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Therapy Trends & Tipping Points in MS: A Case-Based Look at High-Risk Disease and Emerging Treatments
Released: March 13, 2026
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Therapy Trends & Tipping Points in MS: A Case-Based Look at High-Risk Disease and Emerging Treatments
Disclosures
My name is Patricia Coyle. I'm a Distinguished Professor of Neurology, Vice Chair for Academic Affairs and Head of the MS Comprehensive Care Center at Stony Brook University on Long Island in New York. I'm delighted to be here with you.
BTK Inhibitors
So the BTK inhibitors are oral agents that target tyrosine kinase. They’re expressed on all hematopoietic cells except for T‑cells and they really target particularly B‑cells and myeloid cells. Now, each BTK inhibitor is unique. The ones that are being studied in MS are all believed to penetrate into the central nervous system. And that means the myeloid target within the central nervous system would be microglia. And we know that activated microglia, that's most marked in progressive MS. So we're looking at oral BTK inhibitors that penetrate into the CNS that could target not just B‑cells there but also activated microglia cells. And so people are extremely interested.
Each BTK inhibitor is variable, is unique. Is it CNS penetrant or not? Well, all the ones currently being studied in MS are. Do you have irreversible covalent or or reversible binding? What is the selectivity? What is the amount of off‑target effects and what's the domain target? Will all be unique to a given a given BTK inhibitor. And we actually have four that are FDA approved for B‑cell cancers at the current time.
Oral BTK Inhibitors
So the oral BTK inhibitors, as I mentioned, target B‑cells and myeloid cells. They don't kill the B‑cells and the myeloid cells, they block them from activating. They do penetrate the CNS in the case of the ones being studied in MS, and several are being looked at at the current time.
Next Era of Therapy: Immune Reset & Antigen‑Specific Tolerance
In addition, in the new era, we're seeing the immune system reset and antigen‑specific tolerance as a goal. So we're seeing a later stage B‑cells, including plasmablasts and plasma cells targeted. We're seeing inverse vaccine therapy, removing immune system memory for specific antigen. We're seeing CAR T therapy being used. We're seeing rebooting of the autoreactome. New immunological techniques to treat MS. These are all in preliminary testing.
Next Era of Therapy: Next‑Gen Cellular & Neuroinflammation Therapies
And what about the next era of next‑generation cellular and neuroinflammation therapies? Selective cell‑based therapies to target any antigen in any organ might be coming. Viral vector‑based gene delivery to directly engineer CAR T‑cells. Hematopoietic stem cell transplant being done. That's being studied. Hit activated microglia and CD8-positive T‑cells that are pathogenic in MS, even interfering with fibrin deposition and interfering with microglia activation, are new approaches that are being taken to treat MS.
Next Era of Therapy: Future MS Strategy Roadmap
The future MS strategy roadmap. Hit cytotoxic CD8‑positive T‑cells. They turn out to be the most abundant lesions in MS lesions, and they have high clonal expansion. They should probably be a target.
Early treatment key before there's an expansion, before you have epitope spread. Better control of an immune-mediated disease like MS by treating it early.
Could you prevent MS? For example, if Epstein‑Barr virus infection is required to get adult onset MS and you can't develop it if you're not previously infected with EBV, could we by any means create a vaccine that would end infection with EBV? And could that be sufficient to wipe out MS? We don't know, but that has been suggested as a possibility. Could there be a unique gut microbiome sequence that could prevent the development of MS?
And then what about CNS repair strategies? Clemastine is one thing that's been tested. I don't think that's going to make the mark, but we need to get CNS repair strategies for sure.
Foralumab
Foralumab is being given intranasally. It's an anti‑T‑cell, anti‑CD3, monoclonal antibody. It's in – it's been in limited studies, but it's very interesting. They had ten non‑active secondary progressive patients who were treated, and they saw a drop in, in their fatigue level. The fatigue was decreased in 70%. In six patients that had PIRA, progression independent of relapse activity, five of the six showed decreased microglia activation with intranasal delivery of this anti‑CD3 monoclonal antibody. It got into the CNS and drove down microglia. And there's a phase IIA study planned to look at intranasal delivery of this monoclonal antibody. I think that's very very intriguing.
Vidofludimus Calcium
Vidofludimus, a second-generation DHODH inhibitor, is being studied in relapsing and progressive MS. They have two large phase III trials in relapsing MS, ENSURE 1 and 2, that have entered about or are entering about 2,221 relapsing individuals with hints from a phase II earlier trial that this may be positive. So this is being tested. This may be a new treatment we shall see for relapsing and possibly progressive MS.
CNS Repair Strategies
And a whole bunch of CNS repair strategies. Cell transplantation with stem cells, neurotrophic factors, immune modulation, removal of the glial scar, gene transfer, neuroprotective and antioxidant and remyelinating strategies. These are all CNS repair. We have not a single CNS repair therapy documented at the current time.
Stem Cell Therapies for MS
So when we talk about stem cell therapies, it's proposed as CNS repair, not just stabilization, the possibility to make better a fixed deficit. That's why it's so exciting. And there are various types of stem cells. Hematopoietic, mesenchymal, neural, embryonic, induced pluripotent, and various ones are being tested for MS.
Phase II Trial of NG‑01
This is an interesting, NG‑01, these were mesenchymal stem cells that were designed to release a lot of positive growth factors. And this was a phase II trial of this approach of these mesenchymal stem cells, NG‑01, that was actually interpreted as a positive study. In the phase II, they looked at sham intrathecal and IV delivery or mesenchymal stem cell delivery by intravenous route, or mesenchymal stem cell delivery by the intrathecal route into the spinal fluid.
And they concluded that the mesenchymal – that the mesenchymal stem cells were well tolerated, that the intrathecal worked better than the intravenous and they saw positive results with the intrathecal on relapse rate, T2 lesion load, timed 25‑foot walk, nine hole peg test, OCT, cognitive tests and functional MRI issues, particularly in active disease.
Ongoing NG‑01 Trial: Secondary Progressive MS
And there is an ongoing secondary progressive phase IIb MS trial that will be entering 45 secondary progressive MS to test NG‑01 further. So remember, we don't have any CNS repair therapy yet, but this is one example, one thing pulled out, looking at these kind of jazzed up mesenchymal stem cells that is studying. And we're going to see what the data shows. I think people should be very excited about that.
Summary
We now believe that MS is likely a homogeneous disease. We'd like it biologically defined, not clinically defined. And we're seeing artificial intelligence, machine learning studies, that are analyzing very large numbers of MS individuals with their associated laboratory data to see how they would define this homogeneous disease.
It has two distinct inflammatory neuropathologies, one representing relapsing MS, the other representing a progressive MS with smoldering neuroinflammation. And we need better handles on measuring that and judging that.
We clearly need more therapies for progressive MS and that has to be driven by what are the principal and key damage mechanisms in the progressive stage of MS. And we still have not defined that. You saw the whole list, but we don't know if all of that is involved or there are particular mechanisms that are especially involved, or can we break MS into different groups to look at that.
And we have no CNS repair strategy yet, but it's only a matter of time. And CNS repair should be driven by a better understanding of the critical damage factors and what's blocking CNS repair in our MS individuals.
Setting the Stage: Balancing Drug Choice
So, in setting the stage for balancing drug choices, we can start with a – a case. And what comes into the therapeutic toolbox one would offer this individual and what might determine a switch in disease modifying therapy in such an individual. And then we'll look at some of the emerging, potentially new treatment options. And then we'll conclude at the end.
Case Study
So Chris is a 30‑year‑old Black male presenting with acute transverse myelitis that produced a paraparesis. In his brain, he has 15 T2 FLAIR macroscopic lesions and several of those 15 lesions enhance. He has three spinal cord lesions and a T10 lesion enhances. He undergoes cerebrospinal fluid evaluation and has an elevated kappa free light chain index, and he has ten CSF‑specific oligoclonal bands, period. Based on this single attack, but that supportive laboratory data, he's given a diagnosis of relapsing MS, and he's given high dose steroids along with plasmapheresis.
In the discussion subsequently to his DMT options with shared decision‑making, which is always a part of the treatment decision‑making in MS, he was quite adamant about going on a disease modifying therapy that had absolutely no risk of progressive multifocal leukoencephalopathy or PML. And really, that means that you can't go on an immunosuppressive agent. Any immunosuppressive agent does carry a small, typically small, risk of PML. So if that's a make‑or‑break point for a patient, that's going to limit your options. So he winds up going on glatiramer acetate. And two months later, eight weeks later, he has double vision onset. A second attack. And when he's reimaged, he has three new MRI lesions including a contrast brain stem lesion.
So what would we say about this this scenario? First of all, there are a number of things that are indicating that this person may have more significant MS. MS is a variable disease, remember. There are – there'll be people that may seem quite mild and people that may seem quite severe. Everybody is different. But if you're looking at checking factors that indicate more concern, he has several factors to talk about.
Number one, he's a male. Males don't do as well as females with MS.
Number two, he's a minority, Black. The data has really supported that Blacks compared to Whites, have more severe disease. Okay.
Number three, he has a high brain lesion load. Generally they'll use nine macroscopic lesions as a cutoff. He has 15. And he has three spinal cord lesions. Location of lesions in the spinal cord or infratentorial locations are typically considered more severe lesions. He seems to have quite a bit of contrast enhancing lesions on this presentation. So he had one spinal cord lesion and several brain lesions that are enhancing.
We went to spinal fluid on him. And you should be aware that the new 2024 diagnostic criteria for MS introduced kappa free light chain index looking at intrathecal production of kappa free light chains. This may wind up replacing CSF oligoclonal bands because it's cheaper, it's faster, it's completely automated, it doesn't require any personal reading of the study to say yes or no. It's there or not. So he was positive for both of the immune disturbances that one might look at, kappa free light chain index and oligoclonal bands. And that has been associated with some worsening.
And then he has a breakthrough attack about two months later, really kind of reiterating that it wasn't a good idea to put him on a moderate efficacy disease‑modifying therapy.
So what are you going to do if somebody says, “I don't want to go on anything that can give me PML?” Well, you can try to educate, you can try to instruct, you can explain that any immunosuppressive agent has a risk of PML, but it's very low typically. We are not proposing using natalizumab, for example, in this gentleman, which increases the risk for PML. So it could be explained that it might be best for him to really go on a high therapy, and he'll be screened with the surveillance MRI scans that are done and following him clinically. There may have been an education factor that would have explained better to him, that he would be better off going on a high efficacy from the beginning, and the data is really supporting that as well. So there's a lot of things that go into the initial counseling, the shared decision‑making.
But then do we elect to change the treatment? You have to change the treatment here. You have to change the treatment. He's had three new lesions damaging his central nervous system form inside of eight weeks. Okay. This is hot MS, and he needs to be on a high efficacy agent. Thank you very much.