Siponimod and Cognition in Secondary Progressive Multiple Sclerosis

Abstract

ObjectiveTo investigate the effects of siponimod on cognitive processing speed in patients with secondary progressive (SP) multiple sclerosis (MS), by means of a predefined exploratory and post hoc analysis of the Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND) study, a randomized controlled trial comparing siponimod and placebo.MethodsEXPAND was a double-blind, placebo-controlled phase 3 trial involving 1,651 patients with SPMS randomized (2:1) to either siponimod 2 mg/d or placebo. Cognitive function was assessed with the Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), and Brief Visuospatial Memory Test–Revised (BVMT-R) administered at baseline, 6-month intervals, and end of treatment.ResultsBetween-group differences in mean change from baseline in SDMT scores were significantly better in siponimod- vs placebo-treated patients at month 12 (difference 1.08 [95% confidence interval 0.23–1.94]; p = 0.0132), month 18 (1.23 [0.25–2.21); p = 0.0135), and month 24 (2.30 [1.11–3.50]; p = 0.0002). Siponimod-treated patients were at significantly lower risk for having a 4-point sustained decrease in SDMT score (hazard ratio [HR] 0.79 [0.65–0.96]; p = 0.0157), while their chance for having a 4-point sustained increase in SDMT score was higher (HR 1.28 [1.05–1.55]; p = 0.0131). PASAT and BVMT-R scores did not differ significantly between the 2 treatment groups (all p > 0.28).ConclusionSiponimod had a significant benefit on SDMT in patients with SPMS. Siponimod-treated patients were at significantly lower risk for having a ≥4-point decrease in SDMT score and had a significantly higher chance for having a ≥4-point increase in SDMT score, a magnitude of change accepted as clinically meaningful.ClinicalTrials.gov IdentifierNCT01665144.Classification of EvidenceThis study provides Class II evidence that, for patients with SPMS, siponimod had a significant benefit on cognitive processing speed.

Measuring Treatment Response in Progressive Multiple Sclerosis—Considerations for Adapting to an Era of Multiple Treatment Options

“…SDMT was used in the EXPAND clinical trial in which a ≥4-point or ≥10% change in SDMT was considered clinically relevant [ 64 , 65 ]. The necessary time frame to determine disease progression with SDMT is ≥3 months.…”

“…It also correlates less strongly with EDSS and the other performance measures (T25FW and 9HPT), providing additional information by assessing functions not captured by the other measures [ 47 ]. It shows superior reliability, sensitivity, and greater patient acceptability compared to PASAT and, hence, SDMT is recommended for use instead of PASAT [ 64 , 65 , 66 ]. However, its normative values are affected by several factors such as age, sex, education, and cultural background [ 67 ].…”

“…A cut-off of baseline 9HPT ≥ 21 s has been suggested, too, in order to detect a clinically meaningful change [ 52 ]. Moreover, patients with a lower baseline SDMT score (< 43) appear to have a higher chance for disability progression, measured by SDMT [ 64 , 66 ].…”

Effects on cognition of DMTs in multiple sclerosis: moving beyond the prevention of inflammatory activity

“…Emerging data also support the beneficial effects on cognitive functions of siponimod [8] and ozanimod [12,14], two selective modulators of sphingosine 1 phosphate receptors, which have been recently approved for secondary progressive (SP) MS and RMS, respectively.…”

Visualizing Sphingosine-1-Phosphate Receptor 1(S1P1) Signaling During Central Nervous System De- and Re-Myelination

“…EXPAND studies indicate that Siponimod, a selective S1P 1,5 modulator, could reduce neurological injuries and progression of brain atrophy in secondary progressive MS [23,24]. Increasing of S1P levels in cerebrospinal uid, and a decrease of S1P in white matter and CNS lesions of MS patients further highlight the involvement of S1P signaling in neurodegeneration and in ammation [25,26].…”