Cognitive Outcome Measures May Help Predict Disease-Modifying Therapy Response in MS


Using this new methodology, 78% of patients with progressive multiple sclerosis demonstrated large treatment benefits with the siponimod (Mayzent; Novartis) on at least 1 of 4 clinical outcomes.

Ludwig Kappos, MD, FEAN, FAAN, professor of neurology, University of Basel

Ludwig Kappos, MD, FEAN, FAAN

In a new post hoc analysis of the phase 3 EXPAND study (NCT01665144), investigators obtained and validated different responder profiles (RSP) of patients with multiple sclerosis (MS) to a disease-modifying therapy (DMT) using baseline characteristics that were associated with higher treatment effects. In conclusion, cognitive test deficits at baseline were predictive of further deterioration in the course of follow-up.

Overall, 78% (1290 of 1645) of patients were pronounced responders to treatment with siponimod (Mayzent; Novartis), the study drug assessed, on at least 1 of the 4 clinical outcomes. "Cognitive assessment seems to be an important clinical sign of the severity of the disease [MS], not only on a cross-sectional level, but also if we look in the following years,” investigator Ludwig Kappos, MD, FEAN, FAAN, professor of neurology, University of Basel, told NeurologyLive®. "The development of cognitive deficits under treatment or within this study were also prognostic for base response in other aspects of the disease."

EXPAND was a randomized, double-blind, placebo-controlled clinical trial that evaluated siponimod, an FDA-approved DMT, in a cohort of patients with progressive MS. The generated score was based off treatment effects on outcome measures such as Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), and Symbol Digit Modalities Test (SDMT).

Presented at the 2022 American Academy of Neurology (AAN) Annual Meeting, April 2-7, in Seattle, Washington, nonresponders and responders were derived using a parametric scoring system by Zhao et al.2 This system is used as a function of multiple baseline covariates to estimate subject-specific treatment differences. For good generalization, performance training-validation was replicated on 500 bootstrap samples.

READ MORE: Plasma Neurofilament Light Shows Several Associations With Disability Progression in Progressive Multiple Sclerosis

In the whole cohort, the effect on siponimod on time to confirmed progression for each of the 4 outcomes was: EDSS (HR, 0.79; P = .0103), 9HPT (HR, 0.86; P = 0.23), T25FW (HR, 0.95; P = 0.53), and SDMT (HR, 0.75; P = .001). In total, investigators compiled 4 different RSPs, each of which showed a significant interaction with treatment.

RSPs associated to EDSS (n = 341) had an HR of 0.48 (P = .001) vs non-RSPs, who had HRs of 0.89 (P = .308). Among the 403 individuals who had associated response to 9HPT, investigators identified an HR equal to 0.52 (P = .007) compared with HRs of 1.05 (P = .751) to non-RSPs. On T25FW, RSPs (n = 905) had an HR equated to 0.74 (P = .008) vs HR of 1.23 (P = .077) for non-RSPs. Lastly, SDMT RSP (n = 899) had an HR of 0.58 (P = .001) vs HR of 1.00 (P = .988) for non-RSP.

"I’m definitely convinced that cognitive assessment is very important both under the aspects of prognosis, but also as in a measure of treatment effects," Kappos added. "The issue here is that cognitive tests are relatively time consuming, need neuropsychological expertise, which is not so widely available. Importantly, many patients do not like these kinds of tests that are applied."

Recently, new patient data from EXPAND was published in the Multiple Sclerosis Journal and suggested that treatment of secondary progressive MS with siponimod is safe and efficacious over a 5-year treatment period. Compared with a cohort of patients who switched from placebo to siponimod, those treated continuously with a 2-mg/day dose of the selective sphingosine 1-phosphate receptor modulator reduced the risk of 6-month confirmed disability progression by 22% (HR, 0.78; 95% CI, 0.66-0.92; P = .0026), as well as the risk of worsening in cognitive processing speed (HR, 0.77; 95% CI, 0.65-0.92; P = .0047).3

1. Bovis F, Kappos L, Arnould S, Goeril K, Piani-Meier D, Sormani MP. Estimating the profile of responders to treatment in the phase 3 EXPAND trial: do different patients show benefits on different outcomes? Presented at: 2022 AAN Annual Meeting; April 2-7; Seattle, Washington. Abstract 3458
2. Zhao L, Tian L, Cai T, Claggert B, Wei LJ. Effectively selecting a target population for a future comparative study. J Am Stat Assoc. 2013;108(502):527-539. doi:10.1080/01621459.2013.770705
3. Cree BA, Arnold DL, Fox RJ, et al. Long-term efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis: Analysis of EXPAND core and extension data up to >5 years. Mult Scler J. Published online April 5, 2022. doi:10.1177/13524585221083194
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