The Effects of Disease-Modifying Therapy on MS Cognitive Function

Stephen Krieger, MD: Cognitive function is often thought of as a manifestation of cognitive reserve, and that's a manifestation of reserve more broadly. And I think what reserve really relates to is the overall health of the brain and central nervous system. Part of the goal of assessing cognitive function is sort of as an arbiter of overall brain health and wellness. So what we've tried to do at Mount Sinai is to do an annual comprehensive assessment, which includes a neuropsych evaluation, as we talked about, but also looking at someone's diet and exercise, sleep, insomnia, fatigue scores, mood scores—a holistic assessment because all of those things relate to brain health, as do comorbidities. Trying to manage all of those things that can drain brain reserve is a lot of the work that's being done at Mount Sinai by Jim Sumowski, MD, and our other collaborator at Sinai, Ilana Katz-Sand, MD, particularly looking at the diet aspect of it, all of those things I think can boost brain health and boost reserve. That's the principle. Data is continuing to be collected on it, but I think we can take an optimistic stance with our patients as we assess their cognitive function as to all of the various things that we can do about it, even before we get to thinking about the role of the DMTs (disease-modifying therapies).

In addition to the idea that brain health and wellness are important, as an end in itself, I think we've also come to recognize cognitive dysfunction as a harbinger and a sense of disease severity, and potentially, disease progression. So work done over these last several years has shown that people with MS with early cognitive dysfunction are more likely to develop disease progression, in general. I think it's a bit of an indicator of someone's overall brain reserve and brain health. I think assessing cognitive function is important in its own right. It also gives us a little bit of a sense of disease burden or prognostic risk for that patient, and that in particular helps to drive some of our disease-modifying therapy and treatment choices.

I think our data for disease-modifying therapies relating to cognitive function, historically, has been a little bit underwhelming. That may relate to how hard it is to assess in a clinical trial or confounding factors. It also probably relates to the fact that our older generations of disease-modifying therapies simply weren't as effective. And just as their effect on relapses and disability are modest, their effect on cognition was modest as well. I think that has given way to the use of in the study of higher efficacy therapies given via a bunch of different routes, where we're starting to see more compelling data that these really do seem to change the cognitive decline trajectory, stabilizing it, and perhaps even moving it towards improvement for some set of patients.

So within the realm of modern disease-modifying therapies for multiple sclerosis, the S1P modulator class has long been thought to have benefits on brain atrophy. More recently the work with ozanimod (Zeposia; Bristol Myers Squibb), which is now approved for relapsing MS, had shown benefits on gray matter volume, and it's a short line from gray matter volume to cognitive function, so it has made sense to look carefully at that with the ozanimod clinical trials.

DAYBREAK (NCT02576717) has looked at the effect of ozanimod versus interferon, and specifically, when looking at cognitive outcomes, with SDMT [Symbol Digit Modalities Test], there has been consistently more improvement in cognitive function on ozanimod as compared with the interferon preparation that was seen in the core study. And it has been seen now as we go into several years of extension, from those studies, which is helpful. Cognitive function changes slowly for most people, and so with these long-term extensions where you continue to see a benefit of the S1P modulator over interferon, it's pretty assuring that that is a meaningful effect.

In essence, what it has shown is that roughly one-third, sometimes up to 40% of people, on ozanimod have better cognitive function as measured by the SDMT later than when they started in the study. And that move toward improvement is not something that I think was a given. We've always thought of our disease-modifying therapies as preventative. So seeing that a greater percentage of these patients improved on cognitive function than worsened is notable, and I think it's been consistently seen.