Reimagining MS Clinical Trials: Immune System, Neuroprotection, and Meaningful Outcomes

In recent years, reassessment of clinical trial paradigms in multiple sclerosis (MS) has gained momentum as clinicians recognize that traditional end points may not adequately capture long-term disease progression or neurodegeneration. Despite substantial advances in immune-targeted therapies, many individuals with MS continue to experience worsening disability and brain atrophy in the absence of overt inflammatory activity. These observations have led clinicians to explore whether current strategies may overlook key aspects of MS biology.

At the recently concluded 2026 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, held May 27-29, Charlotte, North Carolina, MS specialist Ahmed Obeidat, MD, PhD, associate professor of neurology at the Medical College of Wisconsin, delivered a presentation titled “Changing the Rules: Reimagining Clinical Trials in Multiple Sclerosis.” In his talk, he examined how prevailing approaches that emphasize broad immune suppression and inflammatory activity on MRI may be insufficient as primary indicators of therapeutic success. He also underscored the importance of redefining “highly effective” therapy to include the ability to slow or prevent progression and to preserve brain tissue over time.

In an interview with NeurologyLive^®, Obeidat expanded on these concepts, describing how historical and contemporary data together suggest a more complex role for the immune system in MS than simply driving pathology. He also discussed limitations of current efficacy metrics, including reliance on relapse rates, MRI lesion activity, and the Expanded Disability Status Scale (EDSS), and advocated for incorporation of objective, reproducible biomarkers that directly measure preservation of brain. Obeidat emphasized the need to work with, rather than indiscriminately suppress, the immune system and to design future trials that prioritize neuroprotection and long-term functional outcomes for patients living with MS.

NeuologyLive: How have MS clinical trials and measures of therapeutic efficacy evolved from when you were a medical student to current practice?

Ahmed Obeidat, MD, PhD: This field has really evolved over the years. When I think back to my days as a medical student, we always learned about MS as an autoimmune disease, where there is some sort of immune attack on the nervous system. It was initially thought of more as a T cell–mediated disease.

Things have evolved. People still think it’s an autoimmune or immune-mediated disease, but now there is much more interest in the role of B cells. That’s interesting because when I go back to the older literature, I can see why they were talking more about T cells, macrophages, and all these cells. Now, they are mostly focusing on B cells.

So, I ask myself: do we need to delve back into the “old days,” the old data, and really try to see whether we are oversimplifying things? My plan, and what I’m introduced here at this conference, is to rethink the paradigm. As you can see from the title, it’s changing the rules. I want to change the rules in a very diplomatic way.

It’s a tough area, because a lot of therapeutics have already been developed that target B cells and the immune system, which is considered one of the major drivers of MS. We think of MS as an autoimmune disease. Almost every grant I review, every paper I review or write, starts by saying it’s an autoimmune or immune‑mediated disease. I want to stop there and think more about that.

In this conference, I’m challenging that concept. I want to challenge the idea that the immune system is our enemy in this disease. I’d like to think of it as maybe our friend that’s just a little bit misbehaving and we need to put it back in check. We want to redirect the immune system.

When evaluating MS therapeutics today, what has changed in the methodology for assessing treatment efficacy?

When I think about what we call a highly effective therapy now, we usually define it in MS as a therapy that can reduce relapse rate or attacks—which is a transient neurological worsening—and therapies that can shut down, or significantly reduce, what we call lesion activity on MRI, meaning the formation of new or contrast‑enhancing brain lesions.

So, highly effective therapies are those that can block the immune system from going to the organ of interest, which is the brain. These are what we call highly effective therapies. But we are closing an eye to another dimension of efficacy, how our patients are doing from a progression and worsening standpoint over time.

In many clinics around the globe, you’ll see the same story: patients are doing very well in terms of suppression of relapse activity and MRI lesion activity, yet their neurological function continues to worsen. They continue to lose brain tissue over time, what we call brain atrophy or accelerated brain atrophy. That seems to be a process independent from relapsing activity or MRI activity.

We call this progression independent of relapse activity, sometimes phrased as progression independent of activity. This is another eye‑opening finding: there is something going on in the brain, a neurodegenerative process, that the immune system is failing to control, failing to prevent from getting worse.

A big part of my talk will be about how this progression is escaping what we call immune check or immune regulation. The question is: can we restore immune system function in a way that helps prevent this?

Then, can we define high‑efficacy therapy by those therapies that prevent disease progression and preserve the brain, rather than just those that reduce relapse rate and MRI activity. Because our organ of interest is the brain, and our main interest with therapies is to protect the brain.

I think measuring our success should be about how well we’re able to preserve brain tissue and prevent disease worsening, rather than focusing mainly on relapses and MRI. There is always room for a paradigm shift. We’ve made a lot of progress, but it’s not yet sufficient. Patients still have many unmet needs. That’s where, when we change our thinking, we can get to some of the things we are missing right now.

Looking ahead, what key outcome measures, biomarkers, and process changes would you like to see incorporated into future MS clinical trials?

This is, again, about looking at the future. We have technology now. We have AI. We have a lot of tools we can use to help us improve our measurements. Still, in clinical trials today, we mostly rely on what we call the gold standard, the EDSS. It’s a great tool that was invented a very long time ago, and we still use it today.

The EDSS has problems with sensitivity. It doesn’t really measure preservation of the brain; it mostly measures motor function and is heavily skewed toward ambulation. Ambulation is extremely important, but if we truly want to advance the field, we need more precise, reproducible, objective biomarkers.

The EDSS might seem objective, but the way it’s done in trials is challenging. We’re always tight on time; we do it quickly; it’s inter‑rater dependent. It’s different if I do it or my colleague does it, or if I do it today and then next week, or in the morning versus the afternoon. You can get different results. So, there are problems there.

We do have the ability to develop and improve biomarkers. Those could be imaging biomarkers or fluid biomarkers. The closest fluid source is spinal fluid, which is not very practical, because people don’t want to be in a trial where they get multiple spinal taps. But we have had people who agreed to do that, and that has helped advance science. Maybe, on a smaller scale, we can do proof‑of‑concept studies this way.

Ultimately, though, we should use noninvasive biomarkers that are objective and capable of measuring protection of the brain. What I would envision for the future is using outcome measures in clinical trials that are not just a brief exam, it should be something reproducible and cutting‑edge.

Transcript edited for clarity.Click here for more coverage of CMSC 2026.

REFERENCES
1. Obeidat A. Changing the Rules: Reimagining Clinical Trials in Multiple Sclerosis. Presented at: 2026 CMSC Annual Meeting; May 27-29; Charlotte, North Carolina.