Commentary
Video
Emerging Therapies and the Future of MS: Insights on BTK Inhibitors and CAR T-Cells
Experts discussed the promise and uncertainty surrounding BTK inhibitors and CAR T-cell therapy in addressing progressive multiple sclerosis. [WATCH TIME: 8 minutes]
WATCH TIME: 8 minutes
The 2025 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, held February 27 to March 1, in West Palm Beach, Florida. This CE-accredited meeting featured a single track of scientific and clinical presentations focused on advancing research and treatment for multiple sclerosis (MS) and related disorders. The 2025 theme, "Making Connections," emphasized linking aging to MS pathology, exploring cross-disorder and neuroanatomical connections, bridging data with clinical application, and investigating brain repair and protection. Designed for researchers, clinicians, students, and fellows, the ACTRIMS Forum provided opportunities to engage with experts, optimize MS management, and explore emerging concepts in neuroimmunology.
In collaboration with Cleveland Clinic, NeurologyLive® held a roundtable discussion with MS experts who talked about key advancements in MS treatment and research that were discussed during the 2025 ACTRIMS Forum. The experts shared their thoughts on which sessions from the Forum that could have the most immediate impact on clinical practice and examined how emerging therapies could transform MS treatment in the coming years. They also explored the role of AI and machine learning in MS as well as the increasing focus on aging and MS progression. The panelists in this conversation included neuroimmunologist Moein Amin, MD, neurologist Marisa McGinley, DO, and neurologist Devon Conway, MD, from Cleveland Clinic.
In this episode, experts explored the evolving therapeutic landscape of MS, focusing on Bruton tyrosine kinase (BTK) inhibitors and CAR T-cell therapy. Although BTK inhibitors have shown mixed results in relapsing MS, there is cautious optimism about their potential role in slowing disability progression, particularly as adjunct therapies. The speakers also highlighted the importance of identifying patients with compartmentalized inflammation and emphasized the need for more sensitive imaging and biomarkers in clinical trials. CAR T-cell therapy was discussed as a promising yet early-stage intervention, with an eye on safety and its ability to target previously inaccessible inflammation.
Transcript edited for clarity.
Isabella Ciccone, MPH: I think all of you mentioned a little bit of some of the emerging therapies that were covered in the meeting—BTK inhibitors and CAR T-cell therapy. How do you see those potentially reshaping MS treatment in the next couple of years?
Devon Conway, MD: Well, I think the BTK inhibitors are still an area that is generating some confusion in terms of how they're going to be used in the future. As you're probably aware, the results in relapsing MS have been somewhat disappointing to date, although the fenebrutinib phase 2 study, they presented some of the open-label extension results, and those were very strong in terms of reducing MRI disease activity. But when we heard the results of the GEMINI study, that was definitely not exactly what we were hoping for, and evobrutinib also didn’t pan out as we had hoped. So, we’ll be interested to see the results of the phase 3 studies of fenebrutinib in relapsing MS.
But it kind of begs the question—as we see some reduction in disability progression in the HERCULES study with tolebrutinib—is it possible that this could potentially be an adjunct therapy that we might use in conjunction with some of the treatments that have more profound effects on the relapsing phase of the disease? And if we did do that, how much risk would there be? Particularly given that the BTK inhibitors can sometimes lead to severe liver toxicity, and that there have been deaths associated with that—how safe will it be? But I think we’ll still have to wait to see how that data plays out, especially as we get some of the subgroup analyses from the tolebrutinib studies.
Marisa McGinley, DO: I think those are great points. I think it’s going to be really tricky, right? Because, as you pointed out, the relapsing/remitting data is not as robust, and obviously the biggest need is in progressive [MS]. But the question is are we going to be ready to take people off medications?
And the idea of, like, a combination therapy is not something we’ve thought about in a while in MS, because obviously, previously, we kind of abandoned that topic. But now that we’re thinking about the disease more as a spectrum with these different biological mechanisms, there’s some rationale for it. But obviously, all of these studies were done just with the medication and not in combination.
And I think your safety question is going to be the hard one from, like, a translation-to-clinical-practice standpoint. We're all going to be anxious to kind of help with those progressive, neurodegenerative, chronic active-type lesion biology. But the question is identifying those patients, right, that have predominantly that biology and aren’t going to be at risk still for relapses and new lesions if we don’t find that the BTKis affect that enough to have them on a monotherapy.
So, I think we’re all still waiting on the full trial results and the safety data in the label and show much we’re going to have to monitor these patients. But I’m with you in that it is more attractive to think about it as an adjunct, or like do we start doing more than one therapy, as is done in other disease states, right? I mean, a lot of other autoimmune conditions think about several different treatments, but we’ve not done that yet. So I think that it'll be interesting to see how the field goes there.
Devon Conway, MD: The rheumatologists probably wouldn't ‘bat an eye’ about combining these treatments.
Marisa McGinley, DO: Exactly. I feel like both our patients and neurologists are rather risk-averse. So it'll be good to push us out, because obviously we need to be doing something different when it comes to progression.
Moein Amin, MD: Yep, I also completely agree with what both McGinley and Conway said. Yeah, I think we’re all eagerly awaiting additional data for both CAR T and BTK inhibitors to try to target the compartmentalized inflammation that some of our other immunomodulatory treatments can’t necessarily target as well as they should—to hopefully try to treat the smoldering inflammation that potentially is the main contributor for progression in multiple sclerosis.
And one of the limitations always has been identifying sensitive biomarkers in all of these trials. That’s been a challenge for us. Traditionally, of course, the rate of relapses and new MRI lesions or brain volumes have been used as traditional imaging clinical biomarkers for trials that have been set to study these medications. But with some of these studies perhaps not showing the results that we anticipated them to show, it begs the question of whether we’re using sensitive enough imaging or clinical biomarkers to potentially detect impactful change that these drugs may be exerting.
For example, as McGinley mentioned, it’s useful to use potentially paramagnetic rim lesions as a biomarker for not only selection but perhaps even treatment effect, as some of the sessions did show, for example, the 2-year data with the PRLs with ocrelizumab showed that there wasn’t any change in the count of the PRLs. But the study that was shown or presented at ACTRIMS showed that the actual quantitative measures in the PRLs potentially change over 4 years, and not the actual count. So that’s an area of active research—to try and identify good biomarkers so that in the clinical trial, we can design the trials around them appropriately.
Devon Conway, MD: Like Amin was saying, it’s really exciting that the CAR T therapies might be able to target the compartmentalized inflammation that the treatments we have right now—the antibody treatments—really are not reaching. And what effects that might have, especially on progressive MS.
Obviously, there’s a lot of safety concern that can go along with that, like immune effector cell-associated neurotoxicity syndrome (ICANS), and then also, will targeting CD19 and removing a larger proportion of your B cells lead to more complications than we’ve seen with CD20 therapy so far—those are questions that will still have to be answered. I think CAR T is still very preliminary at this point, but the abstracts that I saw at the conference—mainly posters—nobody reported any serious adverse events that I picked up on, so that was nice to see.
