Siponimod May Have Cognitive Benefit in Secondary Progressive MS

Secondary progressive multiple sclerosis (SPMS) patients treated with siponimod (Mayzent) had significant benefit on the Symbol Digit Modalities Test (SDMT), a measure of cognitive processing speed, compared with placebo, secondary analysis of EXPAND trial data suggested.

“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,” wrote Ralph H. B. Benedict, PhD, of the University at Buffalo, and co-authors in Neurology. “Neuropsychological studies have shown that 4-point changes in SDMT are often associated with clinically meaningful alterations in mental status. Recent studies validate this threshold as being associated with quality of life outcomes and progression of MS disability.”

“This study provides Class II evidence that for patients with secondary progressive multiple sclerosis siponimod had a significant benefit on cognitive processing speed,” they added.

Cognitive function was assessed at baseline and 6-month intervals through 24 months. SDMT 12-month mean change from baseline was better for siponimod versus placebo (difference 1.08 points, 95% CI 0.23-1.94; P=0.0132). At 18 months, the difference was 1.23 points (95% CI 0.25-2.21; P=0.0135), and 24 months it was 2.30 (95% CI 1.11-3.50; P=0.0002), favoring siponimod.

Over the course of the study, the siponimod group had lower risk for sustained 4-point decrease (HR 0.79, 95% CI 0.65-0.96; P=0.0157) and higher chance for sustained 4-point increase (HR 1.28, 95% CI 1.05-1.55; P=0.0131) in SDMT scores.

On both the Paced Auditory Serial Addition Test, which measures working memory and math ability, and the Brief Visuospatial Memory Test-Revised, which measures new learning, episodic memory, and spatial memory, no siponimod versus placebo difference was seen.

“The SDMT is highly sensitive for discriminating individuals with MS from healthy controls, and a useful clinical tool for yielding a quick summary measure of overall cognitive status,” wrote Victoria Leavitt, MD, of Columbia University in New York City, and Maria Rocca, MD, of San Raffaele University in Milan, in an accompanying editorial.

“However, its designation as a measure of cognitive processing speed can be challenged,” they noted. “Latent factor analysis of this test, when administered within comprehensive batteries of 7-10 neuropsychological tests, revealed involvement of not only processing speed, but attention, visuospatial memory, and language/verbal fluency.”

“Each of these domains implicates distinct neural substrates,” Leavitt and Rocca continued. “Additionally, underlying substrates of cognitive impairment partially differ across disease subtypes. For example, whereas memory deficits in relapsing patients are best explained by mesial temporal lobe volume, thalamic volume better predicts memory in progressive patients. These considerations must drive investigations of disease modifying therapies for cognition, lest we fall prey to an imprecise or unguided approach.”

Cognitive impairment in MS is common and is more severe in progressive disease. It often affects cognitive processing speed, commonly measured with SDMT.

“The SDMT is sensitive but it is not specific to the cognitive processing speed domain,” the researchers noted. “SDMT involves paired-associate learning and visual scanning, and so the more demanding the task, the more likely it will measure the effects of cerebral pathology in general. This may explain in part the value of the SDMT in clinical and research applications as noted in a recent consensus report organized by the Multiple Sclerosis Outcome Assessments Consortium.”

Siponimod is oral sphingosine 1-phosphate receptor modulator that won FDA approval to treat relapsing forms of MS in 2019 based on the EXPAND study. EXPAND was a randomized double-blind placebo-controlled phase III trial that randomized 1,651 SPMS patients age 18-60 to oral siponimod 2 mg daily versus placebo. Participants had disease progression on the Expanded Disability Status Scale (EDSS) in the prior 2 years, and EDSS scores of 3.0-6.5 at enrollment.

EXPAND reported findings suggesting siponimod modulation of both inflammatory (reduced new or enlarging T2 or enhancing lesions) and neurodegenerative (reduced disability progression and brain volume loss) dimensions of MS.

In the present analysis, those without baseline cognitive impairment (SDMT ≥43) had a higher chance for sustained improvement in SDMT with siponimod, while those with baseline cognitive impairment (SDMT <43) had lower risk for sustained worsening.

“A possible explanation for this is that patients with more acute disease activity and less cognitive impairment may still have cognitive (i.e., neurological) reserve available to turn the benefit of siponimod on cognitive processing speed into improvement, while in later-stage with more impaired patients, the benefit may be a slowing of further decline,” the researchers observed. “It is also feasible that it might take longer than the median treatment duration of 18 months for treatment effect to be observed in later-stage and more-impaired patients.”

“Studies of patients treated with siponimod for longer duration are needed — the EXPAND extension study is still ongoing and may deliver such information,” they added.

Limitations included no information about education, a proxy for cognitive ability, and a post-hoc study design following consensus on a clinically meaningful difference for the SDMT. “While the EXPAND trial was registered at Clinicaltrials.gov with seven secondary outcomes, no cognitive outcome was included,” the editorialists noted. “Identifying and preregistering scientifically justifiable cognitive endpoints in future disease modifying therapy trials will strengthen the evidence.”

“On a related note, from a mechanistic standpoint it is unclear why, of the three cognitive tests included in the trial, SDMT was expected to show improvement from siponimod,” they added. “The authors note that its selection was made based on a consortium study establishing clinically meaningful change for the measure, a rationale that circumvents mechanism.”

1. Secondary progressive multiple sclerosis patients treated with siponimod had significant benefit on the Symbol Digit Modalities Test, a measure of cognitive processing speed, compared with placebo, secondary analysis of EXPAND trial data suggested.

2. No difference was seen for the Paced Auditory Serial Addition Test or the Brief Visuospatial Memory Test-Revised, the other cognitive assessments in the trial.

Paul Smyth, MD, Contributing Writer, BreakingMED™

Cat ID: 36

Topic ID: 82,36,730,36,192,925