert Fox, MD: Yes. So the Perseus. So that is the same drug tolebrutinib being evaluated in primary progressive MS. And so that trial is ongoing, and I'm involved in that, as well. And so, maybe I can come back and share the results of that once we have...

Glen Stevens, DO, PhD: Well, we hope it's positive.

Robert Fox, MD: ...Yeah. We hope it's positive. So that we do expect those results by the end of this year and look forward to seeing how the same drug works in primary progressive MS.

Glen Stevens, DO, PhD: Well, a lot of exciting stuff going on. I'm so impressed with all the work that you guys are doing over at the Mellen Center.

Robert Fox, MD: Yeah. Well, thanks.

Glen Stevens, DO, PhD: And worldwide.

Robert Fox, MD: Yeah. No, it's been an exciting field to be in and it's exciting to see the progress, particularly in progressive MS.

Glen Stevens, DO, PhD: Things that we haven't discussed that you think are important for our viewers to know?

Robert Fox, MD: Well, I think it's important to realize that the BTK inhibitors do have some risks. And the most notable and remarkable risk is that it can irritate the liver. So there are some patients who have liver irritation and some that can have a very severe liver irritation. So there's about a 0.5% rate, about one in 200 patients that will have a very severe elevation of their liver enzymes. And if it's not identified and caught quickly, it can be fatal. And indeed, there was one patient from the Hercules trial who succumbed to liver failure. That was most certainly secondary to the drug. Now, the good news is that all of the cases of the very severe liver enzyme elevation was in the first three months of treatment. So, there's something about the patient where their liver is going to get unhappy about this drug or not in the first three months. Now we keep monitoring after three months but the biggest risk is the first three months. And the management is very straightforward: stop the drug.

Glen Stevens, DO, PhD: Stop the drug.

Robert Fox, MD: Yeah. It’s just stop the drug. There's no magic potion you have to get within a certain period of time. It's just recognize the problem and stop the drug. So there is a lot of efforts. And this is probably a class effect. So, all the BTK inhibitors in MS seemed to have this risk. And so, very intensive monitoring is going to be needed, probably weekly liver function enzymes for the first three months, which is pretty onerous. But to do it for three months and then we can relax and breathe a little bit easier after that. So that is the biggest risk. There are some other risks, but I think that's the biggest one and that patients will need to think through this very serious risk of a liver injury that can be fatal.

Glen Stevens, DO, PhD: Well, Bob, it's been exciting to hear what's going on. As I mentioned earlier, I'm just thrilled to death about all the progress that's been made in the field, and you guys are helping patients on a daily basis.

Robert Fox, MD: Yeah.

Glen Stevens, DO, PhD: We appreciate all you do.

Robert Fox, MD: Well, pleasure. It's an exciting time in MS, for sure.

Glen Stevens, DO, PhD: Thanks for joining us.

Robert Fox, MD: All right. Thanks Glen.

Closing: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's @CleClinicMD, all one word. And thank you for listening.