Siponimod Improves Cognition in Advanced Multiple Sclerosis

Nancy A. Melville

December 17, 2020

A new multiple sclerosis (MS) drug, siponimod (Mayzent), significantly improves cognition for patients with advanced disease, new research shows.

Results of a randomized placebo controlled trial showed that the drug, a second-generation oral sphingosine 1-phosphate receptor modulator that was approved by the US Food and Drug Administration in 2019, significantly improved cognitive processing speed in patients with secondary progressive MS. A previous study demonstrated that the drug also slows progression of physical disability in this patient population.

"While there are currently no drugs on the market in the United States approved for the treatment of cognitive impairment in MS, our study found that siponimod, which is prescribed to slow the progression of physical disability in MS, may also help improve cognitive processing speed in people with advanced MS," study investigator Ralph H. B. Benedict, PhD, a professor of neurology and psychiatry with the University of Buffalo, Buffalo, New York, said in a statement.

"In addition to a benefit on overall neurological disability, the drug seems to benefit cognitive function," Benedict told Medscape Medical News. He noted that few other drugs have shown similar benefits. However, he added, the inclusion of a cognitive outcome measure is not routine in phase 3 clinical trials.

The findings were published online December 16 in Neurology.

A Core Deficit

Deficits in cognitive processing speed underlie many of the common lifestyle challenges faced by patients with MS, including problems involving driving, employment, adherence to medication, and rehabilitation.

The study is a post hoc analysis of the EXPAND study, a phase 3 double-blind randomized controlled trial of siponimod in 1651 patients with secondary progressive MS.

Participants were randomly assigned in a 2:1 ratio to receive treatment with either siponimod 2 mg/d or placebo for 2 years.

All patients underwent cognitive assessment at baseline and at 6-month intervals using the Symbol Digit Modalities Test (SDMT), the Paced Auditory Serial Addition Test (PASAT), and the Brief Visuospatial Memory Test–Revised (BVMT-R).

The SDMT is considered the most effective measure of cognitive processing speed in MS studies. It is the only test that reflects changes that are considered clinically meaningful, the investigators note.

Baseline SDMT scores regarding cognitive impairment were well below average in 46.7% of patients. Baseline focal inflammatory brain activity was present in about 20% of patients. In terms of physical function, 56% of patients in the study required walking aids at baseline.

Results showed that at 12 months, patients in the siponimod group showed significantly greater cognitive improvement compared to those in the placebo group (difference, 1.08; P = .0132), with increasing improvements vs placebo at month 18 (1.23; P = .0135) and month 24 (2.30; P = .0002).

"Clinically Meaningful"

Patients treated with siponimod also had a significantly lower risk of experiencing a 4-point sustained decline in SDMT score (hazard ratio [HR], 0.79; P = .0157) and a higher likelihood of a 4-point sustained increase in SDMT score (HR, 1.28; P = .0131) compared to patients who received placebo.

Those findings are important, inasmuch as a change of four points on the SDMT have been associated with clinically meaningful changes in mental status. The 4-point threshold has also been linked with quality-of-life outcomes and progression of MS disability, the authors note.

The investigators found no significant differences between the siponimod and placebo groups in PASAT or BVMT-R scores (all P > .28) but were "impressed" with the effect of siponimod on SDMT scores.

Improvements in the siponimod group were found in patients with or without prestudy MS relapses, regardless of the degree of cognitive impairment or level of physical disability prior to the study.

Of note, patients with less advanced MS in the EXPAND study were more likely to show a sustained improvement in SDMT score, whereas the benefit among those with more advanced MS was reflected more in terms of a lower risk of worsening cognitive impairment compared with patients who received placebo.

"A possible explanation for this is that patients with more acute disease activity and less cognitive impairment may still have cognitive (ie neurological) reserve available to turn the benefit of siponimod on cognitive processing speed into improvement," the authors explain.

"While in later-stage with more impaired patients, the benefit may be a slowing of further decline, although it is also possible that this might simply be a floor effect," they write.

"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," the investigators add.

Potential Mechanism

The authors note that the drug "readily crosses the blood–brain barrier and may have direct actions in the central nervous system that limit inflammation and promote remyelination."

The cognitive improvements that were observed are consistent with the changes observed on MRI in the EXPAND trial, they add.

"Treatment effects observed for clinical and imaging outcomes, most notably reduction in brain volume loss as an objective marker of permanent tissue damage and thus likely related to cognitive function are consistent with the results reported here," the authors note.

Among the study's limitations is that it did not include data on fatigue and depression, which are linked to SDMT score and could have a bearing on siponimod's effects on cognition.

Commenting on the findings for Medscape Medical News, Barbara Giesser, MD, Pacific Neuroscience Institute, Santa Monica, California, said that in general, there are fewer disease-modifying therapies for progressive MS than for relapsing/remitting MS, "so any time we have a trial showing an effect on progressive disease, that's encouraging.

"And with cognitive effects occurring in more than 50% of people with MS, the fact that this study seems to indicate a benefit in cognition in this population is very noteworthy," she said.

The study was funded by Novartis Pharma AG. Benedict has consulting and speaking relationships with Novartis. Giesser has disclosed no relevant financial relationships.

Neurology. Published December 16, 2020. Abstract

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