Siponimod Offers Benefit to Cognitive Processing Speed in SPMS

February 22, 2021
Matt Hoffman
Matt Hoffman

Matt Hoffman, Senior Editor for NeurologyLive, has covered medical news for MJH Life Sciences, NeurologyLive’s parent company, since 2017. He hosts the Mind Moments podcast. Follow him on Twitter @byMattHoffman or email him at

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Siponimod (Mayzent; Novartis) improved Symbol Digit Modalities Test scores in patients at 12, 18, and 24 months compared to placebo.

New secondary data analysis from the EXPAND study (NCT01665144) showed that patients with secondary progressive multiple sclerosis (SPMS) treated with siponimod (Mayzent; Novartis) experienced a significant benefit on the Symbol Digit Modalities Test (SDMT), suggesting that the oral selective sphingosine-1-phosphate (S1P) receptor modulator can improve cognitive processing speed.1

The between-group difference for the siponimod vs placebo groups in mean change from baseline in SDMT scores was 1.08 (95% CI, 0.23-1.94; P = .0132) at 12 months, and 1.23 (0.25-2.21; P = .0135) at month 18, and 2.30 (1.11-3.50; P = .0002) at month 24. The data also showed a lower risk of having a decrease of 4 or more points and a higher risk of having an increase of 4 or more points on the SDMT for siponimod-treated patients.

First author Ralph HB Benedict, PhD, professor of neurology, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, and colleagues wrote that the data offer Class II evidence for the benefits of siponimod treatment. They noted that the data are at “a magnitude of change accepted as clinically meaningful.”

EXPAND, or “Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis,” consisted of 1651 patients with SPMS randomized in 2-to-1 fashion to either 2 mg per day siponimod or placebo. In addition to the assessment of change in SDMT scores, Benedict et al also evaluated cognitive performance with the Paced Auditory Serial Addition Test (PASAT), and the Brief Visuospatial Memory Test-Revised (BVMT-R). All outcome measures were administered at baseline, then at 6-month intervals until the end of treatment.

READ MORE: How Big Data Can Drive Advancements in MS Research

Notably, PASAT and BVMT-R scores did not differ significantly between the 2 treatment groups (P >.28 for both).

The patients treated with siponimod were at a significantly lower risk for having a 4-point sustained decrease in SDMT score (hazard ratio [HR], 0.79 [95% CI, 0.65-0.96]; P = .0157), while their chance for having a 4-point sustained increase in SDMT score was significantly higher (HR, 1.28 [95% CI, 1.05-1.55]; P = .0131).

These are just the latest secondary data from EXPAND to be published, with a number of analyses submitted for presentation at the 2020 American Academy of Neurology annual meeting suggesting the Novartis agent’s impact on physical disability progression and cognition.2,3

One of the prior datasets from EXPAND included 1124 patients (74% of randomized patients), all of whom received ≥1 dose of randomized treatment. Those data showed that those who continued on siponimod treatment (n = 878) were less likely to experience both 3-month confirmed disability progression (CDP; P = .0064) and 6-month CDP (= .0048) compared to those who switched from placebo (n = 346). As well, incidence rates of adverse events per 100 patient-years in the long-term follow-up were consistent with the controlled treatment period, with no new safety findings observed.2

That efficacy analyses included time-to-3- and 6-month CDP on the Expanded Disability Status Scale (EDSS), time-to-6-month confirmed worsening—defined as ≥4 points on SDMT—and annualized relapse rate (ARR). A reduction in ARR of 52% was observed for the continuing group (0.054) compared to the switch group (0.097; P <.0001).

As well, a third, post-hoc analysis from EXPAND suggested that siponimod consistently reduced cortical grey matter and thalamic atrophy in those with SPMS. Across all subgroups, the reduction in cortical grey matter atrophy compared to placebo ranged from 48% to 116% (<.01 at both 1 year and 2 years), and thalamic atrophy was reduced by 30% to 68% (P <.05 at both 1 year and 2 years). Although, thalamic atrophy was not significantly reduced for those with a disease duration >15 years after 1 year (= .1029).3

At the 2020 Americas Committee for Treatment and Research in MS (ACTRIMS) Forum, Le Hua, MD, director, Multiple Sclerosis Program, Cleveland Clinic Lou Ruvo Center for Brain Health, discussed the subanalysis findings from EXPAND—which she presented—and what it taught her about the dichotomization of patients with SPMS. “[These data] really [do] get into the question of, can we dichotomize our patients? We know there is a younger group and an older group, and we really wanted to look at if there was a difference in the drug working on one group or the other,” she said.

1. Benedict RHB, Tomic D, Cree BA, et al. Siponimod and Cognition in Secondary Progressive Multiple Sclerosis: EXPAND Secondary Analyses. Neurology. 2021;96(3):e376-e386. doi: 10.1212/WNL.0000000000011275
2. Kappos L, et al. Long-term Efficacy and Safety of Siponimod in Patients with SPMS: EXPAND Extension Analysis up to 5 Years. Neurology. 2020; 94 (15 Supplement): 4128.
3. Fox R, et al. Siponimod Reduces Grey Matter Atrophy in Patients with Secondary Progressive Multiple Sclerosis: Subgroup Analyses from the EXPAND study. Neurology. 2020; 94 (15 Supplement): 4037