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NeuroVoices: Le Hua, MD, on Siponimod’s Efficacy Regardless of Age

SAP Partner | <b>Cleveland Clinic</b>

The director of the Multiple Sclerosis Program at Cleveland Clinic’s Lou Ruvo Center for Brain Health provided context on the EXPAND study, which evaluated treatment efficacy and safety in older and younger patients on siponimod (Mayzent; Novartis).

The EXPAND study (NCT01665144) of siponimod (Mayzent; Novartis) in patients with secondary progressive multiple sclerosis (SPMS) validated the oral, second-generation sphingosine 1-phosphate receptor modulator versus placebo. At the 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), October 13-15, more data were presented from the assessment, the main findings of which showed siponimod provides similar clinical benefits in reducing confirmed disability progression risk in patients older and younger than 50 years.

Adverse events (AEs), a particular greater concern for older patients, were also comparable for siponimod and placebo in patients in the less than 50 years age group (85.6% vs 80.0%), and slightly higher for those in the older age group (88.9% vs 76.3%). Rates of serious AEs and AEs leading to discontinuation were similar between the 2 groups as well. This was not the first assessment of siponimod’s effect in certain age groups, as lead investigator Le Hua, MD, presented a subanalysis looking at patients older and younger than 45 years at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Annual Forum, February 27-29.

Hua, director, Multiple Sclerosis Program, Lou Ruvo Center for Brain Health, Cleveland Clinic, sat down with NeurologyLive for a new iteration of NeuroVoices to provide perspective on the study and the clinical significant of the findings. She expresses the differences in elders with MS, the need to continue research in older populations, and the current unknowns about how the disease progresses.

NeurologyLive: Can you provide an overview on the results you observed?

Le Hua, MD: EXPAND was a study on secondary progressive MS that used 3-month confirmed disability progression as the primary outcome. One of the secondary outcomes was 6-month confirmed disability progression. From the original EXPAND trial, patients with active secondary progressive MS, defined as having at least 1 relapse in the prior 2 years to baseline or greater than 1 gadolinium-enhancing lesion, 3-month confirmed disability progression was reduced by 31%, whereas 6-month confirmed disability progression was reduced by 37%. Both of those numbers were significant.

Did any of the data specifically stand out to you?

What we wanted to look at was a subgroup analysis of those who were younger than 50 years and older than 50 years. This is a follow-up study. We’ve previously looked at younger age differences before, except with 45 years as the cut-off point. The reason we focused on 50 [years old] was because we’re learning more about progressive disease. With CMSC and ECTRIMS [annual meetings going on], there’s been a lot of focus on older patients. We wanted to see, if separated out, whether there was a difference in these 2 patient age groups.

Thankfully, in our study, we were able to see that confirmed disability progression was also reduced in both the under 50 [years old] and over 50 age group. In the less than 50 [years old] age group, 3-month confirmed disability progression was reduced by 31%, and by 37% in the over 50-year-old age group. Again, what’s nice about these data is that EXPAND focused on the secondary progressive patients. Even when we separate out the older vs younger patients, we still see an effect on the older age group. The caution is when we separate out and do the subgroup analysis, the numbers become smaller. Any post-hoc analysis always has the standard limitations we’re aware of; however, those results are still instructive and give us an idea of what to expect.

What is the clinical significance of these data? How can clinicians interpret them?

The clinical significance is that we do see efficacy with siponimod in patients greater than 50 [years old]. Clinicians shouldn’t hesitate to use the drug in those patients that are appropriate. Additionally, what’s clinically relevant is that if we focus on the adverse events and not the efficacy, we didn’t find any adverse events that were higher in the older population. It was consistent with the data in the younger population and in the entire population as well. Overall, we observed similar clinical benefits in reducing disability progression, safety and tolerability profile. From a clinician standpoint, there shouldn’t be any concerns about reduced efficacy or higher adverse events if used on the appropriate patient.

How does MS progress differently in elders? What aspects do we still have more to learn about?

We know a lot about older patients and we’re starting to just scratch the surface. Because we have a lot of therapies that do a significant job of stopping relapses, which is the part of the disease we know we control well. However, we still see disability progression. Now we’re starting to coin the phrase progression independent of relapse activity, or PURA.

Because we’re seeing PURA, we still want to get a better understanding of what drives that process. Aging is part of that, immunosenescence is part of that, different changes happening in the brain, different aging processes, reduced ability to remyelinate, reduced ability to utilize energy, clear debris, and help with oxygenation species are all part of that change in older patients.

On the flip side, because of immunosenescence, safety also becomes a concern for older patients, particularly because of increased infection risks. Knowing all that, we need to start to approach our older patients differently. One of the unfortunate things we don’t have is that most trials have not enrolled older patients. Without enrollment of older patients, we don’t have high quality, prospective data. In terms of efficacy and safety, we’re doing the best we can with retrospective data, large control studies, and subgroup analyses, but formal studies in older patients is what’s needed. As we better understand the underlying disease processes and safety concerns, we can then better design drugs to drive at slowing down progression and disability in MS.

What types of research need to be conducted to further bolster treatment optimization?

I wouldn’t just limit this to siponimod, but all of our therapies need to improve. We need to find a better way to figure out when that transition happens from purely a primarily inflammatory stage to just the leftover, underlying process. We know that starts from the very beginning, but we don’t have a good sense of what happens during that sweet spot of when patients transition.

The diagnostic accuracy of secondary progressive MS can take up to 2 to 3 years. As with everything, time is brain. The better we can accurately capture that transition point, the better we can target therapies. I do like the therapies that have a 2-compartment approach, having both peripheral inflammatory effects, as well as neurodegenerative effects because we know that neurodegeneration starts early on and continues as patients age. I do see in the future maybe having more neurodegenerative targets that might not necessarily have an anti-inflammatory component.

As the disease progresses, we should focus more on the actual processes that underlie neurodegeneration, with either reparative strategies, myelination strategies, or neuroprotective strategies.

Over the last year or so, what has been the greatest advance from within the MS space?

There are so many. The most clinically relevant advance I see is serum neurofilament light, moving more from research to clinical use. I’m still not quite sure how best use those data, but maybe the best option is to use it to assess treatment response. I’m not quite certain of its prognostic indicators yet, I do like GFAP a lot better for prognostication, but that’s still far away. I think we’re getting closer to be able to use serum neurofilament clinically, which then allows us to potentially make treatment changes sooner and be able to determine responders and non-responders earlier.

Transcript edited for clarity.

REFERENCE
Hua LH, Bar-Or A, Lublin FD, et al. Analyses of the effect of baseline age on the efficacy and safety of Siponimod in patients with active secondary progressive multiple sclerosis from the EXPAND study. Presented at ECTRIMS 2021; October 13-15. Poster P637